bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of and Steering to Pharmacies Owned by Insurers and Pharmacy Benefit Managers in Medicare
Authors: Kakani Pragya , Navangul Swayami , Lee Luo Christie , Tormohlen Kayla N. , Kanter Genevieve P. , Landrum Mary Beth , Keating Nancy L. , Bond Amelia M. 
Published: January 2025

ImportanceThe prevalence of pharmacies owned by integrated insurers and pharmacy benefit managers (PBMs), or insurer-PBMs, is of growing regulatory concern. However, little is known about the role of these pharmacies in Medicare, in which pharmacy network protections may influence market dynamics.ObjectiveTo evaluate the prevalence of insurer-PBM–owned pharmacies and the extent to which insurer-PBMs steer patients to pharmacies they own in Medicare.Design, Setting, and ParticipantsThis cross-sectional study used Medicare Part D claims data on prescription fills for a 20% random sample of US beneficiaries enrolled from January 1 through December 31, 2021. Data were analyzed from March to November 2024.ExposuresPrescription fills.Main Outcomes and MeasuresThe main outcome was the share of spending filled by insurer-PBM–owned pharmacies overall, by pharmacy type (specialty and nonspecialty), and by drug class. For the top 100 specialty and nonspecialty molecules by claim volume, 2 quantities were identified for 4 major insurer-PBMs (Cigna, CVS, Humana, and UnitedHealth Group): share of the index firm’s insurer claims filled by its owned pharmacies and share of other firms’ insurer claims filled by the index firm’s owned pharmacies. Differences between these quantities were assessed to evaluate the degree to which insurer-PBMs steered patients to their own pharmacies.ResultsAmong 10 455 726 patients (54.8% women; mean [SD] age, 71.8 [10.7] years), 34.1% of all pharmacy and 37.1% of specialty pharmacy spending occurred through Cigna, CVS, Humana, or UnitedHealth Group pharmacies. Among specialty molecules, market shares varied by drug class (antivirals: 18.5%; antipsychotics: 29.5%; cancer: 32.5%; disease-modifying antirheumatic drugs: 41.1%; multiple sclerosis: 64.8%; pulmonary arterial hypertension and idiopathic pulmonary fibrosis: 89.7%). Across molecule-firm combinations, a 19.8 (95% CI, 18.0-21.6)–percentage point and 13.9 (95% CI, 13.1-14.7)–percentage point greater share of claims were filled at insurer-PBM–owned pharmacies than would be expected without steering for specialty and nonspecialty categories, respectively.Conclusions and RelevanceThis cross-sectional study found that insurer-PBM firms represented an important portion of the Medicare Part D market, especially for certain drug classes, and that insurer-PBM firms steered patients to their own pharmacies, despite certain pharmacy network protections in Medicare. These findings underscore the need to understand the impacts of insurer-PBM and pharmacy integration on medication access and costs for Medicare patients.
Estimating Visual Acuity With Spectacle Correction From Fundus Photos Using Artificial Intelligence
Authors: Zhou Ashley , Li Zhuolin , Paul William , Burlina Philippe , Mocharla Rohita , Joshi Neil , Gu Sophie , Nanegrungsunk Onnisa , Bressler Susan , Cai Cindy X. , Alvin Liu T. Y. , Moini Hadi , Sepehrband Farshid , Bressler Neil M. , Kong Jun 
Published: January 2025

