US System Research Articles

Intersystem and Interoperator Agreement of US Attenuation Coefficient for Quantifying Liver Steatosis.

Background The extent of liver steatosis can be assessed using US attenuation coefficient (AC) algorithms currently implemented in several US systems. However, little is known about intersystem and interoperator variability in measurements. Purpose To assess intersystem and interoperator agreement in US AC measurements for fat quantification in individuals with varying degrees of liver steatosis and to assess the correlation of each manufacturer's AC algorithm results with MRI proton density fat fraction (PDFF). Materials and Methods This prospective study was conducted at Southwoods Imaging, Youngstown, Ohio, September 30-October 1, 2023. Two operators independently obtained AC measurements using eight US systems equipped with an AC algorithm from different manufacturers. On the same day, MRI PDFF measurement was performed by a different operator. Correlation between US AC and MRI PDFF was assessed using a mixed-effects model. Agreement between systems and operators was evaluated using the intraclass correlation coefficient (ICC). Results Twenty-six individuals (mean age, 55.4 years ± 10.7 [SD]; 16 female participants) were evaluated. The correlation of US AC with MRI PDFF was high for five AC algorithms (r range, 0.70-0.86), moderate for two (r = 0.62 for both), and poor for one (r = 0.47). In pairwise comparisons, none of the pairs of systems achieved excellent agreement (overall ICC = 0.33 [95% CI: 0.15, 0.52]). One pair showed good agreement (ICC = 0.79 [95% CI: 0.66, 0.87]), eight pairs showed moderate agreement (ICC range, 0.50 [95% CI: 0.22, 0.69] to 0.73 [95% CI: 0.49, 0.85]), and 19 pairs showed poor agreement (ICC range, 0.11 [95% CI: -0.06, 0.37] to 0.48 [95% CI: 0.20, 0.67]). Interoperator agreement on AC value was excellent for the Samsung Medison algorithm (ICC = 0.90 [95% CI: 0.80, 0.96]), good for the Siemens Healthineers (ICC = 0.76 [95% CI: 0.54, 0.89]) and Canon Medical Systems (ICC = 0.76 [95% CI: 0.16, 0.92]) algorithms, and moderate for the remaining algorithms (ICC range, 0.50 [95% CI: 0.16, 0.73] to 0.74 [95% CI: 0.51, 0.88]). The mean AC value obtained by the two operators did not differ for any system except the system from Canon Medical Systems. Conclusion There was substantial variability in AC values obtained with different US systems, precluding interchangeability between systems for liver steatosis diagnosis and follow-up imaging. Interoperator agreement ranged from moderate to excellent. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Han in this issue.

Differences Between the Chinese and American Higher Education Systems and Implications

Despite receiving considerable global attention, the higher education systems of China and the United States exhibit disparities and complementarities that highlight ongoing deficiencies in educational reform and development. This paper holds a comparative analysis of the strengths, weaknesses, and developmental trends within the higher education frameworks of both nations. It reveals that China's system is defined by its uniform policies and stringent teaching methodologies, characterized by fixed curricula and rigorous mechanisms for teacher training and student selection. In contrast, the US system is celebrated for its diversity, flexible policies, innovative teaching approaches, and diverse curricula. It places a strong emphasis on teacher autonomy and the individualization of student assessments. Based on these findings, this study offers a series of recommendations designed to advance the development of higher education in both countries. These include optimizing the admissions and examination systems, reforming educational philosophies, broadening international perspectives, and enhancing the allocation and fairness of educational resources.

Montelukast deprescribing in outpatient specialty clinics: A single center cross-sectional study

ObjectiveTo identify and evaluate montelukast deprescribing in outpatient specialty clinics. MethodsThis was a single-center, retrospective, cross-sectional study conducted at an academic health system in the southern US including 21 specialty clinics. Subjects included adults ≥18 years with an active prescription for montelukast who attended at least one appointment in pulmonology, otolaryngology, or neurology outpatient specialty clinics between January 1, 2021 to December 31, 2022. Patients <18 years and those with diagnoses of uncontrolled asthma or allergic rhinitis were excluded. Outcomes assessed included the frequency and period prevalence of montelukast deprescribing, defined by a documented montelukast discontinuation within the medical record, and evaluation of reasoning for discontinuation mentioned in visit notes. ResultsThere were 1152 patients who met inclusion criteria. Of these, 43 (3.7 %) experienced a montelukast deprescribing event: 18 (41.9 %) in neurology, 13 (30.2 %) in otolaryngology, and 12 (27.9 %) in pulmonology. Documented reasons for deprescribing were only available for 11 patients (25.6 %); reasons for deprescribing included patient-provider shared decision-making regarding the Black Box Warning [n = 5 (11.6 %)], inadequate treatment response [n = 3 (7.0 %)], suicidal thought development [n = 1 (2.3 %)], adverse drug event [n = 1 (2.3 %)], and pregnancy planning [n = 1 (2.3 %)]. ConclusionMontelukast deprescribing rates were less than 5 % in outpatient specialty clinics. Factors associated with montelukast deprescribing beget further investigation.

