Compact Electrochromic Optical Recording of Bioelectric Potentials.

Electrochromic optical recording (ECORE) is a label-free method that utilizes electrochromism to optically detect electrical signals in biological cells with a high signal-to-noise ratio and is suitable for long-term recording. However, ECORE usually requires a large and intricate optical setup, making it relatively difficult to transport and to study specimens on a large scale. Here, we present a Compact ECORE (CECORE) apparatus that drastically reduces the spatial footprint and complexity of the ECORE setup whilst maintaining high sensitivity. An autobalancing differential photodetector automates common-mode noise rejection, removing the need for manually adjustable optics, and a compact laser module conserves space compared to a typical laser mount. The result is a simple, easy-to-use, and relatively low cost system that achieves a sensitivity of 16.7 µV (within a factor of 5 of the shot noise limit), and reliably detects action potentials from Human-induced pluripotent stem cell (HiPSC) derived cardiomyocytes. This setup can be further improved to within 1.5 dB of the shot noise limit by filtering out power-line interference.

Battlefield Acupuncture vs Ketorolac for Treating Pain in the Emergency Department.

Background: Many patients arrive in the emergency department (ED) with acute pain. Battlefield acupuncture (BFA) uses small, semipermanent acupuncture needles in 5 set points anatomically located on each ear to reduce pain in a few minutes. Pain relief can last months, depending on the pathology of the pain. At the Jesse Brown Veterans Affairs Medical Center (JBVAMC) ED, ketorolac 15 mg is the preferred first-line treatment of acute, noncancer pain. In 2018, BFA was offered first to veterans presenting with acute or acute-on-chronic pain to the ED; however, its effectiveness in pain reduction vs ketorolac has not been evaluated in this patient population. The objective of this study was to determine whether BFA monotherapy was noninferior to ketorolac 15 mg for reducing pain scores in the ED. Methods: This study was a retrospective, electronic chart review of patients who presented to JBVAMC ED with acute pain or acute-on-chronic pain and received ketorolac or BFA. The primary endpoint was the mean difference in the numeric rating scale (NRS) pain score from baseline. Secondary endpoints included the number of patients receiving pain medications, including topical analgesics, at discharge and treatment-related adverse events in the ED. Results: A total of 61 patients were included in the study. Baseline characteristics were similar between the 2 groups except for the average baseline NRS pain score, which was higher in the BFA group (8.7 vs 7.7; P = .02). The mean difference in NRS pain scores from baseline to post-intervention was 3.9 for the BFA group and 5.1 for the ketorolac group. The difference in reducing the NRS pain score between the intervention groups was not statistically significant. No adverse events were observed in either treatment group. Conclusions: For treating acute and acute-on-chronic pain in the ED, BFA did not differ compared with ketorolac 15 mg in NRS pain score reduction. This study's results add to the limited existing literature suggesting that both interventions could result in clinically significant reductions in pain scores for patients presenting to the ED with severe and very severe pain, indicating BFA could be a viable nonpharmacologic treatment option.

Dual-Color Optical Recording of Bioelectric Potentials by Polymer Electrochromism.

Optical recording based on voltage-sensitive fluorescent reporters allows for spatial flexibility of measuring from desired cells, but photobleaching and phototoxicity of the fluorescent labels often limit their sensitivity and recording duration. Voltage-dependent optical absorption, rather than fluorescence, of electrochromic materials, would overcome these limitations to achieve long-term optical recording of bioelectrical signals. Electrochromic materials such as PEDOT:PSS possess the property that an applied voltage can either increase or decrease the light absorption depending on the wavelength. In this work, we harness this anticorrelated light absorption at two different wavelengths to significantly improve the signal detection. With dual-color detection, electrical activity from cells produces signals of opposite polarity, while artifacts, mechanical motions, and technical noises are uncorrelated or positively correlated. Using this technique, we are able to optically record cardiac action potentials with a high signal-to-noise ratio, 10 kHz sampling rate, >15 min recording duration, and no time-dependent degradation of the signal. Furthermore, we can reliably perform multiple recording sessions from the same culture for over 25 days.

Refractive results with SMILE using lower energy settings in the United States.

