METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Production of Magnetic Arsenic-Phosphorus Alloy Nanoribbons with Small Band Gaps and High Hole Conductivities.

Quasi-1D nanoribbons provide a unique route to diversifying the properties of their parent 2D nanomaterial, introducing lateral quantum confinement and an abundance of edge sites. Here, a new family of nanomaterials is opened with the creation of arsenic-phosphorus alloy nanoribbons (AsPNRs). By ionically etching the layered crystal black arsenic-phosphorus using lithium electride followed by dissolution in amidic solvents, solutions of AsPNRs are formed. The ribbons are typically few-layered, several micrometers long with widths tens of nanometers across, and both highly flexible and crystalline. The AsPNRs are highly electrically conducting above 130 K due to their small band gap (ca. 0.035 eV), paramagnetic in nature, and have high hole mobilities, as measured with the first generation of AsP devices, directly highlighting their properties and utility in electronic devices such as near-infrared detectors, quantum computing, and charge carrier layers in solar cells.

Noninvasive Measurement of Oxygen Saturation in Human Retinal Blood Vessels and Tissues With Multispectral Confocal Imaging.

BACKGROUND AND OBJECTIVE: Proof of concept for the first system of noninvasive human retinal vessel and tissue oxygenation measurement in axial and radial directions. MATERIALS AND METHODS: A confocal imaging system capable of calculating and mapping relative retinal blood oxygenation in radial and axial directions from three eyes of two healthy subjects was built. The relationship between oxygenation and retinal depth in vivo was analyzed to illustrate application of this novel system. RESULTS: The system shows capacity for measuring oxygenation along retinal depth for the first time. (1) Arteriovenous oxygenation difference decreases with blood vessel diameter. (2) Artery-tissue oxygenation difference is greater than vein-tissue oxygenation difference in the same region. (3) Intravascular-extravascular oxygenation difference decreases with blood vessel diameter. (4) Oxygenation data reported with a 95% CI are as follows: A1 91.5% ± 18.2%, V1 32.8% ± 18.6%, A2 97.3% ± 17.8%, V2 64.4% ± 11.2%, A3 73.2% ± 19.1%, V3 52.9% ± 15.3%, and Tissue 56.6% ± 00.4%. CONCLUSION: This article demonstrates proof of concept for retinal oxygenation calculation in radial and axial dimensions for the first time. Initial results provide biological validity to this method. Future aims include further characterization of this system's results in healthy subjects and subsequent comparison of oxygenation between diseased and healthy retinae. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:275-283.].

Unconventional quantum vortex matter state hosts quantum oscillations in the underdoped high-temperature cuprate superconductors.

A central question in the underdoped cuprates pertains to the nature of the pseudogap ground state. A conventional metallic ground state of the pseudogap region has been argued to host quantum oscillations upon destruction of the superconducting order parameter by modest magnetic fields. Here, we use low applied measurement currents and millikelvin temperatures on ultrapure single crystals of underdoped [Formula: see text] to unearth an unconventional quantum vortex matter ground state characterized by vanishing electrical resistivity, magnetic hysteresis, and nonohmic electrical transport characteristics beyond the highest laboratory-accessible static fields. A model of the pseudogap ground state is now required to explain quantum oscillations that are hosted by the bulk quantum vortex matter state without experiencing sizable additional damping in the presence of a large maximum superconducting gap; possibilities include a pair density wave.

Reduction in Retinal Thickness Fluctuations After Treatment With Fluocinolone Acetonide Implant for DME: A Post-Hoc Analysis of the USER Study.

