Search

Background: Deep brain stimulation of the central thalamus (CT-DBS) has potential for modulating states of consciousness, but it can also trigger electrographic seizures, including poly-spike-wave trains (PSWT)., Objectives: To report the probability of inducing PSWTs during CT-DBS in awake, freely-moving mice., Methods: Mice were implanted with electrodes to deliver unilateral and bilateral CT-DBS at different frequencies while recording electroencephalogram (EEG). We titrated stimulation current by gradually increasing it at each frequency until a PSWT appeared. Subsequent stimulations to test arousal modulation were performed at the current one step below the current that caused a PSWT during titration., Results: In 2.21% of the test stimulations (10 out of 12 mice), CT-DBS caused PSWTs at currents lower than the titrated current, including currents as low as 20 μA., Conclusion: Our study found a small but significant probability of inducing PSWTs even after titration and at relatively low currents. EEG should be closely monitored for electrographic seizures when performing CT-DBS in both research and clinical settings., Competing Interests: Declaration of competing interest Emery N. Brown holds patents on anesthetic state monitoring and control; holds founding interest in PASCALL, a start-up developing physiological monitoring systems; receives royalties from intellectual property through Massachusetts General Hospital licensed to Masimo. The interests of Emery N. Brown were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. The rest of the authors do not have any interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H 2 O 2 , providing: i) mitochondria-to-plasma-membrane redox signaling, closing K ATP -channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H 2 O 2 -signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA 2 γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA 2 γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H 2 O 2 -monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K + -channels open, and diminishing cytosolic [Ca 2+ ]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS., Competing Interests: Declaration of competing interest There are no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.

Every day, hundreds of thousands of people undergo general anesthesia. One hypothesis is that anesthesia disrupts dynamic stability-the ability of the brain to balance excitability with the need to be stable and controllable. To test this hypothesis, we developed a method for quantifying changes in population-level dynamic stability in complex systems: delayed linear analysis for stability estimation (DeLASE). Propofol was used to transition animals between the awake state and anesthetized unconsciousness. DeLASE was applied to macaque cortex local field potentials (LFPs). We found that neural dynamics were more unstable in unconsciousness compared with the awake state. Cortical trajectories mirrored predictions from destabilized linear systems. We mimicked the effect of propofol in simulated neural networks by increasing inhibitory tone. This in turn destabilized the networks, as observed in the neural data. Our results suggest that anesthesia disrupts dynamical stability that is required for consciousness., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this report is to describe atypical corneal complications associated with dupilumab use., Methods: This is a series of four cases of adult patients with infiltrative or ulcerative keratitis secondary to dupilumab use., Results: All four patients in this series were prescribed dupilumab for the treatment of atopic dermatitis and developed infiltrative or ulcerative corneal lesions. In all cases, corneal disease was successfully managed with immediate discontinuation of dupilumab and topical steroid treatment. In two cases, the patient also received antibiotic eye drops for infection precautions., Conclusions: Although dupilumab is most commonly associated with conjunctivitis, physicians should be aware of potential severe corneal complications for early identification and intervention., Competing Interests: J. J. Kang: Sanofi (C); All other authors: No conflicts of interest to disclose., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)

Introduction: The study aimed to evaluate multi-symptom relief of dry eye manifestations with the use of propylene glycol-hydroxypropyl-guar (PG-HPG) nanoemulsion lubricant eye drops, among subjects with dry eye disease (DED)., Methods: This was a post-marketing, prospective, single-arm study conducted in the USA. Subjects aged ≥ 18 years, with tear breakup time (TBUT) ≤ 10 s for both eyes, dry eye questionnaire-5 (DEQ-5) "watery eyes" symptom score 1-4, symptoms of burning/stinging, sore and tired eyes as determined by impact of dry eye on everyday living-symptom bother (IDEEL-SB) questionnaire, and IDEEL-SB score 16-65 were included. Subjects were required to complete IDEEL-SB and DEQ-5 at days 0, 14 ± 2, and 28 ± 2, and self-administer one drop of PG-HPG four times daily for 28 ± 2 days. Primary endpoints were change from baseline at day 28 in symptoms of sore, stinging/burning, and tired eyes on IDEEL-SB; and symptom of watery eyes on DEQ-5. Other endpoints evaluated were corneal staining and TBUT at baseline and day 28 ± 2; symptom relief (5-point Likert scale) at day 28 ± 2, and safety., Results: Of 119 subjects enrolled, 95 completed the study (mean ± SD age 61.2 ± 13.0 years; female 69.5%). Mean IDEEL-SB scores reduced significantly from baseline at day 28 for symptoms of aching/sore eyes (change from baseline - 1.0 ± 1.1), burning/stinging eyes (change from baseline - 1.1 ± 0.9), and tired eyes (change from baseline - 1.1 ± 1.0) (all p < 0.0001). Mean DEQ-5 score for watery eye symptoms significantly reduced from baseline at day 28 (change from baseline - 0.9 ± 1.0, p < 0.0001). Corneal staining at day 28 was comparable to baseline. TBUT improved from baseline to day 28. On a Likert scale, more than 50% of subjects reported relief from symptoms of sore, stinging, and burning eyes. Three (3.1%) subjects reported treatment-emergent adverse events (non-ocular)., Conclusions: PG-HPG nanoemulsion lubricant eye drops significantly improved multiple dry eye symptoms in subjects with DED over 28 days, with no new safety concerns., Trial Registration: ClinicalTrials.gov Identifier, NCT05056155., (© 2023. The Author(s).)

Objective: Patients who are intubated and sedated are at risk for developing exposure keratopathy, which can lead to permanent vision loss. This retrospective study assesses the incidence of exposure keratopathy (EK) in intensive care unit (ICU) patients before and after implementation of an EK Prevention Order Set., Methods: At one tertiary care hospital (Bronx, NY), an "Exposure Keratopathy Prevention Order Set" was implemented to ameliorate this risk which included the application of white petrolatum-mineral oil lubricating ointment every 6 hours in both eyes. This retrospective chart review study analyzed the incidence of EK diagnosis before and after implementation of this EK Prevention Order Set. Patients who were on mechanical ventilation at the time of ophthalmology consult request between January 1, 2021, and December 31, 2021, were included. Ophthalmology consult notes of patients with EK diagnosis were reviewed for details regarding the consult request, examination findings, diagnosis, and treatment plan., Results: There were 247 and 361 ventilated ICU patients before and after the order set, respectively. The number of ophthalmology consults decreased slightly after the order set from 15 of 247 to 20 of 361 ventilated patients. In addition, the rate of EK among ventilated patients decreased from 4.5% (11 of 247 patients over 151 days) to 2.2% (8 of 361 patients over 212 days; P =0.154) with a risk ratio of 0.50 (95% CI 0.20-1.22)., Conclusion: The number of patients diagnosed with EK trended down after implementation of the EK Prevention Order Set., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Contact Lens Association of Ophthalmologists.)

