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Background/aims: To investigate whether compensating retinal nerve fibre layer (RNFL) thickness measurements for demographic and anatomical ocular factors can strengthen the structure-function relationship in patients with glaucoma., Methods: 600 eyes from 412 patients with glaucoma (mean deviation of the visual field (MD VF) -6.53±5.55 dB) were included in this cross-sectional study. Participants underwent standard automated perimetry and spectral-domain optical coherence tomography imaging (Cirrus; Carl Zeiss Meditec). Compensated RNFL thickness was computed considering age, refractive error, optic disc parameters and retinal vessel density. The relationship between MD VF and RNFL thickness measurements, with or without demographic and anatomical compensation, was evaluated sectorally and focally., Results: The superior arcuate sector exhibited the highest correlation between measured RNFL and MD VF, with a correlation of 0.49 (95% CI 0.37 to 0.59). Applying the compensated RNFL data increased the correlation substantially to 0.62 (95% CI 0.52 to 0.70; p<0.001). Only 61% of the VF locations showed a significant relationship (Spearman's correlation of at least 0.30) between structural and functional aspects using measured RNFL data, and this increased to 78% with compensated RNFL measurements. In the 10°-20° VF region, the slope below the breakpoint for compensated RNFL thickness demonstrated a more robust correlation (slope=1.66±0.18 µm/dB; p<0.001) than measured RNFL (slope=0.27±0.67 µm/dB; p=0.688)., Conclusion: Compensated RNFL data improve the correlation between RNFL measurements and VF parameters. This indicates that creating structure-to-function maps that consider anatomical variances may aid in identifying localised structural and functional loss in glaucoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10 -15 ) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10 -8 ). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease., Competing Interests: Competing interests: Z.G.-O. received consultancy fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Takeda, Jazz Pharmaceuticals, Guidepoint, Lighthouse and Deerfield. R.N.A. received consultation fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Genzyme/Sanofi, Janssen, Servier, SK Biopharmaceuticals, Takeda and Vanqua Bio. Y.X. holds a stock option in NeoCytogen Therapeutics where she is scientific co-founder and Chief Scientific Officer. M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica, LLC by the National Institutes of Health to support open science research. M.A.N. also owns stock in Character Bio, Inc. and Neuron23, Inc. The other authors declare no competing interests., (© 2024. The Author(s).)

Primary open-angle glaucoma typically presents as two subtypes. This study aimed to elucidate the shared and distinct genetic architectures of normal-tension (NTG) and high-tension glaucoma (HTG), motivated by the need to develop intraocular pressure (IOP)-independent drug targets for the disease. We conducted a comprehensive multi-ethnic meta-analysis, prioritized variants based on functional annotation, and explored drug-gene interactions. We further assessed the genetic overlap between NTG and HTG using pairwise GWAS analysis. We identified 22 risk loci associated with NTG, 17 of which have not previously been reported for NTG. Two loci, BMP4 and TBKBP1, have not previously been associated with glaucoma at the genome-wide significance level. Our results indicate that while there is a significant overlap in risk loci between tension subtypes, the magnitude of the effect tends to be lower in NTG compared to HTG, particularly for IOP-related loci. Additionally, we identified a potential role for biologic immunomodulatory treatments as neuroprotective agents., Competing Interests: Competing interests A.P.K. has acted as a paid consultant or lecturer to Abbvie, Aerie, Allergan, Google Health, Heidelberg Engineering, Novartis, Reichert, Santen and Thea. J.H.K. has received research funding from Pfizer, Inc. S.M., J.E.C. and A.W.H. are co-founders of and hold stock in Seonix Pty Ltd. The remaining authors report no other competing interests., (© 2024. The Author(s).)

Importance: Primary open-angle glaucoma (POAG) polygenic risk scores (PRSs) continue to be evaluated in primarily European-ancestry populations despite higher prevalence and worse outcomes in African-ancestry populations., Objective: To evaluate how established POAG PRSs perform in African-ancestry samples from the Genetics in Glaucoma Patients of African Descent (GIGA), Genetics of Glaucoma in Individuals of African Descent (GGLAD), and Million Veteran Program (MVP) datasets and compare these with European-ancestry samples., Design, Setting, and Participants: This was a multicenter, cross-sectional study of POAG cases and controls from Tanzania, South Africa, Nigeria, Ghana, and the US. Included were individuals of African descent from South Africa and Tanzania from the GIGA dataset; individuals of African descent from Ghana, Nigeria, and the US from the GGLAD dataset; and individuals of African or European descent from the US in the MVP dataset. Data were analyzed from January 2022 to July 2023., Exposures: Three PRSs derived from large meta-analyses of European and Asian populations, namely Gharahkhani et al (Gharahkhani PRS), Han et al (Han PRS), and Craig et al (Craig PRS)., Main Outcomes and Measures: Odds ratios (ORs) for POAG risk stratification comparing the highest and lowest quintiles; area under the receiver operating characteristic curve (AUROC), and liability coefficient of determination (R2) for the addition of PRS to a baseline of age, sex, and first 5 principal components., Results: A total of 11 673 cases and 66 432 controls were included in this study across 7 ancestral groups. Mean (SD) age of the total participants was 76.9 (8.7) years, with 74 304 males (95.1%). The following were included in each dataset: GIGA (663 cases, 476 controls), GGLAD (1471 cases, 1482 controls), and MVP (9559 cases, 64 474 controls). Increases in ORs were found for the highest POAG risk quintile ranging from an OR of 1.68 (95% CI, 1.17-2.43) in Ghanaians to 7.05 (95% CI, 2.73-19.6) in the South African multiple ancestry group (which derives from at least 5 distinct ancestral groups: Khoisan, Bantus, Europeans, Indians, and Southeast Asians) with the Gharahkhani PRS. The Han PRS showed OR increases for the highest POAG risk quintile ranging from 2.27 (95% CI, 1.49-3.47) in African American individuals in the GGLAD dataset to 7.24 (95% CI, 6.47-8.12) in Europeans. The Craig PRS predicted OR increases in the highest quintile for all groups ranging from 1.51 (95% CI, 1.05-2.18) in Ghanaians to 6.31 (95% CI, 5.67-7.04) in Europeans. However, AUROC and R2 increases above baseline were lower for all African-ancestry compared with European-ancestry groups in the 3 tested PRSs., Conclusions and Relevance: In this cross-sectional study, despite some improvements in OR-based risk stratification using the Gharahkhani PRSs, Han PRSs, and Craig PRSs, consistently lower improvements in AUROC and R2 for African-ancestry compared with European-ancestry groups highlight the need for risk prediction models tailored to diverse populations.

Studying the early events that occur after viral infection in humans is difficult unless one intentionally infects volunteers in a human challenge study. Here, we use data about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in such a study in combination with mathematical modeling to gain insights into the relationship between the amount of virus in the upper respiratory tract and the immune response it generates. We propose a set of dynamic models of increasing complexity to dissect the roles of target cell limitation, innate immunity, and adaptive immunity in determining the observed viral kinetics. We introduce an approach for modeling the effect of humoral immunity that describes a decline in infectious virus after immune activation. We fit our models to viral load and infectious titer data from all the untreated infected participants in the study simultaneously. We found that a power-law with a power h < 1 describes the relationship between infectious virus and viral load. Viral replication at the early stage of infection is rapid, with a doubling time of ~2 h for viral RNA and ~3 h for infectious virus. We estimate that adaptive immunity is initiated ~7 to 10 d postinfection and appears to contribute to a multiphasic viral decline experienced by some participants; the viral rebound experienced by other participants is consistent with a decline in the interferon response. Altogether, we quantified the kinetics of SARS-CoV-2 infection, shedding light on the early dynamics of the virus and the potential role of innate and adaptive immunity in promoting viral decline during infection., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose: To compare changes in macular curvature following acute IOP elevation across a range of myopic conditions., Methods: We studied 328 eyes from 184 subjects, comprising 32 emmetropic controls (between +2.75 and -2.75 diopters), 50 eyes with high myopia (<-5 diopters; HM), 108 highly myopic with glaucoma (HMG) and 105 pathologic myopia (PM) eyes, and 33 PM with staphyloma (PM+S) eyes. For each eye, we imaged the macula using optical coherence tomography (OCT) under the baseline condition and under acute IOP elevation (to ∼40 mm Hg) achieved through ophthalmodynamometry. We manually aligned the scans (baseline and IOP elevation) using three vascular landmarks in the macula tissue. We then automatically segmented the sclera and the choroid tissues using a deep learning algorithm and extracted the sclera-choroid interface. We calculated the macula curvatures, determined by the radius of curvature of the sclera-choroid interface in the nasal-temporal and superior-inferior direction. Differences in macula curvatures between baseline and elevated IOP scans were calculated at corresponding locations, and the mean curvature difference was reported for each eye., Results: IOP elevation resulted in a significantly higher macula curvature change along the nasal-temporal direction in the PM+S (13.5 ± 8.2 × 10-5 µm-1), PM (9.0 ± 7.9 × 10-5 µm-1), and HMG (5.2 ± 5.1 × 10-5 µm-1) eyes as compared to HM (3.1 ± 2.7 × 10-5 µm-1) eyes (all P < 0.05). Interestingly, HM and HMG eyes had the same curvature change in the nasal-temporal direction as emmetropic control eyes (4.2 ± 4.3 × 10-5 µm-1)., Conclusions: Our findings indicate that the macula in HMG, PM, and PM+S eyes showed greater curvature changes under IOP elevation compared to HM and emmetropic eyes. These preliminary results suggest that HM eyes with conditions such as glaucoma or staphyloma are more sensitive to acute IOP elevation.