Reproducibility and Repeatability of US Shear-Wave and Transient Elastography in Nonalcoholic Fatty Liver Disease.

Background US shear-wave elastography (SWE) and vibration-controlled transient elastography (VCTE) enable assessment of liver stiffness, an indicator of fibrosis severity. However, limited reproducibility data restrict their use in clinical trials. Purpose To estimate SWE and VCTE measurement variability in nonalcoholic fatty liver disease (NAFLD) within and across systems to support clinical trial diagnostic enrichment and clinical interpretation of longitudinal liver stiffness. Materials and Methods This prospective, observational, cross-sectional study (March 2021 to November 2021) enrolled adults with NAFLD, stratified according to the Fibrosis-4 (FIB-4) index (≤1.3, >1.3 and <2.67, ≥2.67), at two sites to assess SWE with five US systems and VCTE with one system. Each participant underwent 12 elastography examinations over two separate days within 1 week, with each day's examinations conducted by a different operator. VCTE and SWE measurements were reported in units of meters per second. The primary end point was the different-day, different-operator reproducibility coefficient (RDCDDDO) pooled across systems for SWE and individually for VCTE. Secondary end points included system-specific RDCDDDO, same-day, same-operator repeatability coefficient (RCSDSO), and between-system same-day, same-operator reproducibility coefficient. The planned sample provided 80% power to detect a pooled RDCDDDO of less than 35%, the prespecified performance threshold. Results A total of 40 participants (mean age, 60 years ± 10 [SD]; 24 women) with low (n = 17), intermediate (n = 15), and high (n = 8) FIB-4 scores were enrolled. RDCDDDO was 30.7% (95% upper bound, 34.4%) for SWE and 35.6% (95% upper bound, 43.9%) for VCTE. SWE system-specific RDCDDDO varied from 24.2% to 34.3%. The RCSDSO was 21.0% for SWE (range, 13.9%-35.0%) and 19.6% for VCTE. The SWE between-system same-day, same-operator reproducibility coefficient was 52.7%. Conclusion SWE met the prespecified threshold, RDCDDDO less than 35%, with VCTE having a higher RDCDDDO. SWE variability was higher between different systems. These estimates advance liver US-based noninvasive test qualification by (a) defining expected variability, (b) establishing that serial examination variability is lower when performed with the same system, and (c) informing clinical trial design. ClinicalTrials.gov Identifier NCT04828551 © RSNA, 2024 Supplemental material is available for this article.

Governing new technologies that stop biological time: Preparing for prolonged biopreservation of human organs in transplantation

Time limits on organ viability from retrieval to implantation shape the US system for human organ transplantation. Preclinical research has demonstrated that emerging biopreservation technologies can prolong organ viability, perhaps indefinitely. These technologies could transform transplantation into a scheduled procedure without geographic or time constraints, permitting organ assessment and potential preconditioning of the recipients. However, the safety and efficacy of advanced biopreservation with prolonged storage of vascularized organs followed by reanimation will require new regulatory oversight, as clinicians and transplant centers are not trained in the engineering techniques involved or equipped to assess the manipulated organs. Although the Food and Drug Administration is best situated to provide that process oversight, the agency has until now declined to oversee organ quality and has excluded vascularized organs from the oversight framework of human cells, tissues, and cellular-based and tissue-based products. Integration of advanced biopreservation technologies will require new facilities for organ preservation, storage, and reanimation plus ethical guidance on immediate organ use versus preservation, national allocation, and governance of centralized organ banks. Realization of the long-term benefit of advanced biopreservation requires anticipation of the necessary legal and ethical oversight tools and that process should begin now.