Objective: By exposing mice carrying a deletion of NADPH oxidase isoform 4, NOX4, specifically in pancreatic β cells (βNOX4-/-) to nutrient excess stimulated by a high-fat diet (HFD), this study aimed to elucidate the role of β-cell redox status in the development of meta-inflammation within the diabetic phenotype., Methods: The authors performed basic phenotyping of βNOX4-/- mice on HFD involving insulin and glycemic analyses, histochemistry of adipocytes, indirect calorimetry, and cytokine analyses. To characterize local inflammation, the study used caspase-1 activity assay, interleukin-1β immunochemistry, and real-time polymerase chain reaction during coculturing of β cells with macrophages., Results: The phenotype of βNOX4-/- mice on HFD was not associated with hyperinsulinemia and hyperglycemia but showed accumulation of excessive lipids in epididymal fat and β cells. Surprisingly, mice showed significantly reduced systemic inflammation. Decreased interleukin-1β protein levels and downregulated NLRP3-inflammasome activity were observed on chronic glucose overload in βNOX4-/- isolated islets and NOX4-silenced INS1-E cells resulting in attenuated proinflammatory polarization of macrophages/monocytes in vitro and in situ and reduced local islet inflammation., Conclusions: Experimental evidence suggests that NOX4 pro-oxidant activity in β cells is involved in NLRP3-inflammasome activation during chronic nutrient overload and participates in local inflammatory signaling and perhaps toward peripheral tissues, contributing to a diabetic inflammatory phenotype., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Fluorescence spectroscopy has numerous applications to characterize natural and human-influenced water bodies regarding dissolved organic matter (DOM) and contamination. Analyzing samples in a timely manner is crucial to gaining valid and reproducible excitation-emission matrices (EEM) but often difficult, specifically in transnational projects with long transport distances. In this study, eight samples of different water sources (tap water, differently polluted rivers, and wastewater treatment plant (WWTP) effluents) were stored under standardized conditions for 59 days and analyzed regularly. With this data set, the sample and fluorescence spectra stability was evaluated. Established analysis methods such as peak picking and fluorescence metrics were compared over time and benchmarked against dissolved organic carbon (DOC) and a maximal change of 10% in terms of their variability. Additional high-performance liquid chromatography (HPLC) data to identify single organic compounds provides insights into these DOM alterations and allows for conclusions about the underlying biological processes. Our results corroborate in a systematic way that the higher the organic or microbial load, the faster the sample must be processed. For all water sources, considerable changes were found between days zero and one, indicating a potential systematic bias between in-situ and laboratory measurements. The absolute signals of individual peaks vary substantially after only a few days. In contrast, relative metrics are robust for a much longer time. For specific metrics, when filtered and stored under cool and dark conditions, tap water may be stored for up to 59 days, non-polluted river water for up to 31-59 days, and WWTP effluents for up to 14-59 days. The storability thus depends both on the specific water source and the analytical plan. By systematizing our understanding of how the specific water source and DOM concentration determine the stability of samples during storage, these conclusions facilitate efforts to establish a standardized protocol., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH., Methods: We used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs)., Results: Single-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism., Conclusion: This study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH., 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 Plecitá-Hlavatá, Brázdová, Křivonosková, Hu, Phang, Tauber, Li, Zhang, Hoetzenecker, Crnkovic, Kwapiszewska and Stenmark.)

Purpose of Review: The aim of this study was to provide an update on perioperative considerations in the evaluation and management of patients undergoing primary corneal and intraocular refractive procedures who are at risk for progressive glaucomatous optic neuropathy., Recent Findings: The necessity of a comprehensive baseline assessment prior to refractive procedures with structural and functional testing, along with documentation of preoperative intraocular pressure (IOP) measurements, is highlighted in recent literature. Substantiation of the increased risk of postoperative IOP elevation in keratorefractive procedures in patients with higher baseline IOP and lower baseline CCT, but not necessarily the degree of myopia, has been variably evidenced. Tonometry methods which are less influenced by postoperative corneal structural change should be considered in patients undergoing keratorefractive procedures. Vigilence in postoperative monitoring for progressive optic neuropathy is suggested given evidence of an increased risk of steroid-response glaucoma in these patients. Additional evidence for the IOP-lowering impact of cataract surgery in patients with an increased risk of glaucoma is provided, irrespective of intraocular lens choice., Summary: Performing refractive procedures on patients at risk for glaucoma remains controversial. Definitive steps to optimize patient selection along with vigilance in disease state monitoring with longitudinal structural and functional testing can help mitigate potential adverse events., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to assess the safety, tolerability, dosing, and efficacy of the active 19 amino acid fragment of lacritin (Lacripep), a broad regulator of ocular surface homeostasis, in the treatment of ocular surface disease associated with primary Sjögren syndrome., Methods: Two hundred four subjects were randomized to receive vehicle, 22 μM Lacripep, or 44 μM Lacripep 3 times daily for 28 days, preceded by a 14-day run-in and followed by 14-day washout. Outcome measures were corneal fluorescein staining (CFS), lissamine conjunctival staining, Schirmer with anesthesia, tear break-up time, SANDE scoring, and visual analog scale assessment of symptoms., Results: This study established the safety and tolerability of topical treatment with Lacripep in patients with primary Sjögren syndrome. There were few adverse events: Only mild irritation was found in less than 3 percent of patients dosed with Lacripep. Total CFS and Eye Dryness Score were not significantly changed at day 28. Post hoc analysis of patients with Eye Dryness Severity scores of 60 or greater at baseline revealed significant improvements in inferior CFS at 14 and 28 days and complaints of burning and stinging at 14 days. Significant improvement in regional lissamine conjunctival staining was seen at 14 and 28 days., Conclusions: This first-in-human study of Lacripep in patients with primary Sjögren syndrome demonstrated clinically significant improvements in specific signs and symptoms on which to base future studies. This study established safety and tolerability and potential metrics of efficacy in patients with moderate to severe disease. Further work on appropriate dosing and concentration is ongoing., Competing Interests: G. W. Laurie: Cofounder and CSO of TearSolutions, Inc; Financial interest in TearSolutions, Inc. E. C. Parsons: Consultant to TearSolutions, Inc. MGO: CMO of Tear Solutions, Inc; Financial interest in TearSolutions, Inc. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To evaluate the efficacy and safety of NOV03 (perfluorohexyloctane) ophthalmic drop in patients with dry eye disease (DED) associated with meibomian gland dysfunction (MGD)., Design: Eight-week, phase 3, multicenter, randomized, double-masked, saline-controlled study., Participants: Adults ≥ 18 years with a history of DED for ≥ 6 months, tear film breakup time of ≤ 5 seconds, Schirmer I test (without anesthesia) score ≥ 5 mm, MGD score ≥ 3 (0-15 scale), and total corneal fluorescein staining (tCFS) score ≥ 4 and ≤ 11 (0-15 National Eye Institute [NEI] scale)., Methods: Patients were randomized 1:1 to NOV03 or hypotonic (0.6%) saline 4 times daily., Main Outcome Measures: The primary sign and symptom end points were change from baseline in tCFS and eye dryness score (0-100 visual analog scale [VAS]) at week 8. Key secondary end points were change from baseline in eye dryness score at week 2, tCFS at week 2, eye burning or stinging score (0-100 VAS) at week 8, and central corneal fluorescein staining (cCFS; 0-3 NEI scale) at week 8., Results: Of the 599 patients randomized, 597 were treated (NOV03, n = 303; saline, n = 294). At week 8, improvement from baseline was significantly greater (P < 0.001) with NOV03 versus saline for tCFS (least square [LS] mean treatment difference, -0.97; 95% confidence interval [CI]: -1.40, -0.55) and VAS dryness score (-7.6; 95% CI: -11.8, -3.4). Improvement from baseline also significantly (P < 0.01) favored NOV03 on all key secondary end points: LS mean treatment difference (95% CI) was -4.7 (-8.2, -1.2) for VAS dryness score at week 2, -0.6 (-0.9, -0.2) for tCFS at week 2, -5.5 (-9.5, -1.6) for VAS burning or stinging score at week 8, and -0.2 (-0.4, -0.1) for cCFS at week 8. Most ocular adverse events (AEs) were mild in severity; no serious ocular AEs occurred. One patient discontinued NOV03 because of an AE (eye irritation)., Conclusions: In patients with DED associated with MGD, NOV03 demonstrated statistically significant and clinically meaningful improvements versus hypotonic saline in signs and symptoms of DED and was well tolerated., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Dry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need., Objective: To assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle., Design, Setting, and Participants: CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study., Interventions: Cyclosporine solution vs vehicle administered 2 times per day for 29 days., Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed., Results: A total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (-4.0 grades) than the vehicle group (-3.6 grades) at day 29 (change [∆] = -0.4; 95% CI, -0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: -12.2 points for cyclosporine and -13.6 points for vehicle (∆ = 1.4; 95% CI, -1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = -4.6; 95% CI, -8.0 to -1.2; P = .007) and blurred vision (Δ = -3.5; 95% CI, -6.6 to -4.0; P = .03) compared with nonresponders., Conclusions and Relevance: The ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group., Trial Registration: ClinicalTrials.gov Identifier: NCT04523129.