ImportanceDetermining spectacle-corrected visual acuity (VA) is essential when managing many ophthalmic diseases. If artificial intelligence (AI) evaluations of macular images estimated this VA from a fundus image, AI might provide spectacle-corrected VA without technician costs, reduce visit time, or facilitate home monitoring of VA from fundus images obtained outside of the clinic.ObjectiveTo estimate spectacle-corrected VA measured on a standard eye chart among patients with diabetic macular edema (DME) in clinical practice settings using previously validated AI algorithms evaluating best-corrected VA from fundus photographs in eyes with DME.Design, Setting, and ParticipantsRetrospective cross-sectional evaluation of deidentified fundus photographs matched to spectacle-corrected VA determined by technicians on eye charts among patients with a history of DME based on optical coherence tomography and at least 2 visits within 1 to 6 months of each other at a university-based clinic between January 2014 and December 2022. Data were analyzed from January 2023 to October 2024.ExposurePreviously validated AI algorithm evaluation of fundus photographs.Main Outcomes and MeasuresAI-determined VA mean absolute error (MAE) compared with actual spectacle-corrected VA.ResultsAmong 141 patients, the mean (SD) age was 63 (13) years, 71 (50%) were male, 2 (1%) were Asian, 42 (30%) were Black or African American, and 88 (63%) were White. Among 282 eyes at visit 1, 66 had nonproliferative diabetic retinopathy (NPDR) and DME, 38 had proliferative diabetic retinopathy (PDR) and DME, 101 had NPDR and no DME, and 77 had PDR and no DME. Among 564 images (282 eyes) at both initial and follow-up visits, MAE (SD) among eyes with NPDR, with or without center-involved DME (CI-DME), was 1.16 (1.00) lines on the eye chart for VA between 20/10 and 20/20 (67 images), and 1.44 (1.15) lines for between VA 20/25 and 20/80 (231 images). MAE (SD) among eyes with PDR, with or without CI-DME, was 1.92 (1.08) lines for VA between 20/10 and 20/20 (50 images), and 1.42 (0.97) lines for spectacle-corrected VA between 20/25 and 20/80 (150 images). Only 65 images had VA 20/100 or worse, precluding meaningful analyses.Conclusions and RelevanceIn this cross-sectional study, AI evaluation of fundus photographs among patients with DME and VA 20/80 or better estimated spectacle-corrected VA within approximately 1 to 1.5 lines of actual spectacle-corrected VA. These results support use of AI evaluation of fundus photographs to determine spectacle-corrected VA among patients with DME globally, beyond ophthalmology offices.
MicroRNA‐204‐5p Deficiency within the vmPFC Region Contributes to Neuroinflammation and Behavioral Disorders via the JAK2/STAT3 Signaling Pathway in Rats
Authors: Chen Xiao , Gan Yeting , Zhang Kaiqi , Wu Yuhan , Li Ye , Lan Tian , Zhuang Xianghua , Chen Shihong , Yu Shuyan 
Published: January 2025

AbstractMajor depressive disorder (MDD) is usually considered associate with immune inflammation and synaptic injury within specific brain regions. However, the molecular mechanisms underlying the neural deterioration resulting in depression remain unclear. Here, it is found that miR‐204‐5p is markedly downregulated in the ventromedial prefrontal cortex (vmPFC) in a chronic unpredictable mild stress (CUMS) induce rat model of depression. Knockdown of miR‐204‐5p in the vmPFC of normal rats results in depression and anxiety‐like behaviors accompanied with the activation of microglia, elevated levels of pro‐inflammatory cytokines, and increased numbers of neural apoptotic cells, effects which appear to be mediated by activation of the JAK2/STAT3 signaling pathway. Electrophysiological recordings further demonstrate that knockdown of miR‐204‐5p induces abnormal excitability of pyramidal neurons. In contrast, upregulation of miR‐204‐5p in the vmPFC of CUMS rats significantly causes inhibition of JAK2/STAT3 signaling pathway, improvements in neuronal impairments, and an abolition of the depression and anxiety‐like behaviors. Moreover, pharmacological blocking of the JAK2/STAT3 signaling pathway significantly ameliorates abnormal behaviors resulting from miR‐204‐5p deficiency within the vmPFC. Collectively, these results provide robust evidence that the miR‐204‐5p/JAK2/STAT3 pathway may critically involve in the pathogenesis of depression, which may serve as potentially critical therapeutic target in the treatment of MDD.
Genetically Programmed Single‐Component Protein Hydrogel for Spinal Cord Injury Repair
Authors: Wei Yi , Zhou Xiaolin , Li Zhenhua , Liu Qing , Ding Han , Zhou Yunlong , Yin Ruo‐feng , Zheng Lifei 
Published: January 2025

