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We report the p+p and p+d differential cross sections measured in the SeaQuest experiment for J/ψ and ψ(2S) production at [Formula presented] beam energy covering the forward x-Feynman (xF) range of 0.5

The electromagnetic form factors of the proton and neutron encode information on the spatial structure of their charge and magnetization distributions. While measurements of the proton are relatively straightforward, the lack of a free neutron target makes measurements of the neutron's electromagnetic structure more challenging and more sensitive to experimental or model-dependent uncertainties. Various experiments have attempted to extract the neutron form factors from scattering from the neutron in deuterium, with different techniques providing different, and sometimes large, systematic uncertainties. We present results from a novel measurement of the neutron magnetic form factor using quasielastic scattering from the mirror nuclei ^{3}H and ^{3}He, where the nuclear effects are larger than for deuterium but expected to largely cancel in the cross-section ratios. We extracted values of the neutron magnetic form factor for low-to-modest momentum transfer, 0.6

Eko Fuji Ariyanto,1,2 Anastasya Kania Farahana,3 Gabriella Sachiko Jannesha Sudirman,3 Erlina Widiarsih,4 Nurul Qomarilla,5 Nurul Setia Rahayu,4 Tenny Putri Wikayani,5 Henhen Heryaman,1 Dwi Wahyudha Wira,1 Rima Destya Triatin,1,2 Muhammad Hasan Bashari,1 Yunisa Pamela,1 Yuni Susanti Pratiwi,1 Mohammad Ghozali1 1Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, Indonesia; 2Research Center for Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 3Undergraduate Program of Medical Doctor, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, Indonesia; 4Molecular Genetics Laboratory, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 5Cell Culture Laboratory, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, IndonesiaCorrespondence: Eko Fuji Ariyanto, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, West Java, Indonesia, Tel +6281316099791, Email fuji@unpad.ac.idPurpose: This study aims to provide new insights into the potential of oyster mushroom (Pleurotus ostreatus) ethanolic extract in preventing obesity through the inhibition of Pparg expression and modulation of methylation level on Pparg promoter during 3T3-L1 adipocyte differentiation.Methods: This in vitro quantitative experimental study was conducted by treating the 3T3-L1 cell line differentiated using 0.5 mM methyl-isobutyl-xanthine, 1 μM dexamethasone, and 10 μg/mL insulin-containing medium with oyster mushroom ethanolic extract. The extract was obtained from 80 g of dried oyster mushroom powder extracted three times with 800 mL of ethanol, filtered, evaporated, and reconstituted in dimethyl sulfoxide (DMSO) to final concentrations of 0, 25, 50, and 100 μg/mL, with DMSO limited to 0.5% in all solutions. Pparg mRNA expression was quantified by qRT-PCR analysis and Pparg promoter methylation levels were measured quantitatively by pyrosequencing of bisulfite-treated DNA samples.Results: The addition of 25 μg/mL oyster mushroom ethanolic extract significantly suppressed Pparg mRNA expression with no significant change in the Pparg promoter methylation levels.Conclusion: Oyster mushroom ethanolic extract inhibited Pparg mRNA expression without altering Pparg promoter methylation, suggesting reduced adipocyte differentiation. This study emphasizes the potential of oyster mushroom in the prevention or treatment of obesity by inhibiting adipocyte differentiation. Keywords: obesity, oyster mushroom, Pparg expression, Pparg methylation, 3T3-L1

BackgroundBoth 1 month of daily (1HP) and 3 months of weekly (3HP) isoniazid-rifapentine are recommended as short-course regimens for TB prevention among people living with HIV (PLHIV). We aimed to assess acceptability and preferences for 1HP vs. 3HP among PLHIV.MethodsIn a cross-sectional survey among PLHIV at an HIV clinic in Kampala, Uganda, participants were randomly assigned to a hypothetical scenario of receiving 1HP or 3HP. Participants rated their level of perceived intention and confidence to complete treatment using a 0-10 Likert scale, and chose between 1HP and 3HP.ResultsAmong 429 respondents (median age: 43 years, 71% female, median time on ART: 10 years), intention and confidence were rated high for both regimens. Intention to complete treatment was rated at least 7/10 by 92% (189/206 randomized to 1HP) and 93% (207/223 randomized to 3HP). Respectively 86% (178/206) and 93% (208/223) expressed high confidence to complete treatment. Overall, 81% (348/429) preferred 3HP over 1HP.ConclusionsBoth 1HP and 3HP were highly acceptable regimens, with 3HP preferred by most PLHIV. Weekly, rather than daily, dosing appears preferable to shorter duration of treatment, which should inform scale-up and further development of short-course regimens for TB prevention.

Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the KCNN3 gene that encodes for small conductance calcium-activated potassium channels type 3 (SK3). However, the functional electrophysiological effects of this variant are not known. SK channels represent a unique family of K+ channels, primarily regulated by cytosolic Ca2+ concentration, and different studies support their critical role in the regulation of atrial excitability and consequently in the development of arrhythmias like AF. Since different studies have shown that both upregulation and downregulation of SK3 channels can lead to arrhythmias by different mechanisms, an important goal is to elucidate whether the rs13376333 risk SNP is a gain-of-function (GoF) or a loss-of-function (LoF) variant. A better understanding of the functional consequences associated with these SNPs could influence clinical practice guidelines by improving genotype-based risk stratification and personalized treatment. Although research using native human atrial cardiomyocytes and animal models has provided useful insights, each model has its limitations. Therefore, there is a critical need to develop a human-derived model that represents human physiology more accurately than existing animal models. In this context, research with human induced pluripotent stem cells (hiPSC) and subsequent generation of cardiomyocytes derived from hiPSC (hiPSC-CMs) has revealed the underlying causes of various cardiovascular diseases and identified treatment opportunities that were not possible using in vitro or in vivo studies with animal models. Thus, the ability to generate atrial cardiomyocytes and atrial tissue derived from hiPSCs from human/patients with specific genetic diseases, incorporating novel genetic editing tools to generate isogenic controls and organelle-specific reporters, and 3D bioprinting of atrial tissue could be essential to study AF pathophysiological mechanisms. In this review, we will first give an overview of SK-channel function, its role in atrial fibrillation and outline pathophysiological mechanisms of KCNN3 risk SNPs. We will then highlight the advantages of using the hiPSC-CM model to investigate SNPs associated with AF, while addressing limitations and best practices for rigorous hiPSC studies.

Ting-Ting Ni, Yuan-Yuan Yao, Xiao-Xia Zhou, Tao Lv, Jing-Cheng Zou, Ge Luo, Jin-Ting Yang, Da-Wei Sun, Qi Gao, Ting-Ting Wang, Rui-Yu Wang, Xin-Chen Tao, Min Yan Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 330100, People’s Republic of ChinaCorrespondence: Min Yan, Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, 330100, People’s Republic of China, Email zryanmin@zju.edu.cnPurpose: Postinduction hypotension (PIH), occurring between anaesthesia induction and surgical incision, is particularly concerning in older adults undergoing transcatheter aortic valve replacement (TAVR) due to their multiple comorbidities and age-related cardiovascular changes. This study aimed to assess the relationship between PIH and postoperative adverse events in TAVR patients.Patients and Methods: A total of 777 patients underwent TAVR at The Second Affiliated Hospital of Zhejiang University School of Medicine from January 1, 2020 to February 28, 2023. Four thresholds of MAP were defined, including two absolute thresholds (< 65, < 60 mmHg) and two relative thresholds (20% and 30% lower than baseline). The relationships between PIH and the composite outcome, which included all-cause in-hospital mortality, stroke, acute kidney injury (AKI), and myocardial infarction (MI), were examined using unadjusted analysis, 1:1 propensity score matching(PSM), and inverse probability of treatment weighting (IPTW).Results: A total of 643 older adults were included in the study ultimately. The composite outcome incidence was significantly greater in patients with PIH than in those without PIH (relative risk [RR]: 2.47, 95% CI: 1.66– 3.73 for MAP < 60 mmHg; RR: 1.66, 95% CI: 1.14– 2.46 for a > 30% decrease from baseline). PIH was significantly associated with stroke (RR: 5.22, 95% CI: 1.98– 17.75) and AKI (RR: 2.82, 95% CI: 1.73– 4.79) with a MAP < 60 mmHg.Conclusion: PIH significantly increases the risk of composite outcomes, especially stroke and AKI, in TAVR patients.Keywords: postinduction hypotension, adverse postoperative outcomes, transcatheter aortic valve replacement, older adults

