Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition.

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

Macrophage-like Cells Are Increased in Patients with Vision-Threatening Diabetic Retinopathy and Correlate with Macular Edema.

Macrophage-like cells (MLCs) are potential inflammatory biomarkers. We previously showed that MLCs are increased in proliferative diabetic retinopathy (PDR) eyes. Vision-threatening diabetic retinopathy (VTDR) includes PDR, severe non-PDR (NPDR), and diabetic macular edema (DME). No prior data exist on MLCs in eyes with severe NPDR or DME. This prospective, cross-sectional optical coherence tomography-angiography (OCT-A) imaging study included 40 eyes of 37 participants who had NPDR classified as non-VTDR (n = 18) or VTDR (n = 22). Repeated OCT-A images were registered, averaged, and used to quantify the main outcome measures: MLC density and percent area. MLC density and percent area were correlated with clinical characteristics, NPDR stage, presence of DME, and OCT central subfield thickness (CST). In VTDR eyes, MLC density (2.6-fold, p < 0.001) and MLC percent area (2.5-fold, p < 0.01) were increased compared with non-VTDR eyes. Multiple linear regression analysis between MLC metrics and clinical characteristics found that MLC density was positively correlated with worse NPDR severity (p = 0.023) and higher CST values (p = 0.010), while MLC percent area was only positively associated with increased CST values (p = 0.006). MLCs are increased in patients with VTDR. Macular edema is the most strongly associated factor with increased MLC numbers in NPDR eyes.

Macrophage-like cells are still detectable on the retinal surface after posterior vitreous detachment.

The identity of vitreoretinal interface macrophage-like cells (MLCs) remains unknown and potential candidates include retinal microglia, perivascular macrophages, monocyte-derived macrophages, and/or vitreal hyalocytes. Since hyalocytes are detectable on the posterior vitreous surface after vitreous extraction in animals, we imaged patients with and without posterior vitreous detachment (PVD) to determine if hyalocytes are the principal MLC component. We performed repeated foveal-centered 3 × 3 mm OCT-A images from 21 eyes (11 no PVD and 10 PVD eyes). Images were registered, segmented, and averaged. The OCT slab from 0 to 3 microns above the internal limiting membrane was used to detect MLCs. We calculated MLC density and distribution in relation to the superficial vascular plexus for 3 vascular regions-on vessels, perivascular, and non-vascular. MLC density was 1.8-fold greater in the PVD group compared to the no PVD group (P = 0.04). MLCs in eyes with PVD were increased 1.9-fold on-vessel (P = 0.07), 1.9-fold in the perivascular region (P = 0.12), and 2.2-fold in non-vascular areas (P = 0.22). MLC density was not severely reduced after PVD, suggesting that the majority of MLCs are not vitreal hyalocytes. PVD status is an important parameter in future MLC studies.

Macrophage-Like Cell Density Is Increased in Proliferative Diabetic Retinopathy Characterized by Optical Coherence Tomography Angiography.

Purpose: To quantitatively characterize macrophage-like cells (MLCs) at the vitreoretinal interface in different severity stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA). Methods: The study included 72 eyes of 72 subjects: 18 healthy controls, 22 diabetes mellitus (DM) without DR, 17 nonproliferative DR (NPDR), and 15 proliferative DR (PDR). We obtained repeated (average, 6.5; range, 3-10) macular OCTA scans for each eye. We registered and averaged the 3-µm OCT slab above the vitreoretinal interface to visualize MLCs. Using a semiautomated method, we binarized and quantified MLCs and compared MLC densities among groups. We also evaluated MLC distribution relative to underlying superficial capillary plexus vasculature and quantified MLCs overlying blood vessels within the perivascular 30-µm watershed region and within ischemic zones (defined as >30 µm from the nearest vessel). Results: MLC density was 2.8- to 3.8-fold higher in PDR compared with all other groups (P < 0.05 for all). MLC density in PDR was most increased in perivascular areas (3.3- to 4.2-fold; P < 0.05 vs. all) and on blood vessels (3.0- to 4.0-fold; P < 0.05 vs. all), and elevated to a lesser extent in ischemic areas (2.3- to 3.4-fold; P < 0.05 vs. all). MLCs were more likely to localize on blood vessels in DM without DR, NPDR, and PDR (P < 0.05 for all), but not healthy eyes. Conclusions: MLC density was significantly increased in PDR. MLCs clustered on blood vessels in diabetic but not in healthy eyes. Further studies are needed to confirm the origin, identity, and function of MLCs during DR.

Tunable transition metal complexes as hole transport materials for stable perovskite solar cells.