Introduction: Adherence to iron-folic acid supplementation (IFAS) has been linked with maternal anaemia. While findings about determinants of IFAS adherence have been mixed across different research, there is inadequate evidence in relation to socioeconomic inequalities. This study aims to examine social determinants and socioeconomic inequalities of adherence to IFAS in urban and rural Indonesia., Methods: We conducted a secondary analysis of the 2017 Indonesia Demographic and Health Survey by including a total of 12 455 women aged 15-49 years. The outcome was adherence to IFAS for at least 90 days. We used multiple logistic regression analysis adjusted for the survey design to analyse factors associated with IFAS adherence. We estimated socioeconomic inequalities using the Wagstaff normalized concentration index and plotted them using the concentration curve., Results: About half of women consumed IFAS for at least 90 days, with a higher proportion in urban areas (59.0%) than in rural areas (47.8%). Social determinants of adherence to IFAS were similar for urban and rural women. Overall, being an older woman, having weekly internet access, antenatal care for at least four visits, and residing in Java and Bali were significantly linked to IFAS adherence. Higher maternal education was significantly linked to IFAS adherence in urban settings, but not in rural settings. There were interactions between place of residence and woman's education (p<0.001) and household wealth (p<0.001). Concentration indices by woman's education and household wealth were 0.102 (p<0.001) and 0.133 (p<0.001), respectively, indicating pro-educated and pro-rich inequalities. However, no significant education-related disparity was found among rural women (p=0.126)., Conclusion: Women (age, education, occupation, birth number, internet access, involvement in decision-making), household (husband's education, household wealth), health care (antenatal care visit) and community (place of residence, geographic region) factors are associated with overall adherence to IFAS. These factors influence the adherence to IFAS in a complex web of deep-seated socioeconomic inequalities. Thus, programs and interventions to improve adherence to IFAS should target women of reproductive age and their families, particularly those from socioeconomically disadvantaged groups residing in rural areas.

Traffic noise exposure has detrimental effects on human health, including both auditory and nonauditory impacts. As one such nonauditory factor, individuals and communities in different countries may exhibit different patterns of noise sensitivity and corresponding tolerance levels, leading to a change in overall noise perception. This paper investigated the cross-country differences in psychophysiological responses to traffic noise exposure between Indian and British individuals. A psychophysiological signal-based [heart rate variability (HRV) and skin conductance response (SCR)] listening experiment was conducted in India and the United Kingdom to analyze changes in noise perception and psychophysiological responses resulting from exposure to the same noise stimuli. HRV analysis indicated greater cardiovascular impact in the British group due to a significant increase in heart rate (W = 653, p < 0.01). Also, a significant increase in the SCR (W = 535, p < 0.001) was noted, indicating a greater level of physiological stress among British participants due to traffic noise stimuli. These findings highlight the difference in noise perception due to cross-country variation using psychophysiological responses. Understanding these cross-country differences can inform targeted interventions and policies to mitigate the adverse effects of traffic noise on human well-being., (© 2024 Acoustical Society of America.)

Background/ Aims: The lack of context for anterior segment optical coherence tomography (ASOCT) measurements impedes its clinical utility. We established the normative distribution of anterior chamber depth (ACD), area (ACA) and width (ACW) and lens vault (LV), and applied percentile cut-offs to detect primary angle closure disease (PACD; ≥180° posterior trabecular meshwork occluded)., Methods: We included subjects from the Singapore Chinese Eye Study with ASOCT scans. Eyes with ocular surgery or laser procedures, and ocular trauma were excluded. A deep-learning algorithm was used to obtain Visante ASOCT (Carl Zeiss Meditec, USA) measurements. Normative distribution was established using 80% of eyes with open angles. Multivariable logistic regression was performed on 80% open and 80% angle closure eyes. Diagnostic performance was evaluated using 20% open and 20% angle closure eyes., Results: We included 2157 eyes (1853 open angles; 304 angle closure) for analysis. ACD, ACA and ACW decreased with age and were smaller in females, and vice versa for LV (all p<0.022). ACD 20th percentile and LV 85th percentile had a balanced accuracy of 84.4% and 84.2% in detecting PACD, respectively. When combined, ACD 20th and LV 85th percentile had 88.68% sensitivity and 88.85% specificity in detecting PACD as compared with a multivariable regression model (ACA, angle opening distance, LV, iris area) with 88.33% sensitivity and 83.75% specificity., Conclusion: Anterior chamber parameters varied with age and gender. The ACD 20th and LV 85th percentile values may be used in silos or in combination to detect PACD in the absence of more sophisticated classification algorithms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Antibiotic resistance (ABR) is a critical and growing global challenge, especially in low- and middle-income countries. Ecuador has made great progress in connecting households to piped water supplies; however, the collection and treatment of domestic wastewater has lagged. This infrastructural gap may be accelerating the spread of ABR into surface waters used downstream for irrigation. We studied the contributions of a small town in Ecuador to the prevalence of extended-spectrum β-lactamase-producing Escherichia coli in a glacial stream used for irrigating crops. The study analyzed water samples upstream (n = 60) and downstream (n = 60) of the town of Píntag as well as 30 lettuce samples irrigated by surface waters downstream of the town. A subset of third generation cephalosporin resistant E. coli (3GCR-EC) isolates (n = 58) were sequenced to characterize antibiotic resistance genes and pathogenic lineages. Our results showed that there was nearly a three-log increase in mean E. coli colony forming units in the downstream samples versus upstream. At the upstream sites above the town of Píntag, 6.7% of water samples were positive for 3GCR-EC compared to 100% of samples collected at the downstream sites. Additionally, 70.1% of sequenced 3GCR-EC isolates collected at downstream sites carried bla CTX-M genes and 3.4% belonged to pandemic lineages ST131 and ST10. As countries develop household piped water infrastructure, attention should focus on how the lack of domestic wastewater collection and treatment may accelerate the spread of ABR in waterways and the food system., (© 2024 The Author(s). Journal of Environmental Quality published by Wiley Periodicals LLC on behalf of American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