AbstractProtein self‐assembly allows for the formation of diverse supramolecular materials from relatively simple building blocks. In this study, a single‐component self‐assembling hydrogel is developed using the recombinant protein CsgA, and its successful application for spinal cord injury repair is demonstrated. Gelation is achieved by the physical entanglement of CsgA nanofibrils, resulting in a self‐supporting hydrogel at low concentrations (≥5 mg mL−1). By leveraging the programmability of the CsgA gene sequence, the bioactive hydrogel is enhanced by fusing functional peptide GHK. GHK is recognized for its anti‐inflammatory, antioxidant, and neurotrophic factor‐stimulating properties, making it a valuable addition to the hydrogel for spinal cord injury repair applications. In vitro experiments demonstrate that the CsgA‐GHK hydrogel can modulate microglial M2 polarization, promote neuronal differentiation of neural stem cells, and inhibit astrocyte differentiation. Additionally, the hydrogel shows efficacy in alleviating inflammation and promotes neuronal regeneration at the injury site, leading to significant functional recovery in a rat model with compression injury spinal cord cavity. These findings lay the groundwork for developing a modular design platform for recombinant CsgA protein hydrogels in tissue repair applications.
Supramolecular Engineering of Nanoceria for Management and Amelioration of Age‐Related Macular Degeneration via the Two‐Level Blocking of Oxidative Stress and Inflammation
Authors: Xu Mingyu , Zhou Yifan , Xu Yufeng , Shao An , Han Haijie , Ye Juan 
Published: January 2025

AbstractAge‐related macular degeneration (AMD), characterized by choroidal neovascularization (CNV), is the global leading cause of irreversible blindness. Current first‐line therapeutics, vascular endothelial growth factor (VEGF) antagonists, often yield incomplete and suboptimal vision improvement, necessitating the exploration of novel and efficacious therapeutic approaches. Herein, a supramolecular engineering strategy to construct moringin (MOR) loaded α‐cyclodextrin (α‐CD) coated nanoceria (M@CCNP) is constructed, where the hydroxy and newly formed carbonyl groups of α‐CD interact with the nanoceria surface via O─Ce conjunction and the isothiocyanate group of MOR inserts deeply into the α‐CD cavity via host–guest interaction. By exploiting the recycling reactive oxygen species (ROS) scavenging capability of nanoceria and the anti‐inflammation properties of MOR, the two‐level strike during AMD pathogenesis can be precisely blocked by M@CCNP. Remarkably, excellent therapeutic efficacy to CNV is observed in vivo, achieving over 80% reduction in neovascularization and over 60% reduction in leakage area. In summary, the supramolecular engineered nanoceria provides an efficient approach for amelioration of AMD by blocking the two‐level strike, and presents significant potential as an exceptional drug delivery platform, particularly for ROS‐related diseases.
ROS‐Responsive Microneedle Patches Enable Peri‐Lacrimal Gland Therapeutic Administration for Long‐Acting Therapy of Sjögren's Syndrome‐Related Dry Eye
Authors: Mu Jingqing , Ding Xiangyu , Song Yapeng , Mi Baoyue , Fang Xiaolong , Chen Baihua , Yao Bin , Sun Xuguang , Yuan Xiaoyong , Guo Shutao , Hua Xia 
Published: January 2025

