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Natalia Mussi, Waqas Haque, Danielle M Robertson Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Danielle M RobertsonDepartment of Ophthalmology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9057, USAEmail Danielle.Robertson@UTSouthwestern.eduPurpose: Risk factors for metabolic syndrome include abdominal obesity, insulin resistance, hypertension, high triglycerides and/or low high-density lipoprotein cholesterol, and hyperglycemia. Risk factors for metabolic syndrome have been associated with dry eye disease; however, their association with meibomian gland disease (MGD), a subtype of dry eye, is unclear. In the present study, we investigated risk factors for metabolic syndrome in a dry eye cohort with and without MGD.Methods: This retrospective case-control study evaluated electronic medical records at a major urban outpatient medical center to identify patients with a known diagnosis of dry eye disease with and without MGD. Males and females were matched for age, smoking status, race, ethnicity, and body mass index (BMI). Patient demographics, anthropometric measurements, medical history, clinical findings, and serologies were analyzed. A diagnosis of MGD was based on clinical signs noted in the medical record.Results: MGD was not associated with BMI, smoking, type 2 diabetes mellitus, hypertension or hyperlipidemia in this dry eye cohort. MGD was associated with male sex and increasing age. While increasing age was weakly correlated with decreased low density lipoprotein cholesterol and non-high density lipoprotein cholesterol, serum lipid levels were not associated with MGD.Conclusion: Importantly, we found that risk factors for metabolic syndrome are not specifically associated with an increase in MGD when compared to non-MGD dry eye subjects. While risk factors for metabolic syndrome are associated with dry eye disease, they likely reflect a chronic systemic state of low-grade inflammation that negatively impacts the function of both lacrimal and meibomian glands.Keywords: meibomian gland disease, cholesterol, fasting blood sugar, dry eye, metabolic syndrome

Hannah Rashdan, Manali Shah, Danielle M RobertsonDepartment of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USAPurpose: Measurement of normal corneal thickness and corneal epithelial thickness is important in keratorefractive surgery, glaucoma, following extended contact lens wear, and in patients with corneal disease. Clinically, a central corneal thickness less than 500 μm is considered to be moderately-to-extremely thin. The purpose of this study was to compare biological differences in patients with clinically thin compared to normal corneal thickness values in healthy young adults using Fourier domain optical coherence tomography.Patients and methods: In total, 168 eyes from 84 patients aged 19–38 years were scanned using an Avanti optical coherence tomographer. To eliminate circadian effects on corneal thickness, all patients were scanned within a 4-hour window. Corneal thickness was measured across the central 6 mm of the cornea. Total central corneal thickness, corneal epithelial thickness, and corneal stromal thickness were compared between males and females and tested for correlations with age, use of systemic hormones, degree of myopia, and corneal curvature.Results: The average central corneal thickness for males and females was 540.5±32.0 μm and 525.2±33.0 μm, respectively (P=0.020). Thirty-eight eyes had corneal thickness measurements below 500 μm; 12% (6 eyes) from males and 28% (16 eyes) from females (P=0.008). All women with corneas below 500 μm were bilaterally thin. This finding differed for men. Corneal thinning was not associated with age, use of systemic hormones, or degree of myopia. Females had steeper keratometry (K) readings (P=0.01 for flat K, P=0.002 for steep K) than males. No differences in layer offset values between normal thickness corneas and thin corneas were evident, suggesting that the reduced thickness was not pathological.Conclusion: The results of this study indicate that a subpopulation of healthy young adults have non-pathologically thin corneas, well below 500 μm; and that these thinner corneas are more frequent in females. This underscores the importance of accurate corneal thickness measurements prior to keratorefractive surgery and when evaluating intraocular pressure in glaucoma.Keywords: cornea, epithelial, stroma, thickness, OCT

Decision makers are often confronted with inadequate information to predict nutrient loads and yields in freshwater ecosystems at large spatial scales. We evaluate the potential of using data mapped at large spatial scales (regional to global) and often coarse resolution to predict nitrogen yields at varying smaller scales (e.g., at the catchment and stream reach level). We applied the SPAtially Referenced Regression On Watershed attributes (SPARROW) model in three regions: the Upper Midwest part of the United States, New Zealand, and the Grande River Basin in southeastern Brazil. For each region, we compared predictions of nitrogen delivery between models developed using novel large-scale datasets and those developed using local-scale datasets. Large-scale models tended to underperform the local-scale models in poorly monitored areas. Despite this, large-scale models are well suited to generate hypotheses about relative effects of different nutrient source categories (point and urban, agricultural, native vegetation) and to identify knowledge gaps across spatial scales when data are scarce. Regardless of the spatial resolution of the predictors used in the models, a representative network of water quality monitoring stations is key to improve the performance of large-scale models used to estimate loads and yields. We discuss avenues of research to understand how this large-scale modelling approach can improve decision making for managing catchments at local scales, particularly in data poor regions., 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 Ltd.)