BACKGROUND AND OBJECTIVE: Assess fluocinolone acetonide implant (FAc) effects on diabetic macular edema (DME) retinal thickness fluctuations. PATIENTS AND METHODS: A post-hoc chart review of the real-world USER study analyzed patients receiving 0.2 µg/day FAc implant. The percentage of eyes with central subfield thickness (CST) of 300 µm or less were compared pre- and post-FAc implant; mean retinal thickness amplitude (RTA), retinal thickness standard deviation (RTSD), and two case studies were analyzed. RESULTS: One hundred thirty patients (mean age: 69.6 years) presented; CST was available for 120 of 160 treated eyes. Mean RTA decreased significantly post-FAc implant (P < .001) regardless of baseline visual acuity (VA). Correlations with last-observed VA (R2) were: RTA, 0.1197; retinal thickness standard deviation (RTSD), 0.1526; and area under the CST-time curve (AUC CST), 0.0981. After FAc implant, the percentage of eyes with CST of 300 µm or less was significantly greater versus baseline (P < .05). CONCLUSIONS: Retinal thickness fluctuations significantly declined after FAc and correlated with improvement in VA. Both RTSD and RTA measures correlated more closely to last observed VA than AUC CST itself. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:298-306.].

The USER Study: A Chart Review of Patients Receiving a 0.2 µg/day Fluocinolone Acetonide Implant for Diabetic Macular Edema.

INTRODUCTION: To determine anatomical, functional, and intraocular pressure (IOP) responses to diabetic macular edema (DME) treatments pre- and post-0.2 µg/day fluocinolone acetonide (FAc) implant administration compared with baseline and the preceding 3 years. METHODS: This was a retrospective, chart review, cohort study in four U.S. centers. Patients received the 0.2 µg/day FAc implant for the treatment of DME in at least one eye before January 1, 2016. DME treatments administered up to 36 months pre-FAc implant and up to 24 months post-FAc implant were recorded, and treatment frequency was calculated. Visual acuity (VA) was assessed using a Snellen eye chart and converted to early treatment diabetic retinopathy study (ETDRS) letters, and central subfield thickness (CST) was measured using optical coherence tomography (OCT). Treatment frequency, mean VA, mean CST, percentage of patients with CST of ≤ 300 µm, mean IOP, IOP events, and IOP treatments pre- and post-FAc implant administration were measured. Positive and negative predictive values for the IOP response to prior steroid therapy were also determined. RESULTS: In total, 160 eyes of 130 patients were studied. VA was maintained at pre-FAc levels from baseline to month 24, despite a significant reduction in treatment frequency from one treatment every 2.9 months pre-FAc implant to one treatment every 14.3 months post-FAc implant. Patients with better baseline VA required fewer DME treatments post-FAc than did patients with worse baseline VA. The majority of patients did not require additional DME treatment during the post-FAc follow-up period. A significant reduction in CST and an increase in the percentage of patients with CST of ≤ 300 µm were seen up to month 21 post-FAc implant. Pre-FAc implant IOP was maintained during the post-FAc implant period; increased IOP with prior steroid therapy was found to be highly predictive of increased IOP post-FAc implant. CONCLUSION: The results of this study confirm the positive safety and efficacy profile of the FAc implant and demonstrate for the first time the effectiveness of the U.S. label indication of FAc in reducing the incidence of post-treatment pressure elevation. The FAc implant significantly reduced treatment burden in the overall population without significantly increasing the risk of steroid-induced pressure elevation. FUNDING: Alimera Sciences.

Central retinal artery occlusion on postoperative day one after vitreoretinal surgery.

PURPOSE: To report two cases of central retinal artery occlusion (CRAO) associated with vitreoretinal surgery. OBSERVATIONS: Two patients underwent vitreoretinal surgery and were diagnosed with CRAO on postoperative day one. Both had received retrobulbar anesthetic blocks, followed by pars plana vitrectomy in one patient and scleral buckling in the other patient. Best-corrected visual acuity at last follow-up was 20/40 and 20/400. CONCLUSIONS/IMPORTANCE: CRAO is a rare but serious adverse event after vitreoretinal surgery. The causative mechanism is not known in these patients.

Secondary Ocular Hypertension and the Risk of Glaucoma Surgery After Dexamethasone Intravitreal Implant in Routine Clinical Practice.

