Radioactive source localization employing resistive electrode array (REA) detector.

Objective.In this feasibility study, we explore an application of a Resistive Electrode Array (REA) for localization of a radioactive point source. The inverse problem posed by multichannel REA detection is studied from mathematical perspective and involves the questions of the minimal configuration of the conductive leads that can achieve this goal. The basic configuration consists of a circularly shaped REA with four opposite electrical lead-pairs at its perimeter.Approach.A robust mathematical reconstruction method for a 3D radioactive source relative to the REA is presented. The characteristic empirical Green's function for the detector response of the REA is determined by numerically solving Laplace equations with appropriate boundary conditions. Based on this model, Monte Carlo simulations of the inverse problem with Gaussian noise are performed and the overall accuracy of the localization is investigated.Main results.The results show a 3D error distribution of localization which is uniform in the (x,y)-plane of the REA and strongly correlated in the orthogonalz-axis. The overall accuracy decreases with higher distance of the source to the detector which is intuitive due to approximate flux dependence following the inverse square law. Further, a saturation in accuracy regarding the number of electrical leads and a linear dependence of the reconstruction error on the measurement noise level are observed.Significance.A broad range of REA detector configurations and their characteristics are investigated by this study for radioactive source localization allowing diverse practical applications with detector diameters ranging from millimeters to meters.

Lessons learned: establishing a CLIA-equivalent laboratory for targeted mass spectrometry assays - navigating the transition from research to clinical practice.

Mass spectrometry (MS) assays offer exceptional capabilities in high multiplexity, specificity, and throughput. As proteomics technologies continue advancements to identify new disease biomarkers, transition of these innovations from research settings to clinical applications becomes imperative. To meet the rigorous regulatory standards of clinical laboratories, development of a clinical protein MS assay necessitates adherence to stringent criteria. To illustrate the process, this project focused on using thyroglobulin (Tg) as a biomarker and an immuno-multiple reaction monitoring (iMRM) MS-based assay as a model for establishing a Clinical Laboratory Improvement Amendments (CLIA) compliant laboratory within the Centers of Genomic and Precision Medicine, National Taiwan University. The chosen example also illustrates the clinical utility of MS assays to complement conventional immunoassay-based methods, particularly in cases where the presence of autoantibodies in 10-30% of patients hinders accuracy. The laboratory design entails a comprehensive coordination in spatial layout, workflow organization, equipment selection, ventilation systems, plumbing, electrical infrastructure, documentation procedures, and communication protocols. Practical aspects of the transformation process, including preparing laboratory facilities, testing environments, instrument validation, assay development and validation, quality management, sample testing, and personnel competency, are discussed. Finally, concordant results in proficiency testing demonstrate the harmonization with the University of Washington Medical Center and the quality assurance of the CLIA-equivalent Tg-iMRM MS assay established in Taiwan. The realization of this model protein MS assay in Taiwan highlights the feasibility of international joint development and provides a detailed reference map to expedite the implementation of more MS-based protein assays in clinical laboratories for patient care.

Engineering Hydroxylase Activity, Selectivity, and Stability for a Scalable Concise Synthesis of a Key Intermediate to Belzutifan.

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.

National Institutes of Health Funding for Tuberculosis Comorbidities Is Disproportionate to Their Epidemiologic Impact.

Tuberculosis (TB) is a leading infectious killer worldwide. We systematically searched the National Institutes of Health Research, Portfolio Online Reporting Tools Expenditures and Results (RePORTER) website to compare research funding for key TB comorbidities-undernutrition, alcohol use, human immunodeficiency virus, tobacco use, and diabetes-and found a large mismatch between the population attributable fraction of these risk factors and the funding allocated to them.

Spillover of Vaccine Hesitancy into Adult COVID-19 and Influenza: The Role of Race, Religion, and Political Affiliation in the United States.

BACKGROUND: Due to its potential to lead to vaccine delays and refusals, vaccine hesitancy has attracted increased attention throughout the COVID-19 pandemic. It is crucial to investigate whether demographic patterns differ between adult general vaccine hesitancy and COVID-19 and flu vaccine non-receipt. METHODS: A cross-sectional survey was conducted online in August 2022. In response to questions about vaccine hesitancy, participants indicated whether they would receive the vaccine given various safety and efficacy profiles. Through logistic regression models, we examined variations between general vaccine hesitancy and COVID-19 non-vaccination. RESULTS: Among the 700 participants, 49% of the respondents were classified as having general vaccine hesitancy, 17% had not received the COVID-19 vaccine, and 36% had not had flu vaccinations. In the multivariable analysis, general vaccine hesitancy and the non-receipt of COVID-19 vaccines were significantly higher in Non-Hispanic Black participants, those with no religious affiliation, and Republicans and Independents. CONCLUSIONS: Patterns of vaccine hesitancy and the non-receipt of the COVID-19 vaccination did not vary, indicating a substantial overlap and potential spillover in vaccine hesitancy over the course of the pandemic. Because changing people's opinions regarding vaccinations is generally a challenge, different interventions specific to demographic subgroups may be necessary.

