bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pharmacokinetics of TNP‐470, a New Angiogenesis Inhibitor
Authors: Figg William D. , Pluda James M. , Lush Richard M. , Saville M. Wayne , Wyvill Kathy , Reed Eddie , Yarchoan Robert 
Published: October 2023

Study Objective. To characterize the pharmacokinetic profile of TNP‐470, a synthetic analog of fumagillin that is a potent inhibitor of angiogenesis and inhibits neovascularization in several solid tumor models.Design. A dose‐escalation phase I clinical trial.Setting. The National Institutes of Health.Patients. Patients with human immunodeficiency virus‐associated Kaposi's sarcoma.Interventions. The TNP‐470 dosage was increased in 13 sequential cohorts using a modified Fibonacci escalation scheme (4.6, 9.3, 15.4, 23.2, and 43.1 mg/m2). The drug was administered as a 1‐hour intravenous infusion. Serial blood samples were collected and assayed by reverse‐phase high‐performance liquid chromatography and the pharmacokinetics were characterized.Measurements and Main Results. There was a linear relationship between the dose of TNP‐470 and both area under the curve to infinity (AUC[inf]) and time to maximum concentration (Cmax). The Cmax ranged between 6.6 ng/ml at the lowest dosage (4.6 mg/m2) and 597.1 ng/ml at the highest dosage (43.1 mg/m2). The agent was rapidly cleared from the circulation with a short terminal half‐life (0.88 ± 2.5 hr), which is consistent with preclinical data. Peak plasma concentrations of AGM‐1883, an active metabolite, ranged between 0.4 and 158.1 ng/ml.Conclusion. Concentrations of TNP‐470 that have in vitro activity were achievable in vivo. The drug was rapidly cleared from the circulation after a single 1‐hour infusion. There was considerable interpatient variability in the clearance, but no evidence of saturable elimination. If more prolonged exposure is necessary for activity, administration of TNP‐470 by continuous infusion may be suitable.
Food Interaction and Steady‐State Pharmacokinetics of Itraconazole Oral Solution in Healthy Volunteers
Authors: Barone Joseph A. , Moskovitz Bruce L. , Guarnieri Joseph , Hassell Alan E. , Colaizzi John L. , Bierman Robert H. , Jessen Lois 
Published: October 2023

Study Objectives. To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) solution under multiple‐dose to steady‐state conditions, and to determine the pharmacokinetics of ITR solution at steady state.Design. Open‐label, randomized, multiple‐dose, crossover study.Setting. University‐affiliated health center.Patients. Thirty healthy men randomized to one of two treatment sequences (fasted‐fed, fed‐fasted).Interventions. Subjects were either fasted or fed a standard breakfast before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases were separated by a 4‐week washout period.Measurements and Main Results. On day 1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were analyzed by high‐performance liquid chromatography for ITR and its major metabolite hydroxyitraconazole (OH‐ITR). Urine was collected on days 1 and 15 before and 0–8 and 8–24 hours after the dose; HP‐β‐CD was measured by size‐exclusion chromatography. Mean bioavailabilities of ITR and OH‐ITR were 43% and 38% higher, respectively, when ITR solution was taken as a single dose under fasted conditions. With multiple dosing, steady state was achieved by day 14. At steady state, mean bioavailabilities were 29% and 17% higher, respectively, in the fasted state; terminal half‐life was similar under fasted and fed conditions (mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH‐ITR, respectively). HP‐β‐CD was eliminated almost exclusively in urine.Conclusion. The bioavailability of ITR and OH‐ITR is enhanced when ITR oral solution is given in the fasted state; this was true for both single and multiple dosing to steady state.
Oral Amiodarone: Historical Overview and Development
Authors: Pollak P. Timothy 
Published: October 2023