Purpose: Evaluate the initial ocular safety and tolerability and efficacy of VVN001 Ophthalmic Solution (VVN001), a small-molecule antagonist of lymphocyte function-associated antigen-1 (LFA-1), in subjects with dry eye disease (DED)., Methods: This was a multi-center, double-masked, randomized, dose-response, vehicle-controlled, parallel-group study conducted in 170 subjects with DED. Subjects were randomized to receive VVN001 (1% or 5%) or its vehicle, twice-daily in both eyes for 84 days. The primary outcome measure was inferior region corneal fluorescein staining (iCFS, 0-4 scale) at Day 84. Visual Analogue Scale eye dryness (VAS, 0-100 scale) was a secondary outcome., Results: The primary and first secondary outcomes were not met. At Day 84 treatment effects in favor of VVN001 5% relative to its vehicle for iCFS were 0.29 units (p = 0.054), and for VAS were 3.18 units (p = 0.533). In other secondary outcomes, treatment effects in favor of VVN001 5% relative to its vehicle were seen in total CFS (1.61 units, 0-20 scale, p = 0.004) and Schirmer score (1.77 and 2.32 mm, p = 0.049 and p = 0.17 at Days 14 and 28 respectively). Adverse events of incidence 5% or greater in either active treatment group were instillation site pain (3/57, 5.3%), dysgeusia (3/56, 5.4%) and urinary tract infection (3/57, 5.3%)., Conclusions: There were no major safety issues of note. Appropriately powered studies will be required with a priori selection of the efficacy endpoints to evaluate VVN001's therapeutic potential., (Copyright © 2022 Elsevier Inc. All rights reserved.)

While most chemical bonds weaken under the action of mechanical force (called slip bond behavior), nature has developed bonds that do the opposite: their lifetime increases as force is applied. While such catch bonds have been studied quite extensively at the single molecule level and in adhesive contacts, recent work has shown that they are also abundantly present as crosslinkers in the actin cytoskeleton. However, their role and the mechanism by which they operate in these networks have remained unclear. Here, we present computer simulations that show how polymer networks crosslinked with either slip or catch bonds respond to mechanical stress. Our results reveal that catch bonding may be required to protect dynamic networks against fracture, in particular for mobile linkers that can diffuse freely after unbinding. While mobile slip bonds lead to networks that are very weak at high stresses, mobile catch bonds accumulate in high stress regions and thereby stabilize cracks, leading to a more ductile fracture behavior. This allows cells to combine structural adaptivity at low stresses with mechanical stability at high stresses.

Purpose: Implantable electronic cardiovascular device such as cardiac pacemakers and implantable defibrillators are common life-saving devices. Device-related complications can arise when undergoing surgical interventions with electrosurgical tools due to electromagnetic interference, based on electrocautery type, implantable electronic cardiovascular device type, electrocautery location, and a number of other factors. The risk of device-related complications due to electrocautery in oculoplastic surgery has not been established. This systematic literature review assesses prevalence, risk factors, and outcomes of electrocautery-related device complications in oculoplastic surgery., Methods: Systematic literature review followed Preferred Reporting Items for Systematic and Meta-Analysis guidelines and used the search terms "pacemaker," "implantable cardioverter defibrillator," "electrocautery," "cautery," and "electrosurgery" through June 2022. Inclusion criteria were full-text articles, discussing ocular, oculoplastic, or other facial surgery. Exclusion criteria were non-English language or surgery focused on other parts of the body. Full-text manuscripts of identified articles were reviewed and relevant data were extracted., Results: Twelve studies met inclusion criteria. Two studies were level I and II evidence, while 10 studies were level III or IV. There were no reports of electromagnetic interference with bipolar cautery use. With monopolar cautery use, cases of electromagnetic interference were reported, but without related significant morbidity or mortality. Safety recommendations to minimize electrical flow through the implantable electronic cardiovascular device are described., Conclusions: There were no reports of implantable electronic cardiovascular device-related complications from bipolar or thermocautery use in ophthalmic or oculoplastic surgeries. Monopolar have been associated with electromagnetic interference, but additional preoperative and perioperative measures can be taken to mitigate this risk., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Working memory has long been thought to arise from sustained spiking/attractor dynamics. However, recent work has suggested that short-term synaptic plasticity (STSP) may help maintain attractor states over gaps in time with little or no spiking. To determine if STSP endows additional functional advantages, we trained artificial recurrent neural networks (RNNs) with and without STSP to perform an object working memory task. We found that RNNs with and without STSP were able to maintain memories despite distractors presented in the middle of the memory delay. However, RNNs with STSP showed activity that was similar to that seen in the cortex of a non-human primate (NHP) performing the same task. By contrast, RNNs without STSP showed activity that was less brain-like. Further, RNNs with STSP were more robust to network degradation than RNNs without STSP. These results show that STSP can not only help maintain working memories, it also makes neural networks more robust and brain-like., Competing Interests: The authors have no competing interests., (Copyright: © 2022 Kozachkov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A 54-year-old man with noncontributory medical history presented to an ophthalmologist in January 2022 after 10 days of irritation in his right eye. The patient recounts having felt something get into his eye and under his contact lens (CL) while he was climbing into his car, but he was unsure what the foreign body may have been. Initial examination by the clinician found uncorrected distance visual acuity of 20/100-2 with a corneal abrasion, 4+ corneal edema, and 3+ conjunctival injection, for which he was placed on topical antibiotics (ocuflox and tobradex) with a bandage CL. 1 week later, visual acuity was 20/80, corneal edema had improved, and he was noted to have corneal scarring and an epithelial defect. Tobradex was continued while prednisolone drops and preservative-free artificial tears were started. 1 week later, the patient had worsening visual acuity to 20/250 and was referred to our tertiary center. On initial consultation, the patient had an uncorrected distance visual acuity of 20/500 and an uncorrected near visual acuity of >J10 in the right eye. Slitlamp examination of the right eye was significant for vortex keratopathy and mild corneal pannus with 360-degree subtle conjunctivalization of the limbus ( Figure 1JOURNAL/jcrs/04.03/02158034-202210000-00022/figure1/v/2022-10-03T121249Z/r/image-tiff ). The corneal topograph was obtained showing significant surface irregularity on the Placido image ( Figure 2JOURNAL/jcrs/04.03/02158034-202210000-00022/figure2/v/2022-10-03T121249Z/r/image-tiff ). Examination of the left eye was unremarkable. The ocular history is significant for myopia of -4.0 diopters and CL use for 20 years. The patient admits to regularly wearing soft CLs for several days straight and only removing them for a few hours. Antibiotics were discontinued, corticosteroid drops were reduced in frequency, and the patient was continued on preservative-free artificial tears. What imaging might you consider? What is your differential diagnosis at this point? What would be the most appropriate surgical and/or medical interventions? What would you counsel in prognosis for this patient?, (Copyright © 2022 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: To assess the COVID-19 exposure risk to consulting ophthalmologists and the pandemic effect on consultations at one of the most impacted hospital systems in New York. Methods: In a retrospective, cross-sectional study, ophthalmology consult notes and COVID-19 test results were collected from the electronic medical record from February to May in 2019 and 2020. Results: Of 2,215 total notes analyzed, consults decreased from 1,374 to 841 between years ( p  = 0.0002). In 2020, 22.5% of all consults were COVID tested and 2.4% were positive within 2 weeks of in-person evaluation. In 2020, 1.8% of consults were electronic. Ventilated patients increased between years (7.5% to 10.8%; p  = 0.04). Conclusions: Although consultations decreased during the Spring 2020 peak, the majority (98.2%) remained as in-person evaluations. While few patients tested COVID positive, this likely reflects the limited availability of testing early in the pandemic. Consulting ophthalmologists remained at high risk of COVID-19 exposure during the pandemic peak.