Quantifying nutrient sources in streams, their temporal and spatial variability, and drivers of that variability can support effective water resources management. Yet a lack of data and modeling capabilities has previously prevented comprehensive quantification across both space and time. Here a dynamic SPARROW (Spatially Referenced Regressions on Watershed attributes) model that accounts for a lagged delivery of nutrients to streams was developed and applied to simulate seasonal and source-specific total nitrogen (TN) and total phosphorus (TP) loads in streams across the Illinois River basin (IRB). Dynamic load predictions from 2000 through 2020 revealed that a third of the TN and a quarter of the TP instream load originated from non-point sources that were lagged in their delivery from land-application to streams by more than a season. This lagged mass was the largest overall TN source-which was estimated as a lagged expression of previous seasonal non-point sources including fertilizer, manure, atmospheric deposition and fixation, and urban land use. Treated wastewater effluent was the largest TP source exported from the basin, contributing 39 % of the TP load and 15 % of the TN load, and dominated the load in the upper Illinois River near Chicago. Loads in the lower river during this period, conversely, were attributed primarily to a mix of agricultural sources and their lagged fractions from headwater tributaries. Instream processes removed 10 % of the TN load while only 4 % of the TP load was removed during instream transport. With appropriate datasets, the models could be extended to other basins or time periods and used to forecast future seasonal nutrient loads., 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., (Published by Elsevier B.V.)

Purpose: Autologous serum is widely used for the treatment of severe ocular surface disease with mixed efficacy. Extracellular vesicles (EVs) are small membrane bound structures present in all body fluids, including serum. This study compared the proteomic, metabolomic, and inflammatory cytokine composition of serum-derived EVs (SDEVs) to that of the soluble free protein fraction and the subsequent capacity of SDEVs to induce corneal epithelial cell migration and inflammation., Methods: SDEVs were isolated from human serum using size exclusion chromatography. SDEVs were analyzed using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. The effects of SDEVs on corneal epithelial cell migration were tested using a standard scratch assay. Inflammatory cytokines in SDEVs and the free protein fraction were quantified using a microarray. A mutli-omics approach was further used to define SDEV cargo. The ability of SDEVs to modulate inflammation in corneal epithelial cells was quantified using ELISAs., Results: Western blot and TEM confirmed the presence of SDEVs. Proinflammatory cytokines, along with complement proteins and TGF-β, were decreased in SDEVs compared to serum. Metabolites present in SDEVs were mostly involved in amino acid biosynthesis, the TCA cycle and oxidative phosphorylation. SDEVs exhibited pro-migratory effects similar to serum however, SDEVs did not induce secretion of IL-6 or IL-8., Conclusions: SDEVs exhibit reduced levels of pro-inflammatory cytokines while retaining the beneficial wound healing properties of serum. Unlike serum, SDEVs do not induce inflammation. SDEVs may represent an alternative option for patients with severe ocular surface disease where traditional autologous serum has failed., Competing Interests: Declaration of Competing Interest None of the authors of this manuscript have any conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Pseudomonas aeruginosa (PA), an opportunistic gram-negative pathogen, is the most common pathogen identified in all culture positive cases of infectious keratitis. Extracellular vesicles (EVs) are released by most cells in the body and function in intercellular communication. We have previously reported a change in the proteome of host-derived EVs from corneal epithelial cells during PA infection. In the present study, we investigated changes in the metabolome of host-derived EVs from PA infected (PA-C EVs) and non-infected cells (C EVs). We found that one metabolite, palmitoyl carnitine (PAMC), was significantly upregulated in PA-C EVs. To determine the significance of PAMC release, we investigated the effect of PAMC treatment on corneal epithelial cells and neutrophils. EVs were isolated from culture media using