A Product Evaluation of Augmented Reality Equipment Coupled to Diagnostic Medical Sonography: A Potential Equipment and Ergonomic Innovation

Objective: The aim of this product evaluation was to investigate the workflow and occupational health benefits of implementing augmented reality (AR) technology (MediView XR Inc, Cleveland, OH) paired with a portable ultrasound equipment system. Materials and Method: A diverse sample of sonography users was consented and ranged in experience levels. They were asked to complete a video training session, a hands-on demonstration, and remote instruction while using the augmented reality ultrasound (AR US) system. The duration of participants’ tasks was assessed during the use of both AR US and the 2-dimensional ultrasound (2D US) system. Participants’ postures and positions were evaluated using the Rapid Upper Limb Assessment (RULA), which assessed ergonomic risk factors, linked to body position and muscle usage. Participants also completed the System Usability Scale (SUS). Finally, participants were invited to complete a qualitative interview session, regarding the use of the AR US system. Results: A total of 20 participants provided data after using both the AR US and 2D US systems. The assessment data revealed positive SUS scores, which reflected favorably on both the product, education, and the training provided. The time spent on simulated work (20 minutes), with both imaging systems, remained consistent. The Rapid Upper Limb Assessment tool (RULA) scores for the cohort indicated a lower (better) median upper body score when using the AR US system. The cohort also had a statistically significant lower median subscore for the neck, trunk, and legs, compared with 2D US ( p &lt; 0.00). Conclusion: Although larger studies are necessary to validate these findings, this cohort identified several opportunities for integrating the AR US system. Preliminary evidence suggests that an AR US system may offer occupational health benefits, as part of the imaging workflow.

The Roles of Ovarian-Adnexal Reporting and Data System US and Ovarian-Adnexal Reporting and Data System MRI in the Evaluation of Adnexal Lesions.

The Ovarian-Adnexal Reporting and Data System (O-RADS) is an evidence-based clinical support system for ovarian and adnexal lesion assessment in women of average risk. The system has both US and MRI components with separate but complementary lexicons and assessment categories to assign the risk of malignancy. US is an appropriate initial imaging modality, and O-RADS US can accurately help to characterize most adnexal lesions. MRI is a valuable adjunct imaging tool to US, and O-RADS MRI can help to both confirm a benign diagnosis and accurately stratify lesions that are at risk for malignancy. This article will review the O-RADS US and MRI systems, highlight their similarities and differences, and provide an overview of the interplay between the systems. When used together, the O-RADS US and MRI systems can help to accurately diagnose benign lesions, assess the risk of malignancy in lesions suspicious for malignancy, and triage patients for optimal management.

The end of Mexico–US migration as we knew it – or back to the future?

Over the last decade, scholars have declared the collapse of the Mexico–US system of undocumented migration. The H2 visa programme, a regime of managed sojourning is replacing the system of unauthorized cross-border mobility. In fiscal year 2023, the US government issued nearly 370,000 H2 temporary work visas to Mexicans. This temporary migrant labour programme is also bringing back circulation, temporary legal stays, and mostly male cross-border mobility – features that are akin to the old Bracero Program (1942–64). We contend that the restoration of these legal and sociodemographic dynamics undermines critical pillars of the system of undocumented labour mobility, limiting and reorienting the role of social networks, and potentially ending the way Mexico–United States has functioned for the past half century. We use ethnographic, interview and survey data to analyse the expansion of this new regime of highly mediated cross-border mobility, the ascent of the brokerage apparatus, and its effect transforming the social infrastructure of migration. We ask, specifically, how does the H2 temporary migrant labour programme constrain and diminish kin and hometown-based social networks, previously seen as ‘the engine of migration’? How does the shift from migrant networks to a brokerage apparatus impact trust, reciprocity and the development of migratory social capital? How is the new regime changing the experience of migration – substituting risk and adventure for certainty and routinized movement? How does the H2 temporary migrant labour programme revert the locus of social reproduction of the labour force back to sending communities, preempting integration at the destination? We frame the answers to these questions in the emerging migration industry and infrastructures paradigm, which examines to the role of migrant and non-migrant actors in the facilitation, control and overall mediation and structuring of cross-border mobility.

The Mayo Leadership Impact Index Adapted for Matrix Leadership Structures: Initial Validity Evidence.