PURPOSE: To report the visual and refractive results of small incision lenticule extraction (SMILE) with low energy settings in the United States (US) and to evaluate outcomes for low astigmatism treatment. SETTING: Private clinical practice. DESIGN: Retrospective cohort study. METHODS: This study retrospectively reviewed 462 consecutive eyes that underwent SMILE with lower energy settings. Inclusion criteria included all patients between the ages of 19-39 with myopic astigmatism up to -11.25 diopters (D) spherical equivalent (sphere up to -10.00 D, astigmatism up to -3.00 D), and corrected distance visual acuity of at least 20/25. Eyes with low astigmatism (0.25 D-0.50 D) were also included. Outcome analysis was performed according to the Standard Graphs for Reporting Refractive Surgery at postoperative month (POM) 1, and POM 3-6 when data were available. RESULTS: The mean preoperative spherical equivalent treated was -4.96 ± 2.07; at POM 1, 92% of eyes achieved uncorrected visual acuity (UCVA) of 20/20 or better and maintained visual stability throughout the remainder of the study. At last visit, 431 eyes (93%) achieved UCVA of 20/20 or better, and 461 eyes (99.8%) were 20/25 or better. Ninety-seven (21%) eyes gained at least 1 Snellen line of corrected distance visual acuity and no eyes lost 2 or more lines. Almost all eyes (n = 453, 98%) were within 0.5D of target; 85% of eyes with low astigmatism had ≤0.25 D at last visit compared to 80% of eyes with moderate astigmatism. CONCLUSIONS: SMILE with U.S.-approved low energy settings is safe, predictable, and efficacious and provides patients with a fast visual recovery.

Optical Electrophysiology: Toward the Goal of Label-Free Voltage Imaging.

Measuring and monitoring the electrical signals transmitted between neurons is key to understanding the communication between neurons that underlies human perception, information processing, and decision-making. While electrode-based electrophysiology has been the gold standard, optical electrophysiology has opened up a new area in the past decade. Voltage-dependent fluorescent reporters enable voltage imaging with high spatial resolution and flexibility to choose recording locations. However, they exhibit photobleaching as well as phototoxicity and may perturb the physiology of the cell. Label-free optical electrophysiology seeks to overcome these hurdles by detecting electrical activities optically, without the incorporation of exogenous fluorophores in cells. For example, electrochromic optical recording detects neuroelectrical signals via a voltage-dependent color change of extracellular materials, and interferometric optical recording monitors membrane deformations that accompany electrical activities. Label-free optical electrophysiology, however, is in an early stage, and often has limited sensitivity and temporal resolution. In this Perspective, we review the recent progress to overcome these hurdles. We hope this Perspective will inspire developments of label-free optical electrophysiology techniques with high recording sensitivity and temporal resolution in the near future.

ERICH3: vesicular association and antidepressant treatment response.

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.

Label-free optical detection of bioelectric potentials using electrochromic thin films.

Understanding how a network of interconnected neurons receives, stores, and processes information in the human brain is one of the outstanding scientific challenges of our time. The ability to reliably detect neuroelectric activities is essential to addressing this challenge. Optical recording using voltage-sensitive fluorescent probes has provided unprecedented flexibility for choosing regions of interest in recording neuronal activities. However, when recording at a high frame rate such as 500 to 1,000 Hz, fluorescence-based voltage sensors often suffer from photobleaching and phototoxicity, which limit the recording duration. Here, we report an approach called electrochromic optical recording (ECORE) that achieves label-free optical recording of spontaneous neuroelectrical activities. ECORE utilizes the electrochromism of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) thin films, whose optical absorption can be modulated by an applied voltage. Being based on optical reflection instead of fluorescence, ECORE offers the flexibility of an optical probe without suffering from photobleaching or phototoxicity. Using ECORE, we optically recorded spontaneous action potentials in cardiomyocytes, cultured hippocampal and dorsal root ganglion neurons, and brain slices. With minimal perturbation to cells, ECORE allows long-term optical recording over multiple days.

Relaxation Dynamics of Hydrated Thymine, Thymidine, and Thymidine Monophosphate Probed by Liquid Jet Time-Resolved Photoelectron Spectroscopy.