Anthony Giuffrida,1 Christy Saia-Owenby,2 Chris Andriano,3,&ast; Douglas Beall,4,&ast; Ashley Bailey-Classen,5,&ast; Patrick Buchanan,6,&ast; Ryan Budwany,7,&ast; Mehul J Desai,8,&ast; Ashley Comer,9,&ast; Andrew Dudas,10,&ast; Vinicius Tieppo Francio,11,&ast; Warren Grace,12,&ast; Benjamin Gill,13,&ast; Betsy Grunch,14,&ast; Andrew Goldblum,13,&ast; Rosa A Garcia,15,&ast; David W Lee,16,&ast; Chad Lavender,17,&ast; Marco Lawandy,18,&ast; Lyric Mandell,2,&ast; Robin Mata,19,&ast; Morteza Rabii,20,&ast; Kiran Patel,21,&ast; Raj G Patel,22,&ast; Ankur A Patel,23,&ast; Dawood Sayed,24,&ast; Gurtej Singh,25,&ast; Natalie Strand,26,&ast; Jordan Tate,27,&ast; Michael E Schatman,28 Timothy Deer29 1Cantor Spine Center, Paley Orthopedic and Spine Institute, Fort Lauderdale, FL, USA; 2MOXY Company, Covington, LA, USA; 3Georgia Pain Care, Stockbridge, GA, USA; 4Oklahoma Spine Hospital, Oklahoma City, OK, USA; 5Trinity Pain Medicine Associates, Fort Worth, TX, USA; 6Spanish Hills Interventional Pain Specialists, Camarillo, CA, USA; 7Center for Pain Relief, Charleston Area Medical Center, Charleston, WV, USA; 8International Spine, Pain, and Performance Center, Washington, DC, USA; 9The Spine and Nerve Centers of the Virginias, Charleston, WV, USA; 10Maya & Schnapp, Neurospine and Pain, Memphis, TN, USA; 11Anesthesiology and Pain Medicine, University of Kansas, Kansas City, KS, USA; 12Redefine Healthcare, Orthopedic Pain and Spine Center, Edison, NJ, USA; 13Physical Medicine and Rehabilitation, University of Missouri, Columbia, MO, USA; 14Longstreet Clinic, Gainesville, GA, USA; 15Larkin Hospital Health Systems, Miami, FL, USA; 16Interventional Pain and Spine, Fullerton Orthopedics, Yorba Linda, CA, USA; 17Department of Orthopaedics, Marshall University, Huntington, WV, USA; 18Physical Medicine and Rehabilitation, Montefiore Medical Center, New York, NY, USA; 19Department of Physical Medicine and Rehabilitation, University of Miami, Miami, FL, USA; 20Crimson Pain Management, Overland Park, KS, USA; 21Pain Medicine and Anesthesiology, Northwell Health, New York, NY, USA; 22Central Texas Interventional Pain Doctor, Capitol Pain Institute, Austin, TX, USA; 23Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX, USA; 24Department of Pain Medicine and Neurology, University of Kansas Health System, Kansas City, KS, USA; 25Department of Pain Medicine, Rehabilitation, and Pain Medicine, the Center for Advance Orthopaedics, Cantonsville, MD, USA; 26Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, AZ, USA; 27Department of Pain Medicine and Physical Medicine and Rehabilitation, Southern Pain and Spine, Jasper, GA, USA; 28Department of Anesthesiology, Perioperative Care, and Pain Medicine at NYU Grossman School of Medicine, New York, NY, USA; 29Department of Pain Management, Spine and Nerve Centers of the Virginias, Charleston, WV, USA&ast;These authors contributed equally to this workCorrespondence: Lyric Mandell, MOXY Company, Covington, LA, USA, Email lyric@moxycompany.comPurpose: The American Society of Pain and Neuroscience (ASPN) identified a significant gap in resources and guidelines that aim to educate healthcare providers for best practices when engaging on social media. As part of the broader initiatives on Spine and Nerve practice, the executive board of ASPN has decided it would be beneficial to include comprehensive guidance for healthcare providers when engaging on social media.Methods: A panel of experts was chosen based on expertise, publications, diversity, and their social media presence. Along with expert guidance, the committee conducted an extensive analysis of peer-reviewed literature in communication and medical journals to determine best practices for healthcare practitioners on social media.Results: Social media messages significantly impact patients’ and colleagues’ perceptions and actions regarding medical issues. As such, providers and their teams must be aware of legal and ethical considerations in healthcare while maintaining a consistent, educational, and digestible persona online.Conclusion: The advancement of communication and medical technologies and systems necessitates continued education and resources to adapt to our rapidly changing media and medical landscape.Keywords: digital communication, social networking sites, healthcare providers, best practices, physician communication, social media, medical marketing, spine

Managers frequently rely on conservation hatcheries to maintain declining fish populations in the wild, which is the case for bonytail Gila elegans, an endangered species endemic to the Colorado River basin, USA. We used a multi-agency database of stocking, capture, and PIT-tag detections during 2013-2021 across the upper Colorado River basin to assess if re-encounter probability of bonytail varied among seasons, stocking habitats (mainstem, tributary, and off-channel), and with length-at-stocking. Because of previous observations of recaptured bonytail in poor body condition, we tested for differences in condition among stocking habitats. Of 325054 stocked bonytail examined, 90% were never re-encountered. Most re-encounters (93%) were PIT-tag detections near stocking locations. Re-encounter probability was low regardless of stocking habitat, and 95% of fish were at large for

Salah satu bentuk perilaku etis yang dilakukan organisasi adalah tidak semata-mata hanya fokus pada pencapaian laba (profit) tetapi juga memberikan perhatian pada aspek lingkungan dan masyarakat agar mampu menjaga keberlanjutan dalam jangka panjang. Penelitian ini dikaitkan dengan Profitabilitas (ROA dan ROE termasuk kedalam rasio Profitabilitas). Eksistensi perusahaan berpotensi besar mengubah lingkungan masyarakat, baik ke arah positif maupun negatif. Keseimbangan antara aspek ekonomi, sosial dan lingkungan dapat diwujudkan dengan pelaksanaan tanggng jawab sosial atau corporate social responsibility (CSR). Tujuan penelitian ini yaitu untuk mengetahui dan menganalisis pengaruh masing-masing variabel CSR, ROA dan ROE terhadap pembangunan berkelanjutan melalui profitabilitas, serta peran perbankan dalam implementasi pembangunan berkelanjutan dan sebagai strategi pembangunan berkelanjutan. Metode penelitian yang digunakan yaitu metde kuantitatif. Populasi sebanyak 6 Bank Umum dengan modal diatas 30 Triliun. Teknik Pengambilan Sampel yang digunakan Purposive Sampling. Metode Analisis yang digunakan adalah metode Analisis Jalur (path Analysis). Hasil penelitian menunjukkan bahwa CSR dapat berpengaruh secara langsung Pembangunan secara langsung pembangunan berkelanjutan melaui profitabilitas. ROA berpengaruh secara langsung Pembangunan secara langsung pembangunan berkelanjutan melaui profitabilitas, ROE dapat berpengaruh secara langsung Pembangunan secara langsung pembangunan berkelanjutan melaui profitabilitas.

Ji-Hyun Kang,1,2,&ast; Jin-Hyuk Jeong,1,&ast; Yong-Bin Kwon,1 Young-Jin Kim,1 Dae Hwan Shin,1 Yun-Sang Park,3 Soonsil Hyun,1 Dong-Wook Kim,4 Chun-Woong Park1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2School of Pharmacy, Institute of New Drug Development, and Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea; 3Research & Development Center, P2K Bio, Cheongju, Republic of Korea; 4College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chun-Woong Park, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea, Tel +82-43-261-3330, Fax +82-43-268-2732, Email cwpark@cbnu.ac.kr Dong-Wook Kim, College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea, Tel +82-63-229-7130, Fax +82-63-850-7309, Email pharmengin@gmail.comPurpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.Results: The nano-micelles, with a particle size of < 100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.Keywords: insulin, polyethylene glycol, cell-penetrating peptide, aerodynamic properties, mucus penetration

One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.