Lithium and mood stabilizers are considered effective augmentation agents of antidepressants for treatment-resistant depression. Thus, this study aimed to estimate the network structure of depression symptom criteria among unipolar depression patients with mood stabilizers, using data from the Research on Asian Psychotropic Prescription Patterns for mood stabilizers (REAP-MS). We estimated a network of the 9 depression symptom criteria among 411 unipolar depression patients in Asia. Each of the depression symptom criteria was considered to be a dichotomous categorical variable. Suicidality (suicidal ideation or attempt) was the most centrally situated within the network of depression symptoms, followed by depressed mood, loss of energy, anhedonia and weight loss or gain. Contrastingly, concentration problem was the least interconnected. The depression symptom criteria were organized into 4 clusters by the community detection method. The findings suggest that suicidality may be one of the significant therapeutic target symptoms in unipolar depression patients with mood stabilizers., Competing Interests: Declaration of Competing Interest Seon-Cheol Park, an editorial board member of the Asian Journal of Psychiatry, was not involved in the evaluation of or decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: The 1st European Workshop on Periodontal Education in 2009 made recommendations regarding the scope of periodontal education at undergraduate (UG), postgraduate (PG) and continuing professional development (CPD) levels, defining competencies and learning outcomes that were instrumental at the time in helping to define periodontal teaching curricula. The 19th European Workshop on Periodontology and 2nd European Consensus Workshop on Education in Periodontology (Education in Periodontology in Europe) was held in 2023 to identify changes and future developments in periodontal education (including those informed by the COVID-19 pandemic) and embracing methods and formats of periodontal teaching and training. The aim of this review was to assess current knowledge regarding education methods in periodontology, including traditional face-to-face (F2F) teaching and the move to student-centred methods, virtual learning methods and use of digital technology, as well as blended teaching and learning (including teaching delivery and assessment) at UG, PG and CPD levels., Materials and Methods: Systematic searches were conducted to identify relevant studies from the literature. Data were extracted and descriptive summaries collated., Results: The pandemic was a major disruptor of traditional F2F teaching but provided opportunities for rapid implementation of alternative and supplementary teaching methods. Although online learning has become an integral part of periodontal education, teachers and learners alike favour some form of F2F teaching. Blended teaching and learning are feasible in many areas of periodontal education, both for knowledge and skills acquisition as well as in assessment. Student-centred methods and blended approaches such as the flipped classroom seem highly effective, and online/virtual classrooms with both synchronous and asynchronous lectures are highly valued. Learning with haptic methods and virtual reality (VR) enhances the educational experience, especially when VR is integrated with traditional methods. The quality of the teacher continues to be decisive for the best knowledge transfer in all its forms., Conclusions: Live F2F teaching continues to be highly trusted; however, all types of student-centred and interactive forms of knowledge transfer are embraced as enhancements. While digital methods offer innovation in education, blended approaches integrating both virtual and traditional methods appear optimal to maximize the achievement of learning outcomes. All areas of periodontal education (UG, PG and CPD) can benefit from such approaches; however, more research is needed to evaluate their benefits, both for knowledge transfer and skills development, as well as in assessment., (© 2024 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Background: Pandemics present challenges for individuals as they face uncertainties, risks, and decisions which influence their attitudes towards public health interventions. This study investigates gender differences in attitudes towards COVID-19 preventive measures and vaccination intentions in the United States, focusing on the link between risk perception and attitudes towards public health guidelines., Methods: We utilised data from the Understanding America Study, a nationally representative longitudinal survey of U.S. adults from March 2020 to March 2022 to assess how gender differences in health risk perception were associated with attitudes, behaviours, and vaccination intentions, while also evaluating how these gender effects changed over time. We used multilevel logistic regression models to adjust for age, level of education, employment status and income., Results: Women had a higher risk perception of COVID-19 and exhibited greater compliance with preventive measures compared to men. Women also showed higher agreement with COVID-19 restraining public policy measures. However, this contrasted with attitudes towards the COVID-19 vaccine, where men displayed more positive views and a higher intention to receive the vaccine. This gender effect was persistent over time., Conclusions: This seemingly paradoxical outcome suggests that while women's heightened risk perception relative to men's leads to greater adherence to non-pharmaceutical COVID-19 preventative public health interventions, it may also result in more negative views towards the novel COVID-19 vaccine. Understanding the complex interactions between risk perception, behaviour, and gender can inform policymakers and health authorities to tailor interventions that address the diverse needs of the population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The study aimed to evaluate the impact of compensating retinal nerve fiber layer (RNFL) thickness for demographic and anatomical factors on glaucoma detection in Chinese and Indian adults. A population-based study included 1995 healthy participants (1076 Chinese and 919 Indians) to construct a multivariable linear regression compensation model. This model was applied to 357 Chinese glaucoma patients, 357 healthy Chinese, and 357 healthy Indians using Cirrus spectral-domain optical coherence tomography (OCT). The compensated RNFL thickness considered age, refractive error, optic disc parameters, and retinal vessel density. Results showed that although the average RNFL thickness was significantly higher in Chinese participants compared to Indians, the compensation model reduced this difference to nonsignificance. Moreover, the compensation model significantly improved the area under the receiver operating characteristic curve (0.90 vs. 0.78; p<0.001), sensitivity (75% vs. 51%), and specificity (67% vs. 32%) in distinguishing Chinese glaucoma patients from healthy Indian individuals. The compensation model significantly enhanced the diagnostic accuracy of RNFL thickness in distinguishing glaucoma in the Chinese ethnic group compared to the OCT instrument's default values. These results suggest that modifying RNFL measurements based on individual characteristics can yield substantial benefits for glaucoma detection across ethnicities., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Metabolite profiling is a powerful approach for the clinical diagnosis of complex diseases, ranging from cardiometabolic diseases, cancer, and cognitive disorders to respiratory pathologies and conditions that involve dysregulated metabolism. Because of the importance of systems-level interpretation, many methods have been developed to identify biologically significant pathways using metabolomics data. In this review, we first describe a complete metabolomics workflow (sample preparation, data acquisition, pre-processing, downstream analysis, etc.). We then comprehensively review 24 approaches capable of performing functional analysis, including those that combine metabolomics data with other types of data to investigate the disease-relevant changes at multiple omics layers. We discuss their availability, implementation, capability for pre-processing and quality control, supported omics types, embedded databases, pathway analysis methodologies, and integration techniques. We also provide a rating and evaluation of each software, focusing on their key technique, software accessibility, documentation, and user-friendliness. Following our guideline, life scientists can easily choose a suitable method depending on method rating, available data, input format, and method category. More importantly, we highlight outstanding challenges and potential solutions that need to be addressed by future research. To further assist users in executing the reviewed methods, we provide wrappers of the software packages at https://github.com/tinnlab/metabolite-pathway-review-docker., (© The Author(s) 2024. Published by Oxford University Press.)

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2., Competing Interests: Competing interests: ASP owns stock in Pfizer. He was also on a Pfizer advisory committee and received an honorarium. The other authors declare that they have no competing interests.

Background: Healthcare workers face burnout from high job demands and prolonged working conditions. While mental health services are available, barriers to access persist. Evidence suggests digital platforms can enhance accessibility. However, there is a lack of systematic reviews on the effectiveness of digital mental health interventions (DMHIs) for healthcare professionals. This review aims to synthesize evidence on DMHIs' effectiveness in reducing burnout, their acceptability by users, and implementation lessons learned., Method: This Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA)-guided review included 12 RCTs on DMHIs for healthcare professionals, published before 31 May 2024. The primary focus was on burnout, with secondary outcomes related to mental health and occupation. Quality appraisal used Cochrane risk of bias tools. A narrative synthesis explored DMHIs' effectiveness, acceptability, utilization, and implementation lessons., Results: Significant improvements in mental health outcomes were observed in 10 out of 16 RCTs. Burnout and its constructs showed significant improvement in five RCTs. Studies that measured the acceptability of the interventions reported good acceptability. Factors such as attrition, intervention design and duration, cultural sensitivities, flexibility and ease of use, and support availability were identified as key implementation considerations., Conclusions: Web-based DMHIs positively impact burnout, mental health, and occupational outcomes among healthcare professionals, as shown in most RCTs. Future research should enhance DMHIs' effectiveness and acceptability by addressing identified factors. Increasing awareness of DMHIs' benefits will foster acceptance and positive attitudes. Lessons indicate that improving user engagement and effectiveness requires a multifaceted approach., (© The Author(s) 2024.)

Purpose: To use finite element (FE) analysis to assess what morphologic and biomechanical factors of the iris and anterior chamber are more likely to influence angle narrowing during pupil dilation., Methods: The study consisted of 1344 FE models comprising the cornea, sclera, lens, and iris to simulate pupil dilation. For each model, we varied the following parameters: anterior chamber depth (ACD = 2-4 mm) and anterior chamber width (ACW = 10-12 mm), iris convexity (IC = 0-0.3 mm), iris thickness (IT = 0.3-0.5 mm), stiffness (E = 4-24 kPa), and Poisson's ratio (v = 0-0.3). We evaluated the change in (△∠) and the final dilated angles (∠f) from baseline to dilation for each parameter., Results: The final dilated angles decreased with a smaller ACD (∠f = 53.4° ± 12.3° to 21.3° ± 14.9°), smaller ACW (∠f = 48.2° ± 13.5° to 26.2° ± 18.2°), larger IT (∠f = 52.6° ± 12.3° to 24.4° ± 15.1°), larger IC (∠f = 45.0° ± 19.2° to 33.9° ± 16.5°), larger E (∠f = 40.3° ± 17.3° to 37.4° ± 19.2°), and larger v (∠f = 42.7° ± 17.7° to 34.2° ± 18.1°). The change in angles increased with larger ACD (△∠ = 9.37° ± 11.1° to 15.4° ± 9.3°), smaller ACW (△∠ = 7.4° ± 6.8° to 16.4° ± 11.5°), larger IT (△∠ = 5.3° ± 7.1° to 19.3° ± 10.2°), smaller IC (△∠ = 5.4° ± 8.2° to 19.5° ± 10.2°), larger E (△∠ = 10.9° ± 12.2° to 13.1° ± 8.8°), and larger v (△∠ = 8.1° ± 9.4° to 16.6° ± 10.4°)., Conclusions: The morphology of the iris (IT and IC) and its innate biomechanical behavior (E and v) were crucial in influencing the way the iris deformed during dilation, and angle closure was further exacerbated by decreased anterior chamber biometry (ACD and ACW).