Competing Interests: The authors have no financial or conflicts of interest to disclose.

Background: Allergic conjunctivitis (AC) is an ocular inflammatory disease with symptoms driven by eosinophils and mast cells. Allergic comorbidities are common. Current treatments are often ineffective in severe AC and limited by potential side effects. Lirentelimab is an anti-sialic acid-binding immunoglobulin-like lectin-8 mAb that depletes eosinophils and inhibits mast cells., Objective: We sought to determine safety and preliminary efficacy of lirentelimab in an open-label, phase 1b study., Methods: Patients with chronic, severely symptomatic atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC, and who had history of topical or systemic corticosteroid use, were enrolled to receive up to 6 monthly lirentelimab infusions (dose 1: 0.3 mg/kg, dose 2: 1 mg/kg, subsequent doses: 1 or 3 mg/kg). Changes from baseline in peripheral blood eosinophils, changes in patient-reported symptoms (measured by daily Allergic Conjunctivitis Symptom Questionnaire, including atopic comorbidities), changes in investigator-reported ocular signs and symptoms (Ocular Symptom Scores), changes in quality of life, and changes in tear cytokine and chemokine levels were assessed., Results: Thirty patients were enrolled (atopic keratoconjunctivitis n = 13, vernal keratoconjunctivitis n = 1, perennial AC n = 16), 87% of whom had atopic comorbidities. After lirentelimab treatment, mean improvement was observed in Allergic Conjunctivitis Symptom Questionnaire score (-61%; 95% CI, -75% to -48%) and Ocular Symptom Scores (-53%; 95% CI, -76% to -31%), consistent across atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC groups. There was substantial improvement in atopic comorbidities, with -55% (95% CI, -78% to -31%), -50% (95% CI, -82% to -19%), and -63% (95% CI, -87% and -38%) reduction in symptoms of atopic dermatitis, asthma, and rhinitis, respectively. Levels of key mediators of inflammation were reduced in patient tears after lirentelimab treatment. The most common adverse effects were mild to moderate infusion-related reactions., Conclusions: Lirentelimab was well tolerated, improved severe AC and concomitant atopic symptoms, and reduced inflammatory mediators in patient tears., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To describe the significance of meibomian gland dysfunction (MGD) in corneal refractive surgery and to describe available approaches to preoperative evaluation and treatment based on current research., Recent Findings: There are several methods available for the evaluation and treatment of MGD. These are relevant for refractive surgeons to understand, as the presence of MGD preoperatively plays a role in the severity of MGD after corneal refractive surgery. Refractive surgery itself can exacerbate MGD. Treatment of MGD prior to surgery may have a meaningful impact on postoperative MGD., Summary: Surgeons should include meibomian gland assessment in the preoperative refractive evaluation and should treat MGD proactively prior to performing refractive surgery. Relevant information in this field is growing; additional prospectively designed studies are needed to further enhance our understanding., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The ACTION treatment program was developed as a school-based CBT program for girls in grades 3 to 6 to address depression. It has shown to be effective in reducing depressive symptoms and disorders. The treatment relies on a strong case conceptualization and follows a treatment protocol that is used to help children learn and apply coping skills, problem-solving, and cognitive restructuring. A case description is presented to give a detailed example of how this treatment protocol can be applied in individual therapy, and an emphasis on the therapists' thoughts and decision-making points is highlighted. Many subtle aspects to treating depressed youth are described., (© Copyright 2022 Springer Publishing Company, LLC.)

Soft network materials exist in numerous forms ranging from polymer networks, such as elastomers, to fiber networks, such as collagen. In addition, in colloidal gels, an underlying network structure can be identified, and several metamaterials and textiles can be considered network materials as well. Many of these materials share a highly disordered microstructure and can undergo large deformations before damage becomes visible at the macroscopic level. Despite their widespread presence, we still lack a clear picture of how the network structure controls the fracture processes of these soft materials. In this Perspective, we will focus on progress and open questions concerning fracture at the mesoscopic scale, in which the network architecture is clearly resolved, but neither the material-specific atomistic features nor the macroscopic sample geometries are considered. We will describe concepts regarding the network elastic response that have been established in recent years and turn out to be pre-requisites to understand the fracture response. We will mostly consider simulation studies, where the influence of specific network features on the material mechanics can be cleanly assessed. Rather than focusing on specific systems, we will discuss future challenges that should be addressed to gain new fundamental insights that would be relevant across several examples of soft network materials.