size exclusion chromatography. EVs were then characterized using nanoparticle tracking analysis, transmission electron microscopy, and western blot. Metabolomics was performed using an untargeted approach. We found that palmitoyl carnitine (PAMC) was the most abundant metabolite present in PA-C EVs and was increased more than 3 fold compared to C EVs. Treatment of corneal epithelial cells with increasing levels of PAMC increased nuclear translocation of the NF-κB subunit p65. This was associated with an increase in IL-8 production and neutrophil migration. PAMC also increased levels of mitochondrial calcium. Upon inoculation of corneal epithelial cells with PA, 50 μM PAMC completely eradicated intracellular PA, but stimulated growth of extracellular PA. Taken together, these findings suggest that PA exploits EV release by host cells to deplete PAMC from the intracellular environment.

Pseudomonas aeruginosa (PA) is a gram-negative opportunistic pathogen that can infect the cornea as a result of trauma or contact lens wear. In addition to their known energy producing role, mitochondria are important mediators of immune signaling and host defense. While certain pathogens have developed strategies to evade host defenses by modulating host mitochondrial dynamics and metabolism, the ability of PA to harness host cell mitochondria during corneal infection is unknown. Using a combination of biochemical and imaging techniques, we show that PA infection of corneal epithelial cells induced mitochondrial fission in a DRP1-dependent manner that preceded PINK1/Parkin and FUNDC1-mediated mitophagy. PA also impaired NADH-linked respiration through a reduction in complex 1. This corresponded to a decrease in metabolic pathways related to glycolysis and the TCA cycle. Metabolomics analysis further demonstrated an upregulation of the pentose phosphate pathway, arginine, purine, and pyrimidine metabolism in PA infected cells. These pathways may provide a key source of nucleotides, amino acids, and nitrogen for both the host cell and PA, in addition to antioxidant functions. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA. Taken together, these data demonstrate that mitochondrial dysfunction and metabolic rewiring in host cells is triggered by extracellular PA, but once inside, PA requires healthy mitochondria to ensure host cell survival.

Background: Pseudomonas aeruginosa (PA) is an opportunistic pathogen that can cause sight threatening infections in the eye and fatal infections in the cystic fibrosis airway. Extracellular vesicles (EVs) are released by host cells during infection and by the bacteria themselves; however, there are no studies on the composition and functional role of host-derived EVs during PA infection of the eye or lung. Here we investigated the composition and capacity of EVs released by PA infected epithelial cells to modulate innate immune responses in host cells., Methods: Human telomerase immortalized corneal epithelial cells (hTCEpi) cells and human telomerase immortalized bronchial epithelial cells (HBECs) were treated with a standard invasive test strain of Pseudomonas aeruginosa, PAO1, for 6 h. Host derived EVs were isolated by qEV size exclusion chromatography. EV proteomic profiles during infection were compared using mass spectrometry and functional studies were carried out using hTCEpi cells, HBECs, differentiated neutrophil-like HL-60 cells, and primary human neutrophils isolated from peripheral blood., Results: EVs released from PA infected corneal epithelial cells increased pro-inflammatory cytokine production in naïve corneal epithelial cells and induced neutrophil chemotaxis independent of cytokine production. The EVs released from PA infected bronchial epithelial cells were also chemotactic although they failed to induce cytokine secretion from naïve HBECs. At the proteomic level, EVs derived from PA infected corneal epithelial cells exhibited lower complexity compared to bronchial epithelial cells, with the latter having reduced protein expression compared to the non-infected control., Conclusions: This is the first study to comprehensively profile EVs released by corneal and bronchial epithelial cells during Pseudomonas infection. Together, these findings show that EVs released by PA infected corneal and bronchial epithelial cells function as potent mediators of neutrophil migration, contributing to the exuberant neutrophil response that occurs during infection in these tissues., (© 2024. The Author(s).)