Clusters of galaxies trace the most non-linear peaks in the cosmic density field. The weak gravitational lensing of background galaxies by clusters can allow us to infer their masses. However, galaxies associated with the local environment of the cluster can also be intrinsically aligned due to the local tidal gradient, contaminating any cosmology derived from the lensing signal. We measure this intrinsic alignment in Dark Energy Survey (DES) Year 1 REDMAPPER clusters. We find evidence of a non-zero mean radial alignment of galaxies within clusters between redshifts 0.1–0.7. We find a significant systematic in the measured ellipticities of cluster satellite galaxies that we attribute to the central galaxy flux and other intracluster light. We attempt to correct this signal, and fit a simple model for intrinsic alignment amplitude (AIA) to the measurement, finding AIA = 0.15 ± 0.04, when excluding data near the edge of the cluster. We find a significantly stronger alignment of the central galaxy with the cluster dark matter halo at low redshift and with higher richness and central galaxy absolute magnitude (proxies for cluster mass). This is an important demonstration of the ability of large photometric data sets like DES to provide direct constraints on the intrinsic alignment of galaxies within clusters. These measurements can inform improvements to small-scale modelling and simulation of the intrinsic alignment of galaxies to help improve the separation of the intrinsic alignment signal in weak lensing studies.

Evidence for a flavor asymmetry between the ū and d¯ quark distributions in the proton has been found in deep-inelastic scattering and Drell-Yan experiments. The pronounced dependence of this flavor asymmetry on x (fraction of nucleon momentum carried by partons) observed in the Fermilab E866 Drell-Yan experiment suggested a drop of the d¯(x)/ū(x) ratio in the x>0.15 region. We report results from the SeaQuest Fermilab E906 experiment with improved statistical precision for d¯(x)/ū(x) in the large x region up to x=0.45 using the 120 GeV proton beam. Two different methods for extracting the Drell-Yan cross section ratios, σpd/2σpp, from the SeaQuest data give consistent results. The d¯(x)/ū(x) ratios and the d¯(x)-ū(x) differences are deduced from these cross section ratios for 0.13

Indoor photovoltaics are receiving tremendous attention due to the continuous development of the Internet of Things. The present study reports how the fast processing of the triple halide perovskite enables the retention of chlorine and the beneficial role of chlorine in enhancing the indoor light harvesting of a wide bandgap triple anion (TA) perovskite CH3NH3PbI2.6Br0.2Cl0.2. The kinetics of chlorine incorporation/escape investigated by in situ grazing incidence wide-angle X-ray scattering revealed the escape of chlorine after the first ten minutes of thermal annealing and the findings were corroborated with elemental analysis by wavelength dispersive X-ray spectroscopy. The best-performing TA perovskite indoor-photovoltaic device achieved a steady-state power conversion efficiency (PCE) of 25.1% with an output power density of ∼75 μW cm−2 under 1000 lux indoor illumination (0.3 mW cm−2 irradiance). Improved crystalline quality, reduced density of trap states and longer carrier lifetime were achieved by the triple anion alloying method. The detrimental role of the commonly used hole transporting layer (HTL) of Spiro-MeOTAD under indoor lighting conditions leading to J-V hysteresis was also investigated, which could then be effectively suppressed by replacing Spiro-MeOTAD with undoped P3HT. The optimized TA perovskite indoor PV cells were then successfully used to wirelessly power a textile fiber-based temperature sensor. The results from the present study demonstrate a novel route to incorporate chlorine effectively and maximize the steady state power output from halide perovskite indoor photovoltaic devices and their promising potential for the IoT industry.

BACKGROUND: Twelve weeks of weekly isoniazid and rifapentine (3HP) prevents TB disease among people with HIV (PWH), but the costs to people of taking TB preventive treatment is not well described.METHODS: We surveyed PWH who initiated 3HP at a large urban HIV/AIDS clinic in Kampala, Uganda, as part of a larger trial. We estimated the cost of one 3HP visit from the patient perspective, including both out-of-pocket costs and estimated lost wages. Costs were reported in 2021 Ugandan shillings (UGX) and US dollars (USD; USD1 = UGX3,587)RESULTS: The survey included 1,655 PWH. The median participant cost of one clinic visit was UGX19,200 (USD5.36), or 38.5% of the median weekly income. Per visit, the cost of transportation was the largest component (median: UGX10,000/USD2.79), followed by lost income (median: UGX4,200/USD1.16) and food (median: UGX2,000/USD0.56). Men reported greater income loss than women (median: UGX6,400/USD1.79 vs. UGX3,300/USD0.93), and participants who lived further than a 30-minute drive to the clinic had higher transportation costs than others (median: UGX14,000/USD3.90 vs. UGX8,000/USD2.23).CONCLUSION: Patient-level costs to receive 3HP accounted for over one-third of weekly income. Patient-centered approaches to averting or defraying these costs are needed.

Yang Zhao,1,&ast; Yi-Han Wang,2,&ast; Wei-Chao Tu,1 Da-Wei Wang,1 Mu-Jun Lu,3,4 Yuan Shao1 1Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, 201800, People’s Republic of China; 2Department of Urology, Sixth People’s Hospital South Campus Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Urology and Andrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Shanghai Institute of Andrology, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mu-Jun Lu; Yuan Shao, Email lumujun@163.com; shaoyuan10772@163.comBackground: Chronic kidney disease (CKD) is a significant worldwide health concern that leads to high mortality rates. The bioactive substance costunolide (CTD) has demonstrated several pharmacological effects and holds promise as a CKD treatment. This study aims to investigate the impact of CTD on CKD and delve into its mechanisms of action.Methods: Unilateral ureteral obstruction (UUO) methods and renal fibrosis mice models were created. Various concentrations of CTD were injected into UUO mice models to investigate the therapeutic effects of CTD on renal fibrosis of mice. Then, renal morphology, pathological changes, and the expression of genes related to fibrosis, inflammation and ferroptosis were analysed. RNA sequencing was utilized to identify the main biological processes and pathways involved in renal injury. Finally, both overexpression and inhibition of IKKβ were studied to examine their respective effects on fibrosis and inflammation in both in vitro and in vivo models.Results: CTD treatment was found to significantly alleviate fibrosis, inflammation and ferroptosis in UUO-induced renal fibrosis mice models. The results of RNA sequencing suggested that the IKKβ acted as key regulatory factor in renal injury and the expression of IKKβ was increased in vitro and in vivo renal fibrosis model. Functionally, down-regulated IKKβ expression inhibits ferroptosis, inflammatory cytokine production and collagen deposition. Conversely, IKKβ overexpression exacerbates progressive renal fibrosis. Mechanistically, CTD alleviated renal fibrosis and inflammation by inhibiting the expression of IKKβ and attenuating IKKβ/NF-κB pathway.Conclusion: This study demonstrates that CTD could mitigate renal fibrosis, ferroptosis and inflammation in CKD by modulating the IKKβ/NF-κB pathway, which indicates targeting IKKβ has an enormous potential for treating CKD. Keywords: chronic kidney disease, costunolide, renal fibrosis, IKKβ/NF-κB pathway