AbstractSjögren's syndrome‐related dry eye (SSDE) is a severe dry eye subtype characterized by significant immune cell attacks on the lacrimal gland. However, delivering immunosuppressive drugs to the lacrimal glands for SSDE therapy safely and sustainably poses significant challenges in clinical practice. Herein, a ROS‐responsive microneedle patch with detachable functionality (CE‐MN) is developed to enable straightforward and minimally invasive administration to the lacrimal gland area by penetrating the periocular skin. CE‐MN is loaded with immunosuppressive cyclosporin A and anti‐inflammatory drug epigallocatechin gallate, the latter also serving as a cross‐linker for the microneedle matrix. Poly(N‐isopropylacrylamide‐co‐butylacrylate), a temperature‐sensitive polymer is utilized to fabricate separable layers that allow controlled detachment of the base from the needle, reducing patient discomfort. CE‐MN is capable of modulating drug release by responding to ROS, facilitating on‐demand release, and drug accumulation to the lacrimal gland. Compared to traditional eye drops, the CE‐MN patch facilitated long‐acting drug delivery to the lacrimal gland for more than 48 h, demonstrating potent anti‐inflammatory and immunosuppressive effects in an SSDE mouse model by scavenging ROS and inhibiting the proliferation of Th1, Th17 cells, and macrophages. Overall, this long‐acting microneedle patch potentially offers a novel clinical approach for treating SSDE and other ocular chronic diseases.
Novel Leech Antimicrobial Peptides, Hirunipins: Real‐Time 3D Monitoring of Antimicrobial and Antibiofilm Mechanisms Using Optical Diffraction Tomography
Authors: Kumar S. Dinesh , Park Jeongwon , Radhakrishnan Naveen Kumar , Aryal Yam Prasad , Jeong Geon‐Hwi , Pyo In‐Hyeok , Ganbaatar Byambasuren , Lee Chul Won , Yang Sungtae , Shin Younhee , Subramaniyam Sathiyamoorthy , Lim Yu‐jin , Kim Sung‐Hak , Lee Seongsoo , Shin Song Yub , Cho Sung‐Jin 
Published: January 2025

AbstractAntimicrobial peptides (AMPs) are promising agents for treating antibiotic‐resistant bacterial infections. Although discovering novel AMPs is crucial for combating multidrug‐resistant bacteria and biofilm‐related infections, their clinical potential relies on precise, real‐time evaluation of efficacy, toxicity, and mechanisms. Optical diffraction tomography (ODT), a label‐free imaging technology, enables real‐time visualization of bacterial morphological changes, membrane damage, and biofilm formation over time. Here, a computational analysis of the leech transcriptome using an advanced AI‐based peptide screening strategy with ODT to identify potential AMPs is employed. Among the 19 potential AMPs identified, hirunipin 2 demonstrates potent antibacterial activity, low mammalian cytotoxicity, and minimal hemolytic effects. It demonstrates efficacy comparable to melittin, resistance to physiological salts and human serum, and a low likelihood of inducing bacterial resistance. Microscopy and 3D‐ODT confirm its disruption of bacterial membranes and intracellular aggregation, leading to cell death. Notably, hirunipin 2 effectively inhibits biofilm formation, eradicates preformed biofilms, and synergizes with antibiotics against multidrug‐resistant Acinetobacter baumannii (MDRAB) by enhancing membrane permeability. Additionally, hirunipin 2 significantly suppresses pro‐inflammatory cytokine expression in LPS‐stimulated macrophages, highlighting its anti‐inflammatory properties. These findings highlight hirunipin 2 as a strong candidate for developing novel antibacterial, anti‐inflammatory, and antibiofilm therapies, particularly against multidrug‐resistant bacterial infections.
Toward Large‐Scale Photonic Chips Using Low‐Anisotropy Thin‐Film Lithium‐Tantalate
Authors: Huang Fei , Shen Xiaowan , Wang Siyuan , Xu Haochen , Liu Hongxuan , Wang Zexu , Gao He , Yao Xinmin , Cao Hengzhen , Chen Bin , Wang Xijie , Zhang Jizhi , Wu Zhile , Zhu Mingyu , Xiong Hongzhi , Zhao Weike , Li Huan , Yu Zejie , Liu Liu , Shi Yaocheng , Dai Daoxin 
Published: January 2025