Physician burnout has reached crisis levels. Supportive leadership is one of the strongest drivers of physician well-being, and monitoring supervisor support is key to developing well-being focused leadership skills. Existing measures of leader support were designed within "direct report" supervision structures limiting their applicability to matrixed leadership reporting structures where direct reports are not the predominant norm. Antecedently, no measure of leadership support is validated specifically for implementation in matrixed leadership structures. Adapt and validate the Mayo Leadership Impact Index (MLII) for settings with matrixed leadership structures. A psychometric validation study utilizing classical test theory and item response theory. A tripartite hospital system in the southwestern US. Physician-respondents to a 2023 cross-sectional survey. After pilot testing, the adapted MLII was examined using a unidimensional graded response model and confirmatory factor analyses. Convergent validity was investigated via correlations with professional fulfillment, perceived autonomy support, self-valuation, and peer connectedness/respect. Divergent validity was tested via correlations with burnout. Of the three candidate revisions of the MLII, the 9-item adaptation was selected for its superior validity/reliability indices. Standardized Cronbach's and Ordinal alpha coefficients were 0.958 and 0.973, respectively. CFA loadings exceeded 0.70 (p < 0.001), and coefficients of variation (R2) exceeded 0.60 for all items. GRM slope parameters indicated "high" to "very high" item discrimination. Items 2, 5, and 8 were the most informative. Positive correlations of the adapted MLII with professional fulfillment, perceived autonomy support, and peer connectedness/respect were observed, supporting convergent validity. Negative correlation with overall burnout supports divergent validity. The findings provide evidence of the adapted MLII's validity, reliability, and appropriateness for implementation within matrixed leadership settings. Prior to this study, no leadership support measure had been validated for use among the growing number of healthcare systems with matrixed leadership reporting structures.

Nitrous oxide fluxes during a winter cover crop season in a Mississippi corn cropping system

Agroecosystems are the largest source of anthropogenic N2O fluxes. While cover crops (CC) offer benefits for soil health, their impacts on greenhouse gas fluxes are inconsistent. In the southeastern US, where intensive agriculture and low CC adoption are prevalent, few studies have investigated CC impact on soil N2O fluxes. Our study explored the effects of CC species and management practices on soil N2O fluxes during the winter CC growing season in Mississippi, which was conducted in a non-tilled corn cropping system with seven CC treatments. We measured in situ soil N2O fluxes, along with soil moisture and temperature, throughout the CC growing season from 2022 to 2023. Surface soil samples were also collected to analyze soil mineral nitrogen (N) content and enzyme activity. Over the study period (a total of 188 days), cumulative N2O fluxes were 0.50–1.03 ​kg N2O–N ha−1, with the lowest values from the annually-rotated Elbon rye treatment and the highest from the annually-rotated Austrian winter pea. Our results show that both CC treatments and sampling time significantly affected soil N2O fluxes. There was a strong positive correlation (r ​= ​0.34, p ​< ​0.05) between N2O fluxes and NO3–N content, which was lowest under continuous rye and rotated-rye treatments (0.31 and 0.34 ​mg ​kg−1 ). The results suggest that Elbon rye effectively reduced soil N2O fluxes during this period by lowering the soil NO3–N content, the primary substrate for denitrification. This study is one of the few studies to examine the impacts of cover crops on soil N2O fluxes in cropping systems in the southeastern US, offering insights into the cover crop effects on soil N2O fluxes during their growing season.

A state-dependent international CAPM for partially integrated markets: Using local and US risk factors

This study investigates the impact of emerging economies' trade levels with the US and exchange rate systems on their interdependency with the US market. We employ a comprehensive approach, analyzing both local factors (such as illiquidity and dividend yield) and US risk factors (including the S&P500 Index, US effective exchange rate, and term spread) to discern various market phases and capture equity returns. Utilizing a State-dependent International CAPM framework, we reveal a common trend among market returns: the reduced informativeness of both US and local variables during transitions from low to high volatility states. Notably, the majority of emerging markets respond to signals from the US equity market during bullish periods. We also highlight the critical role of exchange rate regimes in explaining the sensitivity of emerging markets to US risk factors. While the illiquidity ratio emerges as a significant local risk factor, its informativeness wanes during bear markets. These findings offer valuable insights for asset allocation, diversification, and risk management strategies tailored to the dynamic nature of emerging markets.