Tsing Hong Wang,1 Tin Aung,2– 4 Da-Wen Lu,5 Ronnie George,6 Sirisha Senthil,7 Fenghe Lu,8 Noriko Odani-Kawabata,9 Ki Ho Park10 1Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan; 2Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; 3Duke-NUS Medical School, Singapore; 4Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 5Department of Ophthalmology, Tri-Service General Hospital, Taipei, Taiwan; 6Sankara Nethralaya, Chennai, India; 7VST Centre for Glaucoma Care, Kallam Anji Reddy Campus, Hyderabad, India; 8Santen Pharmaceuticals, Inc, Emeryville, CA, USA; 9Santen Pharmaceuticals, Ltd, Osaka, Japan; 10Department of Ophthalmology, Seoul National University, Seoul, Republic of KoreaCorrespondence: Tsing Hong Wang, Department of Ophthalmology National Taiwan University Hospital, Taipei, Taiwan, Email thwangglaucoma@ntu.edu.twPurpose: To compare the efficacy and safety of omidenepag isopropyl (OMDI) 0.002% with latanoprost 0.005% once daily in Asian subjects with open-angle glaucoma (OAG)/ocular hypertension (OHT).Methods: In this Phase III randomized, observer-masked, active-controlled, multinational trial (NCT02981446), subjects aged ≥ 18 years with OAG/OHT in both eyes and baseline intraocular pressure (IOP) ≥ 22 mmHg and ≤ 34 mmHg were randomized 1:1 to OMDI or latanoprost. IOP was measured at 9AM, 1PM, and 5PM at baseline, 1 week, 6 weeks, and 3 months. Adverse events (AEs) were recorded. Non-inferiority of OMDI to latanoprost was tested for primary and key secondary endpoints.Results: Each group included 185 subjects. Mean diurnal IOP from baseline to month 3 was reduced 7.1 mmHg (28.8%) with OMDI and 7.8 mmHg (31.3%) with latanoprost, with the least-squares mean difference (OMDI minus latanoprost) being 0.6 mmHg (95% CI: 0.0, 1.2 mmHg; p = 0.0366), indicating non-inferiority. Mean IOP reductions at the nine timepoints were − 5.8 to − 7.3 mmHg (23.5– 29.5%) for OMDI and − 6.1 to − 7.9 mmHg (24.3– 31.7%) for latanoprost. Non-inferiority per FDA criteria was also met. Rates of all AEs, ocular AEs, and ocular AEs associated with treatment were 40.0%, 36.8%, and 23.2%, respectively, for OMDI and 29.7%, 21.1%, and 11.9%, respectively, for latanoprost. Conjunctival hyperemia rates were higher with OMDI than latanoprost (11.9% vs 5.4%). Most AEs were mild, with no serious ocular AEs.Conclusion: OMDI safely and effectively reduces IOP in Asian subjects with OAG/OHT, with mean diurnal IOP at Month 3 and per-timepoint IOP reductions non-inferior to those of latanoprost.Plain Language Summary: PEONY Study: Testing How Well and How Safely Omidenepag Isopropyl Eye Drops Treat People with Glaucoma or Ocular Hypertension Compared with Latanoprost.Who took part in the study?Three hundred and seventy participants average age of 57 years, from 34 centers across four Asian countries who had glaucoma or high pressure in both eyes were randomly divided into two groups. One group (185 people; 50%) was given OMDI, and the other group (185 people; 50%) latanoprost for 3 months. The intraocular pressure of both eyes was measured in all participants at three time points (9 AM, 1 PM, and 5 PM) after 1 week, 6 weeks, and 3 months of treatment. The primary endpoint was the average of the daily eye pressure after 3 months of treatment. The safety of OMDI was also assessed.Study results.After 3 months of treatment, OMDI decreased the eye pressure by 29%. This was similar to latanoprost, which decreased the eye pressure by 31% over the same time period. OMDI was safe and well tolerated by those participants who received it. The most common side-effect in people receiving OMDI or latanoprost was conjunctival hyperemia (red eye) (experienced by 22 people receiving OMDI, and 10 people receiving latanoprost).ConclusionsAfter 3 months of use, OMDI was found to safely reduce high eye pressure to a similar level as latanoprost in Asian people with glaucoma or high eye pressure.Keywords: omidenepag isopropyl, latanoprost, intraocular pressure, glaucoma, ocular hypertension

John D Hong,1 Elliot H Choi,1 Susie Suh,1 Joseph H Bui,1 Annabelle M Storch,1 Kimberly R Walker,1 Kourosh Shahraki,1 Carolina Yanez,1 Diana Torres,1 Jennifer Espinoza,1 Iliana Molina,2,&ast; Donny W Suh1,&ast; 1Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA, USA; 2Shiley Eye Institute, Department of Ophthalmology, University of California, San Diego, CA, USA&ast;These authors contributed equally to this workCorrespondence: Donny W Suh, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, 850 Health Sciences Road, Irvine, CA, 92697, USA, Tel +1 949 824-4122, Email donnys@hs.uci.edu Iliana Molina, Shiley Eye Institute, Department of Ophthalmology, University of California, San Diego, 9415 Campus Point Dr, San Diego, CA, 92037, USA, Tel +1 858 822-2585, Email imolina@health.ucsd.eduPurpose: Uncorrected refractive errors (REs) and amblyopia can lead to visual impairment with deleterious effects on quality of life and academic performance. Early detection and treatment by community vision care programs, such as the UCI EyeMobile for Children, can aid in addressing preventable vision loss.Methods: A total of 5074 children between the ages of 3 and 10 years were screened at 153 locations, including preschools, head start programs, and elementary schools within Orange County (OC), California (CA). Subsequently, 1024 children presented for comprehensive eye examinations. A retrospective analysis of all examined children was conducted, determining the frequency and severity of REs and amblyopia and the spectacle prescription rate by age. Propensity score matching analysis evaluated the effect of median household income on RE and amblyopia frequency.Results: Among those who failed initial screening and were subsequently examined, significant rates of REs and amblyopia were detected: myopia (24.4%), hyperopia (35.4%), astigmatism (71.8%), anisometropia (8.9%), amblyopia (7.0%), and amblyopia risk (14.4%). A majority (65.0%) of those examined received prescription spectacles from UCI EyeMobile, with around a third requiring a new or updated prescription. The frequency of REs and amblyopia and the spectacle prescription rate were uniform across OC congressional districts. Myopia and amblyopia risk was positively and negatively associated with household income, respectively.Conclusion: The UCI EyeMobile for Children serves as a vital vision care program, providing free vision screening, comprehensive eye examinations, and spectacles. A significant number of children required examination, and a high frequency of REs and amblyopia were detected in examined children, with subsequent provision of prescription spectacles to most children.Keywords: pediatrics, refractive error, amblyopia, spectacles, mobile clinic, screening

Siân Rizzo,1 Mathieu Varache,1 Edward J Sayers,2 Arwyn T Jones,2 Alex Tonks,3 David W Thomas,1 Elaine L Ferguson1 1Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK; 2School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK; 3Department of Haematology, School of Medicine, Cardiff University, Cardiff, UKCorrespondence: Elaine L Ferguson, Advanced Therapies Group, School of Dentistry, Cardiff University, Cardiff, UK, Tel +44 2922 510663, Email FergusonEL@cardiff.ac.ukIntroduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different ‘subtypes’ in combination with current chemotherapies. We have previously developed dextrin–colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin’s anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin–colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin’s cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic.Results: Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization.Discussion: Whilst clinical translation of dextrin–colistin conjugates for the treatment of AML is unlikely due to the potential to promote antimicrobial resistance (AMR) and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation. Keywords: polymer therapeutics, biodegradable, internalization, polysaccharide, antibiotic

Sai-Hong Ignatius Ou,1 Xiuning Le,2 Misako Nagasaka,1 Thanyanan Reungwetwattana,3 Myung-Ju Ahn,4 Darren WT Lim,5 Edgardo S Santos,6 Elaine Shum,7 Sally CM Lau,7 Jii Bum Lee,8 Antonio Calles,9 Fengying Wu,10 Gilberto Lopes,11 Virote Sriuranpong,12 Junko Tanizaki,13 Hidehito Horinouchi,14 Marina C Garassino,15 Sanjay Popat,16 Benjamin Besse,17 Rafael Rosell,18 Ross A Soo19 1University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA; 2University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 4Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5Duke-NUS School of medicine, National Cancer Center Singapore, Republic of Singapore; 6Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA; 7NYU Langone Perlmutter Cancer Center, NY, NY, USA; 8Yonsei Cancer Center Yonsei University, Seoul, Republic of Korea; 9Department of Medicine, Division of Medical Oncology, Early Drug Development and Phase I Unit, Hospital General Universitario Gregorio Marañón, Madrid, 28007, Spain; 10Shanghai Chest hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 11Department of Medicine, Division of Medical Oncology, Sylvester Comprehensive Cancer Center at the University of Miami and the Miller School of Medicine, Miami, FL, 33136, USA; 12Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 13Department of Medicine, Kindai University School of Medicine, Osaka, Japan; 14Department of Thoracic Oncology, National Cancer Center Hospital Tokyo, Tokyo, Japan; 15Department of Medicine, Division of Medical Oncology-Hematology, University of Chicago Medicine, Chicago, IL, USA; 16Royal Marsden Hospital, London, Imperial College, London, UK; 17Gustave Roussy Cancer Campus, Villejuif, France; Paris-Saclay University, Orsay, France; 18Department of Hematology-Oncology, National University Cancer Institute, National University Hospital Singapore, Republic of Singapore; 19IOR, Quirón-Dexeus University Institute; ICO, Catalan Institute of Oncology; IGTP, Germans Trias i Pujol Research Institute, Barcelona, SpainCorrespondence: Sai-Hong Ignatius Ou, University of California School of Medicine, Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, 200 South Manchester Avenue, Suite 400, Orange, CA, 92868, USA, Tel +1 714-456-5153, Fax +1 714-456-2242, Email Siou@hs.uci.eduAbstract: The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential “cure” in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described “discoveries” of activating EGFR mutations (del19, L858R, exon 20 insertions, and “uncommon” mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered “honorable mention” and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as “syllabus” for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).Keywords: EGFR mutations, expert panel, top 20 papers, 20th anniversary, NSCLC

We cross-match and compare characteristics of galaxy clusters identified in observations from two sky surveys using two completely different techniques. One sample is optically selected from the analysis of 3 years of Dark Energy Survey observations using the redMaPPer cluster detection algorithm. The second is X-ray selected from XMM observations analysed by the XMM Cluster Survey. The samples comprise a total area of 57.4 deg2, bounded by the area of four contiguous XMM survey regions that overlap the DES footprint. We find that the X-ray-selected sample is fully matched with entries in the redMaPPer catalogue, above λ > 20 and within 0.1