Purpose: To describe the long-term outcomes of phacotrabeculectomy from a tertiary glaucoma service in Singapore., Design: Retrospective case series., Methods: Seven hundred ninety-six eyes of 698 patients who underwent phacotrabeculectomy surgery at the Singapore National Eye Centre between 2005 and 2007 with a minimum follow-up of three years were included. The primary outcome measure was intraocular pressure (IOP). Secondary outcomes included best-corrected visual acuity (BCVA), number of glaucoma medications, and surgical complications., Results: The mean age was 69.5 years, 51 % were male, and 86 % were Chinese. Most eyes had primary glaucoma (90.6 %). The mean follow-up duration was 9.4 years. The overall success rate at three years was 97 % if surgical success was defined as IOP ≤ 21 mm Hg, 92 % if IOP ≤ 18 mm Hg, 66 % if IOP ≤ 15 mm Hg. By Kaplan-Meier survival analysis over 13 years, the cumulative success rate fell from 98.1 % to 89.1 % if IOP ≤ 21 mm Hg, 98.1-76.9 % if IOP ≤ 18 mm Hg, 98-50.3 % if IOP ≤ 15 mm Hg. The postoperative IOP improved significantly at all time points (P < 0.05) and 72 % had at least 20 % IOP reduction. There was a slight improvement in postoperative BCVA (P < 0.05). The mean number of glaucoma medications was reduced postoperatively (P < 0.001). There were no significant risk factors for surgical failure., Conclusions: Phacotrabeculectomy was found to be safe, resulting in clinically significant IOP lowering for 13 years with reduced dependency on glaucoma medications and improved BCVA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Site-specific nucleases are crucial for genome engineering applications in medicine and agriculture. The ideal site-specific nucleases are easily reprogrammable, highly specific in target site recognition, and robust in nuclease activities. Prokaryotic Argonaute (pAgo) proteins have received much attention as biotechnological tools due to their ability to recognize specific target sequences without a protospacer adjacent motif, but their lack of intrinsic dsDNA unwinding activity limits their utility in key applications such as gene editing. Recently, we developed a pAgo-based system for site-specific DNA cleavage at physiological temperatures independently of the DNA form, using peptide nucleic acids (PNAs) to facilitate unwinding dsDNA targets. Here, we fused catalytically dead pAgos with the nuclease domain of the restriction endonuclease FokI and named this modified platform PNA-assisted FokI-(d)pAgo (PNFP) editors. In the PNFP system, catalytically inactive pAgo recognizes and binds to a specific target DNA sequence based on a programmable guide DNA sequence; upon binding to the target site, the FokI domains dimerize and introduce precise dsDNA breaks. We explored key parameters of the PNFP system including the requirements of PNA and guide DNAs, the specificity of PNA and guide DNA on target cleavage, the optimal concentration of different components, reaction time for invasion and cleavage, and ideal temperature and reaction buffer, to ensure efficient DNA editing in vitro. The results demonstrated robust site-specific target cleavage by PNFP system at optimal conditions in vitro. We envision that the PNFP system will provide higher editing efficiency and specificity with fewer off-target effects in vivo., Competing Interests: Conflicts of interest Authors have a pending patent application on the PNFP editors and their diverse uses and applications in diverse organisms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To compare intraocular pressure (IOP) and anterior segment parameters between eyes with unilateral primary angle closure glaucoma (PACG) and their fellow eyes with primary angle closure (PAC) or primary angle closure suspect (PACS)., Methods: Subjects underwent anterior segment imaging using 360-degree swept-source optical coherence tomography (SS-OCT, CASIA Tomey, Nagoya, Japan) and ocular investigations including gonioscopy and IOP measurement. Each SS-OCT scan (divided into 8 frames, 22.5 degrees apart) was analysed and an average was obtained for the following anterior segment parameters: iridotrabecular contact (ITC), angle opening distance (AOD750), iris thickness and curvature, anterior chamber width, depth and area (ACW, ACD and ACA) and lens vault (LV)., Results: Among 132 unilateral PACG subjects (mean age: 62.91 ± 7.2 years; 59.1% male), eyes with PACG had significantly higher presenting IOP (24.81 ± 0.94 vs. 18.43 ± 0.57 mmHg, p < 0.001), smaller gonioscopic Shaffer grade (2.07 ± 0.07 vs. 2.31 ± 0.07, p < 0.001) and a greater extent of peripheral anterior synechiae (PAS, 1.21 ± 0.21 vs. 0.54 ± 0.16 clock hours, p = 0.001). PACG eyes also exhibited increased ITC, ITC area, greater LV and smaller AOD750, ACD and ACA (all p < 0.05). Using the forward stepwise regression model, an increase in 1 mmHg in presenting IOP before laser peripheral iridotomy (LPI) increases the odds of having PACG by 9% (95% confidence interval 5%-14%)., Conclusions: PACG eyes have higher presenting IOP, smaller anterior segment parameters, greater extent of PAS, and larger LV compared to their fellow eyes with angle closure. Narrower anterior chamber dimensions and higher presenting IOP before LPI may increase risk of chronic elevated IOP and glaucomatous optic neuropathy after LPI., (© 2024 Royal Australian and New Zealand College of Ophthalmologists.)

Prcis: The combination of surgical peripheral iridectomy, goniosynechialysis, and goniotomy is a safe and effective surgical approach for advanced primary angle closure glaucoma without cataract., Purpose: To evaluate the efficacy and safety of surgical peripheral iridectomy (SPI), goniosynechialysis (GSL), and goniotomy (GT) in advanced primary angle closure glaucoma (PACG) eyes without cataract., Patients and Methods: A prospective multicenter observational study was performed for patients who underwent combined SPI, GSL, and GT for advanced PACG without cataract. Patients were assessed before and after the operation. Complete success was defined as achieving intraocular pressure (IOP) between 6 and 18 mm Hg with at least a 20% reduction compared with baseline, without the use of ocular hypotensive medications or reoperation. Qualified success adopted the same criteria but allowed medication use. Factors associated with surgical success were analyzed using logistic regression., Results: A total of 61 eyes of 50 advanced PACGs were included. All participants completed 12 months of follow-up. Thirty-six eyes (59.0%) achieved complete success, and 56 eyes (91.8%) achieved qualified success. Preoperative and postsurgical at 12 months mean IOPs were 29.7±7.7 and 16.1±4.8 mm Hg, respectively. The average number of ocular hypotensive medications decreased from 1.9 to 0.9 over 12 months. The primary complications included IOP spike (n=9), hyphema (n=7), and shallow anterior chamber (n=3). Regression analysis indicated that older age (odds ratio [OR]=1.09; P =0.043) was positively associated with complete success, while a mixed angle closure mechanism (OR=0.17; P =0.036) reduced success rate., Conclusions: The combination of SPI, GSL, and GT is a safe and effective surgical approach for advanced PACG without cataract. It has great potential as a first-line treatment option for these patients., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess the safety of replacing the postoperative week 1 (POW1) clinic visit with a nurse-conducted telephone call., Design: Retrospective observational study that included cases from January 2019 to June 2021., Participants: Patients who had undergone uncomplicated phacoemulsification surgery with an unremarkable postoperative day 1 (POD1) examination., Methods: All patients were seen in clinic on POD1 by an ophthalmologist. They then had a telephone conversation with a nurse at POW1 and subsequently an in-person postoperative month 1 (POM1) clinic consultation with an ophthalmologist. Main outcome measure was the incidence of unexpected management changes related to cataract surgery within POM1. Data also were collected on the reasons for unscheduled patient-initiated visits, additional procedures or medications, and postoperative visual acuity worse than 6/12 at POM1., Results: Of the 20,475 patients, 541 patients (2.64%) had an unexpected management change within POM1. There were 565 patients (2.76%) who had self-initiated unscheduled visits between POD1 to POM1. There were 23 patients (0.11%) who required additional surgery within POM1 and 1 patient (0.005%) with endophthalmitis. The most common indication for additional surgical procedures was retained lens material (7 patients, 30.43%). Visual acuity was worse than 6/12 in 1,199 patients (6.22%), with the most common causes attributed to preexisting ocular conditions., Conclusions: These results suggest that replacing the POW1 visit with a nurse-conducted telephone consult for patients who have undergone uncomplicated phacoemulsification surgery and had a normal POD1 consultation is safe., Competing Interests: Footnotes and Disclosure The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