Comparing methadone policy and practice in France and the US: Implications for US policy reform

Despite being among the most effective treatments for opioid use disorder, methadone is largely unavailable in the United States, due primarily to federal and other policies that limit its availability and regulate clinical decisions about doses, visit frequency, and drug testing. There is unprecedented momentum to change decades-old US methadone policies. Yet uncertainty remains as to whether reforms will be adopted and how policies will be implemented. France has among the best methadone access and lowest overdose death rates worldwide. 87 % of French people with opioid use disorder receive methadone or buprenorphine, versus an estimated 13-20 % in the US. France's opioid-related overdose rates are far lower than the US. This article compares French and US systems, including current and proposed US policies, and underscores potential implications for US policymakers.In France, methadone can be initiated in specialty addiction settings and hospitals, with subsequent handoff to primary care. Methadone can be dispensed in community pharmacies and filled like other opioids, without requirements for supervised dosing. Decisions about visit frequency, medication doses, and drug testing are governed by clinical best practices and patient-clinician shared decision-making. In the US, methadone for opioid use disorder is regulated unlike any other medication (including methadone for pain) and is governed by strict federal controls, including from law enforcement and healthcare. With few exceptions, methadone for opioid use disorder is only available in Opioid Treatment Programs. US clinicians cannot prescribe methadone for opioid use disorder. Federal rules determine minimum visit frequency, initial dose limits, and other conditions of treatment, which states may further limit.Policies assert strong influence on patient experience, treatment access, and health outcomes. Despite being less restrictive than the US, the French model includes limits designed to avoid or minimize potential harms. French policies have important implications for potential US reforms.

Ultrasound backscatter coefficient for fat quantification is affected by the measurement depth.

It has been reported that the estimate of ultrasound attenuation coefficient (AC) is affected by depth of measurement, with linear decrease of values with depth. It is unknown whether backscatter coefficient (BSC) has similar behavior. This retrospective study was performed with Sequoia US system equipped with ultrasound derived fat fraction (UDFF) algorithm (Siemens Healthineers, Issaquah, WA, USA) that combines BSC with AC. UDFF was obtained positioning upper edge of the region of interest at 1.5,2,3,4,5cm below liver capsule. BSC data were extracted from UDFF offline. A fractional polynomial regression, which selects the best model considering the polynomial development of the variables of interest, was used. Covariates included were age, sex, skin-to-liver-capsule distance, stiffness. Distance was included as linear factor or with a power ranging from -2 to 3, and the best fitting model was chosen according to partial F test. Body mass index (BMI) was not included because of collinearity with skin-to-liver capsule distance. 104 individuals (56 females; age: 57.9 ± 13.0years; BMI: 29.0 ± 6.5kg/m2; skin-to-liver-capsule distance: 2.3 ± 0.7cm; liver stiffness: 7.5 ± 5.5 kiloPascal) were studied. Best fitting model for BSC included a combination of depth as linear factor and square root. BSC showed a decrease of -13.98dB/cm-steradian for each logarithmic increase of 1cm depth (coefficient: -13.98; 95% CI: -21.016; -5.379; p = .001). Skin-to-liver-capsule distance and stiffness also were independent predictors of BSC. The estimation of the BSC in the liver exhibits a depth dependence that significantly affects results. A standardized acquisition protocol is needed to compare results and reliably assess changes over time.

Evaluating economic feasibility of liquid air energy storage systems in US and European markets

Liquid air energy storage is a clean and scalable long-duration energy storage technology capable of delivering multiple gigawatt-hours of storage. The inherent locatability of this technology unlocks nearly universal siting opportunities for grid-scale storage, which were previously unavailable with traditional technologies such as pumped hydro energy storage and compressed air energy storage. While the technical viability of liquid air energy storage has been established, its economic viability has not yet been rigorously assessed across diverse electricity markets. In this work, a mixed-integer linear program was used to conduct a high-level economic analysis of this technology in US and European markets. By simultaneously optimizing the design and operation of liquid air energy storage systems to maximize their net present value, a yes/no indication of their economic viability can be obtained. Using this approach, the economic viability of this technology was established for the West load zone of Texas through identification of a system with an optimal net present value of $10.4 million and a levelized cost of storage of $119/MWh. Sensitivity analyses were also performed to elucidate how improved technical performance and economic incentives might affect the economic feasibility and, consequently, the adoption of this technology more broadly in the future.

Current honey bee stressor investigations and mitigation methods in the United States and Canada.