Objectives. To review the historical development of amiodarone and the changing perceptions of the drug, and discuss its electrophysiologic, pharmacologic, and pharmacokinetic properties.Methods. Review of relevant literature.Results. In the 1970s and 1980s a plethora of new antiarrhythmic agents, including amiodarone, was introduced. Amiodarone is predominately a class III antiarrhythmic, but also possesses class I, II, and IV effects. By 1977 it was described as the ideal antiarrhythmic agent. However, clinicians underestimated potential difficulties caused by misunderstanding its variable absorption, slow initial response at nonloading dosages, and extended half‐life. Elevated dosages also produced frequent adverse effects. Thus, early enthusiasm for the drug's efficacy was gradually replaced by a focus on its toxicity. The 1990s witnessed reacceptance of the agent as more logical initial regimens and lower maintenance dosages decreased adverse effects, and amiodarone emerged as one of the few drugs effective in suppressing and preventing arrhythmias that does not increase mortality. Remaining challenges include delineation of an optimal oral regimen, identification of markers useful in clinical monitoring, and elucidation of the relationship between dose‐tissue concentration and response and dose‐toxicity associations.Conclusion. Amiodarone is an increasingly valuable component of today's antiarrhythmic therapy.
Rationale, Development, and Clinical Outcomes of a Multidisciplinary Amiodarone Clinic
Authors: Sanoski Cynthia A. , Schoen Marieke D. , Gonzalez Rose C. , Avitall Boaz , Bauman Jerry L. 
Published: October 2023

Objectives. To review the rationale and development of a multidisciplinary amiodarone clinic, and document the clinical outcomes resulting from its implementation.Methods. A clinic was established to provide an ambulatory setting in which patients receiving amiodarone could be followed according to published guidelines by a multidisciplinary team of cardiovascular health care specialists. Patients receiving amiodarone were referred to the clinic by their primary physicians. A data base containing each patient's medical history, current drug therapy, and baseline laboratory values was developed during the initial visit. Liver function tests, thyroid function tests, and chest radiographs were performed every 6 months, and pulmonary function tests were scheduled on an annual basis. Dosage adjustments were performed in select patients.Results. Since November 1996, 60 patients have been referred to the amiodarone clinic. Mean length of follow‐up before and after referral was 16.3 ± 25.5 and 9.2 ± 5.5 months, respectively. Laboratory tests were performed according to accepted guidelines in 14 (23%) patients before referral compared with 54 (90%) patients after enrollment (p<0.001). Previously unrecognized adverse events were detected in 21 (35%) patients, including pulmonary fibrosis, QT prolongation, liver enzyme elevation, hypothyroidism, hyperthyroidism, and asthma exacerbation. Amiodarone was discontinued in six patients, four of whom had suspected pulmonary toxicity. The dose of amiodarone was adjusted in 29 (48.4%) patients.Conclusion. Many patients receiving amiodarone are not being followed according to published recommendations. Implementation of a specialized, multidisciplinary amiodarone clinic improves outcomes by monitoring for early detection of drug‐related toxicities and by facilitating proper dosage modifications.
The impact of IFRS 9 on the cyclicality of loan loss provisions
Authors: Hansen Smilla , Charifzadeh Michel , Herberger Tim A. 
Published: October 2023

AbstractThrough their procyclical behavior, loan loss provisions have been determined as one of the factors that contribute to financial instability during a crisis. IFRS 9 was introduced in 2018 with an expected credit loss model replacing the incurred loss model of IAS 39 to mitigate the effect in the future. Our study aims to analyze loan loss provisions of major banks in the Eurozone to determine for the first time if the implementation of IFRS 9, as intended by regulators, has a dampening effect on procyclicality, especially during the stressed situation under COVID‐19. We analyze 51 banks from 12 countries of the European Monetary Union using 2856 firm‐year observations. While no robust evidence of less procyclicality can be found after the implementation of IFRS 9 until the pandemic, we find evidence that loan loss provisions moved countercyclical during 2020, indicating an alleviating effect at the beginning of the exogenous shock.
Diagnostic certainty during in‐person and telehealth autism evaluations
Authors: Ludwig Natasha N. , Holingue Calliope , Hong Ji Su , Kalb Luther G. , Pfeiffer Danika , Reetzke Rachel , Menon Deepa , Landa Rebecca 
Published: October 2023