Significance: Given the significance of meibomian gland dysfunction subjects in evaporative dry eye, its chronic and progressive nature, limited promising treatment options, and novel treatment techniques are important. This randomized clinical study evaluated the noninferiority of SYSTANE iLux with LipiFlow in meibomian gland dysfunction treatment at 12 months., Purpose: This study aimed to demonstrate noninferiority of SYSTANE iLux compared with LipiFlow at 12 months after single treatment in meibomian gland dysfunction subjects with evaporative dry eye., Methods: In this prospective, randomized, multicenter, assessor-masked, parallel-group trial, subjects (N = 236; aged ≥18 years) with meibomian gland score (MGS) of ≤12 in lower eyelids, noninvasive tear breakup time (NITBUT; first breakup) of <10 seconds, and Impact of Dry Eye on Everyday Life-Symptom Bother (IDEEL-SB) module score of >16 were randomized (1:1) to receive SYSTANE iLux (n = 119) or LipiFlow (n = 117). Subjects attended a total of eight visits, including screening, treatment, and follow-up visits at 2 weeks and at 1, 3, 6, 9, and 12 months/exit, to evaluate change from baseline in MGS, NITBUT, IDEEL-SB module score, and safety outcomes., Results: A total of 227 subjects completed the study (mean ± standard deviation age, 57.3 ± 13.8 years). At 12 months, least squares mean change from baseline in MGS was similar between iLux and LipiFlow (17.4 ± 1.97 vs. 17.8 ± 1.98). Noninferiority of SYSTANE iLux compared with LipiFlow in change from baseline in MGS (95% lower confidence limit of least squares mean difference, >-5), NITBUT (>-2.5 seconds), and IDEEL-SB score (95% upper confidence limit, <12) was achieved at all post-treatment visits. No other serious ocular or device-related adverse events were reported., Conclusions: The treatment outcomes with SYSTANE iLux were noninferior to LipiFlow during the 12-month follow-up in subjects with dry eye-associated meibomian gland dysfunction., Competing Interests: Conflict of Interest Disclosure: GW is a consultant for Alcon, Aerie, Allergan, Bausch, BioTissue, Coopervision, Johnson & Johnson, OcuSoft, Optovue, Orasis, and Tarsus Medical. CH is an educational consultant for Valley Contax. SM and BF are consultants for Alcon. JT was paid as a clinical investigator with a research grant from Alcon. DK was paid as a researcher for Alcon. KB, JD, BG, JM, DL, and SK have no financial interests to disclose. SS and VM are employees of Alcon. This research was funded by Alcon., (Copyright © 2022 American Academy of Optometry.)

Mitochondrial Ca 2+ -independent phospholipase A 2 γ (iPLA 2 γ/PNPLA8) was previously shown to be directly activated by H 2 O 2 and release free fatty acids (FAs) for FA-dependent H + transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLA 2 γ in the brain is not completely understood. Here, using wild-type and iPLA 2 γ-KO mice, we demonstrate the ability of tert -butylhydroperoxide (TBHP) to activate iPLA 2 γ in isolated brain mitochondria, with consequent liberation of FAs and lysophospholipids. The liberated FA caused an increase in respiratory rate, which was fully inhibited by carboxyatractyloside (CATR), a specific inhibitor of ANT. Employing detailed lipidomic analysis, we also demonstrate a typical cleavage pattern for TBHP-activated iPLA 2 γ, reflecting cleavage of glycerophospholipids from both sn -1 and sn -2 positions releasing saturated FAs, monoenoic FAs, and predominant polyunsaturated FAs. The acute antioxidant role of iPLA 2 γ-released FAs is supported by monitoring both intramitochondrial superoxide and extramitochondrial H 2 O 2 release. We also show that iPLA 2 γ-KO mice were more sensitive to stimulation by pro-inflammatory lipopolysaccharide, as reflected by the concomitant increase in protein carbonyls in the brain and pro-inflammatory IL-6 release in the serum. These data support the antioxidant and anti-inflammatory role of iPLA 2 γ in vivo. Our data also reveal a substantial decrease of several high molecular weight cardiolipin (CL) species and accumulation of low molecular weight CL species in brain mitochondria of iPLA 2 γ-KO mice. Collectively, our results support a key role of iPLA 2 γ in the remodeling of lower molecular weight immature cardiolipins with predominantly saturated acyl chains to high molecular weight mature cardiolipins with highly unsaturated PUFA acyl chains, typical for the brain.

The stress response of polymer double networks depends not only on the properties of the constituent networks but also on the interactions arising between them. Here, we demonstrate, via coarse-grained simulations, that both their global stress response and their microscopic fracture mechanics are governed by load sharing through these internetwork interactions. By comparing our results with affine predictions, where stress redistribution is by definition homogeneous, we show that stress redistribution is highly inhomogeneous. In particular, the affine prediction overestimates the fraction of broken chains by almost an order of magnitude. Furthermore, homogeneous stress distribution predicts a single fracture process, while in our simulations, fracture of sacrificial chains takes place in two steps governed by load sharing within a network and between networks, respectively. Our results thus provide a detailed microscopic picture of how inhomogeneous stress redistribution after rupture of chains governs the fracture of polymer double networks., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Purpose: NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED., Methods: SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment., Results: The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID (P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes., Conclusions: The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease., Competing Interests: J. Tauber, D. L. Wirta, and K. Sall all received research grants for the study. D. Willen and S. Krösser are employees of Novaliq. The other author has no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Operational data over 2 years from three large Austrian wastewater treatment plants (WWTPs) with design capacities of 4 million, 950,000 and 110,000 population equivalent (PE) were examined. Salt peaks, due to thawing road salt were detected and quantified by electrical conductivity, temperature and chloride measurement in the inflow of the WWTPs. Daily NaCl inflow loads up to 1,147 t/d and PE-specific loads of 0.26-0.5 kg NaCl/(PE · y) were found. To mimic the plants' behaviour in a controlled environment, NaCl was dosed into the inflow of a laboratory-scale activated sludge plant. The influence of salt peaks on important activated sludge parameters such as sludge volume index, settling velocity and floc size were investigated. Influent and effluent were sampled extensively to calculate removal rates. Respiration measurements were performed to quantify activated sludge activity. Particle size distributions of the activated sludge floc sizes were measured using laser diffraction particle sizing and showed a decrease of the floc size by approximately two-thirds. The floc structure was examined and documented using light microscopy. At salt concentrations below 1 g/L, increased respiration was found for autotrophic biomass, and between 1 and 3 g NaCl/L respiration was inhibited by up to 30%.