There is little information available on antibiotic resistance (ABR) within shrimp aquaculture environments. The aim of this study was to investigate the presence of antibiotic resistance genes (ARGs) in shrimp farming operations in Atacames, Ecuador. Water samples ( n = 162) and shrimp samples ( n = 54) were collected from three shrimp farming operations. Samples were cultured and a subset of isolates that grew in the presence of ceftriaxone, a third-generation cephalosporin, were analyzed using whole-genome sequencing (WGS). Among the sequenced isolates ( n = 44), 73% of the isolates contained at least one ARG and the average number of ARGs per isolate was two, with a median of 3.5 ARGs. Antibiotic resistance genes that confer resistance to the β-lactam class of antibiotics were observed in 65% of the sequenced isolates from water (20/31) and 54% of the isolates from shrimp (7/13). We identified 61 different ARGs across the 44 sequenced isolates, which conferred resistance to nine antibiotic classes. Over half of all sequenced isolates (59%, n = 26) carried ARGs that confer resistance to more than one class of antibiotics. ARGs for certain antibiotic classes were more common, including beta-lactams (26 ARGs); aminoglycosides (11 ARGs); chloramphenicol (three ARGs); and trimethoprim (four ARGs). Sequenced isolates consisted of a diverse array of bacterial orders and species, including Escherichia coli (48%), Klebsiella pneumoniae (7%), Aeromonadales (7%), Pseudomonadales (16%), Enterobacter cloacae (2%), and Citrobacter freundii (2%). Many ARGs were shared across diverse species, underscoring the risk of horizontal gene transfer in these environments. This study indicated the widespread presence of extended-spectrum β-lactamase (ESBL) genes in shrimp aquaculture, including bla CTX-M , bla SHV , and bla TEM genes. Increased antibiotic resistance surveillance of shrimp farms and identification of aquaculture operation-level risk factors, such as antibiotic use, will likely be important for mitigating the spread of ARGs of clinical significance.

Aim: To evaluate reproducibility and agreement of angle closure assessment by a novel hyperparallel optical coherence tomography (OCT) system (HP-OCT, Cylite Optics, Melbourne, Australia), in comparison with swept-source OCT (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) and gonioscopy., Methods: Cross-sectional study. Phakic subjects >40 years, with no relevant ophthalmic history were consecutively recruited from the glaucoma clinic. Subjects underwent same-day evaluation with HP-OCT, SS-OCT and gonioscopy. The primary outcome was the presence of angle closure, defined as iridotrabecular contact in HP-OCT and SS-OCT images at 0°-180° meridional and as non-visibility of the posterior trabecular meshwork (TM) by gonioscopy. Visibility of TM was also assessed (secondary outcome). Intra and interdevice agreement analysis (Gwet AC1) and logistic regression analysis were performed for primary and secondary outcomes, respectively., Results: 154 sectors from horizontal scans of 77 subjects were analysed. The reproducibility of angle closure assessment by HP-OCT was excellent (AC1 of 0.95 for temporal angle and 1.00 for nasal). Agreement for angle closure detection was very good between HP-OCT and SS-OCT (AC1 of 0.88 for temporal and 0.81 for nasal angle) and good between HP-OCT and gonioscopy (AC1 of 0.71 for temporal and 0.78 for nasal angle). TM was identifiable in 64.4% (94/146) of unprocessed HP-OCT images (both open and closed angles), however not visible in any of the SS-OCT unprocessed images., Conclusions: HP-OCT showed excellent reproducibility for angle closure assessment and good agreement with SS-OCT and gonioscopy. HP-OCT technology also provides a unique capability to visualise regions around TM and Schlemm's canal, opening new avenues for clinical research of distal outflow pathways., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

During the metastatic cascade, cancer cells travel through the bloodstream as circulating tumor cells (CTCs) to a secondary site. Clustered CTCs have greater shear stress and treatment resistance, yet their biology remains poorly understood. We therefore engineered a tunable superhydrophobic array device (SHArD). The SHArD-C was applied to culture a clinically relevant model of CTC clusters. Using our device, we cultured a model of cancer cell aggregates of various sizes with immortalized cancer cell lines. These exhibited higher E-cadherin expression and are significantly more capable of surviving high fluid shear stress-related forces compared to single cells and model clusters grown using the control method, helping to explain why clustering may provide a metastatic advantage. Additionally, the SHArD-S, when compared with the AggreWell 800 method, provides a more consistent spheroid-forming device culturing reproducible sizes of spheroids for multiple cancer cell lines. Overall, we designed, fabricated, and validated an easily tunable engineered device which grows physiologically relevant three-dimensional (3D) cancer models containing tens to thousands of cells.

Prcis: The microvasculature of the optic disc and macula in eyes with acute primary angle closure and primary angle closure glaucoma was lower across the disease spectrum, but the significant difference was only observed in primary angle closure glaucoma., Purpose: To assess the microvasculature in the optic nerve head (ONH) and macula across primary angle-closure disease (PACD) spectrum using optical coherence tomography angiography (OCTA)., Methods: OCTA (AngioVue, Fremont, CA) imaging was performed on 122 PACD subjects. Flow area (FA) and vessel density (VD) in the ONH, radial peripapillary capillary (RPC) network, and superficial and deep capillary plexuses of the macula were calculated and compared across the PACD spectrum using linear regression models with generalized estimating equations adjusted for inter-eye correlation., Results: A total of 234 eyes including 44 primary angle-closure suspects (PACS), 93 primary angle-closure (PAC), 79 primary angle-closure glaucoma (PACG) and 18 PAC with history of previous acute primary angle-closure (APAC) were included in the analysis. Compared to other groups, PACG eyes showed smaller FA in the ONH (1.35±0.02 mm2), RPC (0.78±0.03 mm2), and the superficial retinal layer (1.08±0.03 mm2) (all P<0.05). Lower VD was also observed in the "whole image", "inside disc", and "peripapillary" regions of the ONH and RPC, and the "whole image" and "parafoveal" regions of the retinal layer in the PACG group when compared with other groups (all P<0.05). No significant differences were found for the other groups (all P>0.05). Lower VD in the ONH, RPC, and superficial retinal layer significantly correlated with worse visual field loss in PACG eyes (all P<0.05)., Conclusions: Significant reduction in the microvasculature of the optic disc and macula in PACG suggests that glaucoma development may contribute to lower VD in these regions., Competing Interests: Conflict of Interest: No conflicting relationship exists for any author., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Negative CCTA can effectively exclude significant CAD, eliminating the need for further noninvasive or invasive testing. However, in the presence of severe CAD, the accuracy declines, thus necessitating additional testing. The aim of our study was to evaluate the diagnostic performance of noninvasive cFFR derived from CCTA, compared to ICA in detecting hemodynamically significant stenoses in participants with high CAC scores (>400)., Methods: This study included 37 participants suspected of having CAD who underwent CCTA and ICA. CAC was calculated and cFFR analyses were performed using an on-site machine learning-based algorithm. Diagnostic accuracy parameters of CCTA and cFFR were calculated on a per-vessel level., Results: The median total CAC score was 870, with an IQR of 642-1370. Regarding CCTA, sensitivity and specificity for RCA were 60% and 67% with an AUC of 0.639; a LAD of 87% and 50% with an AUC of 0.688; an LCX of 33% and 90% with an AUC of 0.617, respectively. Regarding cFFR, sensitivity and specificity for RCA were 60% and 61% with an AUC of 0.606; a LAD of 75% and 54% with an AUC of 0.647; an LCX of 50% and 77% with an AUC of 0.647. No significant differences between AUCs of coronary CTA and cFFR for each vessel were found., Conclusions: Our results showed poor diagnostic accuracy of CCTA and cFFR in determining significant ischemia-related lesions in participants with high CAC scores when compared to ICA. Based on our results and study limitations we cannot exclude cFFR as a method for determining significant stenoses in people with high CAC. A key issue is accurate and detailed lumen segmentation based on good-quality CCTA images.