The relaxation dynamics of thymine and its derivatives thymidine and thymidine monophosphate are studied using time-resolved photoelectron spectroscopy applied to a water microjet. Two absorption bands are studied; the first is a bright ππ* state which is populated using tunable-ultraviolet light in the range 4.74-5.17 eV and probed using a 6.20 eV probe pulse. By reversing the order of these pulses, a band containing multiple ππ* states is populated by the 6.20 eV pulse and the lower energy pulse serves as the probe. The lower lying ππ* state is found to decay in ∼400 fs in both thymine and thymidine independent of pump photon energy, while thymidine monophosphate decays vary from 670 to 840 fs with some pump energy dependence. The application of a computational quantum mechanical/molecular mechanical scheme at the XMS-CASPT2//CASSCF/AMBER level of theory suggests that conformational differences existing between thymidine and thymidine monophosphate in solution account for this difference. The higher lying ππ* band is found to decay in ∼600 fs in all three cases, but it is only able to be characterized when the 5.17 eV probe pulse is used. Notably, no long-lived signal from an nπ* state can be identified in either experiment on any of the three molecules.

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

Control of Interfacial Cl2 and N2O5 Reactivity by a Zwitterionic Phospholipid in Comparison with Ionic and Uncharged Surfactants.

Gas-liquid scattering experiments reveal that charge-separated but neutral (zwitterionic) surfactants catalyze the oxidation of dissolved Br- to Br2 by gaseous Cl2 at the surface of a 0.3 M NaBr/glycerol solution. Solutions of NaBr dissolved in glycerol with no surfactant were compared with solutions coated with zwitterionic, cationic, and anionic surfactants at dilute surface concentrations of 1.1 to 1.5 × 1014 cm-2 (less than 65% of maximum chain packing). The zwitterionic phospholipid enhances Cl2 conversion of Br- to Br2 by a factor of 1.61 ± 0.15, in comparison with a 14-fold enhancement by a cationic surfactant (tetrahexylammonium) and a five-fold suppression by an anionic surfactant (dodecyl sulfate). Further studies indicate that even an uncharged surfactant, monododecanoylglycerol, enhances Cl2 → Br2 production. Similar behavior is observed for the oxidation of Br- to Br2 by N2O5; it is just slightly suppressed by the phospholipid and strongly enhanced by the cationic surfactant. Collectively, these results suggest that attractions and repulsions between the negative Br- ions and the positive and negative charges of the surfactant headgroups draw Br- ions to the surface or repel them away. At low coverages, ion-induced dipole and dispersion interactions between the CH2 groups and Br- or Cl2 may also enhance reactivity. These results demonstrate that the hydrocarbon chains of loosely packed surfactants do not necessarily block gas-liquid reactions but that positively charged, and even uncharged, groups can instead facilitate reactions by bringing gas-phase and solution-phase reagents together in the interfacial region.

Corneal edema and keratitis following selective laser trabeculoplasty.

PURPOSE: To describe three cases of keratitis following Selective Laser Trabeculoplasty (SLT). OBSERVATIONS: Three females with a history of glaucoma presented with corneal edema, keratitis (endothelial, epithelial) and decreased visual acuity shortly after SLT. There was variable resolution of symptoms after starting treatment with oral antiherpetics and topical steroids. CONCLUSIONS AND IMPORTANCE: With the increase in usage of SLT as a treatment for glaucoma and subsequent reports of keratitis, it is imperative for ophthalmic surgeons to be aware of herpes simplex as a possible risk factor. Prompt treatment with antivirals and steroids can potentially prevent scarring and permanent damage to the cornea.

Lichen Nitidus of the Eyelids.

Lichen nitidus is a rare, idiopathic inflammatory condition that typically presents as small, flat-topped papules on the chest, abdomen, and upper extremities. The lesions are benign and often asymptomatic and self-resolve. The pediatric population is most often affected. The authors report a case of lichen nitidus presenting as isolated bilateral eyelid lesions increasing in number for several years. Eventual excision and antibiotic/steroid ointment prompted regression.

Rapidly progressive cataract formation associated with non-small-cell lung cancer therapy.

We report 6 patients who developed rapidly progressive hypermature cataracts after starting treatment with rociletinib, a non-small-cell lung cancer therapy with known side effects of hyperglycemia, fatigue, and prolonged QT. Early cataract detection and surgery may prevent complications during future cataract removal. Although rociletinib development has been suspended, there are patients who have been treated and will continue to be treated with this medication based on their physician's judgment. These physicians should know about the potential for rapid vision loss due to cataracts as a manageable side effect. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

Double-C loop platform in combination with hydrophobic and hydrophilic acrylic intraocular lens materials.