Transition metal complexes offer cost-effective alternatives as hole-transport materials (HTMs) in perovskite solar cells. However, the devices suffer from low performance. We boost the power conversion efficiency of devices with transition metal complex HTMs from 2% to above 10% through energy level tuning. We further demonstrate the excellent photostability of the device based on the additive-free HTM.

Passivation by pyridine-induced PbI2 in methylammonium lead iodide perovskites.

Defects at discontinuities of the perovskite lattice limit the performance of the perovskite solar cell (PSC). Lead iodide (PbI2) and pyridine have been shown to passivate these defects. We treat methylammonium lead iodide (MAPbI3) films with pyridine solutions to investigate the effects of the two passivators. By comparing confocal fluorescence microscopy (CFM) images at 405 nm excitation and then at 559 nm excitation we demonstrate the pyridine treatment passivates and forms PbI2 crystallites which cause additional passivation.

Strategically Constructed Bilayer Tin (IV) Oxide as Electron Transport Layer Boosts Performance and Reduces Hysteresis in Perovskite Solar Cells.

Nanostructured tin (IV) oxide (SnO2 ) is emerging as an ideal inorganic electron transport layer in n-i-p perovskite devices, due to superior electronic and low-temperature processing properties. However, significant differences in current-voltage performance and hysteresis phenomena arise as a result of the chosen fabrication technique. This indicates enormous scope to optimize the electron transport layer (ETL), however, to date the understanding of the origin of these phenomena is lacking. Reported here is a first comparison of two common SnO2 ETLs with contrasting performance and hysteresis phenomena, with an experimental strategy to combine the beneficial properties in a bilayer ETL architecture. In doing so, this is demonstrated to eliminate room-temperature hysteresis while simultaneously attaining impressive power conversion efficiency (PCE) greater than 20%. This approach highlights a new way to design custom ETLs using functional thin-film coatings of nanomaterials with optimized characteristics for stable, efficient, perovskite solar cells.

Planar perovskite solar cells with long-term stability using ionic liquid additives.

Solar cells based on metal halide perovskites are one of the most promising photovoltaic technologies1-4. Over the past few years, the long-term operational stability of such devices has been greatly improved by tuning the composition of the perovskites5-9, optimizing the interfaces within the device structures10-13, and using new encapsulation techniques14,15. However, further improvements are required in order to deliver a longer-lasting technology. Ion migration in the perovskite active layer-especially under illumination and heat-is arguably the most difficult aspect to mitigate16-18. Here we incorporate ionic liquids into the perovskite film and thence into positive-intrinsic-negative photovoltaic devices, increasing the device efficiency and markedly improving the long-term device stability. Specifically, we observe a degradation in performance of only around five per cent for the most stable encapsulated device under continuous simulated full-spectrum sunlight for more than 1,800 hours at 70 to 75 degrees Celsius, and estimate that the time required for the device to drop to eighty per cent of its peak performance is about 5,200 hours. Our demonstration of long-term operational, stable solar cells under intense conditions is a key step towards a reliable perovskite photovoltaic technology.

Mouse models of X-linked juvenile retinoschisis have an early onset phenotype, the severity of which varies with genotype.

X-linked juvenile retinoschisis (XLRS) is an early-onset inherited condition that affects primarily males and is characterized by cystic lesions of the inner retina, decreased visual acuity and contrast sensitivity and a selective reduction of the electroretinogram (ERG) b-wave. Although XLRS is genetically heterogeneous, all mouse models developed to date involve engineered or spontaneous null mutations. In the present study, we have studied three new Rs1 mutant mouse models: (1) a knockout with inserted lacZ reporter gene; (2) a C59S point mutant substitution and (3) an R141C point mutant substitution. Mice were studied from postnatal day (P15) to 28 weeks by spectral domain optical coherence tomography and ERG. Retinas of P21-22 mice were examined using biochemistry, single cell electrophysiology of retinal ganglion cells (RGCs) and by immunohistochemistry. Each model developed intraretinal schisis and reductions in the ERG that were greater for the b-wave than the a-wave. The phenotype of the C59S mutant appeared less severe than the other mutants by ERG at adult ages. RGC electrophysiology demonstrated elevated activity in the absence of a visual stimulus and reduced signal-to-noise ratios in response to light stimuli. Immunohistochemical analysis documented early abnormalities in all cells of the outer retina. Together, these results provide significant insight into the early events of XLRS pathophysiology, from phenotype differences between disease-causing variants to common mechanistic events that may play critical roles in disease presentation and progression.

Neuraxial Anesthesia in a Patient With a History of Spontaneous Intracranial Hypotension: A Case Report.