BACKGROUND AND OBJECTIVES: To determine the rate of ocular hypertension (OHT) after dexamethasone intravitreal implant in routine clinical practice and identify patient characteristics associated with a risk for glaucoma surgery. PATIENTS AND METHODS: The charts of 260 eyes from 221 patients with diabetic macular edema, retinal vein occlusion, uveitis, and macular edema secondary to various causes treated with one or more dexamethasone implants were reviewed. Intraocular pressure (IOP), medications, and glaucoma interventions were collected before and after implantation. RESULTS: The mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg, and after receiving dexamethasone implant(s), 26.2% and 7.7% of patients had IOP greater than 25 mm Hg and 35 mm Hg, respectively. There was evidence (P < .001) of an association between preexisting glaucoma or glaucoma suspect status (103 eyes) and need for glaucoma surgery, and 4.62% (12 eyes) required glaucoma surgery. CONCLUSIONS: Secondary OHT induced by the dexamethasone implant can usually be controlled by medications, but the incidence of OHT requiring glaucoma surgery was high (4.62%) in our study relative to rates previously reported in the literature. All patients, especially those with preexisting glaucoma, should be advised of the possible need for glaucoma surgery prior to undergoing treatment with the dexamethasone implant. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:680-685.].

Replication of the Ordered, Nonredundant Library of Pseudomonas aeruginosa strain PA14 Transposon Insertion Mutants.

Pseudomonas aeruginosa is a phenotypically and genotypically diverse and adaptable Gram-negative bacterium ubiquitous in human environments. P. aeruginosa is able to form biofilms, develop antibiotic resistance, produce virulence factors, and rapidly evolve in the course of a chronic infection. Thus P. aeruginosa can cause both acute and chronic, difficult to treat infections, resulting in significant morbidity in certain patient populations. P. aeruginosa strain PA14 is a human clinical isolate with a conserved genome structure that infects a variety of mammalian and nonvertebrate hosts making PA14 an attractive strain for studying this pathogen. In 2006, a nonredundant transposon insertion mutant library containing 5,459 mutants corresponding to 4,596 predicted PA14 genes was generated. Since then, distribution of the PA14 library has allowed the research community to better understand the function of individual genes and complex pathways of P. aeruginosa. Maintenance of library integrity through the replication process requires proper handling and precise techniques. To that end, this manuscript presents protocols that describe in detail the steps involved in library replication, library quality control and proper storage of individual mutants.

Waste treatment and energy production from small-scale wastewater digesters.

Three tubular anaerobic digestion (AD) systems were installed in Haiti to treat black water (toilet-based wastewater), including a three cell 36m3 clinic digester (CD), a two cell 2m3 hotel digester (HD), and a three-cell 3m3 farm digester (FD) for worker use. During digestion, total coliforms were reduced by 99.1%, E. coli by 98.5%, and chemical oxygen demand (COD) by 93.6%. Nutrients in the effluent averaged 99.4mg/L NH4+ and 10.6mg/L PO42-, producing an effective organic fertilizer. Average biogas production in CD was 108L/d, with 65.4% CH4. Survey participants (n=573) were willing to pay $0.10-0.30 per use for sanitation facilities. Seventy-two percent of the rural population surveyed in Cange, Haiti lacked access to improved sanitation due to financial constraints. The economic analysis calculated an investment cost for a shared toilet AD systems of $16-$47 (USD) per person based on daily use at design capacity.

Neutrophil-Derived Cytosolic PLA2α Contributes to Bacterial-Induced Neutrophil Transepithelial Migration.