The correlation between the broad line region radius and continuum luminosity (R-L relation) of active galactic nuclei (AGNs) is critical for single-epoch mass estimates of supermassive black holes (SMBHs). At z ∼ 1-2, where AGN activity peaks, the R-L relation is constrained by the reverberation mapping (RM) lags of the Mg II line. We present 25 Mg II lags from the Australian Dark Energy Survey RM project based on 6 yr of monitoring. We define quantitative criteria to select good lag measurements and verify their reliability with simulations based on both the damped random walk stochastic model and the rescaled, resampled versions of the observed light curves of local, well-measured AGN. Our sample significantly increases the number of Mg II lags and extends the R-L relation to higher redshifts and luminosities. The relative iron line strength RFe has little impact on the R-L relation. The best-fitting Mg II R-L relation has a slope α = 0.39 ± 0.08 with an intrinsic scatter σrl = 0.15+−000203. The slope is consistent with previous measurements and shallower than the H β R-L relation. The intrinsic scatter of the new R-L relation is substantially smaller than previous studies and comparable to the intrinsic scatter of the H β R-L relation. Our new R-L relation will enable more precise single-epoch mass estimates and SMBH demographic studies at cosmic noon.

We cross-correlate positions of galaxies measured in data from the first three years of the Dark Energy Survey with Compton-y maps generated using data from the South Pole Telescope (SPT) and the Planck mission. We model this cross-correlation measurement together with the galaxy autocorrelation to constrain the distribution of gas in the Universe. We measure the hydrostatic mass bias or, equivalently, the mean halo bias-weighted electron pressure (bh Pe), using large-scale information. We find (bh Pe) to be [0.16+−000403, 0.28+−000504, 0.45+−001006, 0.54+−000708, 0.61+−000608, 0.63+−000807] meV cm−3 at redshifts z ∼ [0.30, 0.46, 0.62, 0.77, 0.89, 0.97]. These values are consistent with previous work where measurements exist in the redshift range. We also constrain the mean gas profile using small-scale information, enabled by the high-resolution of the SPT data. We compare our measurements to different parametrized profiles based on the cosmo-OWLS hydrodynamical simulations. We find that our data are consistent with the simulation that assumes an AGN heating temperature of 108.5 K but are incompatible with the model that assumes an AGN heating temperature of 108.0 K. These comparisons indicate that the data prefer a higher value of electron pressure than the simulations within r500c of the galaxies’ haloes.

Recent cosmological analyses with large-scale structure and weak lensing measurements, usually referred to as 3 × 2pt, had to discard a lot of signal to noise from small scales due to our inability to accurately model non-linearities and baryonic effects. Galaxy–galaxy lensing, or the position–shear correlation between lens and source galaxies, is one of the three two-point correlation functions that are included in such analyses, usually estimated with the mean tangential shear. However, tangential shear measurements at a given angular scale θ or physical scale R carry information from all scales below that, forcing the scale cuts applied in real data to be significantly larger than the scale at which theoretical uncertainties become problematic. Recently, there have been a few independent efforts that aim to mitigate the non-locality of the galaxy–galaxy lensing signal. Here, we perform a comparison of the different methods, including the Y-transformation, the point-mass marginalization methodology, and the annular differential surface density statistic. We do the comparison at the cosmological constraints level in a combined galaxy clustering and galaxy–galaxy lensing analysis. We find that all the estimators yield equivalent cosmological results assuming a simulated Rubin Observatory Legacy Survey of Space and Time (LSST) Year 1 like set-up and also when applied to DES Y3 data. With the LSST Y1 set-up, we find that the mitigation schemes yield ∼1.3 times more constraining S8 results than applying larger scale cuts without using any mitigation scheme.

The polariton-polariton interaction strength is an important parameter for all kinds of applications using the nonlinear properties of polaritons, such as optical switching and single-photon blockade devices. In this paper, we review and compare the results of a series of experiments on polariton-polariton interactions in GaAs/AlxGa1-xAs microcavity polariton structures and present an updated analysis of these experiments. We show that not just the energy shift of the spectral lines but also the results of measurements sensitive to the polariton scattering rate are important for the calibration of the interaction parameter at low excitation density. We find that when adjustments are made to correct for recent understanding of the experiments, the value of the interaction parameter at low density is lower than previous reported, but still significantly higher than theoretically predicted.

We characterize the properties and evolution of bright central galaxies (BCGs) and the surrounding intracluster light (ICL) in galaxy clusters identified in the Dark Energy Survey and Atacama Cosmology Telescope Survey (DES-ACT) overlapping regions, covering the redshift range 0.20 < z < 0.80. Over this redshift range, we measure no change in the ICL’s stellar content (between 50 and 300 kpc) in clusters with log10(M200m,SZ/M☉) >14.4. We also measure the stellar mass–halo mass (SMHM) relation for the BCG+ICL system and find that the slope, β, which characterizes the dependence of M200m,SZ on the BCG+ICL stellar mass, increases with radius. The outskirts are more strongly correlated with the halo than the core, which supports that the BCG+ICL system follows a two-phase growth, where recent growth (z < 2) occurs beyond the BCG’s core. Additionally, we compare our observed SMHM relation results to the IllustrisTNG300-1 cosmological hydrodynamic simulations and find moderate qualitative agreement in the amount of diffuse light. However, the SMHM relation’s slope is steeper in TNG300-1 and the intrinsic scatter is lower, likely from the absence of projection effects in TNG300-1. Additionally, we find that the ICL exhibits a colour gradient such that the outskirts are bluer than the core. Moreover, for the lower halo mass clusters (log10(M200m,SZ/M☉) < 14.59), we detect a modest change in the colour gradient’s slope with lookback time, which combined with the absence of stellar mass growth may suggest that lower mass clusters have been involved in growth via tidal stripping more recently than their higher mass counterparts.

Recent cosmological analyses rely on the ability to accurately sample from high-dimensional posterior distributions. A variety of algorithms have been applied in the field, but justification of the particular sampler choice and settings is often lacking. Here, we investigate three such samplers to motivate and validate the algorithm and settings used for the Dark Energy Survey (DES) analyses of the first 3 yr (Y3) of data from combined measurements of weak lensing and galaxy clustering. We employ the full DES Year 1 likelihood alongside a much faster approximate likelihood, which enables us to assess the outcomes from each sampler choice and demonstrate the robustness of our full results. We find that the ellipsoidal nested sampling algorithm MULTINEST reports inconsistent estimates of the Bayesian evidence and somewhat narrower parameter credible intervals than the sliced nested sampling implemented in POLYCHORD. We compare the findings from MULTINEST and POLYCHORD with parameter inference from the Metropolis–Hastings algorithm, finding good agreement. We determine that POLYCHORD provides a good balance of speed and robustness for posterior and evidence estimation, and recommend different settings for testing purposes and final chains for analyses with DES Y3 data. Our methodology can readily be reproduced to obtain suitable sampler settings for future surveys.

Reverberation mapping measurements have been used to constrain the relationship between the size of the broad-line region and luminosity of active galactic nuclei (AGN). This R-L relation is used to estimate single-epoch virial black hole masses, and has been proposed to use to standardize AGN to determine cosmological distances. We present reverberation measurements made with Hβ from the 6-yr Australian Dark Energy Survey (OzDES) Reverberation Mapping Program. We successfully recover reverberation lags for eight AGN at 0.12 < z < 0.71, probing higher redshifts than the bulk of Hβ measurements made to date. Our fit to the R-L relation has a slope of α = 0.41 ± 0.03 and an intrinsic scatter of σ = 0.23 ± 0.02 dex. The results from our multi-object spectroscopic survey are consistent with previous measurements made by dedicated source-by-source campaigns, and with the observed dependence on accretion rate. Future surveys, including LSST, TiDES, and SDSS-V, which will be revisiting some of our observed fields, will be able to build on the results of our first-generation multi-object reverberation mapping survey.

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e,e′p) cross section in parallel kinematics using a natural titanium target. In this paper, we report the analysis of the dataset obtained in different kinematics for our solid natural titanium target. Data were obtained in a range of missing momentum and missing energy between 15?pm?250 MeV/c and 12?Em?80 MeV, respectively, and using an electron beam energy of 2.2 GeV. We measured the reduced cross section with ∼7% accuracy as a function of both missing momentum and missing energy. Our Monte Carlo simulation, including both a model spectral function and the effects of final-state interactions, satisfactorily reproduces the data.