Demographic Differences in Compliance with COVID-19 Vaccination Timing and Completion Guidelines in the United States.

BACKGROUND: The development of vaccines has been a significant factor in eliminating the pandemic caused by the novel coronavirus (SARS-CoV-2). However, the primary series vaccination rate still falls short of our expectations, with an even lower rate of uptake for booster shots. This study examined demographic patterns of COVID-19 vaccination compliance by assessing patterns in the timing of the vaccine series start and vaccination completion and characterizing people by compliance with vaccination recommendations. METHODS: A cross-sectional survey was conducted online in August 2022. Participants answered questions about the COVID-19 vaccine and questions related to their personal backgrounds. We assessed the impact of demographic factors on COVID-19 vaccination using multivariable regression modeling. RESULTS: Among 700 eligible participants, 61% (389) were highly adherent (i.e., started by late 2020 and received a booster dose), 22% (184) were moderately adherent (i.e., started later than June 2021, and/or did not receive the booster dose), and 17% (127) were unvaccinated. Compliance was relatively low among non-Hispanic Black Americans, those with no religious affiliation, and among Independents and Republicans. CONCLUSION: Vaccination compliance varies across demographic groups. Race/ethnicity, religion, and political affiliation are highly associated with vaccination compliance. To promote vaccination compliance and decrease vaccine hesitancy, the government and healthcare institutions should establish a positive image to obtain public trust and adopt effective vaccine education and intervention.

Resistive electrode array (REA) for radiotherapy beam monitoring and quality assurance.

We have developed a new type of detector array for monitoring of radiation beams in radiotherapy. The detector has parallel-plane architecture with multiple large-area uniform thin-film electrodes. At least one of the electrodes is resistive and has multiple signal readouts spread out along its perimeter. The integral dose deposited in the detector gives rise to multiple signals that depend on the distribution of radiation with respect to resistive electrode array (REA) geometry. The purpose of the present study was to experimentally determine basic detector response to MLC collimated x-ray fields. Two detector arrays have been characterized: circular and rectangular. The current and electrostatic potential distribution within the resistive electrode are governed by the Laplace and continuity equations with boundary conditions at the border with the readouts. Measurements for pencil beams showed that signal strength depends primarily on the distances between the location of the pencil beam and the readouts. Measurements for larger irregular MLC showed that signals as a function of time are quasi-linear with respect to MLC position and are proportional to the MLC area. Derivation of clinically relevant radiation beam parameters from REA signals, such as MLC position, MLC gap size and monitor unit per MLC segment relies on the detector response model with empirical model parameters. An approximate analytical detector response model was proposed and used to fit experiment data.

Changes in Buprenorphine Treatment After Medicaid Expansion.

OBJECTIVE: The authors examined changes in buprenorphine treatment following Medicaid expansion, including the contribution of Medicaid-financed prescriptions. METHODS: Buprenorphine pharmacy claims for patients were identified in the 2012-2018 IQVIA Longitudinal Prescription Data (LRx) data set, including 79.8% of U.S. retail prescriptions in 2012, increasing to 92.0% in 2018. A cohort analysis was used to assess the mean number of patients in a yearly quarter filling one or more buprenorphine prescriptions during preexpansion (2012-2013) and postexpansion (2014-2018) periods in expansion and nonexpansion states. Interrupted time-series analysis estimated associations of Medicaid expansion period with change in Medicaid-financed treatment. Separate analyses evaluated changes in duration and dose of new treatment episodes focused on mean quarterly number of patients treated with buprenorphine and proportions of new treatment episodes ≥180 days long and with ≥16 mg/day. RESULTS: Between preexpansion and postexpansion, the mean quarterly number of patients taking buprenorphine increased by 93,300 in expansion states and by 84,960 in nonexpansion states. Corresponding changes for Medicaid-financed patients were 28,760 and 4,050, respectively. The fastest growth in Medicaid-financed treatment occurred among patients ages 25-44. Among new Medicaid-financed treatment episodes, little change was found in the proportion reaching the 180-day threshold, and declines were observed in the proportion receiving ≥16 mg/day. CONCLUSIONS: The findings are consistent with previous research indicating that Medicaid expansion has increased Medicaid-financed buprenorphine treatment. However, because of offsetting changes in other payment groups, the overall increase in expansion states was similar to the increase in nonexpansion states.

Tie Decay and Dissolution: Contentious Prescribing Practices in the Prescription Drug Epidemic.