Eicosanoids are a group of bioactive lipids that are shown to be important mediators of neutrophilic inflammation; selective targeting of their function confers therapeutic benefit in a number of diseases. Neutrophilic airway diseases, including cystic fibrosis, are characterized by excessive neutrophil infiltration into the airspace. Understanding the role of eicosanoids in this process may reveal novel therapeutic targets. The eicosanoid hepoxilin A3 is a pathogen-elicited epithelial-produced neutrophil chemoattractant that directs transepithelial migration in response to infection. Following hepoxilin A3-driven transepithelial migration, neutrophil chemotaxis is amplified through neutrophil production of a second eicosanoid, leukotriene B4 (LTB4). The rate-limiting step of eicosanoid generation is the liberation of arachidonic acid by phospholipase A2, and the cytosolic phospholipase A2 (cPLA2)α isoform has been specifically shown to direct LTB4 synthesis in certain contexts. Whether cPLA2α is directly responsible for neutrophil synthesis of LTB4 in the context of Pseudomonas aeruginosa-induced neutrophil transepithelial migration has not been explored. Human and mouse neutrophil-epithelial cocultures were used to evaluate the role of neutrophil-derived cPLA2α in infection-induced transepithelial signaling by pharmacological and genetic approaches. Primary human airway basal stem cell-derived epithelial cultures and micro-optical coherence tomography, a new imaging modality that captures two- and three-dimensional real-time dynamics of neutrophil transepithelial migration, were applied. Evidence from these studies suggests that cPLA2α expressed by neutrophils, but not epithelial cells, plays a significant role in infection-induced neutrophil transepithelial migration by mediating LTB4 synthesis during migration, which serves to amplify the magnitude of neutrophil recruitment in response to epithelial infection.

Development of a Primary Human Co-Culture Model of Inflamed Airway Mucosa.

Neutrophil breach of the mucosal surface is a common pathological consequence of infection. We present an advanced co-culture model to explore neutrophil transepithelial migration utilizing airway mucosal barriers differentiated from primary human airway basal cells and examined by advanced imaging. Human airway basal cells were differentiated and cultured at air-liquid interface (ALI) on the underside of 3 µm pore-sized transwells, compatible with the study of transmigrating neutrophils. Inverted ALIs exhibit beating cilia and mucus production, consistent with conventional ALIs, as visualized by micro-optical coherence tomography (µOCT). µOCT is a recently developed imaging modality with the capacity for real time two- and three-dimensional analysis of cellular events in marked detail, including neutrophil transmigratory dynamics. Further, the newly devised and imaged primary co-culture model recapitulates key molecular mechanisms that underlie bacteria-induced neutrophil transepithelial migration previously characterized using cell line-based models. Neutrophils respond to imposed chemotactic gradients, and migrate in response to Pseudomonas aeruginosa infection of primary ALI barriers through a hepoxilin A3-directed mechanism. This primary cell-based co-culture system combined with µOCT imaging offers significant opportunity to probe, in great detail, micro-anatomical and mechanistic features of bacteria-induced neutrophil transepithelial migration and other important immunological and physiological processes at the mucosal surface.

Illuminating dynamic neutrophil trans-epithelial migration with micro-optical coherence tomography.

A model of neutrophil migration across epithelia is desirable to interrogate the underlying mechanisms of neutrophilic breach of mucosal barriers. A co-culture system consisting of a polarized mucosal epithelium and human neutrophils can provide a versatile model of trans-epithelial migration in vitro, but observations are typically limited to quantification of migrated neutrophils by myeloperoxidase correlation, a destructive assay that precludes direct longitudinal study. Our laboratory has recently developed a new isotropic 1-µm resolution optical imaging technique termed micro-optical coherence tomography (µOCT) that enables 4D (x,y,z,t) visualization of neutrophils in the co-culture environment. By applying µOCT to the trans-epithelial migration model, we can robustly monitor the spatial distribution as well as the quantity of neutrophils chemotactically crossing the epithelial boundary over time. Here, we demonstrate the imaging and quantitative migration results of our system as applied to neutrophils migrating across intestinal epithelia in response to a chemoattractant. We also demonstrate that perturbation of a key molecular event known to be critical for effective neutrophil trans-epithelial migration (CD18 engagement) substantially impacts this process both qualitatively and quantitatively.

Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds.

The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps from 2',4',6'-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this class of compounds. Two derivatives, the simple prenylated phloroglucinols 12 and 13, were found to have comparable antiplasmodial activities to that of mallotojaponin C.

Improving Outcomes for Patients With Diabetic Macular Edema.