ABSTRACT: We present a method for mapping variations between probability distribution functions and apply this method within the context of measuring galaxy redshift distributions from imaging survey data. This method, which we name PITPZ for the probability integral transformations it relies on, uses a difference in curves between distribution functions in an ensemble as a transformation to apply to another distribution function, thus transferring the variation in the ensemble to the latter distribution function. This procedure is broadly applicable to the problem of uncertainty propagation. In the context of redshift distributions, for example, the uncertainty contribution due to certain effects can be studied effectively only in simulations, thus necessitating a transfer of variation measured in simulations to the redshift distributions measured from data. We illustrate the use of PITPZ by using the method to propagate photometric calibration uncertainty to redshift distributions of the Dark Energy Survey Year 3 weak lensing source galaxies. For this test case, we find that PITPZ yields a lensing amplitude uncertainty estimate due to photometric calibration error within 1 per cent of the truth, compared to as much as a 30 per cent underestimate when using traditional methods.

Melissa H Roberts,1 David M Mannino,2,3 Douglas W Mapel,4 Orsolya Lunacsek,5 Shahla Amin,5 Eileen Farrelly,5 Norbert Feigler,6 Michael F Pollack6 1College of Pharmacy, University of New Mexico, Albuquerque, NM, USA; 2College of Medicine, University of Kentucky, Lexington, KY, USA; 3COPD Foundation, Miami, FL, USA; 4Northern Arizona Pulmonary Associates, Flagstaff, AZ, USA; 5Global Consulting, Cencora, Conshohocken, PA, USA; 6BioPharmaceuticals, US Medical, AstraZeneca, Wilmington, DE, USACorrespondence: Michael F Pollack, BioPharmaceuticals, Global Medical Evidence, AstraZeneca, Wilmington, DE, USA, Email michael.pollack1@astrazeneca.comPurpose: Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with reduced life expectancy, increased morbidity, mortality, and cost. This study characterized the US COPD burden, including socioeconomic and health-related quality of life (HRQoL) outcomes.Study Design and Methods: In this retrospective, cross-sectional study using nationally representative estimates from Medical Expenditures Survey (MEPS) data (2016– 2019), adults (≥ 18 years) living with and without COPD were identified. Adults living without COPD (control cohort) and with COPD were matched 5:1 on age, sex, geographic region, and entry year. Demographics, clinical characteristics, socioeconomic, and generic HRQoL measures were examined to include a race-stratified analysis of people living with COPD.Results: A total of 4,135 people living with COPD were identified; the matched dataset represented a weighted non-institutionalized population of 11.3 million with and 54.2 million people without COPD. Among people living with COPD, 66.3% had ≥ 1 COPD-related condition; 62.7% had ≥ 1 cardiovascular condition, compared to 33.5% and 50.5% without COPD. More people living with COPD were unemployed (56.2% vs 45.3%), unable to work due to illness/disability (30.1% vs 12.1%), had problems paying bills (16.1% vs 8.8%), reported poorer perceived health (fair/poor: 36.2% vs 14.4%), missed more working days due to illness/injury per year (median, 2.5 days vs 0.0 days), and had limitations in physical functioning (40.1% vs 19.4%) (all P< 0.0001). In race-stratified analyses for people living with COPD, people self-reporting as Black had higher prevalence of cardiovascular-risk conditions, poorer socioeconomic and HRQoL outcomes, and higher healthcare expenses than White or Other races.Conclusion: Adults living with COPD had higher clinical disease burden, lower socioeconomic status, and reduced HRQoL than those without, with greater disparities among Black people living with COPD compared to White and other races. Understanding the characteristics of patients helps address care disparities and access challenges.Keywords: COPD, burden of illness, healthcare cost, race/ethnicity

Dawood Sayed,1 Timothy Ray Deer,2 Jonathan M Hagedorn,3 Asim Sayed,4 Ryan S D’Souza,3 Christopher M Lam,1 Nasir Khatri,5 Zohra Hussaini,1 Scott G Pritzlaff,6 Newaj Mohammad Abdullah,7 Vinicius Tieppo Francio,1 Steven Michael Falowski,8 Yussr M Ibrahim,9 Mark N Malinowski,10 Ryan R Budwany,2 Natalie Holmes Strand,11 Kamil M Sochacki,12 Anuj Shah,13 Tyler M Dunn,11 Morad Nasseri,14 David W Lee,15 Leonardo Kapural,16 Marshall David Bedder,17,18 Erika A Petersen,19 Kasra Amirdelfan,20 Michael E Schatman,21,22 Jay Samuel Grider23 1Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 2Pain Services, Spine and Nerve Center of the Virginias, Charleston, WV, USA; 3Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 4Podiatry/Surgery, Susan B. Allen Memorial Hospital, El Dorado, KS, USA; 5Interventional Pain Medicine, Novant Spine Specialists, Charlotte, NC, USA; 6Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 7Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 8Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 9Pain Medicine, Northern Light Eastern Maine Medical Center, Bangor, ME, USA; 10OhioHealth Neurological Physicians, OhioHealth, Columbus, OH, USA; 11Anesthesiology and Pain Medicine, Mayo Clinic, Phoenix, AZ, USA; 12Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson, New Brunswick, NJ, USA; 13Department of Physical Medicine and Rehabilitation, Detroit Medical Center, Detroit, MI, USA; 14Interventional Pain Medicine / Neurology, Boomerang Healthcare, Walnut Creek, CA, USA; 15Pain Management Specialist, Fullerton Orthopedic, Fullerton, CA, USA; 16Carolinas Pain Institute, Winston Salem, NC, USA; 17Chief of Pain Medicine Service, Augusta VAMC, Augusta, GA, USA; 18Associate Professor and Director, Addiction Medicine Fellowship Program, Department Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA; 19Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 20Director of Clinical Research, Boomerang Healthcare, Walnut Creek, CA, USA; 21Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 22Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 23Anesthesiology, Division of Pain Medicine, University of Kentucky College of Medicine, Lexington, KY, USACorrespondence: Dawood Sayed, Anesthesiology and Pain Medicine, the University of Kansas Medical Center, Kansas City, KS, USA, Tel +1 785-550-5800, Email dsayed@kumc.eduIntroduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN.Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN.Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process.Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria.Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.Keywords: diabetes, painful diabetic neuropathy, neuropathy, spinal cord stimulation, chronic pain, diabetic neuropathy

Ernest Moles,1– 4 David W Chang,1– 3 Friederike M Mansfeld,1– 3 Alastair Duly,1,2 Kathleen Kimpton,1 Amy Logan,1– 4 Christopher B Howard,5 Kristofer J Thurecht,5,6 Maria Kavallaris1– 4 1Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia; 2UNSW Australian Centre for Nanomedicine, Faculty of Engineering, UNSW, Sydney, NSW, 2052, Australia; 3School of Clinical Medicine, Faculty of Medicine & Health, UNSW, Sydney, NSW, 2052, Australia; 4UNSW RNA Institute, Faculty of Science, UNSW, Sydney, NSW, 2052, Australia; 5Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD, 4072, Australia; 6Centre for Advanced Imaging, ARC Training Centre for Innovation in Biomedical Imaging Technologies, University of Queensland, St Lucia, QLD, 4072, AustraliaCorrespondence: Ernest Moles; Maria Kavallaris, Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, 2052, Australia, Email emoles@ccia.org.au; m.kavallaris@ccia.unsw.edu.auIntroduction: Despite improvements in chemotherapy and molecularly targeted therapies, the life expectancy of patients with advanced non-small cell lung cancer (NSCLC) remains less than 1 year. There is thus a major global need to advance new treatment strategies that are more effective for NSCLC. Drug delivery using liposomal particles has shown success at improving the biodistribution and bioavailability of chemotherapy. Nevertheless, liposomal drugs lack selectivity for the cancer cells and have a limited ability to penetrate the tumor site, which severely limits their therapeutic potential. Epidermal growth factor receptor (EGFR) is overexpressed in NSCLC tumors in about 80% of patients, thus representing a promising NSCLC-specific target for redirecting liposome-embedded chemotherapy to the tumor site.Methods: Herein, we investigated the targeting of PEGylated liposomal doxorubicin (Caelyx), a powerful off-the-shelf antitumoral liposomal drug, to EGFR as a therapeutic strategy to improve the specific delivery and intratumoral accumulation of chemotherapy in NSCLC. EGFR-targeting of Caelyx was enabled through its complexing with a polyethylene glycol (PEG)/EGFR bispecific antibody fragment. Tumor targeting and therapeutic potency of our treatment approach were investigated in vitro using a panel of NSCLC cell lines and 3D tumoroid models, and in vivo in a cell line-derived tumor xenograft model.Results: Combining Caelyx with our bispecific antibody generated uniform EGFR-targeted particles with improved binding and cytotoxic efficacy toward NSCLC cells. Effects were exclusive to cancer cells expressing EGFR, and increments in efficacy positively correlated with EGFR density on the cancer cell surface. The approach demonstrated increased penetration within 3D spheroids and was effective at targeting and suppressing the growth of NSCLC tumors in vivo while reducing drug delivery to the heart.Conclusion: EGFR targeting represents a successful approach to enhance the selectivity and therapeutic potency of liposomal chemotherapy toward NSCLC. Keywords: targeted drug delivery, bispecific antibodies, PEGylated liposomal doxorubicin, EGFR targeting, non-small cell lung cancer