PURPOSE: To analyze the behavior of a new double-C-loop quadripod symmetrical intraocular lens (IOL) platform combined with a hydrophilic lens material and a new hydrophobic glistening-free acrylic lens material, Ankoris and Podeye, respectively, in silico (computer simulation), in vitro (laboratory investigation), and in vivo (rabbit model). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA, and Physiol S.A., Liege, Belgium. DESIGN: Experimental study. METHODS: An in silico simulation investigation was performed using finite elements software, an in vitro investigation according to the International Organization for Standardization (ISO11979-3:2012), and an in vivo implantation in a rabbit model with 4 weeks of follow-up. Postmortem data were collected by Miyake-Apple gross examination and histopathologic analyses. Biocompatibility and IOL centration were tested. RESULTS: Both IOLs demonstrated statistically insignificant variations in posterior and anterior capsule opacification and Soemmerring ring formation. They were well biotolerated with no signs of toxicity, inflammation, or neovascularization. Axial and centration stability were noted in vitro and in vivo as a result of significant contact between surrounding tissues and haptics and the posterior portion of the optic. CONCLUSION: The results suggest suitability of the double-C loop IOL platform for the manufacturing of premium (ie, multifocal, toric, and multifocal toric) IOLs. FINANCIAL DISCLOSURE: Drs. Bozukova, Gobin, and Pagnoulle are employees of Physiol S.A., Liege, Belgium. Dr. Pagnoulle has a proprietary interest in the tested intraocular lenses. No other author has a financial or proprietary interest in any material or method mentioned.

Pathologic evidence of pseudoexfoliation in cases of in-the-bag intraocular lens subluxation or dislocation.

PURPOSE: To provide complete histopathologic evaluation of explanted capsular bags that spontaneously dislocated in the late postoperative period, with the main objective being to assess the presence of pseudoexfoliation (PXF) material. SETTING: Goethe-University Frankfurt, Frankfurt, Germany, and John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Retrospective case series. METHODS: Standard gross and light microscopy and complete histopathology were performed on explanted subluxated and dislocated capsular bags containing an intraocular lens (IOL) or a capsular tension ring (CTR) and an IOL. Questionnaires were sent to explanting surgeons, and a patient chart review was performed, when available. RESULTS: The specimens were represented by capsular bags containing an IOL (n = 37) or an IOL-CTR (n = 3). The IOLs included 3-piece hydrophobic acrylic (n = 13), 1-piece hydrophobic acrylic (n = 7), 3-piece silicone (n = 6), 1-piece hydrophilic acrylic (n = 6), 3-piece hydrophilic acrylic (n = 2), and 1-piece poly(methyl methacrylate) (PMMA) (n = 6) designs; all CTRs were PMMA. Soemmering ring formation was mild in 8 specimens, moderate in 18 specimens, and severe in 14 specimens. Excessive contraction of the capsular bag with capsulorhexis phimosis was observed in 24 specimens. Twenty-six specimens had histopathologic evidence of PXF; 13 had a clinical history or evidence of PXF. CONCLUSIONS: Pseudoexfoliation might be implicated in a larger proportion of late in-the-bag IOL subluxations and dislocations than previously thought as a result of significant clinical underdiagnosis. This might indicate a need for new considerations during the preoperative and postoperative cataract surgery assessments and follow-up.

Light transmittance of 1-piece hydrophobic acrylic intraocular lenses with surface light scattering removed from cadaver eyes.

PURPOSE: To assess the potential effect of surface light scattering on light transmittance of 1-piece hydrophobic acrylic intraocular lenses (IOLs) with or without a blue-light filter. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Intraocular lenses were obtained from human cadavers (49 IOLs total; 36 with blue-light filter) and from finished-goods inventory (controls). The IOLs were removed from cadaver eyes and the power and model matched to unused controls. After surface proteins were removed, the IOLs were hydrated for 24 hours at room temperature. Surface light scattering was measured with a Scheimpflug camera (EAS-1000 Anterior Segment Analysis System). Light transmittance was measured with a Lambda 35 UV/Vis spectrophotometer (single-beam configuration; RSA-PE-20 integrating sphere). RESULTS: Hydrated scatter values ranged from 4.8 to 202.5 computer-compatible tape (CCT) units for explanted IOLs with blue-light filter and 1.5 to 11.8 CCT units for controls; values ranged from 6.0 to 137.5 CCT units for explanted IOLs without a blue-light filter and 3.5 to 9.6 CCT units for controls. In both groups, there was a tendency toward increasing scatter values with increasing postoperative time. No differences in light transmittance were observed between explanted IOLs and controls in both groups (IOLs with blue-light filter: P=.407; IOL with no blue-light filter: P=.487; both paired t test). CONCLUSIONS: Although surface light scattering of explanted IOLs was significantly higher than that of controls and appeared to increase with time, no effect was observed on light transmittance of 1-piece hydrophobic acrylic IOLs with or without a blue-light filter.