Background: This review outlines clinical data and characteristics of current Food and Drug Administration (FDA)-approved implants in cervical disc replacement/cervical disc arthroplasty (CDR/CDA) to provide a centralized resource for spine surgeons., Methods: Randomized controlled trials (RCTs) on CDR/CDA were identified using a search of the PubMed, Web of Science, and Google Scholar databases. The initial search identified 69 studies. Duplicates were removed, and the following inclusion criteria were applied when determining eligibility of RCTs for the current review: (1) discussing CDR/CDA prosthesis and (2) published within between 2010 and 2020. Studies without clinical data or that were not RCTs were excluded. All articles were reviewed independently by 2 authors, with the involvement of an arbitrator to facilitate consensus on any discrepancies., Results: A total of 34 studies were included in the final review. Findings were synthesized into a comprehensive table describing key features and clinical results for each FDA-approved CDR/CDA implant and are overall suggestive of expanding indications and increasing utilization., Conclusions: RCTs have provided substantial evidence to support CDR/CDA for treating single- and 2-level cervical degenerative disc disease in place of conventional anterior cervical discectomy and fusion., Clinical Relevance: This review provides a resource that consolidates relevant clinical data for current FDA-approved implants to help spine surgeons make an informed decision during preoperative planning., Competing Interests: Declaration of Conflicting Interests : No funding was received for this study. Djani Robertson, Andy Ton, Michael Brown, Shane Shahrestani, and Emily S. Mills have nothing to disclose. Jeffrey C. Wang has received intellectual property royalties from Zimmer Biomet, NovApproach, SeaSpine, and DePuy Synthes. Raymond J. Hah has received grant funding from SI bone, consulting fees from NuVasive, and support from the North American Spine Society to attend meetings. Ram K. Alluri has received grant funding from NIH, consulting fees from HIA Technologies, and payment from Eccentrial Robotics for lectures and presentations., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2024 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Continued large-scale public investment in declining ecosystems depends on demonstrations of "success". While the public conception of "success" often focuses on restoration to a pre-disturbance condition, the scientific community is more likely to measure success in terms of improved ecosystem health. Using a combination of literature review, workshops and expert solicitation we propose a generalized framework to improve ecosystem health in highly altered river basins by reducing ecosystem stressors, enhancing ecosystem processes and increasing ecosystem resilience. We illustrate the use of this framework in the Mississippi-Atchafalaya River Basin (MARB) of the central United States (U.S.), by (i) identifying key stressors related to human activities, and (ii) creating a conceptual ecosystem model relating those stressors to effects on ecosystem structure and processes. As a result of our analysis, we identify a set of landscape-level indicators of ecosystem health, emphasizing leading indicators of stressor removal (e.g., reduced anthropogenic nutrient inputs), increased ecosystem function (e.g., increased water storage in the landscape) and increased resilience (e.g., changes in the percentage of perennial vegetative cover). We suggest that by including these indicators, along with lagging indicators such as direct measurements of water quality, stakeholders will be better able to assess the effectiveness of management actions. For example, if both leading and lagging indicators show improvement over time, then management actions are on track to attain desired ecosystem condition. If, however, leading indicators are not improving or even declining, then fundamental challenges to ecosystem health remain to be addressed and failure to address these will ultimately lead to declines in lagging indicators such as water quality. Although our model and indicators are specific