Background: Half of patients with heart failure with preserved ejection fraction (HFpEF) remain undiagnosed by resting evaluation alone. Therefore, exercise testing is proposed. The diastolic stress test (DST), however, has limited sensitivity. We aimed to determine the clinical significance of adding the mean pulmonary artery pressure over cardiac output (mPAP/CO) slope to the DST in suspected HFpEF., Methods and Results: In this prospective cohort study, consecutive patients (n=1936) with suspected HFpEF underwent exercise echocardiography with simultaneous respiratory gas analysis. These patients were stratified by exercise E over e ' (exE/ e ') and mPAP/CO slope, and peak oxygen uptake, natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and score-based HFpEF likelihood were compared. Twenty-two percent of patients (n=428) had exE/ e '<15 despite a mPAP/CO slope>3 mm Hg/L per min, 24% (n=464) had a positive DST (exE/ e '≥15), and 54% (n=1044) had a normal DST and slope. Percentage of predicted oxygen uptake was similar in the group with exE/ e '<15 but high mPAP/CO slope and the positive DST group (-2% [-5% to +1%]), yet worse than in those with normal DST and slope (-12% [-14% to -9%]). Patients with exE/ e '<15 but a high slope had NT-proBNP levels and H 2 FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder; filling pressure) scores intermediate to the positive DST group and the group with both a normal DST and slope., Conclusions: Twenty-two percent of patients with suspected HFpEF presented with a mPAP/CO slope>3 mm Hg/L per min despite a negative DST. These patients had HFpEF characteristics and a peak oxygen uptake as low as patients with a positive DST. Therefore, an elevated mPAP/CO slope might indicate HFpEF irrespective of the DST result.

An estimated 82-89% of ecological research and 85% of medical research has limited or no value to the end user because of various inefficiencies. We argue that registration and registered reports can enhance the quality and impact of ecological research. Drawing on evidence from other fields, chiefly medicine, we support our claim that registration can reduce research waste. However, increasing registration rates, quality and impact will be very slow without coordinated effort of funders, publishers and research institutions. We therefore call on them to facilitate the adoption of registration by providing adequate support. We outline several aspects to be considered when designing a registration system that would best serve the field of ecology. To further inform the development of such a system, we call for more research to identify the causes of low registration rates in ecology. We suggest short- and long-term actions to bolster registration and reduce research waste., (© 2024. Springer Nature Limited.)

We present the case of an infant with rapidly progressing orbital tumor that had initial radiological and clinical features of both rhabdomyosarcoma and capillary hemangioma. The patient was eventually diagnosed with malignant rhabdoid tumor of the orbit. We discuss the salient histological and radiological features of our case and review the literature on orbital malignant rhabdoid tumors., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Prcis: The combination of phacoemulsification, goniosynechialysis and goniotomy is an effective treatment for primary angle closure glaucoma patients with cataract, and this is not linked to the extent of preoperative peripheral anterior synechiae., Purpose: To evaluate the impact of the extent of peripheral anterior synechiae (PAS) on the effectiveness and safety of combined phacoemulsification (PEI), goniosynechialysis (GSL), and goniotomy (GT) in eyes with primary angle closure glaucoma (PACG) and cataract., Patients and Methods: This study included patients diagnosed with PACG and cataracts who underwent combined PEI and 120 degrees GSL plus GT (PEI+GSL+GT) between April 2020 and October 2022 at 10 ophthalmic institutes. Eligible patients were divided into 3 groups based on the extent of PAS: 180°≤PAS<270°, 270°≤PAS<360°, and PAS=360°. Data on intraocular pressure (IOP), the number of ocular hypotensive medications, and complications were collected and compared. The study defined complete success as postoperative IOP within the 6-18 mm Hg range and a 20% reduction from baseline without the use of topical medications. Qualified success was defined in the same way as complete success, but it allowed for the use of ocular hypotensive medications., Results: Three hundred four eyes of 283 patients were included. The mean follow-up was 12.50±1.24 months. All groups experienced a significant reduction in IOP after the surgery ( P <0.05). There were no significant differences in final IOP, number of medications, and cumulative complete and qualified success rates among the 3 groups ( P >0.05). The groups with 270°≤PAS<360°had a higher frequency of hyphema compared with 180°≤PAS<270° ( P = 0.044)., Conclusions: PEI+GSL+GT has proven to be an effective treatment for PACG with cataracts over a 1 year period. However, the outcome was not correlated with the preoperative extent of PAS., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Topical prostaglandin analogues are commonly used to treat patients with glaucoma, but may cause periocular and periorbital complications known as prostaglandin-associated periorbitopathy syndrome (PAPS)., Methods: A literature review was conducted on PAPS. Given the lack of consensus on grading PAPS, glaucoma specialists from Asia convened to evaluate current PAPS grading systems and propose additional considerations in grading PAPS., Results: Existing grading systems are limited by the lack of specificity in defining grades and consideration for patients' subjective perception of symptoms. Patient-reported symptoms (e.g., via a self-assessment tool) and additional clinical assessments (e.g., exophthalmometry, lid laxity, differences between tonometry results, baseline measurements, and external ocular photographs) would be beneficial for grading PAPS systematically., Conclusions: Effective management of PAPS could be facilitated by a common clinical grading system to consistently and accurately diagnose and characterise symptoms. Further research is required to validate specific recommendations and approaches to stage and monitor PAPS.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption., Competing Interests: JMC is a consultant for Excision Biotherapeutics and Merck. The other authors declare no competing interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Aims: To compare the diagnostic performance of 360° anterior segment optical coherence tomography assessment by applying normative percentile cut-offs versus iris trabecular contact (ITC) for detecting gonioscopic angle closure., Methods: In this multicentre study, 394 healthy individuals were included in the normative dataset to derive the age-specific and angle location-specific normative percentiles of angle open distance (AOD500) and trabecular iris space area (TISA500) which were measured every 10° for 360°. 119 healthy participants and 170 patients with angle closure by gonioscopy were included in the test dataset to investigate the diagnostic performance of three sets of criteria for detection of gonioscopic angle closure: (1) the 10th and (2) the 5th percentiles of AOD500/TISA500, and (3) ITC (ie, AOD500/TISA500=0 mm/mm 2 ). The number of angle locations with angle closure defined by each set of the criteria for each eye was used to generate the receiver operating characteristic (ROC) curve for the discrimination between gonioscopic angle closure and open angle., Results: Of the three sets of diagnostic criteria examined, the area under the ROC curve was greatest for the 10th percentile of AOD500 (0.933), whereas the ITC criterion AOD500=0 mm showed the smallest area under the ROC (0.852) and the difference was statistically significant with or without adjusting for age and axial length (p<0.001). The criterion ≥90° of AOD500 below the 10th percentile attained the best sensitivity 87.6% and specificity 84.9% combination for detecting gonioscopic angle closure., Conclusions: Applying the normative percentiles of angle measurements yielded a higher diagnostic performance than ITC for detecting angle closure on gonioscopy., Competing Interests: Competing interests: XZ, MA, SL and CK-SL have received support from Tomey in the form of instrument and speaker honorarium. SL is consultant to Aerie, Iridex, Bausch & Lomb and Allergan. TA is consultant to Allergan, Alcon, Novartis, Santen, Sun Pharma and Belkin Laser, and has received research support from Allergan and Santen. CK-SL has received research support in the form of research grant and instruments from Carl Zeiss Meditec, Topcon and Heidelberg Engineering; he has been an advisory board member for Alcon, Novartis, Santen, Aerie and Allergan. The study instruments (CASIA2, Tomey Corporation, Nagoya, Japan) were on loan from Tomey Corporation during the study period., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This manuscript describes the development of a resource module that is part of a learning platform named 'NIGMS Sandbox for Cloud-based Learning' (https://github.com/NIGMS/NIGMS-Sandbox). The module delivers learning materials on Cloud-based Consensus Pathway Analysis in an interactive format that uses appropriate cloud resources for data access and analyses. Pathway analysis is important because it allows us to gain insights into biological mechanisms underlying conditions. But the availability of many pathway analysis methods, the requirement of coding skills, and the focus of current tools on only a few species all make it very difficult for biomedical researchers to self-learn and perform pathway analysis efficiently. Furthermore, there is a lack of tools that allow researchers to compare analysis results obtained from different experiments and different analysis methods to find consensus results. To address these challenges, we have designed a cloud-based, self-learning module that provides consensus results among established, state-of-the-art pathway analysis techniques to provide students and researchers with necessary training and example materials. The training module consists of five Jupyter Notebooks that provide complete tutorials for the following tasks: (i) process expression data, (ii) perform differential analysis, visualize and compare the results obtained from four differential analysis methods (limma, t-test, edgeR, DESeq2), (iii) process three pathway databases (GO, KEGG and Reactome), (iv) perform pathway analysis using eight methods (ORA, CAMERA, KS test, Wilcoxon test, FGSEA, GSA, SAFE and PADOG) and (v) combine results of multiple analyses. We also provide examples, source code, explanations and instructional videos for trainees to complete each Jupyter Notebook. The module supports the analysis for many model (e.g. human, mouse, fruit fly, zebra fish) and non-model species. The module is publicly available at https://github.com/NIGMS/Consensus-Pathway-Analysis-in-the-Cloud. This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The inclusion of a connecting path in a porous implant can promote nutrient diffusion to cells and enhance bone ingrowth. Consequently, this study aimed to evaluate the biomechanical, radiographic, and histopathological performance of a novel 3D-printed porous suture anchor in a rabbit femur model., Methods: Three test groups were formed based on the type of suture anchor (SA): Commercial SA (CSA, Group A, n = 20), custom solid SA (CSSA, Group B, n = 20), and custom porous SA (CPSA, Group C, n = 20). The SAs were implanted in the lateral femoral condyle of the right leg in each rabbit. The rabbits (New Zealand white rabbits, male, mean body weight of 2.8 ± 0.5 kg, age 8 months) underwent identical treatment and were randomized into experimental and control groups via computer-generated randomization. Five rabbits (10 femoral condyles) were euthanized at 0, 4, 8, and 12 weeks post-implantation for micro-CT, histological analysis, and biomechanical testing., Results: At 12 weeks, the CPSA showed a higher BV/TV (median 0.7301, IQR 0.7276-0.7315) than the CSSA and CSA. The histological analysis showed mineralized osteocytes near the SA. At 4 weeks, new bone was observed around the CPSA and had penetrated its porous structure. By 12 weeks, there was no significant difference in ultimate failure load between the CSA and CPSA., Conclusions: We demonstrated that the innovative 3D-printed porous suture anchor exhibited comparable pullout strength to conventional threaded suture anchors at the 12-week postoperative time-point period. Furthermore, our porous anchor design enhanced new bone formation and facilitated bone growth into the implant structure, resulting in improved biomechanical stability., (© 2024. The Author(s).)