AbstractPhotonic manipulation of large‐capacity data with the advantages of high speed and low power consumption is a promising solution for explosive growth demands in the era of post‐Moore. A well‐developed lithium‐niobate‐on‐insulator (LNOI) platform has been widely explored for high‐performance electro‐optic (EO) modulators to bridge electrical and optical signals. However, the photonic waveguides on the x‐cut LNOI platform suffer serious polarization‐mode conversion/coupling issues because of strong birefringence, making it hard to realize large‐scale integration. Here, low‐birefringence photonic integrated circuits (PICs) based on lithium‐tantalate‐on‐insulator (LTOI) are proposed and demonstrated, which enables high‐performance passive photonic devices as well as EO modulators, showing great potential for large‐scale photonic chips. Analysis of mode conversion and evolution behaviors with both low‐ and high‐birefringence shows undesired mode hybridizations can be effectively suppressed. A simple and universal fabrication process is developed and various representative passive photonic devices are demonstrated with impressive performances. Finally, a wavelength‐division‐multiplexed optical transmitter is developed with a data rate of 1.6 Tbps by monolithically integrating 8 EO modulators and an 8‐channel arrayed waveguide grating. Therefore, the demonstrated low‐birefringence LTOI platform shows strong ability in both passively and actively controlling photon behaviors on a chip, indicating great potential for ultrafast processing and communicating large‐capacity data.
Co‐Atomic Interface Minimizing Charge Transfer Barrier in Polytypic Perovskites for CO2 Photoreduction
Authors: Zhong Fengyi , Sheng Jianping , Du Chenyu , He Ye , Zhang Fengying , Sun Yanjuan , Zhou Ying , Dong Fan 
Published: January 2025

AbstractHeterojunctions, known for their decent separation of photo‐generated electrons and holes, are promising for photocatalytic CO2 reduction. However, a significant obstacle in traditional post‐assembled heterojunctions is the high interfacial barrier for charge transfer caused by atomic lattice mismatch at multiphase interfaces. Here, as research prototypes, the study creates a lattice‐matched co‐atomic interface within CsPbBr3‐CsPb2Br5 polytypic nanocrystals (113‐125 PNs) through the proposed in situ hybrid strategy to elucidate the underlying charge transfer mechanism within this unique interface. Compared to CsPbBr3 nanocrystals, the 113–125 PNs exhibit a remarkable 3.6‐fold increase in photocatalytic CO2 reduction activity (173.3 µmol−1 g−1 within 5 h). Furthermore, Kelvin probe force microscopy results reveal an increase in the built‐in electric field within this lattice‐matched co‐atomic interface from 43.5 to 68.7 mV, providing a stronger driving force for charge separation and directional migration. Additionally, ultrafast transient absorption spectroscopy uncovers the additional charge carrier transfer pathways across this lattice‐matched co‐atomic interface. Thus, this unique co‐atomic interface significantly promotes the interfacial electronic coupling and mitigates the charge transfer barrier, thus facilitating efficient charge separation and transfer. These insights underscore the importance of interfacial structure in heterojunction design and comprehending the intricate interplay between interface and carrier dynamics.
Sequential Targeting Chondroitin Sulfate‐Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages
Authors: Deng Caifeng , Xiao Yongbing , Zhao Xuan , Li Hui , Chen Yuxiao , Ai Kelong , Jiang Ting , Wei Jie , Chen Xiaoyuan , Lei Guanghua , Zeng Chao 
Published: January 2025