to the MARB, we believe that the generalized framework and the process of model and indicator development will be valuable in an array of altered river basins., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Increases in fluxes of nitrogen (N) and phosphorus (P) in the environment have led to negative impacts affecting drinking water, eutrophication, harmful algal blooms, climate change, and biodiversity loss. Because of the importance, scale, and complexity of these issues, it may be useful to consider methods for prioritizing nutrient research in representative drainage basins within a regional or national context. Two systematic, quantitative approaches were developed to (1) identify basins that geospatial data suggest are most impacted by nutrients and (2) identify basins that have the most variability in factors affecting nutrient sources and transport in order to prioritize basins for studies that seek to understand the key drivers of nutrient impacts. The "impact" approach relied on geospatial variables representing surface-water and groundwater nutrient concentrations, sources of N and P, and potential impacts on receptors (i.e., ecosystems and human health). The "variability" approach relied on geospatial variables representing surface-water nutrient concentrations, factors affecting sources and transport of nutrients, model accuracy, and potential receptor impacts. One hundred and sixty-three drainage basins throughout the contiguous United States were ranked nationally and within 18 hydrologic regions. Nationally, the top-ranked basins from the impact approach were concentrated in the Midwest, while those from the variability approach were dispersed across the nation. Regionally, the top-ranked basin selected by the two approaches differed in 15 of the 18 regions, with top-ranked basins selected by the variability approach having lower minimum concentrations and larger ranges in concentrations than top-ranked basins selected by the impact approach. The highest ranked basins identified using the variability approach may have advantages for exploring how landscape factors affect surface-water quality and how surface-water quality may affect ecosystems. In contrast, the impact approach prioritized basins in terms of human development and nutrient concentrations in both surface water and groundwater, thereby targeting areas where actions to reduce nutrient concentrations could have the largest effect on improving water availability and reducing ecosystem impacts., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-specific paracrine factors which regulate ovarian cumulus cell (CC) functions. This study aimed to investigate if BMP15 and GDF9 bound to CCs can be characterized, quantified, and show an association with IVF outcomes in infertile women. BMP15 and GDF9 ELISAs were validated and applied to discarded CC extracts. Pooled CCs from individual patients were collected from 120 (cohort 1; BMP15 only) and 81 infertility patients (cohort 2; BMP15 and GDF9) undergoing superovulation. BMP15 and GDF9 levels expressed per CC DNA were correlated with maternal age, clinical and embryology data. Total BMP15 and GDF9 were highly correlated with each other (r = 0.9, p < 0.001). The GDF9:BMP15 ratio was unrelated to oocyte number or age. BMP15/CC DNA and GDF9/CC DNA were unaffected by the type of superovulation and were not related to oocyte/embryo outcomes., Competing Interests: Declaration of competing interest AHR, WLL, DMR and RBG are inventors on a patent, and are co-directors and shareholders of Anlagen Pty. Ltd., which are relevant to this work. All other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperosmolarity of the ocular surface triggers inflammation and pathological damage in dry eye disease (DED). In addition to a reduction in quality of life, DED causes vision loss and when severe, blindness. Mitochondrial dysfunction occurs as a consequence of hyperosmolar stress. We have previously reported on a role for the insulin-like growth factor binding protein-3 (IGFBP-3) in the regulation of mitochondrial ultrastructure and metabolism in mucosal surface epithelial cells; however, this appears to be context-specific. Due to