Honey bees are the most important managed insect pollinators in the US and Canadian crop systems. However, the annual mortality of colonies in the past 15 years has been consistently higher than historical records. Because they are eusocial generalist pollinators and amenable to management, honey bees provide a unique opportunity to investigate a wide range of questions at molecular, organismal, and ecological scales. Here, the American Association of Professional Apiculturists (AAPA) and the Canadian Association of Professional Apiculturists (CAPA) created 2 collections of articles featuring investigations on micro and macro aspects of honey bee health, sociobiology, and management showcasing new applied research from diverse groups studying honey bees (Apis mellifera) in the United States and Canada. Research presented in this special issue includes examinations of abiotic and biotic stressors of honey bees, and evaluations and introductions of various stress mitigation measures that may be valuable to both scientists and the beekeeping community. These investigations from throughout the United States and Canada showcase the wide breadth of current work done and point out areas that need further research.

Initiating Mental Health Services for Youth Involved in the Juvenile Justice System in Indonesia: Lessons from the US Systems of Care

The children’s mental health service has become an inseparable part of the juvenile justice system in developed countries. The United States has successfully reformed the children’s mental health system by utilizing the systems of care framework, embracing its principles and values in the juvenile’s mental health treatments. In contrary, Indonesia as a developing country is still struggling with finding the directions and determining the mental health services framework to design mental health programs, policies, treatments, and services. The juvenile justice system in this country even has no concept of the importance of providing the mental health services for the juveniles. Therefore, this paper aims to examine and to explain the possible efforts that can be implemented in Indonesia by learning from the systems of care practice in the US related to the juvenile mental health services. [Pelayanan kesehatan mental anak menjadi bagian yang tak terpisahkan dalam sistem peradilan bagi remaja di negara maju. Amerika Serikat telah berhasil mereformasi sistem kesehatan mental anak dengan memanfaatkan kerangka berpikir sistem perawatan (systems of care), menganut prinsip-prinsip dan nilai-nilai yang terkanding di dalamnya dalam perawatan kesehatan mental remaja. Sebaliknya, Indonesia sebagai negara berkembang masih berjuang untuk menemukan arah serta menentukan kerangka berpikir pelayanan kesehatan mental untuk digunakan dalam menyusun program, kebijakan, perawatan, dan pelayanan kesehatan mental. Sistem peradilan bagi remaja di negara ini bahkan tidak menyebutkan konsep tentang pentingnya menyediakan pelayanan kesehatan mental bagi remaja. Oleh karena itu, makalah ini bertujuan untuk membahas dan menjelaskan upaya yang memungkinkan untuk diterapkan di Indonesia dengan belajar dari praktek sistem perawatan di Amerika Serikat terkait dengan layanan kesehatan mental remaja.]

Re-examining the compatibility of US fair use with Korean copyright law: challenges and suggestions for Korean fair use

Abstract Korea introduced the fair use provision into the Korean Copyright Act following the model of the US system. Despite its adoption into the Korean Copyright Act, it has not been significantly relied upon by the courts of Korea. This article asserts that strong and robust fair use is crucial for achieving the objectives of Korean copyright law, which is a cultivating culture through copyright protection and facilitating the fair use of copyrighted works. Particularly important in the digital era, fair use serves as a pivotal tool for adapting the copyright system to rapid technological changes. Taking a legal transplant theory perspective, this paper evaluates the process of transplanting US fair use into Korean copyright law. It contends that the oversight of essential considerations during this process has led to a lack of balance between certainty and flexibility in Korean fair use. Following this analysis, this article offers recommendations to refine Korean fair use within the context of successful legal transplants. These recommendations will cover legislative revision, the roles of the courts and the involvement of legal experts to enhance legal certainty, ensure appropriate flexibility, and ultimately, promote the widespread use of Korean fair use.

Intracellular Pharmacokinetics of Activated Drugs in a Prodrug-Enzyme-Ultrasound System: Evaluations on ZD2767P+CPG2+US.