Purpose: To assess the activity of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, relative to vehicle in patients with dry eye disease (DED) DESIGN: Randomized, double-masked, vehicle-controlled Phase 2b trial METHODS: Three hundred patients with DED were randomly assigned 1:1:1 at multiple US sites to receive 0.1% topical ocular reproxalap, 0.25% topical ocular reproxalap, or vehicle. Eyes were treated bilaterally 4 times daily for 12 weeks. Standard signs and symptoms of DED were assessed at baseline and at Weeks 2, 4, 8, and 12., Results: A dose response was observed for signs and symptoms of DED. Relative to vehicle over 12 weeks of therapy, the largest symptomatic improvement was observed in ocular dryness (0.25%, P = .047), and the largest objective sign improvement was observed in nasal region fluorescein staining (0.25%, P = .030). A greater proportion of patients receiving 0.25% reproxalap vs. vehicle reported dryness scores of 0 (P = .012). Improvements in combined DED symptoms were evident by the first post-baseline visit (Week 2, 0.25%, P < .0001) in patients with baseline scores greater than or equal to median values. No significant changes in safety measures were observed., Conclusion: The novel RASP inhibitor reproxalap demonstrated rapid, broad, and clinically relevant symptomatic control, in conjunction with statistically significant improvement over vehicle in signs of DED as demonstrated by fluorescein staining, in DED patients over 12 weeks of therapy. The results represent the first vehicle-controlled evidence for the therapeutic potential of RASP inhibition to mitigate the signs and symptoms of dry eye disease., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The subcutaneous cardioverter-defibrillator (S-ICD) may be a valuable option in patients after successful transvenous lead extraction (TLE) without indication for pacemaker therapy and persistent risk of sudden cardiac death. The aim of this study was to evaluate device performance, postoperative outcome, and safety in patients who received a S-ICD after TLE compared to patients who underwent de-novo S-ICD implantation., Methods: A retrospective analysis of all patients included into our institution's S-ICD database between September 2010 and May 2019 was conducted.The patients were divided in two groups, depending on whether they had received their S-ICD after TLE (n = 31) or de-novo (n = 113)., Results: The TLE group was significantly older with a mean age of 54.3 ± 15.7 versus 46.7 ± 14.4 years; p = .007. Leading S-ICD indication in the TLE group was previous infection (50%), whereas in the de-novo group the S-ICD was primarily chosen due to young patient age (74.6%). Median duration of follow-up was 527.0 versus 472.5 days, respectively; p = .576. Most common complication during follow-up was inappropriate ICD therapy (12.9% vs. 13.3%); p = 1.000. Pocket erosion/infection occurred in 3.2% versus 3.5% with no reported cases of systemic (re-)infection in either group; p = 1.000. All-cause mortality was low (6.2% vs. 2.7%) and entirely unrelated to S-ICD implantation or the device itself; p = .293., Conclusion: The S-ICD is a safe and effective alternative for patients after TLE with very similar results regarding device performance and postoperative outcome, when compared to patients who underwent de-novo S-ICD implantation., (© 2020 Wiley Periodicals LLC.)

The greenhouse gas nitrous oxide (N 2 O) is produced in activated sludge tanks as a byproduct of nitrification and heterotrophic denitrification. Insufficient knowledge on how microbiological N 2 O generation and degradation pathways impact N 2 O emissions in activated sludge tanks still hampers the development of effective mitigation strategies. Our research contributes to overcome this gap by quantifying N 2 O emissions through extensive measurement campaigns at ten full-scale wastewater treatment plants and correlating them to relevant operating parameters by multivariate regression analysis. Measurements revealed that N 2 O production depends mainly on the activity of nitrifying bacteria and is triggered by high ammonium concentrations. In contrast, well-performing heterotrophic denitrification plays a key role as a sink of N 2 O in activated sludge tanks. Following these patterns, low loaded plants achieving high nitrogen removal (83-92%) exhibited the lowest N 2 O emission intensity (0.0012 ± 0.001 kg N 2 O-N emitted per kg TKN in the influent wastewater). The regression analysis corroborated these results by revealing a negative linear correlation between the N 2 O emission factor and the total nitrogen removal degree of the plants. The regression model represents a novel estimation method that links N 2 O emissions with plant performance and provides a significant improvement over approaches applying fixed N 2 O emission factors., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H 2 O 2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K + channel (K ATP ) can only be closed when both ATP and H 2 O 2 are elevated. Otherwise ATP would block K ATP , while H 2 O 2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed K ATP ensemble is insufficient to reach the -50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca 2+ channels. Open synergic NSCCs or Cl - channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca 2+ -increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca 2+ -influx (fortified by endoplasmic reticulum Ca 2+ ). ATP plus H 2 O 2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H 2 O 2 diffusion or hypothetical SH relay via peroxiredoxin "redox kiss" to target proteins.

Background: Teleophthalmology programs are expanding, but have not been adapted into many emergency departments (EDs) in the United States. Introduction: Determining the potential demand for teleophthalmology services in the United States. EDs could enable development of new strategies to improve access to eye care in resource-limited regions. Methods: Telephone surveys were administered to ED physicians and nurses in Florida. Perceptions of ophthalmologist availability, equipment availability, and perceived utility of teleophthalmology services were measured. Results: Responses were from 104 of 207 facilities (50.2%); 88/181 (48.6%) designated as nonrural hospitals (NRHs) and 16/26 (61.5%) as rural hospitals (RHs). NRHs reported a median of 1 ophthalmologist available on call compared with a median of 0 at RHs (p < 0.001). NRHs were more likely to have a slit lamp (98.9% NRH, 50.0% RH; p < 0.001) and tonometer (100% NRH, 75.0% RH; p < 0.001). On a scale from 1 (lowest) to 5, most (68/93; 73.1%) perceived the value of teleophthalmology for remote consults as a 4 or 5. The most common perceived benefit of teleophthalmology use was to provide second/expert opinion (26.5% of responses). The most commonly cited perceived disadvantage was the physical unavailability of an ophthalmologist for examination and follow-up care (35.5% of responses). Discussion: RHs have less access to ophthalmologists and ophthalmic equipment when managing eye-related complaints in the ED. At both RHs and NRHs, providers face limitations in managing eye complaints and perceived teleophthalmology as a potentially valuable tool for remote expert consultation. Conclusions: Results suggest teleophthalmology services may be used to improve access to expert ophthalmic care, particularly in rural communities.

We study the influence of thermal fluctuations on the fracture of elastic networks, via simulations of the uniaxial extension of central-force spring networks with varying rigidity. Studying their failure response, both at the macroscopic and microscopic level, we find that an increase in temperature corresponds to a more homogeneous stress (re)distribution and induces thermally activated failure of springs. As a consequence, the material strength decreases upon increasing temperature, the microscopic damage spreads over a larger area and a more ductile fracture process is observed. These effects are modulated by network rigidity and can therefore be tuned via the network connectivity and the rupture threshold of the springs. Knowledge of the interplay between temperature and rigidity improves our understanding of the fracture of elastic network materials, such as (biological) polymer networks, and can help to refine design principles for tough soft materials.

Aims: Glucose-stimulated insulin secretion (GSIS) in pancreatic β cells was expected to enhance mitochondrial superoxide formation. Hence, we elucidated relevant redox equilibria. Results: Unexpectedly, INS-1E cells at transitions from 3 (11 m M ; pancreatic islets from 5 m M ) to 25 m M glucose decreased matrix superoxide release rates (MitoSOX Red monitoring validated by MitoB) and H 2 O 2 (mitoHyPer, subtracting mitoSypHer emission). Novel double-channel fluorescence lifetime imaging, approximating free mitochondrial matrix NADH F, indicated its ∼20% decrease. Matrix NAD + F increased on GSIS, indicated by the FAD-emission lifetime decrease, reflecting higher quenching of FAD by NAD + F . The participation of pyruvate/malate and pyruvate/citrate redox shuttles, elevating cytosolic NADPH F (iNAP1 fluorescence monitoring) at the expense of matrix NADH F , was indicated, using citrate (2-oxoglutarate) carrier inhibitors and cytosolic malic enzyme silencing: All changes vanished on these manipulations. 13 C-incorporation from 13 C-L-glutamine into 13 C-citrate reflected the pyruvate/isocitrate shuttle. Matrix NADPH F (iNAP3 monitored) decreased. With decreasing glucose, the suppressor of Complex III site Q electron leak (S3QEL) suppressor caused a higher Complex I I F site contribution, but a lower superoxide fraction ascribed to the Complex III site III Qo . Thus, the diminished matrix NADH F /NAD + F decreased Complex I flavin site I F superoxide formation on GSIS. Innovation: Mutually validated methods showed decreasing superoxide release into the mitochondrial matrix in pancreatic β cells on GSIS, due to the decreasing matrix NADH F /NAD + F (NADPH F /NADP + F ) at increasing cytosolic NADPH F levels. The developed innovative methods enable real-time NADH/NAD + and NADPH/NADP + monitoring in any distinct cell compartment. Conclusion: The export of reducing equivalents from mitochondria adjusts lower mitochondrial superoxide production on GSIS, but it does not prevent oxidative stress in pancreatic β cells.

