Phosphate-Based Dechlorination of Electrorefiner Salt Waste using a Phosphoric Acid Precursor.

Electrochemical processing of spent nuclear fuel in molten chloride salts results in radioactive salt waste. Chlorine removal from the salt has been identified as an effective and efficient first step in the management of high-level waste. In this work, a simple salt was dechlorinated with a phosphoric acid phosphate precursor, resulting in a glassy dechlorinated product. The dechlorination efficacy was evaluated in air and argon environments. This work serves as an initial step to advance the Technological Readiness Level of H3PO4-based dechlorination step toward implementation of iron phosphate waste forms to immobilize electrochemical fuel reprocessing salt waste streams.

Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1-95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7- 63.3) against any COVID-19, and 95.3% (80.5-98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Inspired anatomy education: Might God be relevant?

Anatomy education is essential for developing healthcare professionals, and discussion continues about factors that impact and improve the anatomy learning environment. Neglected in this discussion is a consideration of the diverse religious assumptions and beliefs that college students bring to anatomy learning. Surveys of religion among United States college students indicate that many identify as religious and Christian. This viewpoint commentary summarizes main elements of Christian theology and anthropology, discusses the holistic and positive view of the body presented in Christian scripture, and outlines how these Christian beliefs inform and impact student preparation for anatomy education and human body dissection, address ethical issues in body donation, and support professionalism for future career practice.

Nanocavity-Mediated Purcell Enhancement of Er in TiO2 Thin Films Grown via Atomic Layer Deposition.

The use of trivalent erbium (Er3+), typically embedded as an atomic defect in the solid-state, has widespread adoption as a dopant in telecommunication devices and shows promise as a spin-based quantum memory for quantum communication. In particular, its natural telecom C-band optical transition and spin-photon interface make it an ideal candidate for integration into existing optical fiber networks without the need for quantum frequency conversion. However, successful scaling requires a host material with few intrinsic nuclear spins, compatibility with semiconductor foundry processes, and straightforward integration with silicon photonics. Here, we present Er-doped titanium dioxide (TiO2) thin film growth on silicon substrates using a foundry-scalable atomic layer deposition process with a wide range of doping controls over the Er concentration. Even though the as-grown films are amorphous after oxygen annealing, they exhibit relatively large crystalline grains, and the embedded Er ions exhibit the characteristic optical emission spectrum from anatase TiO2. Critically, this growth and annealing process maintains the low surface roughness required for nanophotonic integration. Finally, we interface Er ensembles with high quality factor Si nanophotonic cavities via evanescent coupling and demonstrate a large Purcell enhancement (≈300) of their optical lifetime. Our findings demonstrate a low-temperature, nondestructive, and substrate-independent process for integrating Er-doped materials with silicon photonics. At high doping densities this platform can enable integrated photonic components such as on-chip amplifiers and lasers, while dilute concentrations can realize single ion quantum memories.

Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements.

Theta burst stimulation (TBS) is a noninvasive brain stimulation technique that can be used to modulate neural networks underlying psychiatric and neurological disorders. TBS can be delivered intermittently or continuously. The conventional intermittent TBS protocol is approved by the U.S. Food and Drug Administration to treat otherwise treatment-resistant depression, but the 6-week duration limits the applicability of this therapy. Accelerated TBS protocols present an opportunity to deliver higher pulse doses in shorter periods of time, thus resulting in faster and potentially more clinically effective treatment. However, the acceleration of TBS delivery raises questions regarding the relative safety, efficacy, and durability compared with conventional TBS protocols. In this review paper, we present the data from accelerated TBS trials to date that support the safety and effectiveness of accelerated protocols while acknowledging the need for more durability data. We discuss the stimulation parameters that seem to be important for the efficacy of accelerated TBS protocols and possible avenues for further optimization.

Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Magnon-mediated qubit coupling determined via dissipation measurements.

Controlled interaction between localized and delocalized solid-state spin systems offers a compelling platform for on-chip quantum information processing with quantum spintronics. Hybrid quantum systems (HQSs) of localized nitrogen-vacancy (NV) centers in diamond and delocalized magnon modes in ferrimagnets-systems with naturally commensurate energies-have recently attracted significant attention, especially for interconnecting isolated spin qubits at length-scales far beyond those set by the dipolar coupling. However, despite extensive theoretical efforts, there is a lack of experimental characterization of the magnon-mediated interaction between NV centers, which is necessary to develop such hybrid quantum architectures. Here, we experimentally determine the magnon-mediated NV-NV coupling from the magnon-induced self-energy of NV centers. Our results are quantitatively consistent with a model in which the NV center is coupled to magnons by dipolar interactions. This work provides a versatile tool to characterize HQSs in the absence of strong coupling, informing future efforts to engineer entangled solid-state systems.