AbstractThe infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low‐grade inflammation in joint‐related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self‐assembling, licofelone‐loaded nanoparticle (termed LCF‐CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation. LCF‐CSBN is internalized by M1 macrophages via CD44‐mediated endocytosis and targets the Golgi apparatus accompanied with the reactive oxygen species‐responsive release of licofelone (LCF, dual inhibitor of arachidonic acid metabolism). LCF‐CSBN effectively promotes M1 to M2 macrophage transition by reprogramming the Golgi apparatus‐related sphingolipid metabolism and arachidonic acid metabolism. Intra‐articularly injected LCF‐CSBN retains in the joint for up to 28 days and accumulates into M1 macrophages. Moreover, LCF‐CSBN can effectively attenuate joint inflammation, oxidative stress, and cartilage degeneration in OA model rats. These findings indicate the promising potential of lipid‐metabolism‐reprogramming LCF‐CSBN in the targeted therapy of OA.
Skin‐Integrated Electrogenetic Regulation of Vasculature for Accelerated Wound Healing
Authors: Guha Ray Preetam , Rajasekaran Ragavi , Pratihar Bitan , De Sirshendu , Dhara Santanu , Fussenegger Martin 
Published: January 2025

AbstractNeo‐vascularization plays a key role in achieving long‐term viability of engineered cells contained in medical implants used in precision medicine. Moreover, strategies to promote neo‐vascularization around medical implants may also be useful to promote the healing of deep wounds. In this context, a biocompatible, electroconductive borophene–poly(ε‐caprolactone) (PCL) 3D platform is developed, which is called VOLT, to support designer cells engineered with a direct‐current (DC) voltage‐controlled gene circuit that drives secretion of vascular endothelial growth factor A (VEGFA). The VOLT platform consists of a 3D‐printed borophene‐PCL honeycomb‐shaped matrix decorated with borophene‐PCL nanofibers by electrospinning. The honeycomb structure provides mechanical stability, while the nanofibers facilitate the adhesion, migration, and proliferation of the engineered cells. The cells incorporate a DC‐powered reactive oxygen species (ROS)‐sensing gene circuit wired to an engineered synthetic promoter that triggers secretion of VEGFA to promote vascularization in the adjacent extracellular matrix. Cells engineered with this gene circuit and enclosed in the VOLT matrix, termed the VOLTVEGFA system, can be simply triggered using off‐the‐shelf AA batteries, utilizing the established ability of a brief DC bias to generate non‐cytotoxic levels of ROS. For proof‐of‐concept, a subcutaneous wound‐healing model in rats is chosen. Electrostimulation of a VOLTVEGFA implant (5 V, 20 s per day) induced secretion of VEGFA, and significantly accelerated neovascularization and granulation tissue formation, resulting in faster wound closure compared with non‐stimulated controls. Complete re‐epithelialization and dermal regeneration are observed within 15 days of application.
Radiative Warming Glass for High‐Latitude Cold Regions
Authors: Zhou Zhengui , Liu Rong , Huang Zhen , Hu Bin , Long Yi 
Published: January 2025

AbstractTraditional window glazing, with inherently adverse energy‐efficient optical properties, leads to colossal energy losses. Energy‐saving glass requires a customized optical design for different climate zones. Compared with the widely researched radiative cooling technology which is preferable to be used in low‐altitude hot regions; conversely in high‐latitude cold regions, high solar transmittance (Tsol) and low mid‐infrared thermal emissivity (εMIR) are the key characteristics of high‐performance radiative warming window glass, while the current low‐emissivity (low‐e) glass is far from ideal. To address this issue, Drude's theory is used to numerically design a near‐ideal film with specified electron density (ne) and electron mobility (µe). The fabricated hydrogen‐doped indium oxide (IHO) could achieve high Tsol (0.836) and low εMIR (0.117). Energy‐saving simulations further reveal a substantial decrease in annual heating energy consumption up to 6.6% across high‐latitude regions (climate zones 6 to 8), translating to a corresponding reduction in CO2 emissions (20.0 kg m−2), outperforming 1165 high performance commercial low‐e glass. This radiative warming glass holds the promise of making a significant contribution to sustainable building energy savings specifically for high‐latitude cold regions, advancing the goal of carbon neutrality.