AbstractBackgroundMany diagnostic evaluations abruptly shifted to telehealth during the COVID‐19 pandemic; however, little is known about the impact on diagnosis patterns for children evaluated for autism spectrum disorder (ASD). The purpose of this clinical research study was to examine (1) the frequency of diagnoses evaluated beyond ASD; (2) the frequency of diagnoses made, including ASD; and (3) clinician diagnostic certainty for all diagnoses evaluated for children who received an evaluation due to primary concerns about ASD via telehealth during the pandemic compared to those evaluated in person before the pandemic at an ASD specialty clinic.MethodsThe sample included 2192 children, 1–17 years (M = 6.5 years; SD = 3.9), evaluated by a physician/psychologist at an ASD specialty center. A total of 649 children were evaluated in‐person September 1, 2019–March 13, 2020 (pre‐pandemic) and 1543 were evaluated via telehealth March 14, 2020–July 26, 2021 (during pandemic). Upon completion of each evaluation, clinicians provided a final diagnostic determination (i.e., “Yes,” “No,” “Possible,” or “Not Assessed”) for the following DSM‐5 conditions: ASD, attention‐deficit/hyperactivity disorder (ADHD), intellectual developmental disorder (IDD), anxiety (ANX), depression (DEP), and behavioral disorder (BD). “Possible” indicated lower certainty and the diagnosis was not provided. “Not Assessed” indicated the disorder was not evaluated.ResultsDiagnostic certainty for ASD and ADHD was lower and clinicians evaluated for and made diagnoses of IDD less often during evaluations that occurred via telehealth during the pandemic versus in person before the pandemic. DEP and BD were diagnosed more frequently, diagnostic certainty of DEP was lower, and no differences in the frequency of ANX diagnoses emerged during evaluations conducted via telehealth during the pandemic compared to those conducted in person before the pandemic.ConclusionsDifferences emerged in the frequency of diagnoses evaluated and made and diagnostic certainty for evaluations conducted via telehealth during the pandemic compared to in person before the pandemic, which likely impacted patients and reflect real‐word challenges. Future work should examine whether these patterns are generalizable and the mechanisms that contribute to these differences.
Investigating the prognostic role of lncRNAs associated with disulfidptosis‐related genes in clear cell renal cell carcinoma
Authors: Sun Zhou , Wang Jie , Fan Zheqi , Yang Yongjin , Meng Xiangdi , Ma Zhaosen , Niu Jiqiang , Guo Rui , Tran Lisa Jia , Zhang Jing , Jiang Tianxiao , Liu Yunfei , Yang Qiwei , Ma Baoluo 
Published: October 2023

AbstractIntroductionRenal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC).MethodsThree sets of ccRCC cohorts, ICGC_RECA‐EU (n = 91), GSE76207 (n = 32) and TCGA‐KIRC (n = 607), were included in our study, the batch effect of which was removed using the “combat” function. Correlation was calculated using the “rcorr” function of the “Hmisc” package for Pearson analysis, which was visualized using the “pheatmap” package. Principal component analysis was performed by the “vegan” package, visualized using the “scatterplot3d” package. Long non‐coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups.ResultsA total of 1822 disulfidptosis‐related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis‐related lncRNAs, namely, AP000439.3, RP11‐417E7.1, RP11‐119D9.1, LINC01510, SNHG3, AC156455.1, RP11‐291B21.2, EMX2OS, AC093850.2, HAGLR and RP11‐389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy.ConclusionWe developed a prognosis predicting model based on 11 selected disulfidptosis‐related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.
A non‐canonical role of endothelin converting enzyme 1 (ECE1) in promoting lung cancer development via directly targeting protein kinase B (AKT)
Authors: Chen Li , Lu Yikai , Zhao Mengmeng , Xu Junfang , Wang Yan , Xu Qinghua , Cao Yajuan , Liu Haipeng 
Published: October 2023