the finding that IGFBP-3 expression is decreased in response to hyperosmolar stress in vitro and in an animal model of DED, we next sought to determine whether the hyperosmolar stress-mediated decrease in IGFBP-3 alters mitophagy, a key mitochondrial quality control mechanism. Here we show that hyperosmolar stress induces mitophagy through differential regulation of BNIP3L/NIX and PINK1-mediated pathways. In corneal epithelial cells, this was independent of p62. The addition of exogenous IGFBP-3 abrogated the increase in mitophagy. This occurred through regulation of mTOR, highlighting the existence of a new IGFBP-3-mTOR signaling pathway. Together, these findings support a novel role for IGFBP-3 in mediating mitochondrial quality control in DED and have broad implications for epithelial tissues subject to hyperosmolar stress and other mitochondrial diseases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Oocyte-secreted growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are critical paracrine regulators of female fertility. Recent studies demonstrated that serum concentrations are associated with the number of oocytes retrieved during IVF, and therefore potential clinical use as biomarkers. However, it is unknown if the presence of endometriosis affects serum GDF9 or BMP15. An exploratory case-control study was prospectively performed on 60 women who underwent laparoscopy between April 2017 and August 2018 at two hospitals. GDF9 and BMP15 were measured by validated immunoassays in pre-operative serum samples. Data were analysed relative to laparoscopic assessment of endometriosis and staging. There were 35 women with confirmed laparoscopic diagnosis of endometriosis and 25 controls with no evidence of endometriosis at laparoscopy. GDF9 was detectable in 40% of controls and 48% of cases. There was no difference in median GDF9 concentrations between controls (20.0 pg/ml, range 20.0-2504 pg/ml) and cases (20.0 pg/ml, range 20.0-2963 pg/ml). BMP15 was detectable in 48% of controls and 58% of cases, with no difference in median concentrations between controls (26.5 pg/ml, range 24.0-1499 pg/ml) and cases (24.0 pg/ml, range 24.0-796 pg/ml). Furthermore, there were no significant differences in the proportion of detectable samples or concentrations of GDF9 or BMP15 with differing severities of endometriosis. In conclusion, serum concentrations of oocyte-secreted factors, GDF9 and BMP15 did not differ between control patients and patients with endometriosis. For clinical application in reproductive medicine, GDF9 and BMP15 serum biomarker quantitation is unlikely to be aberrant in the presence of endometriosis., (© 2022. The Author(s).)

The cornea is the clear dome that covers the front portion of the globe. The primary functions of the cornea are to promote the refraction of light and to protect the eye from invading pathogens, both of which are essential for the preservation of vision. Homeostasis of each cellular layer of the cornea requires the orchestration of multiple processes, including the ability to respond to stress. One mechanism whereby cells respond to stress is autophagy, or the process of "self-eating." Autophagy functions to clear damaged proteins and organelles. During nutrient deprivation, amino acids released from protein breakdown via autophagy are used as a fuel source. Mitophagy, a selective form of autophagy, functions to clear damaged mitochondria. Thus, autophagy and mitophagy are important intracellular degradative processes that sustain tissue homeostasis. Importantly, the inhibition or excessive activation of these processes result in deleterious effects on the cell. In the eye, impairment or inhibition of these mechanisms have been associated with corneal disease, degenerations, and dystrophies. This review summarizes the current body of knowledge on autophagy and mitophagy at all layers in the cornea in both non-infectious and infectious corneal disease, dystrophies, and degenerations. It further highlights the critical gaps in our understanding of mitochondrial dysfunction, with implications for novel therapeutics in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ayilam Ramachandran, Sanches and Robertson.)