Nasrul Wathoni,1 Cecep Suhandi,1 Muhammad Fadhil Ghassani Purnama,1 Annisa Mutmainnah,1 Neng Sani Nurbaniyah,1 Desra Widdy Syafra,1 Khaled M Elamin2 1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, 45363, Indonesia; 2Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973, JapanCorrespondence: Nasrul Wathoni, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, 45363, Indonesia, Tel +62-22-842-888-888, Email nasrul@unpad.ac.idAbstract: Untreated topical infections can become chronic, posing serious health issues. Optimal skin adherence is crucial in addressing such infections. In this context, chitosan and alginate emerge as promising candidates for use as a foundation in the development of topical hydrogels. The aim of this review is to examine the literature on topical hydrogel formulations that use chitosan and alginate as foundations, specifically in the context of topical antibacterial agents. The research methodology involves a literature review by examining articles published in databases such as PubMed, Scopus, ScienceDirect, and Google Scholar. The keywords employed during the research were “Alginate”, “Chitosan”, “Hydrogel”, and “Antibacterial”. Chitosan and alginate serve as bases in topical hydrogels to deliver various active ingredients, particularly antibacterial agents, as indicated by the search results. Both have demonstrated significant antibacterial effectiveness, as evidenced by a reduction in bacterial colony counts and an increase in inhibition zones. This strongly supports the idea that chitosan and alginate could be used together to make topical hydrogels that kill bacteria that work well. In conclusion, chitosan and alginate-based hydrogels show great potential in treating bacterial infections on the skin surface. The incorporation of chitosan and alginate into hydrogel formulations aids in retaining antibacterial agents, allowing for their gradual release over an optimal period. Therefore, hydrogels specifically formulated with chitosan and alginate have the potential to serve as a solution to address challenges in the treatment of topical bacterial infections.Keywords: Alginate, chitosan, hydrogel, topical, antibacterial agent

Aiming Lv,1,2 Bian Ba Zhuo Ma,3 De Qiong,2 Da Wa Zhuo Ma,2 Pu Bu Zhuo Ma,3 Donghua Yao,4 Da Zhen,2 Chunxiu Tang,2 Bian Ba Zhuo Ma,2 Youzhi Lu,2 Long Cai,2 Yutong Zhang,2 Jinyu Yin,2 Tong Ding,2 Lang Ji Qu Zhen,2 Da Wa Cang,5 Meng Wu,5 Yulan Chen,5 Ye Li1 1Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women and Children’s Hospital of Tibet Autonomous Region, Lhasa City, TB, People’s Republic of China; 3Department of Obstetrics and Gynecology, Lhasa People’s Hospital, Lhasa, TB, 850000, People’s Republic of China; 4Department of Obstetrics and Gynecology, Nyingchi People’s Hospital, Nyingchi City, TB, People’s Republic of China; 5Department of Obstetrics and Gynecology, Tibet University Medical School, Lhasa City, TB, People’s Republic of ChinaCorrespondence: Ye Li, Department of Obstetrics and Gynecology, Beijing Hospital, National center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China, No. 1 DaHua Road, Dong Dan, Beijing, 100730, People’s Republic of China, Tel +86 13611118475, Fax +86 10 85136220, Email liyewtfy@126.comPurpose: To explore the effect of coronavirus disease 2019 (COVID-19) infection on neonates in plateau regions.Methods: Cases of newborns born to pregnant women infected with COVID-19 who received prenatal care or treatment at the Women and Children’s Hospital of the Tibet Autonomous Region and the Lhasa People’s Hospital between January 2020 and December 2022 (infected group) and newborns born to healthy pregnant women (non-infected group) who were included by age, underlying disease and length of hospital stay were retrospectively collected. According to the inclusion and exclusion criteria, 381 patients in the infected group and 314 patients in the non-infected group were included in the study.Results: The results of multivariate analysis showed that admission to the neonatal intensive care unit (OR = 3.342, 95% CI = 1.564– 6.764), shortness of breath (OR = 2.853, 95% CI = 1.789– 3.154), irregular breathing (OR = 2.465, 95% CI = 1.879– 4.112) and neonatal jaundice (OR = 2.324, 95% CI = 1.989– 2.445) were the factors influencing the low Apgar scores of neonates in the infected group (all P < 0.05).Conclusion: Neonates born to pregnant women infected with COVID-19 had lower Apgar scores and higher incidences of complications, such as shortness of breath, groaning, irregular breathing and neonatal jaundice, than newborns born to pregnant women not infected with COVID-19.Keywords: COVID-19, pregnant women, newborn

Xue-hua Xu,1,&ast; Jie-rong Cai,2,&ast; Hui-feng Fan,1,&ast; Ting-ting Shi,1 Di-yuan Yang,1 Li Huang,3 Dong-wei Zhang,1 Gen Lu1 1Department of Respiratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Pediatrics, Guangzhou Panyu District Central Hospital, Guangdong, Guangdong, People’s Republic of China; 3Pediatric Intensive Care Unit, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gen Lu, Department of Respiratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China, Tel +86 20 38076135, Fax +86 20 38076626, Email lugen5663330@sina.comPurpose: Plastic bronchitis (PB), a rare complication of respiratory infection characterized by the formation of casts in the tracheobronchial tree, can lead to airway obstruction and severe condition. Adenovirus is one of the common pathogens of PB caused by infection. This study aimed to evaluate the clinical features and risk factors for PB in children with severe adenovirus pneumonia.Methods: A retrospective study of children with severe adenovirus pneumonia with bronchoscopy results at Guangzhou Women and Children’s Hospital between January 2018 and January 2020 was performed. Based on bronchoscopy, we divided children with severe adenovirus pneumonia into two groups: PB and non-PB. Binary logistic regression analysis was used to identify independent risk factors for PB in patients with severe adenovirus pneumonia after univariate analysis.Results: Our study examined 156 patients with severe adenovirus pneumonia with bronchoscopy results in hospital. Among them, 18 developed PB and 138 did not. On multivariate analysis, the independent risk factors of PB in children with severe adenovirus pneumonia were history of allergies (OR 10.147, 95% CI 1.727– 59.612; P=0.010), diminished breath sounds (OR 12.856, 95% CI 3.259– 50.713; P=0.001), and increased proportion of neutrophils (> 70%; OR 8.074, 95% CI 1.991– 32.735; P=0.003).Conclusion: Children with severe adenovirus pneumonia with a history of allergies, diminished breath sounds, and increased the proportion of neutrophils > 70% may show higher risk of PB.Keywords: plastic bronchitis, severe adenovirus pneumonia, risk factors, children