AbstractBackgroundLung cancer is the second most common malignancy in the world, and lung adenocarcinoma (LUAD) in particular is the leading cause of cancer death worldwide. Endothelin converting enzyme 1 (ECE1) is a membrane‐bound metalloprotease involved in endothelin‐1 (ET‐1) processing and regulates vasoconstriction. However, very few studies have reported the involvement of ECE1 in regulating tumor cell proliferation, and the mechanism remains poorly understood. Therefore, we aimed to determine the role of ECE1 in lung cancer development.MethodsThe Cancer Genome Atlas database and Kaplan–Meier plotter were used to assess the association between ECE1 and lung cancer. The expression of ECE1 was detected using immunohistochemistry staining and western blotting. A variety of in vitro assays were performed to evaluate the effects of ECE1 on the colony formation, proliferation, migration and invasion using ECE1 knockdown lung cancer cells. The gene expression profiles regulated by ECE1 were investigated by RNA sequencing. An immunoprecipitation assay and immunofluorescence assay were used to evaluate the mechanism underlying the regulatory effect of ECE1 on protein kinase B (AKT). The effect of ECE1 on tumor development was assessed by xenografted lung cancer cells in either C57BL/6 mice or nude mice.ResultsECE1 was upregulated in LUAD and correlated with the poor prognosis of patients with LUAD. Functional studies showed that knockdown of ECE1 retarded the progression of tumors formed by lung cancer cells at least partly by inhibiting tumor cell proliferation. Moreover, ECE1 accelerated tumor cell proliferation through promoting AKT activation dispensable of its canonical target ET‐1. Mechanically, ECE1 interacted with the pleckstrin homology (PH) domain of AKT and facilitated its translocation to the plasma membrane for activation. Furthermore, the inhibition of AKT activity counteracted the lung cancer cell growth inhibition observed both in vitro and in xenografts caused by ECE1 suppression.ConclusionsThe present study reveals a non‐canonical function of ECE1 in regulating AKT activation and cell proliferation, which provides the basis for the development of a novel strategy for the intervention of cancer including LUAD by abrogating ECE1‐AKT signaling.
Hardware Implementation of Ultra‐Fast Obstacle Avoidance Based on a Single Photonic Spiking Neuron
Authors: Gao Shuang , Xiang Shuiying , Song Ziwei , Han Yanan , Zhang Yuna , Guo Xingxing , Zhang Yahui , Hao Yue 
Published: October 2023

AbstractVisual obstacle avoidance is widely applied to unmanned aerial vehicles (UAVs) and mobile robot fields. A simple system architecture, low power consumption, optimized processing, and real‐time performance are extremely needed due to the limited payload of some mini UAVs. To address these issues, an obstacle avoidance system harnessing the rate encoding features of a photonic spiking neuron based on a Fabry–Pérot (FP) laser is proposed, which simulates the monocular vision. Here, time to collision is used to describe the distance of obstacles. The experimental results show that the FP laser excites ultra‐fast spike responses in real time for the following cases, facilitating the generation of control commands by motor neurons to realize accurate decision‐making. Four cases of mobile obstacle avoidance scenarios, including “Constant velocity approach”, “Approach and retreat”, “The motion state involving stays”, and “Approach with different velocities”, and obstacle avoidance problems with multiple stationary obstacles appearing simultaneously are experimentally analyzed. The system exhibits a spike response rate of up to 5 GHz. This work proves the feasibility of applying the ultra‐fast photonic obstacle avoidance system to UAVs and other fields in the future and highlights the potential of photonic neuromorphic processor platforms.
Asymptotic expected T$T$‐functionals of random polytopes with applications to Lp$L_p$ surface areas
Authors: Hoehner Steven , Li Ben , Roysdon Michael , Thäle Christoph 
Published: October 2023