Pseudomonas aeruginosa keratitis occurs following trauma, in immunocompromised patients, and in otherwise healthy contact lens wearers. Characterized by a light-blocking infiltrate, P. aeruginosa keratitis is the most serious complication associated with contact lens wear and, in severe cases, can lead to vision loss. Bacterial extracellular vesicles (B EVs) are membrane-enclosed nanometer-scale particles secreted from bacteria and are packed with bioactive molecules. B EVs have been shown to mediate biological functions that regulate host pathogenic responses. In the present study, we isolated P. aeruginosa-derived EVs using size exclusion chromatography and compared the proteomic compositions and functional activities of P. aeruginosa-derived EVs and P. aeruginosa-derived free protein (FP) on corneal epithelial cells and neutrophils. Importantly, P. aeruginosa-derived EVs and FP exhibited unique protein profiles, with EVs being enriched in P. aeruginosa virulence proteins. P. aeruginosa-derived EVs promoted corneal epithelial cell secretion of interleukin-6 (IL-6) and IL-8, whereas these cytokines were not upregulated following treatment with FP. In contrast, FP had a negative effect on the host inflammatory response and impaired neutrophil killing. Both P. aeruginosa-derived EVs and FP promoted intracellular bacterial survival in corneal epithelial cells. Collectively, these data suggest that P. aeruginosa-derived EVs and FP may play a critical role in the pathogenesis of corneal infection by interfering with host innate immune defense mechanisms.

Objective: Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are critical paracrine regulators of female fertility and are predominantly expressed by oocytes. However, it is unknown if serum concentrations reflect changes in ovarian function and/or reproductive endocrine disorders. This study aimed to determine if serum GDF9/BMP15 are associated with ovarian, pituitary, oestrogenic, androgenic and metabolic characteristics and the ovarian pathologies, polycystic ovarian morphology (PCOM) and polycystic ovary syndrome (PCOS)., Design: Women aged 21-45 years (n = 381) were included from a cross-sectional study at the National University Hospital, Singapore., Patients: Participants were volunteers and patients with possible PCOS., Measurements: Anthropometric measurements, transvaginal ultrasound scans and serum sampling were performed and a questionnairecompleted. Serum GDF9 and BMP15 concentrations were matched with menstrual cycle length, ovarian protein and steroid hormone production, pituitary hormone production and metabolic assessments in women with PCOM or PCOS and those with neither (control)., Results: Serum GDF9 and BMP15 were detectable in 40% and 41% of women, respectively and were positively correlated with each other (r = 0.08, p = 0.003). GDF9, but not BMP15, was positively correlated with ovarian volume (p = 0.02) and antral follicle count (AFC) (p = 0.004), but not with anti-Müllerian hormone (p = 0.05). However, serum GDF9 and BMP15 concentrations were not significantly different between control, PCOM and PCOS women, nor associated with androgenic or metabolic PCOS features. However, the relationship between GDF9 and AFC differed between control, PCOM and PCOS women (p = 0.02)., Conclusions: Serum GDF9 and BMP15 concentrations somewhat reflect ovarian but not androgenic or metabolic characteristics of PCOS, with increased GDF9 reflecting high AFC as seen in PCOM/PCOS., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

The Pediatric Heart Network (PHN) trial showed similar efficacy of β-blockers (BB) and angiotensin receptor blockers (ARB) for aortic root dilation in Marfan syndrome, but the impact on prescription practices is unknown. We hypothesized BB and ARB prescriptions would increase after the trial results were published (2014). Prescription data (2007-2016) were obtained from outpatient encounters (IBM Marketscan) for Marfan syndrome patients (6 months-25 years old). Excluding 2014 as a washout period, we analyzed two intervals: 2007-2013 and 2015-2016. Medication categories included BB, ARB, angiotensin converting enzyme inhibitors (ACEI), combination (BB/ARB and/or BB/ACEI), and no drug. Interrupted time-series analysis assessed immediate level change after publication and change in slope for the trend pre- and post-publication. Odds ratios (OR) and 95% confidence intervals from logistic regressions and generalized estimating equation methods accounted for correlation of prescriptions within patients. In 1499 patients (age 14.1 ± 6.1 years, 59% female) seen 2007-2013, BB trended lower [OR 0.91 (0.89, 0.93), p < 0.001] and ARB trended higher [OR 1.12 (1.07, 1.18), p < 0.001], while combination, ACEI, and no drug remained stable. This trend persisted, but was not significant, for BB [OR 0.54 (0.27, 1.08), p = 0.37] and ARB [OR 1.91 (0.55, 6.69), p = 0.31] in 2015-2016. Combination, ACEI, and no drug remained similar. In short term follow-up, changes in prescription practices following publication of the PHN trial were not statistically significant. This may be due to a change seen prior to publication with early adoption of ARBs that was maintained after confirmation of their effectiveness., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Lay Abstract: There has been growing interest in offending and contact with the criminal justice system (CJS) by people with autism spectrum disorder (ASD). However, it is not clear whether people with ASD offend more than those without ASD. Studies have started to look at whether there are particular offences people with ASD are more likely to commit and whether there are any factors that can affect whether someone comes into contact with the CJS as a potential suspect. This study looked at the patients who attended an ASD diagnostic service over a 17-year period to see the rate of contact with the CJS of those who were diagnosed with ASD and whether there were any particular factors that might increase the risk of CJS contact. Nearly a quarter of the ASD group had some contact with the CJS as a potential suspect. Factors that seemed to increase whether someone with ASD was more likely to have contact with the CJS were being male, being diagnosed with ADHD, and being diagnosed with psychosis. This study is one of the largest studies to investigate the rate of CJS contact as a potential suspect in a sample of adults with ASD in an attempt to give a clearer picture of what might influence someone with ASD to engage in offending behaviour in order to try to see what mental health services can offer to reduce the likelihood of someone with ASD coming into contact with the CJS, for example, treatment for another condition or support.

Objective: Seventy percent of Fuchs' endothelial corneal dystrophy (FECD) cases are caused by an intronic trinucleotide repeat expansion in the transcription factor 4 gene ( TCF4 ). The objective of this study was to characterize the corneal subbasal nerve plexus and corneal haze in patients with FECD with (RE+) and without the trinucleotide repeat expansion (RE-) and to assess the correlation of these parameters with disease severity., Design: Cross-sectional, single-center study., Participants: Fifty-two eyes of 29 subjects with a modified Krachmer grade of FECD severity from 1 to 6 were included in the study. Fifteen of the 29 subjects carried an expanded TCF4 allele length of ≥ 40 cytosine-thymine-guanine repeats (RE+)., Main Outcomes Measures: In vivo confocal microscopy assessments of corneal nerve fiber length (CNFL), corneal nerve branch density, corneal nerve fiber density (CNFD), and anterior corneal stromal backscatter (haze); Scheimpflug tomography densitometry measurements of haze in anterior, central, and posterior corneal layers., Results: Using confocal microscopy, we detected a negative correlation between FECD severity and both CNFL and CNFD in the eyes of RE+ subjects (Spearman ρ = -0.45, P  = 0.029 and ρ = -0.62, P  = 0.0015, respectively) but not in the eyes of RE- subjects. Additionally, CNFD negatively correlated with the repeat length of the expanded allele in the RE+ subjects (Spearman ρ = -0.42, P  = 0.038). We found a positive correlation between anterior stromal backscatter and severity in both the RE+ and RE- groups (ρ = 0.60, P  = 0.0023 and ρ = 0.44, P  = 0.024, respectively). The anterior, central, and posterior Scheimpflug densitometry measurements also positively correlated with severity in both the RE+ and RE- groups ( P  = 5.5 × 10 -5 , 2.5 × 10 -4 , and 2.9 × 10 -4 , respectively, after adjusting for the expansion status in a pooled analysis. However, for patients with severe FECD (Krachmer grades 5 and 6), the posterior densitometry measurements were higher in the RE+ group than in the RE- group ( P < 0.05)., Conclusions: Loss of corneal nerves in FECD supports the classification of the TCF4 trinucleotide repeat expansion disorder as a neurodegenerative disease. Haze in the anterior, central, and posterior cornea correlate with severity, irrespective of the genotype. Quantitative assessments of corneal nerves and corneal haze may be useful to gauge and monitor FECD disease severity in RE+ patients., (© 2022 by the American Academy of Ophthalmology.)