One commonly cited complication of neuraxial techniques is postdural puncture headache. Patients with spontaneous intracranial hypotension may present with a similar constellation of symptoms in the absence of any neuraxial instrumentation. The underlying physiology of spontaneous intracranial hypotension is similar to postdural puncture headache, but cerebrospinal fluid leaks may develop spontaneously at multiple levels of the neuraxis due to a variety of proposed mechanisms. We present a patient with a history of spontaneous intracranial hypotension who underwent a total knee arthroplasty under spinal anesthesia without complication and discuss the pathophysiology, proposed etiologies and treatments, and safety of neuraxial anesthesia in spontaneous intracranial hypotension.

Degradation Kinetics of Inverted Perovskite Solar Cells.

We explore the degradation behaviour under continuous illumination and direct oxygen exposure of inverted unencapsulated formamidinium(FA)0.83Cs0.17Pb(I0.8Br0.2)3, CH3NH3PbI3, and CH3NH3PbI3-xClx perovskite solar cells. We continuously test the devices in-situ and in-operando with current-voltage sweeps, transient photocurrent, and transient photovoltage measurements, and find that degradation in the CH3NH3PbI3-xClx solar cells due to oxygen exposure occurs over shorter timescales than FA0.83Cs0.17Pb(I0.8Br0.2)3 mixed-cation devices. We attribute these oxygen-induced losses in the power conversion efficiencies to the formation of electron traps within the perovskite photoactive layer. Our results highlight that the formamidinium-caesium mixed-cation perovskites are much less sensitive to oxygen-induced degradation than the methylammonium-based perovskite cells, and that further improvements in perovskite solar cell stability should focus on the mitigation of trap generation during ageing.

Tracking Photoexcited Carriers in Hybrid Perovskite Semiconductors: Trap-Dominated Spatial Heterogeneity and Diffusion.

We use correlated confocal and wide-field fluorescence microscopy to probe the interplay between local variations in charge carrier recombination and charge carrier transport in methylammonium lead triiodide perovskite thin films. We find that local photoluminescence variations present in confocal imaging are also observed in wide-field imaging, while intensity-dependent confocal measurements show that the heterogeneity in nonradiative losses observed at low excitation powers becomes less pronounced at higher excitation powers. Both confocal and wide-field images show that carriers undergo anisotropic diffusion due to differences in intergrain connectivity. These data are all qualitatively consistent with trap-dominated variations in local photoluminescence intensity and with grain boundaries that exhibit varying degrees of opacity to carrier transport. We use a two-dimensional kinetic model to simulate and compare confocal time-resolved photoluminescence decay traces with experimental data. The simulations further support the assignment of local variations in nonradiative recombination as the primary cause of photoluminescence heterogeneity in the films studied herein. These results point to surface passivation and intergrain connectivity as areas that could yield improvements in perovskite solar cells and optoelectronic device performance.

Emergency Manuals Improved Novice Physician Performance During Simulated ICU Emergencies.

Background: Emergency manuals, which are safety essentials in non-medical high-reliability organizations (e.g., aviation), have recently gained acceptance in critical medical environments. Of the existing emergency manuals in anesthesiology, most are geared towards intraoperative settings. Additionally, most evidence supporting their efficacy focuses on the study of physicians with at least some meaningful experience as a physician. Our aim was to evaluate whether an emergency manual would improve the performance of novice physicians (post-graduate year [PGY] 1 or first year resident) in managing a critical event in the intensive care unit (ICU). Methods: PGY1 interns (n=41) were assessed on the management of a simulated critical event (unstable bradycardia) in the ICU. Participants underwent a group allocation process to either a control group (n=18) or an intervention group (emergency manual provided, n=23). The number of successfully executed treatment and diagnostic interventions completed was evaluated over a ten minute (600 seconds) simulation for each participant. Results: The participants using the emergency manual averaged 9.9/12 (83%) interventions, compared to an average of 7.1/12 (59%) interventions (p < 0.01) in the control group. Conclusions: The use of an emergency manual was associated with a significant improvement in critical event management by individual novice physicians in a simulated ICU patient (23% average increase).

Perovskite-perovskite tandem photovoltaics with optimized band gaps.

We demonstrate four- and two-terminal perovskite-perovskite tandem solar cells with ideally matched band gaps. We develop an infrared-absorbing 1.2-electron volt band-gap perovskite, FA0.75Cs0.25Sn0.5Pb0.5I3, that can deliver 14.8% efficiency. By combining this material with a wider-band gap FA0.83Cs0.17Pb(I0.5Br0.5)3 material, we achieve monolithic two-terminal tandem efficiencies of 17.0% with >1.65-volt open-circuit voltage. We also make mechanically stacked four-terminal tandem cells and obtain 20.3% efficiency. Notably, we find that our infrared-absorbing perovskite cells exhibit excellent thermal and atmospheric stability, not previously achieved for Sn-based perovskites. This device architecture and materials set will enable "all-perovskite" thin-film solar cells to reach the highest efficiencies in the long term at the lowest costs.