Net prices of new antiobesity medications.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP1s) are effective antiobesity drugs and the subject of intense debate around insurance coverage due to the large prevalence of obesity and overweight. The estimation of the budget impact associated with GLP1 insurance coverage requires estimates of GLP1 prices that account for manufacturer discounts. The authors applied a peer-reviewed method to estimate the net prices of GLP1s after manufacturer discounts. METHODS: The authors estimated manufacturer discounts for each product as the difference between the gross sales estimated at list price and manufacturer-reported revenue. From this difference, the authors subtracted discounts to government programs, including 340B, Medicaid, and the Medicare Part D coverage gap, and attributed the remaining amount to manufacturer discounts provided in the commercial market. RESULTS: Manufacturer discounts for GLP1s approved for obesity were estimated at 41%, which translated into net prices of $717 to $761 per month of supply. Manufacturer discounts for GLP1s approved for type 2 diabetes ranged from 54% to 59%, which translated into net prices of $312 to $469 per month of supply. CONCLUSIONS: The magnitude of manufacturer discounts underscores the need to consider net price information in studies that inform private and public payers' decision-making around coverage of GLP1s for obesity.

Medicare drug price negotiation: The complexities of selecting therapeutic alternatives for estimating comparative effectiveness.

Under the 2022 Inflation Reduction Act, the Centers for Medicare and Medicaid Services (CMS) are able to negotiate prices for topselling drugs in the Medicare Part B and D programs. In determining initial price offers, CMS will compare the prices and clinical benefits of the drugs subject to negotiation to the prices and clinical benefits of therapeutic alternatives. Despite the central role that the selection of therapeutic alternatives will play in the price negotiations, the available guidance published by CMS provides few details about how the organization will undertake this process, which will be particularly complex for drugs approved for more than one indication. To better inform the selection process, we identified all US Food and Drug Administration-approved indications for the first 10 drugs subject to negotiation. Using 2020-2021 Medicare claims data, we identified Medicare Part D beneficiaries using each of the 10 drugs. We extracted medical claims with diagnosis codes for each of the approved indications to report the relative treated prevalence of use by indication for each drug. We reviewed published clinical guidelines to identify relevant therapeutic alternatives for each of the indications. We integrated the evidence on the relative treated prevalence of indications and clinical guidelines to propose therapeutic alternatives for each of the 10 drugs. We describe challenges that CMS may face in selecting therapeutic alternatives.

A practical approach for adoption of a hub and spoke model for cell and gene therapies in low- and middle-income countries: framework and case studies.

In the rapidly evolving landscape of biotechnologies, cell and gene therapies are being developed and adopted at an unprecedented pace. However, their access and adoption remain limited, particularly in low- and middle-income countries (LMICs). This study aims to address this critical gap by exploring the potential of applying a hub and spoke model for cell and gene therapy delivery in LMICs. We establish the identity and roles of relevant stakeholders, propose a hub and spoke model for cell and gene therapy delivery, and simulate its application in Brazil and the Middle East and North Africa. The development and simulation of this model were informed by a comprehensive review of academic articles, grey literature, relevant websites, and publicly available data sets. The proposed hub and spoke model is expected to expand availability of and access to cell and gene therapy in LMICs and presents a comprehensive framework for the roles of core stakeholders, laying the groundwork for more equitable access to these lifesaving therapies. More research is needed to explore the practical adoption and implications of this model.

Budget impact of oral nirmatrelvir/ritonavir in adults at high risk for progression to severe COVID-19 in the United States.

BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is indicated for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19. NMV/r has also been authorized for emergency use by the US Food and Drug Administration for the treatment of mild-to-moderate COVID-19 in pediatric patients (aged 226512 years and weighing at least 40 kg) who are at high risk for progression to severe COVID-19. Understanding the budget impact of introducing NMV/r for the treatment of adults with COVID-19 is of key interest to US payers. OBJECTIVE: To estimate the annual budget impact of introducing NMV/r in a US commercial health plan setting in the current Omicron COVID-19 era. METHODS: A budget impact model was developed to assess the impact of NMV/r on health care costs in a hypothetical 1-million-member commercial health insurance plan over a 1-year period in the US population; clinical and cost inputs were derived from published literature with a focus on studies in the recent COVID-19 era that included vaccinated population and predominance of the Omicron variant. In the base-case analysis, it was assumed the only effect of NMV/r was a reduction in incidence (not severity) of hospitalization or death; its potential effect on post-COVID conditions was assessed in a scenario analysis. Outcomes included the number of hospitalizations, total cost, per patient per year (PPPY) costs, and per member per month (PMPM) costs. Sensitivity and scenario analyses were conducted to assess uncertainty around key model inputs. RESULTS: An estimated 29,999 adults were eligible and sought treatment with oral antiviral for COVID-19 over 1 year. The availability of NMV/r was estimated to reduce the number of hospitalizations by 647 with a total budget impact of $2,733,745, $91 PPPY, and $0.23 PMPM. NMV/r was cost saving when including post-COVID conditions with a -$1,510,780 total budget impact, a PPPY cost of -$50, and a PMPM cost of -$0.13. Sensitivity analyses indicated results were most sensitive to the risk of hospitalization under supportive care, risk of hospitalization with NMV/r treatment and cost of NMV/r. CONCLUSIONS: Treatment with NMV/r in the current COVID-19 era is estimated to result in substantial cost offsets because of reductions in hospitalization and modest budget impact to potential overall cost savings.

Using infrared cameras in drones to detect bleeding events.

BACKGROUND: Hemorrhage is one of the main causes of death in trauma. Critical bleeding in patients needs to be detected as soon as possible to save the patient. Drones are gaining increasing importance in emergency services and can support rescue forces in accident scenarios such as a mass casualty incident. METHODS: In this study, a simulated pelvic hemorrhage was detected using a drone from 7 m above the ground over a time span of 30 s. RESULTS: The results allow a good detection of the pelvic hemorrhage. Nevertheless, the simulated blood cools down quickly. After 30 s, there was no significant temperature difference compared to the rest of the body. At this point, further assessment is only possible via the RGB image. CONCLUSION: The findings suggest that bleeding from an open and continuously bleeding wound would most likely be detectable using the drone's thermal imaging camera, even over a longer period of time.

Reimbursement to Pharmacies for Generic Drugs by Medicare Part D Sponsors.

This study evaluates whether organizations that offer Medicare Part D plans (referred to as Part D sponsors) overpay pharmacies for generic drugs.

The effects of dietary amino acid balance on post-embryonic development in a lubber grasshopper.

Effects of dietary protein quality on insect development (not just growth) are unclear. Dietary amino acid blends matching yolk proteins support reproduction and juvenile development in Drosophila melanogaster. We matched amino acids to vitellogenin and tested development of juvenile male lubber grasshoppers, which do not produce vitellogenin. Last instars were fed classic dry diets with amino acids substituted for proteins. Matching amino acids to vitellogenin allowed molting to adulthood, while an unmatched isonitrogenous diet did not. Health on dry diets was poor, so we developed wet diets with agar, horse feed, and amino acids. Juveniles fed these diets matched to vitellogenin developed comparably to juveniles fed lettuce. However, wet diets with amino acids dissimilar to vitellogenin (low-quality) slowed development but maintained size at adulthood. We observed no compensatory feeding on low-quality diets. Theory suggests accumulation of proteins permits development. To detect a threshold, we started last juvenile instars on high-quality diets, then abruptly switched them to low-qualities diets. When switched to the poor-quality diet at 6d, grasshoppers molted at a similar age (∼17d) to grasshoppers continuously on the high-quality diet. Total hemolymph proteins levels were unaffected by the timing of diet switches. Last, methionine is essential but can be noxious at high levels. Diets with low-quality protein except for methionine slowed growth early but did not alter the time or size at molt. Overall, the feeding threshold is solely due to essential amino acids, and low-quality protein diets slowed development but did not affect adult size.

Intervention Nonadherence in the TrACER (S1415CD) Study: A Pragmatic Randomized Trial of a Standardized Order Entry for CSF Prescribing.