Light scattering and light transmittance of cadaver eye-explanted intraocular lenses of different materials.

PURPOSE: To evaluate light scattering and light transmittance in cadaver eye-explanted intraocular lenses (IOLs) manufactured from different materials. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Forty-nine pseudophakic cadaver eyes were selected according to IOL material/type and implantation duration, and the IOLs were explanted. Hydrophobic acrylic, hydrophilic acrylic, poly(methyl methacrylate) (PMMA), and silicone IOLs were included. Gross and light microscopy was performed for all IOLs. Light scattering was measured with an EAS 1000 Scheimpflug camera, and light transmittance was assessed using a Lambda 35 UV/Vis spectrophotometer (single-beam configuration with an RSA PE-20 integrating sphere). Analyses were performed at room temperature in the hydrated state and compared with analyses of controls. RESULTS: The highest levels of surface light scattering were measured for 3-piece hydrophobic acrylic, which was also the IOL type with the longest implantation duration among the Acrysof hydrophobic acrylic IOLs. Hydrophilic acrylic, PMMA, and silicone IOLs exhibited relatively low light-scattering levels. The lowest light-scattering levels were observed with PMMA IOLs (1-piece looped and 3-piece) and plate silicone IOLs, which represent the IOL types with the longest implantation duration in this series. Light transmittance values measured for all IOL types appeared to be similar to the values of the corresponding control IOLs. CONCLUSIONS: The phenomenon of surface light scattering (nanoglistenings) is more particularly related to hydrophobic acrylic IOLs and increases with implantation time. No significant effect of surface light scattering on IOL light transmittance was found.

Capsulorhexis phimosis with anterior flexing of an accommodating IOL: case report and histopathological analyses.

We describe the case of a patient who had cataract surgery with implantation of an accommodating hydrophilic acrylic intraocular lens (IOL) that exhibited capsulorhexis phimosis and in-the-bag IOL luxation leading to explantation of the IOL-capsular bag complex 10 years after implantation. Constriction of the capsular bag secondary to fibrosis caused significant anterior flexing of the haptic elements of the IOL. Histopathological analysis revealed dense anterior subcapsular fibrosis and fibrous metaplasia of the anterior lens epithelial cells. No signs suggestive of pseudoexfoliation were found. This case raises concerns related to the continuously evolving indications for implantation of accommodating and other highly flexible IOLs (eg, microincision IOLs), particularly in patients with no clear predisposition to zonular weakness and, accordingly, excessive capsular bag contraction.

Capsular bag opacification with a new accommodating intraocular lens.

PURPOSE: To evaluate the biocompatibility and capsular bag opacification of an accommodating intraocular lens (IOL) containing large haptic elements that separate the anterior and posterior capsules. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Bilateral phacoemulsification with IOL implantation was performed in 6 New Zealand rabbits. Each animal received a study (accommodating) IOL and a control (1-piece hydrophobic acrylic) IOL. Eyes were examined at the slitlamp from 1 day through 6 weeks postoperatively. The globes were then enucleated and evaluated grossly. Capsular bag opacification was scored from the posterior aspect (Miyake-Apple view). The eyes were then processed for complete histopathologic evaluation. RESULTS: At 6 weeks, the mean posterior capsule opacification (PCO) clinical score was 0.5 ± 0.3 (SD) in the study group and 3.0 ± 0.9 in the control group (P=.001, 2-tail paired t test). Anterior capsule opacification was practically absent in the study group and mild in the control group. Miyake-Apple posterior view showed a mean central PCO score of 0 ± 0 in the study group and 3.0 ± 1.1 in the control group (P=.001), peripheral PCO score of 0.7 ± 0.4 and 3.5 ± 0.8 (P=.0006), respectively, and Soemmerring ring score of 2.3 ± 0.8 and 7.0 ± 2.8 (P=.01), respectively. Histopathology showed no signs of toxicity in any eye. CONCLUSIONS: The study IOL maintained an expanded capsular bag secondary to the large size of the haptic elements, which appears to prevent capsular bag opacification.