Purpose: To compare the efficacy and safety of omidenepag isopropyl (OMDI) 0.002% with latanoprost 0.005% once daily in Asian subjects with open-angle glaucoma (OAG)/ocular hypertension (OHT)., Methods: In this Phase III randomized, observer-masked, active-controlled, multinational trial (NCT02981446), subjects aged ≥18 years with OAG/OHT in both eyes and baseline intraocular pressure (IOP) ≥22 mmHg and ≤34 mmHg were randomized 1:1 to OMDI or latanoprost. IOP was measured at 9AM, 1PM, and 5PM at baseline, 1 week, 6 weeks, and 3 months. Adverse events (AEs) were recorded. Non-inferiority of OMDI to latanoprost was tested for primary and key secondary endpoints., Results: Each group included 185 subjects. Mean diurnal IOP from baseline to month 3 was reduced 7.1 mmHg (28.8%) with OMDI and 7.8 mmHg (31.3%) with latanoprost, with the least-squares mean difference (OMDI minus latanoprost) being 0.6 mmHg (95% CI: 0.0, 1.2 mmHg; p = 0.0366), indicating non-inferiority. Mean IOP reductions at the nine timepoints were -5.8 to -7.3 mmHg (23.5-29.5%) for OMDI and -6.1 to -7.9 mmHg (24.3-31.7%) for latanoprost. Non-inferiority per FDA criteria was also met. Rates of all AEs, ocular AEs, and ocular AEs associated with treatment were 40.0%, 36.8%, and 23.2%, respectively, for OMDI and 29.7%, 21.1%, and 11.9%, respectively, for latanoprost. Conjunctival hyperemia rates were higher with OMDI than latanoprost (11.9% vs 5.4%). Most AEs were mild, with no serious ocular AEs., Conclusion: OMDI safely and effectively reduces IOP in Asian subjects with OAG/OHT, with mean diurnal IOP at Month 3 and per-timepoint IOP reductions non-inferior to those of latanoprost., Competing Interests: Tsing Hong Wang is a consultant to AbbVie, Bausch & Lomb, Santen, and Viatris. Tin Aung is a consultant to Santen, AbbVie, Belkin Laser, Sun Pharma, and Novartis. Ronnie George is a consultant to AbbVie, Alcon, Santen, Sun Pharma, and Novartis. Ki Ho Park is a consultant to Santen, AbbVie, Novartis, and Sensimed. Noriko Odani-Kawabata is an employee of Santen. Fenghe Lu was an employee of Santen at the time of the study. The authors report no other conflicts of interest in this work., (© 2024 Wang et al.)

Background: Acne is an inflammatory condition of the pilosebaceous unit. Previous studies have established a link between acne and vitamin D deficiency and the potential effectiveness of vitamin D supplementation in treatment. However, the efficacy of vitamin D as an adjuvant treatment for acne remains unknown., Objective: To evaluate the efficacy of weekly vitamin D2 oral administration as an adjunctive treatment to standard topical care for acne., Methods: This study was a randomized, double-blind, placebo-controlled trial including subjects with mild-to-moderate acne. Topical 2.5% benzoyl peroxide was applied twice daily for 12 weeks to all subjects. Subjects were randomly allocated to receive either oral vitamin D2 40,000 IU weekly or placebo weekly during the treatment period. No additional treatment was administered during the 4-week follow-up period., Results: A total of 44 subjects were included in this study. All of them had inadequate 25(OH)D levels. Both regimens showed significant improvement in acne during the treatment period. Weekly vitamin D2 supplementation significantly prevented the relapse of inflammatory acne lesions ( P = .048) at the follow-up visit. No adverse effects or biochemical changes were observed., Limitations: There were no subjects of severe acne vulgaris., Conclusion: Adjunctive weekly vitamin D2 supplementation to standard topical benzoyl peroxide could reduce relapses of inflammatory lesions in mild-to-moderate acne., Competing Interests: None., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Women’s Dermatologic Society.)

Physiological or pathophysiological changes lead to posttranslational changes in the sialic acid content of human serum transferrin (hTf), an essential mediator of iron transport in the human body, resulting in a significantly increased concentration of desialylated hTf. The intrinsic fluorescence quenching upon binding of iron to hTf was successfully modeled using the binding polynomial for two iron-binding sites, allowing measurements in a high-throughput format. Removal of sialic acid residues resulted in a 3-fold increase in iron binding affinity for both sites of hTf at pH 7.4. The pH-dependence of iron binding showed significant differences in equilibrium constants, resulting in a 10-fold increase in binding affinity for desialylated hTf at pH 5.9. The changes in hTf sialylation apparently result in tuning of the stability of the conformational state, which in turn contributes to the stability of the diferric hTf. The observed differences in the conditional thermodynamic equilibrium constants suggest that the desialylated protein has a higher preference for diferric hTf over monoferric hTf species down to pH 6.5, which may also influence the interaction with transferrin receptors that preferentially bind to diferric hTf. The results suggest a link between changes in hTf glycan structure and alterations in iron binding equilibrium associated with tissue acidosis.