Intracellular pharmacokinetics (PK) of activated drugs is a window to understanding the pharmacodynamics of prodrug-enzyme-ultrasound therapy. Herein PK of ZD2767D (i.e., activated drug) in the ZD2767P+CPG2+US system on A549, A549/DDP, SKOV3, and SKOV3/DDP cells were evaluated (A549/DDP and SKOV3/DDP were cisplatin-resistant sublines). The noncompartment model under extravascular input mode was deemed appropriate for evaluating drug level vs time curves; Cmax, AUClast, MRTlast, Vz, and Cl can reflect the PK feature, but t1/2, AUCinf, and MRTinf were irrational; higher accumulation and slower elimination characterized the PK mechanism of ZD2767P+CPG2+US; enhanced permeability and retention effect can be assessed with Cmax, AUClast, MRTlast, and tlast; ultrasound equivalently modulated Cmax and AUClast in sensitive and resistant cells. The experimental design and dose proportionality were discussed.

Validity of inpatient electronic health record-based measures of oxygen-related therapy in the United States: Lessons applicable for studying COVID-19 endpoints.

During the COVID-19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID-19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID-19 hospitalization in administrative data versus nursing documentation. We identified 319 553 adult hospitalizations with a COVID-19 diagnosis, February 2020-October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi-structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID-19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. In nursing documentation, the prevalence of MV and O2 supplementation among COVID-19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). In comparison to nursing documentation, administrative data under-ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID-19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID-19 or other respiratory illnesses.

Abstract 68: Imaging Endothelial PD-L1 expression with ultrasound molecular imaging to stratify immune checkpoint inhibitor responders

Abstract Immune checkpoint blockade therapies (ICTs) have revolutionized oncology through substantial and lasting treatment outcomes, but only in 15-20% of patients. Non-invasive diagnostic tools to select patients that are most likely to respond to ICT and guide treatment regimens, and thus minimize toxicities to non-responder patients, are in high demand. Program death-1 ligand (PD-L1) marker evaluation in the tumor vasculature and tumor microenvironment is an essential criterion for identifying a suitable patient for PD-L1 based ICT, and it also serves as a prognostic marker in tumor response evaluation. Ultrasound molecular imaging (USMI) is an up-and-coming non-invasive imaging modality that enables longitudinal characterization of endothelial-specific markers. We are developing USMI methods to image immune markers expressed specifically on endothelial cells (EC) of tumors as a decision-support tool for guiding ICT strategies. In this work, we demonstrate for the first time the potential of imaging EC-specific immunosuppressive markers such as PD-L1 and investigate whether it can act as a marker for predicting ICT response. Target-ready microbubble (MB) was used (Trust Bio-sonics, Taiwan) to generate PD-L1 antibody (Ab) linked MBs (TMBs). DSPE-PEG was functionalized to anti-PD-L1 Ab or isotype-Ab (control) to generate stable TMBs (~5 × 107 MBs/mL) to target PD-L1 expressing ECs in vivo. We studied the treatment effect of anti-PD-L1-Ab and isotype-Ab using a syngeneic CT-26 tumor in mice and demonstrated the targeting potency of TMB or iso-Ab-MB (NMB). US imaging was performed using Vevo 2100 high-frequency US system with M250 transducer to evaluate and quantify the differentially targeted enhancement parameter (dTE). We observed that TMBs bound PD-L1 expressing ECs in vivo, with high and low enhancement for TMB and NMB, respectively, in tumors validated by dTE quantification through characterization of the slower washout kinetics. Furthermore, TMBs exhibited increased tumor retention and prolonged binding with average differential targeted enhancement values (dTE) (+/- SD) of 5.2 ± 7.4 for TMBs compared to 2.4 ± 3.9 for NMBs (p=0.14). Preliminary results of USMI (dTE values of TMBs) indicate that PD-L1-treated mice showed a higher response (4.5 ± 5.2; n=9) to the treatment group than control mice that did not receive Ab (1.4 ± 0.8; n=4). The tumor growth rate for the treated mice group was 5.4 -fold retarded compared to the control group which correlated with USMI dTE values. The USMI signals correlated with IHC performed on tumor tissue ex vivo from the respective mouse used for US imaging. Overall, our pre-clinical study suggests that USMI using TMBs may contribute to non-invasive assessment of IC expression on tumor ECs, and that it may serve as a predictive biomarker of ICT response. This novel TMB agent could be a game changer for CE USMI-based cancer prognosis in ICB therapy. Citation Format: Arutselvan Natarajan, Farbod Tabesh, Mahsa Bataghva, Ramasamy Paulmurugan, Ahmed Nagy El Kaffas. Imaging Endothelial PD-L1 expression with ultrasound molecular imaging to stratify immune checkpoint inhibitor responders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 68.