A Universal Deposition Protocol for Planar Heterojunction Solar Cells with High Efficiency Based on Hybrid Lead Halide Perovskite Families.

A robust and expedient gas quenching method is developed for the solution deposition of hybrid perovskite thin films. The method offers a reliable standard practice for the fabrication of a non-exhaustive variety of perovskites exhibiting excellent film morphology and commensurate high performance in both regular and inverted structured solar cell architectures.

Structured Organic-Inorganic Perovskite toward a Distributed Feedback Laser.

A general strategy for the in-plane structuring of organic-inorganic perovskite films is presented. The method is used to fabricate an industrially relevant distributed feedback (DFB) cavity, which is a critical step toward all-electrially pumped injection laser diodes. This approach opens the prospects of perovskite materials for much improved optical control in LEDs, solar cells, and also toward applications as optical devices.

Chronic high-fat feeding increases GIP and GLP-1 secretion without altering body weight.

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), enhance postprandial insulin secretion, promote adipogenesis, and regulate gastrointestinal motility and food intake. To date, a consensus on how the incretin response is altered in obesity is lacking. We investigated the effects of chronic high-fat (HF) feeding on incretin secretion in the lymph fistula rat model. Male Sprague-Dawley rats (8 wk) were provided a semipurified AIN93M HF or low-fat (LF) diet ad libitum for 3 or 13 wk; a HF pair-fed (HF-PF) group was included as a control during the 3-wk feeding trial. Energy intake, body weight, and body composition were regularly monitored. At the culmination of the feeding period, an intestinal lymphatic duct cannula and duodenal infusion tube were installed. All animals were challenged with a 3-ml Ensure bolus (3.125 kcal/animal) to measure lymphatic incretin secretion. Despite a significantly higher energy intake, both the 3-wk and 13-wk HF-fed animals did not have an increase in body weight and only a slight increase in body fat compared with LF-fed rats. Following the duodenal Ensure challenge, the 3-wk and 13-wk HF-fed rats had significantly greater lymphatic GIP and GLP-1 secretion than the LF-fed animals. Additionally, the HF-PF group displayed a secretion profile similar to the HF-fed animals for GIP but a similar pattern to the LF-fed animals for GLP-1. The HF-PF data suggest that the increased GIP secretion is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is driven by the excess caloric intake.

C60 as an Efficient n-Type Compact Layer in Perovskite Solar Cells.

Organic-inorganic halide perovskite solar cells have rapidly evolved over the last 3 years. There are still a number of issues and open questions related to the perovskite material, such as the phenomenon of anomalous hysteresis in current-voltage characteristics and long-term stability of the devices. In this work, we focus on the electron selective contact in the perovskite solar cells and physical processes occurring at that heterojunction. We developed efficient devices by replacing the commonly employed TiO2 compact layer with fullerene C60 in a regular n-i-p architecture. Detailed spectroscopic characterization allows us to present further insight into the nature of photocurrent hysteresis and charge extraction limitations arising at the n-type contact in a standard device. Furthermore, we show preliminary stability data of perovskite solar cells under working conditions, suggesting that an n-type organic charge collection layer can increase the long-term performance.

Low-temperature processed electron collection layers of graphene/TiO2 nanocomposites in thin film perovskite solar cells.

The highest efficiencies in solution-processable perovskite-based solar cells have been achieved using an electron collection layer that requires sintering at 500 °C. This is unfavorable for low-cost production, applications on plastic substrates, and multijunction device architectures. Here we report a low-cost, solution-based deposition procedure utilizing nanocomposites of graphene and TiO2 nanoparticles as the electron collection layers in meso-superstructured perovskite solar cells. The graphene nanoflakes provide superior charge-collection in the nanocomposites, enabling the entire device to be fabricated at temperatures no higher than 150 °C. These solar cells show remarkable photovoltaic performance with a power conversion efficiency up to 15.6%. This work demonstrates that graphene/metal oxide nanocomposites have the potential to contribute significantly toward the development of low-cost solar cells.

Anomalous Hysteresis in Perovskite Solar Cells.

Perovskite solar cells have rapidly risen to the forefront of emerging photovoltaic technologies, exhibiting rapidly rising efficiencies. This is likely to continue to rise, but in the development of these solar cells there are unusual characteristics that have arisen, specifically an anomalous hysteresis in the current-voltage curves. We identify this phenomenon and show some examples of factors that make the hysteresis more or less extreme. We also demonstrate stabilized power output under working conditions and suggest that this is a useful parameter to present, alongside the current-voltage scan derived power conversion efficiency. We hypothesize three possible origins of the effect and discuss its implications on device efficiency and future research directions. Understanding and resolving the hysteresis is essential for further progress and is likely to lead to a further step improvement in performance.