AbstractAn asymptotic formula is proved for the expected ‐functional of the convex hull of independent and identically distributed random points sampled from the Euclidean unit sphere in according to an arbitrary positive continuous density. As an application, the approximation of the sphere by random polytopes in terms of surface area differences is discussed.
A prospect theory extension of data envelopment analysis model for wave‐wind energy site selection in New Zealand
Authors: Wang Chia‐Nan , Nguyen Hoang‐Kha , Nhieu Nhat‐Luong , Hsu Hsien‐Pin 
Published: October 2023

AbstractRenewable energy sources have been utilized by countries worldwide, but offshore energy exploitation projects remain highly promising for both the world and New Zealand specifically. The selection of equipment installation locations can be challenging and requires significant investment, prompting the need for optimization in offshore energy exploitation. Wind and wave location (WWL) integrated sites offer a highly potential solution for reducing installation costs and enhancing efficiency in renewable energy exploitation. However, the decision‐making process for selecting equipment locations is crucial and directly affects the outcome. This study aims to evaluate and consider sustainable and effective equipment installation sites based on both quantitative indicators and behavioral psychology of decision making. To achieve this goal, the study utilizes the prospect theory Data Envelopment Analysis (PT‐DEA) model, which builds on PT to analyze and evaluate the effectiveness of offshore installation site selection with consideration for human psychology. By combining the results of quantitative indicators and decision‐making behavior, the study identifies sustainable and effective offshore installation sites, recommending appropriate equipment installation locations WWL. The study is also compared and referenced with relevant plans, projects, and development policies in New Zealand for confirmation.
Robust stochastic optimization of needle configurations for robotic HDR prostate brachytherapy
Authors: Gerlach Stefan , Siebert Frank‐André , Schlaefer Alexander 
Published: October 2023

AbstractBackgroundIdeally, inverse planning for HDR brachytherapy (BT) should include the pose of the needles which define the trajectory of the source. This would be particularly interesting when considering the additional freedom and accuracy in needle pose which robotic needle placement enables. However, needle insertion typically leads to tissue deformation, resulting in uncertainty regarding the actual pose of the needles with respect to the tissue.PurposeTo efficiently address uncertainty during inverse planning for HDR BT in order to robustly optimize the pose of the needles before insertion, that is, to facilitate path planning for robotic needle placement.MethodsWe use a form of stochastic linear programming to model the inverse treatment planning problem. To account for uncertainty, we consider random tissue displacements at the needle tip to simulate tissue deformation. Conventionally for stochastic linear programming, each simulated deformation is reflected by an addition to the linear programming problem which increases problem size and computational complexity substantially and leads to impractical runtime. We propose two efficient approaches for stochastic linear programming. First, we consider averaging dose coefficients to reduce the problem size. Second, we study weighting of the slack variables of an adjusted linear problem to approximate the full stochastic linear program. We compare different approaches to optimize the needle configurations and evaluate their robustness with respect to different amounts of tissue deformation.ResultsOur results illustrate that stochastic planning can improve the robustness of the treatment with respect to deformation. The proposed approaches approximating stochastic linear programming better conform to the tissue deformation compared to conventional linear programming. They show good correlation with the plans computed after deformation while reducing the runtime by two orders of magnitude compared to the complete stochastic linear program. Robust optimization of needle configurations takes on average 59.42 s. Skew needle configurations lead to mean coverage improvements compared to parallel needles from 0.39 to 2.94 percentage points, when 8 mm tissue deformation is considered. Considering tissue deformations from 4 to 10 mm during planning with weighted stochastic optimization and skew needles generally results in improved mean coverage from 1.77 to 4.21 percentage points.ConclusionsWe show that efficient stochastic optimization allows selecting needle configurations which are more robust with respect to potentially negative effects of target deformation and displacement on the achievable prescription dose coverage. The approach facilitates robust path planning for robotic needle placement.