Although a substantial body of work has investigated drivers of tie formation, there is growing interest in understanding why relationships decay or dissolve altogether. The networks literature has tended to conceptualize tie decay as driven by processes similar to those underlying tie formation. Yet information that is revealed through ongoing interactions can exert different effects on tie formation and tie decay. This paper investigates how tie decay and tie formation processes differ by focusing on contentious practices. To the extent that information about dissimilarities in contentious practices is learned through ongoing interactions, it can exert diverging effects on tie formation and tie decay. Using a longitudinal data set of 141,543 physician dyads, we find that differences in contentious prescribing led ties to weaken or dissolve altogether but did not affect tie formation. The more contentious the practice and the more information available about the practice, the stronger the effect on tie decay and dissolution. Collectively, these findings contribute to a more nuanced understanding of relationship evolution as an unfolding process through which deeper-level differences are revealed and shape the outcome of the tie.

Buprenorphine Treatment By Primary Care Providers, Psychiatrists, Addiction Specialists, And Others.

Substantial increases in opioid-related morbidity and mortality have motivated the implementation of federal policies to expand the buprenorphine prescribing capacity of primary care providers and other clinicians. Using a national prescription database that covered 72-92 percent of the US population during 2010-18, we analyzed trends in buprenorphine treatment by prescriber specialty. Buprenorphine treatment rates by primary care providers increased from 12.9 people per 10,000 population in 2010 to 27.4 in 2018. The numbers for psychiatrists and addiction medicine specialists increased from 8.7 to 12.0 per 10,000 and those for other prescribers from 5.8 to 16.3 per 10,000. However, treatment of people ages 15-24 by primary care providers and by psychiatrists and addiction medicine specialists declined significantly. Across all patient age and provider groups, most patients were not retained on buprenorphine for the benchmark period of at least 180 days. Despite a recent national increase in buprenorphine treatment fueled primarily by nonspecialists, challenges persist with buprenorphine access-especially for younger people-and with retaining patients in long-term treatment.

Stable recombinant production of codon-scrambled lubricin and mucin in human cells.

Widespread therapeutic and commercial interest in recombinant mucin technology has emerged due to the unique ability of mucin glycoproteins to hydrate, protect, and lubricate biological surfaces. However, recombinant production of the large, highly repetitive domains that are characteristic of mucins remains a challenge in biomanufacturing likely due, at least in part, to the inherent instability of DNA repeats in the cellular genome. To overcome this challenge, we exploit codon redundancy to encode desired mucin polypeptides with minimal nucleotide repetition. The codon-scrambling strategy was applied to generate synonymous genes, or "synDNAs," for two mucins of commercial interest: lubricin and mucin 1. Stable, long-term recombinant production in suspension-adapted human 293-F cells was demonstrated for the synonymous lubricin complementary DNA (cDNA), which we refer to as SynLubricin. Under optimal conditions, a 293-F subpopulation produced recombinant SynLubricin at more than 200 mg/L of media and was stable throughout 2 months of continuous culture. Functionality tests confirmed that the recombinant lubricin could effectively inhibit cell adhesion and lubricate cartilage explants. Together, our work provides a viable workflow for cDNA design and stable mucin production in mammalian host production systems.

Measurement of neosaxitoxin in human plasma using liquid-chromatography tandem mass spectrometry: Proof of concept for a pharmacokinetic application.

Neosaxitoxin, a member of the saxitoxin family of paralytic shellfish poisoning toxins, has shown potential as an effective, long-acting, anesthetic. We describe the development and validation of a highly sensitive method for measurement of neosaxitoxin in human plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS) and provide evidence for its use in a human pharmacokinetic study. Samples were prepared using cation exchange solid phase extraction followed by hydrophilic interaction liquid chromatography and MS/MS detection in positive electrospray ionization mode. Multiple reaction monitoring was used to monitor neosaxitoxin (m/z 316.17>220.07) and the internal standard analogue decarbamoylneosaxitoxin (m/z 273.12>180.00). The method was validated for lower limit of quantification, precision, accuracy, linearity and matrix effect. The stability of neosaxitoxin in plasma matrix at various storage conditions was also investigated. Standard curves for calibration were linear (r>0.995) across the assay calibration range, 10 to 1000pg/mL. The analytical measurable range of the assay was 10-10,000pg/mL in plasma matrix. This method has demonstrated excellent sensitivity demonstrating a lower limit of quantification in human plasma of 10pg/mL. The mean, inter-batch variation was <5.2% across the concentration range 30 to 800pg/mL. This method was successfully used in a phase 1 trial to investigate the pharmacokinetic profile of neosaxitoxin in humans following the intravenous administration of the drug at a range of doses up to 40µg. We conclude that our high-sensitivity method for measurement of neosaxitoxin in human plasma is capable of supporting future clinical trials.