Purpose: To evaluate symptom relief in patients with dry eye disease (DED) following a single drop of propylene glycol-hydroxypropyl guar (PG-HPG) nanoemulsion (Systane ® Complete) lubricant eye drops., Methods: This was a Phase IV, multicenter, open-label, interventional study in adult patients with DED of aqueous-deficient, evaporative, and mixed subtypes. Patients instilled one drop of PG-HPG in each eye at Day 1. Endpoints included change from baseline in dry eye symptom and soothing sensation scores on Day 1 at 0, 4, and 8 hours post-dose. Symptom scores were assessed on a 0-10 scale (0=no symptoms; 10=worst imaginable symptom). Tolerability of the drop was assessed based on assessment score on Day 1 following instillation for overall cohort and by DED subtype., Results: A total of 134 patients received treatment (mean age: 56.6 years; female: 75.4%). Median changes from baseline at Day 1 in dry eye symptom scores were -1.0 (95% confidence interval [CI]:-3.0,-1.0), -2.0 (95% CI:-3.0,-2.0), and -2.0 (95% CI:-2.0,-1.0) at 0, 4, and 8 hours respectively. Subgroup analysis showed a median change from baseline in dry eye symptom score of -2 (95% CI:-3.0,-1.0) for aqueous-deficient and evaporative subtypes and -1 (95% CI:-3.0,-1.0) for mixed subtype at 8 hours. Median soothing sensation scores were 3 at 0 and 4 hours and 3.5 at 8 hours, with a range of 0-10. Median (range) tolerability assessment scores were 0 (0-8) for burning sensation, stinging sensation, blurring, and 0 (0-10) for foreign body sensation. Tolerability assessment scores by DED subtype confirmed that the majority of patients reported scores in the range of 0-5 for all components and in all subgroups analyzed., Conclusion: Our study demonstrated that PG-HPG nanoemulsion provided instant/immediate and sustained symptom relief for 8 hours post-single application and was well tolerated in patients with DED, demonstrated by their responses on each of the assessment scales., Competing Interests: Steven Silverstein: Consultant and research for Alcon. Elizabeth Yeu: Consultant for Alcon, Allergan, Avedro, Avellino, Bausch + Lomb, BioTissue/Tissue Tech, Bruder, BVI, CorneaGen, EyePoint Pharm. Expert Opinion for Glaukos, iOptics, J&J Vision, LENSAR, Kala Pharm., Merck, Mynosys, Novartis, Ocular Science, Ocular Therapeutix, OcuSoft, Omeros Oyster Point Pharm, Science Based Health, Shire, Sun Pharm, TearLab Corp, Carl Zeiss. Investor in Avellino, CorneaGen, Melt, Modernizing Medicine, Mynosys, Ocular Science, Strathspey Crown. Research for Alcon, Allergan, TopCon, AcuFocus. Clinical investigator for Novartis. Joseph Tauber: Research for Alcon. Michel Guillon: Consultant and Financial Support for Alcon and reports grants from Optometric Technology Group Ltd. Lyndon Jones: Consultant and/or serves on an advisory board for Alcon, CooperVision, J&J Vision, Novartis and Ophtecs. Research support or lectureship honoraria from Alcon, Allergan, CooperVision, GL Chemtec, iMed Pharma, J&J Vision, Lubris, Menicon, Nature’s Way, Novartis, Ote, PS Therapy, Safilens, Santen, Shire, SightGlass and Visioneering. David Galarreta: Consultant to Alcon, Bausch + Lomb, Novartis, Santen, Shire, Thea, VISUfarma. Research for Alcon, Allergan, Nicox, Novartis, Sifi. Sruthi Srinivasan and Venkiteshwar Manoj: Employees of Alcon. The authors report no other conflicts of interest in this work., (© 2020 Silverstein et al.)

Transcript levels for selected ATP synthase membrane F O -subunits-including DAPIT-in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F 1 α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency.

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islets (PIs) of β-cells through an as yet unknown mechanism. We found NADPH oxidase isoform 4 (NOX4) to be the main producer of cytosolic H 2 O 2 , which is essential for GSIS; an increase in ATP alone was insufficient for GSIS. The fast GSIS phase was absent from PIs from NOX4-null, β-cell-specific knockout mice (NOX4βKO) (though not from NOX2 knockout mice) and from NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H 2 O 2 rescued GSIS in PIs from NOX4βKO mice. NOX4 silencing suppressed Ca 2+ oscillations, and the patch-clamped K ATP channel opened more frequently when glucose was high. Mitochondrial H 2 O 2 , decreasing upon GSIS, provided alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxides through electron-transfer flavoprotein:Q-oxidoreductase. Unlike GSIS, such insulin secretion was blocked with mitochondrial antioxidant SkQ1. Both NOX4 knockout and NOX4βKO mice exhibited impaired glucose tolerance and peripheral insulin resistance. Thus, the redox signaling previously suggested to cause β-cells to self-check hypothetically induces insulin resistance when it is absent. In conclusion, increases in ATP and H 2 O 2 constitute an essential signal that switches on insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (it does so partially for fatty acids). Redox signaling could be impaired by cytosolic antioxidants; hence, those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage., (© 2020 by the American Diabetes Association.)