Background/aims: To identify ocular determinants of iridolenticular contact area (ILCA), a recently introduced swept-source optical coherence tomography (SSOCT) derived parameter, and assess the association between ILCA and angle closure., Methods: In this population-based cross-sectional study, right eyes of 464 subjects underwent SSOCT (SS-1000, CASIA, Tomey Corporation, Nagoya, Japan) imaging in the dark. Eight out of 128 cross-sectional images (evenly spaced 22.5° apart) were selected for analysis. Matlab (Matworks, Massachusetts, USA) was used to measure ILCA, defined as the circumferential extent of contact area between the pigmented iris epithelium and anterior lens surface. Gonioscopic angle closure (GAC) was defined as non-visibility of the posterior trabecular meshwork in two or more angle quadrants., Results: The mean age of subjects was 62±6.6 years, with the majority being female (65.5%). 143/464 subjects (28.6%) had GAC. In multivariable linear regression analysis, ILCA was significantly associated with anterior chamber width (β=1.03, p=0.003), pupillary diameter (β=-1.9, p<0.001) and iris curvature (β=-17.35, p<0.001). ILCA was smaller in eyes with GAC compared with those with open angles (4.28±1.6 mm 2 vs 6.02±2.71 mm 2 , p<0.001). ILCA was independently associated with GAC (β=-0.03, p<0.001), iridotrabecular contact index (β=-6.82, p<0.001) or angle opening distance (β=0.02, p<0.001) after adjusting for covariates. The diagnostic performance of ILCA for detecting GAC was acceptable (AUC=0.69)., Conclusions: ILCA is a significant predictor of angle closure independent of other biometric factors and may reflect unique anatomical information associated with pupillary block. ILCA represents a novel biometric risk factor in eyes with angle closure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To evaluate the effectiveness of glaucoma screening using glaucoma suspect (GS) referral criteria assessed on colour fundus photographs in Singapore's Integrated Diabetic Retinopathy Programme (SiDRP)., Methods: A case-control study. This study included diabetic subjects who were referred from SiDRP with and without GS between January 2017 and December 2018 and reviewed at Singapore National Eye Centre. The GS referral criteria were based on the presence of a vertical cup-to-disc ratio (VCDR) of ≥0.65 and other GS features. The final glaucoma diagnosis confirmed from electronic medical records was retrospectively matched with GS status. The sensitivity, specificity and positive predictive value (PPV) of the test were evaluated., Results: Of 5023 patients (2625 with GS and 2398 without GS) reviewed for glaucoma, 451 (9.0%, 95% CI 8.2% to 9.8%) were confirmed as glaucoma. The average follow-up time was 21.5±10.2 months. Using our current GS referral criteria, the sensitivity, specificity and PPV were 81.6% (95% CI 77.7% to 85.1%), 50.6% (95% CI 49.2% to 52.1%) and 14.0% (95% CI 13.4% to 14.7%), respectively, resulting in 2257 false positive cases. Increasing the VCDR cut-off for referral to ≥0.80, the specificity increased to 93.9% (95% CI 93.1% to 94.5%) but the sensitivity decreased to 11.3% (95% CI 8.5% to 14.6%), with a PPV of 15.4% (95% CI 12.0% to 19.4%)., Conclusions: Opportunistic screening for glaucoma in a lower VCDR group could result in a high number of unnecessary referrals. If healthcare infrastructures are limited, targeting case findings on a larger VCDR group with high specificity will still be beneficial., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute respiratory distress syndrome (ARDS) is a severe complication that can lead to fatalities in multiple trauma patients. Nevertheless, the incidence rate and early prediction of ARDS among multiple trauma patients residing in high-altitude areas remain unknown., Methods: This study included a total of 168 multiple trauma patients who received treatment at Shigatse People's Hospital Intensive Care Unit (ICU) between January 1, 2019 and December 31, 2021. The clinical characteristics of the patients and the incidence rate of ARDS were assessed. Univariable and multivariable logistic regression models were employed to identify potential risk factors for ARDS, and the predictive effects of these risk factors were analyzed., Results: In the high-altitude area, the incidence of ARDS among multiple trauma patients was 37.5% (63/168), with a hospital mortality rate of 16.1% (27/168). Injury Severity Score (ISS) and thoracic injuries were identified as significant predictors for ARDS using the logistic regression model, with an area under the curve (AUC) of 0.75 and 0.75, respectively. Furthermore, a novel predictive risk score combining ISS and thoracic injuries demonstrated improved predictive ability, achieving an AUC of 0.82., Conclusions: This study presents the incidence of ARDS in multiple trauma patients residing in the Tibetan region, and identifies two critical predictive factors along with a risk score for early prediction of ARDS. These findings have the potential to enhance clinicians' ability to accurately assess the risk of ARDS and proactively prevent its onset., Competing Interests: The authors declare that they have no competing interests., (© 2024 Tu et al.)

Background: Malnutrition is common among children under 5 years of age in Indonesia, with the rates varying between urban and rural areas. The minimum acceptable diet (MAD) assesses nutrient quality and quantity. This study aimed to identify the potential variables for MAD in 6-23-month-old children in both urban and rural Indonesia., Methods: We used the data from the 2017 Indonesia Demographic and Health Survey to conduct this nationally representative study. A total of 4,688 children aged 6-23 months were included in the study. MAD was classified using the 2017 World Health Organization global nutrition monitoring framework. The determinants of MAD were analyzed using multiple logistic regression., Results: Overall, 45% of children aged 6-23 months received the required MAD, with 47.4% receiving the MAD in urban areas and 35.7% in rural areas. Children's age, fathers' age, parents' education level, mothers' employment, and wealth index were strongly linked to MAD in both rural and urban homes. The factor specifically related to MAD in urban areas was mother living with her husband. For rural households, mothers' involvement in decisionmaking and a minimum of four antenatal care (ANC) visits significantly increased the likelihood of their children's MAD status., Conclusion: MAD status was determined by increased child age, higher parent education, younger father, working mother, and higher wealth index in children aged 6-23 months in both urban and rural settings. Mothers living with a spouse determined the MAD status only in urban areas. More frequent ANC visits and mother participation in household decisions were other factors related to MAD status in rural areas.

The continuous discharge of organic dyes into freshwater resources poses a long-term hazard to aquatic life. The advanced oxidation Fenton process is a combo of adsorption and degradation of pollutants to detoxify toxic effluents, such as anti-bacterial drugs, antibiotics, and organic dyes. In this work, an activated attapulgite clay-loaded iron-oxide (A-ATP@Fe 3 O 4 ) was produced using a two-step reaction, in which attapulgite serves as an enrichment matrix and Fe 3 O 4 functions as the active degrading component. The maximum adsorption capacity (q t ) was determined by assessing the effect of temperature, pH H 2 O 2 , and adsorbent. The results showed that the A-ATP@Fe 3 O 4 achieves the highest removal rate of 99.6% under optimum conditions: 40 °C, pH = 3, H 2 O 2 25 mM, and 0.1 g dosage of the composite. The dye removal procedure achieved adsorption and degradation equilibrium in 120 and 30 min, respectively, by following the same processes as the advanced oxidation approach. Catalytic activity, kinetics, and specified surface characteristics suggest that A-ATP@Fe 3 O 4 is one of the most promising candidates for advanced oxidation-enrooted removal of organic dyes.

Canine kobuvirus (CaKoV) is a pathogen associated with canine gastrointestinal disease (GID). This study examined 327 rectal swabs (RS), including 113 from Vietnam (46 healthy, 67 with GID) and 214 from Thailand (107 healthy and 107 with GID). CaKoV was detected in both countries, with prevalences of 28.3% (33/113) in Vietnam and 7.9% (17/214) in Thailand. Additionally, CaKoV was found in both dogs with diarrhea and healthy dogs. CaKoV was mainly found in puppies under six months of age (30.8%). Co-detection with other canine viruses were also observed. The complete coding sequence (CDS) of nine Vietnamese and four Thai CaKoV strains were characterized. Phylogenetic analysis revealed a close genetic relationship between Vietnamese and Thai CaKoV strains, which were related to the Chinese strains. CDS analysis indicated a distinct lineage for two Vietnamese CaKoV strains. Selective pressure analysis on the viral capsid (VP1) region showed negative selection, with potential positive selection sites on B-cell epitopes. This study, the first of its kind in Vietnam, provides insights into CaKoV prevalence in dogs of different ages and healthy statuses, updates CaKoV occurrence in Thailand, and sheds light on its molecular characteristics and immune evasion strategies., (© 2024. The Author(s).)

Asthma is a chronic lung disease characterized by reversible bronchoconstriction and inflammation of the bronchi. Its increasing prevalence in childhood as well as different triggers make asthma a challenging disease in several ways: defining its phenotype/endotype, the diagnostic approach (especially in younger children), therapeutic options, and systematic follow-up. Considering these problems, this review approaches the current status and limitations of guidelines used for asthma management in children. It also emphasizes the key points which could lead to a better understanding and the direction to take in future studies.