Xue-Jun Dou,1,&ast; Run-Yang Ma,1,&ast; De-Wang Ren,1 Qiang Liu,2 Peng Yan3 1Department of Thoracic Surgery, Aerospace Center Hospital, Beijing, 100049, People’s Republic of China; 2Department of Thoracic Surgery, Peking University International Hospital, Beijing, 102206, People’s Republic of China; 3Department of Respiratory Medicine, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, 100071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Liu, Department of Thoracic Surgery, Peking University International Hospital, Beijing, 102206, People’s Republic of China, Tel +86 15901472799, Email liuqiang8548@163.com Peng Yan, Department of Respiratory Medicine, China Aerospace Science & Industry Corporation 731 hospital, Beijing, 100071, People’s Republic of China, Email yanpeng301@163.comObjective: This study aimed to investigate the effectiveness and tolerability of anlotinib plus PD-1 blockades in patients with previously immunotherapy treated advanced non-small-cell lung cancer (NSCLC).Methods: A total of 67 patients with previously immunotherapy treated advanced NSCLC who received anlotinib plus PD-1 blockades in clinical practice were screened retrospectively. All the PD-1 blockades used in this study were approved in China and consisted of sintilimab, camrelizumab, tislelizumab and pembrolizumab. Effectiveness and safety of anlotinib plus PD-1 blockades were assessed, and all patients were followed up regularly. Clinical significance between response status to previous immune-related treatment regimens and therapeutic outcomes of anlotinib plus PD-1 blockades was further explored.Results: The best overall response among the 67 patients suggested that a partial response was observed in 16 patients, stable disease was noted in 41 patients and progressive disease was found in 10 patients, which yielded an objective response rate of 23.9% (95% CI: 14.3– 35.9%) and a disease control rate of 85.1% (95% CI: 74.3– 92.6%). Prognostic outcomes indicated that the median progression-free survival (PFS) was 6.1 months (95% CI: 2.37– 9.83) and the median overall survival (OS) was 16.5 months (95% CI: 10.73– 22.27). Exploratory analysis highlighted that patients who were intolerant to previous immune-related regimens (17 patients) might have a superior prognosis (median OS: 22.3 months vs 12.5 months, P=0.024). Additionally, adverse reactions with any grades during anlotinib plus PD-1 blockades administration were observed in 62 patients (92.5%), of which 31 patients (46.3%) had ≥grade 3 adverse reactions. Most common adverse reactions were fatigue, hypertension, diarrhea and hepatotoxicity.Conclusion: Anlotinib plus PD-1 blockades demonstrated promising effectiveness and tolerable safety in patients with previously immunotherapy treated advanced NSCLC. Those who were intolerant to previous immune-related regimens might benefit significantly from treatment with anlotinib plus PD-1 blockades. This conclusion should be confirmed in future studies.Keywords: previously immunotherapy treated NSCLC, anlotinib, PD-1 blockades, effectiveness, safety

Vinith Yathindranath,1,2 Nura Safa,1,2 Mateusz Marek Tomczyk,1,3 Vernon Dolinsky,1,3 Donald W Miller1,2 1Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada; 2PrairieNeuro Research Centre, Health Science Centre, Winnipeg, MB, Canada; 3Children’s Hospital Research Institute Manitoba, Health Science Centre, Winnipeg, MB, CanadaCorrespondence: Donald W Miller, Tel +1 204 789 3278, Email donald.miller@umanitoba.caPurpose: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lingering threat to public health has fueled the search for effective therapeutics to treat SARS-CoV-2. This study aimed to develop lipid nanoparticle (LNP) inhibitors of SARS-CoV-2 entry to reduce viral infection in the nose and upper airway.Methods: Two types of LNP formulations were prepared following a microfluidic mixing method. The LNP-Trap consisted of DOPC, DSPC, cholesterol, and DSPE-PEG-COOH modified with various spike protein binding ligands, including ACE2 peptide, recombinant human ACE2 (rhACE2) or monoclonal antibody to spike protein (mAb). The LNP-Trim consisted of ionizing cationic DLin-MC3-DMA, DSPC, cholesterol, and DMG-PEG lipids encapsulating siACE2 or siTMPRSS2. Both formulations were assayed for biocompatibility and cell uptake in airway epithelial cells (Calu-3). Functional assessment of activity was performed using SARS-CoV-2 spike protein binding assays (LNP-Trap), host receptor knockdown (LNP-Trim), and SARS-CoV-2 pseudovirus neutralization assay (LNP-Trap and LNP-Trim). Localization and tissue distribution of fluorescently labeled LNP formulations were assessed in mice following intranasal administration.Results: Both LNP formulations were biocompatible based on cell impedance and MTT cytotoxicity studies in Calu-3 cells at concentrations as high as 1 mg/mL. LNP-Trap formulations were able to bind spike protein and inhibit pseudovirus infection by 90% in Calu-3 cells. LNP-Trim formulations reduced ACE2 and TMPRSS2 at the mRNA (70% reduction) and protein level (50% reduction). The suppression of host targets in Calu-3 cells treated with LNP-Trim resulted in over 90% inhibition of pseudovirus infection. In vivo studies demonstrated substantial retention of LNP-Trap and LNP-Trim in the nasal cavity following nasal administration with minimal systemic exposure.Conclusion: Both LNP-Trap and LNP-Trim formulations were able to safely and effectively inhibit SARS-CoV-2 pseudoviral infection in airway epithelial cells. These studies provide proof-of-principle for a localized treatment approach for SARS-CoV-2 in the upper airway. Keywords: lipid nanoparticles, SARS-CoV-2, antiviral, gene knockdown, intranasal drug delivery

Da-Sol Kim,1,2,&ast; Nam-Gyu Jo,3,&ast; Dong-Won Lee,4,5 Myoung-Hwan Ko,1,2 Jeong-Hwan Seo,1,2 Gi-Wook Kim1,2,4 1Department of Physical Medicine & Rehabilitation, Jeonbuk National University Medical School, Jeonju, Republic of Korea; 2Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea; 3Department of Physical Medicine and Rehabilitation, Hansol Convalescence Rehabilitation Hospital, Jeonju, Republic of Korea; 4Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Republic of Korea; 5Department of Polymer Nano Science and Technology, Jeonbuk National University, Jeonju, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Gi-Wook Kim, Department of Physical Medicine & Rehabilitation, Jeonbuk National University Medical School, Geonjiro 20, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea, Tel +82-63-259-3144, Fax +82-10-254-4145, Email k26@jbnu.ac.krPurpose: Peripheral nerve damage lacks an appropriate diagnosis consistent with the patient’s symptoms, despite expensive magnetic resonance imaging or electrodiagnostic assessments, which cause discomfort. Ultrasonography is valuable for diagnosing and treating nerve lesions; however, it is unsuitable for detecting small lesions. Poly(vanillin-oxalate) (PVO) nanoparticles are prepared from vanillin, a phytochemical with antioxidant and anti-inflammatory properties. Previously, PVO nanoparticles were cleaved by H2O2 to release vanillin, exert therapeutic efficacy, and generate CO2 to increase ultrasound contrast. However, the role of PVO nanoparticles in peripheral nerve lesion models is still unknown. Herein, we aimed to determine whether PVO nanoparticles can function as contrast and therapeutic agents for nerve lesions.Methods: To induce sciatic neuritis, rats were administered a perineural injection of carrageenan using a nerve stimulator under ultrasonographic guidance, and PVO nanoparticles were injected perineurally to evaluate ultrasonographic contrast and therapeutic effects. Reverse transcription-quantitative PCR was performed to detect mRNA levels of pro-inflammatory cytokines, ie, tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2.Results: In the rat model of sciatic neuritis, PVO nanoparticles generated CO2 bubbles to increase ultrasonographic contrast, and a single perineural injection of PVO nanoparticles suppressed the expression of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2, reduced the expression of F4/80, and increased the expression of GAP43.Conclusion: The results of the current study suggest that PVO nanoparticles could be developed as ultrasonographic contrast agents and therapeutic agents for nerve lesions.Keywords: neuroinflammation, ultrasonography, contrast media, polymer nanoparticles, hydrogen peroxide

We evaluate the consistency between lensing and clustering based on measurements from Baryon Oscillation Spectroscopic Survey combined with galaxy-galaxy lensing from Dark Energy Survey (DES) Year 3, Hyper Suprime-Cam Subaru Strategic Program (HSC) Year 1, and Kilo-Degree Survey (KiDS)-1000. We find good agreement between these lensing data sets. We model the observations using the Dark Emulator and fit the data at two fixed cosmologies: Planck (S8 = 0.83), and a Lensing cosmology (S8 = 0.76). For a joint analysis limited to large scales, we find that both cosmologies provide an acceptable fit to the data. Full utilization of the higher signal-to-noise small-scale measurements is hindered by uncertainty in the impact of baryon feedback and assembly bias, which we account for with a reasoned theoretical error budget. We incorporate a systematic inconsistency parameter for each redshift bin, A, that decouples the lensing and clustering. With a wide range of scales, we find different results for the consistency between the two cosmologies. Limiting the analysis to the bins for which the impact of the lens sample selection is expected to be minimal, for the Lensing cosmology, the measurements are consistent with A = 1; A = 0.91 ± 0.04 (A = 0.97 ± 0.06) using DES+KiDS (HSC). For the Planck case, we find a discrepancy: A = 0.79 ± 0.03 (A = 0.84 ± 0.05) using DES+KiDS (HSC). We demonstrate that a kinematic Sunyaev-Zeldovich-based estimate for baryonic effects alleviates some of the discrepancy in the Planck cosmology. This analysis demonstrates the statistical power of small-scale measurements; however, caution is still warranted given modelling uncertainties and foreground sample selection effects.