Diabetic macular edema (DME) is one of the most common causes of vision loss in patients who have diabetes, and all of these patients are at risk for developing DME. The onset is often painless, difficult to detect, and can occur at any stage of diabetes. Ideally, DME is preventable, but treatment must be considered when preventative methods fail. Although physicians have several different treatment options for patients with DME, some patients who receive treatment can respond poorly and may even lose vision. Until recently, laser photocoagulation was regarded as the standard of care for DME; however, pharmaceutical treatments are rapidly replacing this standard as the desire to maximize systemic treatment of DME increases. A panel of experts gathered during the 2015 annual meeting of the Association for Research in Vision and Ophthalmology for a roundtable discussion designed to focus on improving outcomes for patients with DME using pharmaceutical treatment, including the use of anti-VEGFs and corticosteroids, based on the most current research and clinical data.

Antiproliferative Trihydroxyalkylcyclohexenones from Pleiogynium timoriense.

Investigation of a DCM extract of the bark of Pleiogynium timoriense from the former Merck collection of natural product extracts for antiproliferative activity indicated that it was active with an IC50 value of 1.3 µg/mL against the A2780 ovarian cancer cell line. Bioassay-directed fractionation of this extract yielded the three new bioactive trihydroxyalkylcyclohexenones 1-3. Their structures were determined by a combination of spectroscopic and chemical methods. Compounds 1-3 exhibited submicromolar antiproliferative activity against the A2780 human ovarian cancer cell line, with IC50 values of 0.8, 0.7, and 0.8 µM, respectively.

Bioactive oleanane glycosides from Polyscias duplicata from the Madagascar dry forest.

As part of the International Cooperative Biodiversity Group (ICBG) program, in a search for antiproliferative compounds, an ethanol extract of Polyscias duplicata was investigated due to its antiproliferative activity against the A2780 human ovarian cell cancer line (IC50 6 µg/mL). Seven known oleanane glycosides, 3ß-[(α-L-arabinopyranosyl)oxy]-16α-hydroxyolean-12-en-28-oic acid (1, IC50 8 µM), 3ß-[(α-L-arabinopyranosyl)oxy]-16α,23-dihydroxyolean-12-en-18-oic acid (2, IC50 13 µM), 3ß-[(O-ß-D-glucopyranosyl-(t-->3)-α-L-arabinopyranosyl)oxy]-16α-hydroxyolean-12-en-28-oic acid (3, IC50 7 µM), 3ß-[(O-α-L-rhamnopyranosyl-(1-2)-α-L-arabinopyranosyl)oxy]-16α-hydroxyolean-12-en-28-oic acid (4, IC50 2.8 µM), 3ß-[(O-ß-D-glucopyranosyl-(l-->3)-α-L- arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (5, IC50 10 µM), ß-[(O-α-L-rhamnopyranosyl-(-1.2)-α-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (6, IC50 3.4 µM), and 3ß-[(α-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (7, IC50 3.4 µM) were isolated, and their structures determined using spectroscopic methods.

Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension.

PURPOSE: The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. METHODS: A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. RESULTS: An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5' end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-ß. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. CONCLUSIONS: Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH.

Injection force comparison of the old and new dexamethasone implant insertion needles in porcine eyes and synthetic sclera.

BACKGROUND AND OBJECTIVE: Determine whether the new dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) injector needle design can reduce the force needed for insertion when compared to the original needle design. MATERIALS AND METHODS: In vitro testing assessed the force required for insertion from five new-design and five old-design Ozurdex needles on a synthetic test medium and explanted porcine eyes. Maximum penetration force was measured in grams-force, while the total work of the needle was measured in joules. RESULTS: The new design required 29% and 68% less overall work to perform an injection in the synthetic medium (P = .0002) and porcine eyes (P = .009), respectively. The maximum force required to insert the new needle was 25% and 61% that of the old needle in the synthetic medium (P = .001) and porcine eyes (P = .007), respectively. CONCLUSION: The new needle design significantly reduces the force and work needed for insertion, which should improve physician control as well as patient safety and comfort.