Purpose: The aim of this study was to compare the efficacy of two lipid-based lubricant eye drops in patients with lipid-deficient dry eye., Methods: This Phase IV, multicenter, prospective, double-masked study enrolled adults (aged ≥18 years) who had a tear film breakup time (TFBUT) of ≤15 seconds(s), and unanesthetized Schirmer I test of ≥3 mm to ≤12 mm in at least one eye, at both screening and baseline visits. Eligible patients (n=231) were randomized (1:1) and received either Systane ® Balance (SYSB; n=117) or Refresh ® Optive Advanced (RFO-Ad, n=114), four-times a day, for 35 days. The primary endpoint was non-inferiority for change from baseline in TFBUT at Day 35 (non-inferiority was established if the lower limit of the 95% confidence interval (CI) for the difference between the treatment groups was > -1.0 s); secondary endpoints (test of superiority) were change in TFBUT and global ocular discomfort visual analog scale (VAS) score at Day 35. Other endpoints included the impact of dry eye on everyday life (IDEEL) treatment satisfaction scores (inconvenience and effectiveness) and safety., Results: At Day 35, the mean change from baseline in TFBUT was 0.998 s in the SYSB and 0.868 s in the RFO-Ad groups with a treatment difference: 0.130 s; (95% CI -0.34, 0.60; P <0.0001) demonstrating non-inferiority of SYSB to RFO-Ad. The global ocular discomfort VAS scores improved in both groups, with a mean change from baseline of -9.7 and -8.8 in SYSB and RFO-Ad groups (treatment difference -0.8; P =0.62), respectively. No meaningful difference was observed in IDEEL treatment effectiveness and treatment inconvenience scores between SYSB vs RFO-Ad ( P >0.05 for treatment difference). Both treatments were well tolerated., Conclusion: SYSB lubricant eye drops were non-inferior to RFO-Ad for improvement in TFBUT in patients with lipid-deficient dry eye. Both lubricant eye drops improved TFBUT and ocular discomfort scores in patients with lipid-deficient dry eye., Competing Interests: Dr Louis Tong reports research funding, advisory boards, travel sponsorship from Alcon, Novartis, Santen, Allergan, Bausch and Lomb. Dr Jacqueline Tan reports grants from Allergan, Azura Ophthalmics, and Stiltec, outside the submitted work. Dr Joseph Tauber reports grants from Alcon, during the conduct of the study. Dr Gary Jerkins is affiliated with Advancing Vision Research, LLC. Dr Sruthi Srinivasan is an employee of Alcon Research, LLC. The authors report no other conflicts of interest in this work., (© 2020 Jerkins et al.)

Purpose: To report on 5-year multimodal imaging of ocular findings in a patient with thiamine-responsive megaloblastic anemia., Methods: Observational case report., Results: A 20-year-old-man with a history of thiamine-responsive megaloblastic anemia demonstrated a symmetric bull's eye maculopathy. Spectral domain optical coherence tomography revealed disruption of the parafoveal ellipsoid zone, fundus autofluorescence demonstrated foveal hypoautofluorescence, and full-field electroretinogram testing revealed a decreased photopic and scotopic response consistent with cone-rod dystrophy. His best-corrected visual acuity remained stable over 5 years at 20/50 in the right eye and 20/40 in the left eye, and visual field testing remained stable over time., Conclusion: Ocular manifestations in thiamine-responsive megaloblastic anemia are uncommon and variable. In this case, multimodal imaging and electroretinogram findings are consistent with cone-rod degeneration. The patient is taking daily thiamine supplementation, and visual acuity, funduscopic examination, spectral domain optical coherence tomography, and autofluorescence remained stable over a 5-year period.

Collagen forms the structural scaffold of connective tissues in all mammals. Tissues are remarkably resistant against mechanical deformations because collagen molecules hierarchically self-assemble in fibrous networks that stiffen with increasing strain. Nevertheless, collagen networks do fracture when tissues are overloaded or subject to pathological conditions such as aneurysms. Prior studies of the role of collagen in tissue fracture have mainly focused on tendons, which contain highly aligned bundles of collagen. By contrast, little is known about fracture of the orientationally more disordered collagen networks present in many other tissues such as skin and cartilage. Here, we combine shear rheology of reconstituted collagen networks with computer simulations to investigate the primary determinants of fracture in disordered collagen networks. We show that the fracture strain is controlled by the coordination number of the network junctions, with less connected networks fracturing at larger strains. The hierarchical structure of collagen fine-tunes the fracture strain by providing structural plasticity at the network and fiber level. Our findings imply that low connectivity and plasticity provide protective mechanisms against network fracture that can optimize the strength of biological tissues., Competing Interests: The authors declare no competing interest.

Purpose: Meibomian gland dysfunction (MGD) is present in most cases of dry eye disease. MGD involves both inflammatory and obstructive etiologies. We compared efficacy and safety of treatment to reduce inflammation (lifitegrast) versus obstruction [thermal pulsation procedure (TPP)] in patients with inflammatory MGD over 42 days., Methods: This was a single-center, 6-week, prospective, randomized, single-masked study of adults with inflammatory MGD, defined as having all of the following: burning, stinging, dryness; thickened secretions or occlusion of glands; eyelid redness; and elevated matrix metalloproteinase-9. Patients received lifitegrast ophthalmic solution 5% twice daily for 42 days or one TPP treatment at day 0. Seven symptoms and 8 objective measures of dry eye disease were assessed., Results: Overall, 40 of 50 randomized patients (80%) were women with mean (SD) age 65.8 (8.9) years. Lifitegrast-treated (n = 25) versus TPP-treated (n = 25) patients had greater improvement from baseline to day 42 in eye dryness [mean (SD) change from baseline: -1.05 (0.79), lifitegrast; -0.48 (0.96), TPP; P = 0.0340], corneal staining [-0.55 (0.80), lifitegrast; 0.12 (1.09), TPP; P = 0.0230], and eyelid redness [-0.77 (0.43), lifitegrast; -0.38 (0.58), TPP; P = 0.0115]; trend favored lifitegrast for best corrected visual acuity and gland patency. Unexpectedly, TPP treatment did not improve lipid layer thickness or gland patency compared with lifitegrast. No adverse events were reported., Conclusions: Although MGD is often considered a disease of gland obstruction, these findings demonstrate antiinflammatory treatment with lifitegrast significantly improved patient symptoms and signs compared with treatment for obstruction (TPP). Lifitegrast should be included in treatment for inflammatory MGD.

By performing extensive simulations with unprecedentedly large system sizes, we unveil how rigidity influences the fracture of disordered materials. We observe the largest damage in networks with connectivity close to the isostatic point and when the rupture thresholds are small. However, irrespective of network and spring properties, a more brittle fracture is observed upon increasing system size. Differently from most of the fracture descriptors, the maximum stress drop, a proxy for brittleness, displays a universal nonmonotonic dependence on system size. Based on this uncommon trend it is possible to identify the characteristic system size L^{*} at which brittleness kicks in. The more the disorder in network connectivity or in spring thresholds, the larger L^{*}. Finally, we speculate how this size-induced brittleness is influenced by thermal fluctuations.

In this research, sources of methane emissions of an anaerobic digester (AD) system at a municipal wastewater treatment plant (WWTP) with 260,000 population equivalent (PE) capacity were detected by a non-dispersive infrared (NDIR) camera. The located emissions were evaluated qualitatively and were documented with photographs and video films. Subsequently, the emission sources were quantified individually using different methods like the Flux-Chamber method and sampling from the digester's circulation pipe. The dissolved methane in the sludge digester was measured via gas chromatography-mass spectrometry (GC-MS) and 6.8% oversaturation compared to the equilibrium after Henry's law was found. Additionally, the residual gas potential of the digestate was measured using batch tests with 10 days' additional stabilisation time. The PE-specific residual gas production of the full-scale AD was calculated to 12.4 g CH 4 /(PE · y). An extended chemical oxygen demand (COD) balance including methane emissions for the whole digester system was calculated. Also the measured methane loads were calculated and summed up. The total methane loss of the AD was calculated at 24.6 g CH 4 /(PE · y), which corresponds to 0.4% of the produced biogas (4,913 g CH 4 /(PE · y)). PE-specific methane emission factors are presented for each investigated (point) source like the sludge outlet at the digester's head, a leaking manhole sealing and cracks in the concrete structure.