PURPOSE: We conducted a pragmatic, cluster-randomized trial to test whether a guideline-based standing order entry (SOE) improves use of primary prophylactic CSF (PP-CSF) prescribing for patients receiving myelosuppressive chemotherapy. We investigated variability in adherence to the intervention. METHODS: We conducted a cluster-randomized trial among 32 oncology clinics from the NCI Community Oncology Research Program. Clinics were randomized 3:1 to a guideline-based PP-CSF SOE or usual care. Among SOE sites, automated orders for PP-CSF were included for regimens at high risk for febrile neutropenia (FN) and an alert not to use PP-CSF for low FN risk. A secondary 1:1 randomization was done among intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for patients receiving intermediate risk-regimens. Providers were allowed to override the SOE. RESULTS: Overall, PP-CSF use among patients receiving high FN risk treatment was high and not different between arms; however, rates of PP-CSF use varied widely by site, ranging from 48.6% to 100%. Among those receiving low FN risk regimens, PP-CSF use was low and not different between arms; however, PP-CSF use ranged from 0% to 19.4% across sites. In the intermediate-risk substudy, PP-CSF was five-fold higher among sites randomized to SOE; however, there was considerable variability in adherence to intervention assignment: PP-CSF use ranged from 0% to 75% among sites randomized to SOE. Despite an alert to not prescribe, PP-CSF prescribing ranged from 0% to 33%. CONCLUSION: In this randomized pragmatic trial aimed at improving PP-CSF prescribing, there was substantial variability in site adherence to the intervention assignment. Although the ability to opt out of the intervention is a feature of pragmatic trials, planning to estimate nonadherence is critical to ensure adequate power.

Drug use and spending under a formulary informed by cost-effectiveness.

BACKGROUND: The National Academy of Medicine has called for value-based drug formularies to address health plan prescription drug spending while maintaining access to high-value medicines. Thirty employer-sponsored plans implemented a "Value-Based Formulary-essentials" (VBF-e) program that uses cost-effectiveness evidence to inform cost-sharing and coverage exclusion. OBJECTIVE: To evaluate if the VBF-e was associated with changes in medication use and patient out-of-pocket spending and health plan spending on prescription drugs and other health care. METHODS: This was a cohort study using a difference-in-differences design from 2015 through 2019 with 1 year of follow-up after VBF-e implementation at Premera Blue Cross, the largest nonprofit health plan in the Pacific Northwest. The VBF-e exposure group was composed of all individuals aged younger than 65 years and enrolled at least 12 months prior to their employer group's VBF-e implementation date. The contemporaneous control group was composed of propensity score-matched individuals with the same inclusion criteria but their employer group that did not implement VBF-e. We prespecified the following outcomes: days of medication on hand overall and by VBF-e tier (high-value generic, brand, and specialty drugs were in tiers 1 to 3, respectively, and low-value drugs were in tier 4 or excluded from coverage); prescription drug spending; and other health care use (emergency department visits, hospital days, and outpatient visits). RESULTS: Comparing 12,111 exposed (mean age = 36.0; 49.8% female sex) participants with 24,222 control participants (mean age = 34.7; 49.6% female sex), VBF-e reduced use of low-value drugs by 0.3 days per member per month (PMPM) (95% CI = -0.5 to -0.1; 17% decrease) for tier 4 drugs and 0.4 days PMPM (95% CI = -0.5 to -0.4; 83% decrease) for excluded drugs. High-value specialty drug use increased by 0.1 days PMPM (95% CI = 0.0-0.1; 123% increase). Health plan spending decreased by $14 PMPM (95% CI = -26 to -4) and member out-of-pocket spending increased by $1 PMPM (95% CI = 1-2). Other health care use did not change significantly. CONCLUSIONS: An exclusion formulary informed by cost-effectiveness evidence reduced low-value drug use, increased high-value specialty drug use, reduced health plan spending, and increased member out-of-pocket spending without increasing acute care use. DISCLOSURES: This research was supported by a grant from the Patrick and Catherine Weldon Donaghue Medical Research Foundation's Greater Value Portfolio Program. Study Registration Number: NCT04904055.

Impact of treatment experience on patient knowledge of colony-stimulating factors among patients receiving cancer chemotherapy: evidence from S1415CD-a large pragmatic trial.

PURPOSE: Primary prophylactic granulocyte colony-stimulating factors (PP-CSFs) are prescribed alongside chemotherapy regimens that carry a significant risk of febrile neutropenia (FN). As part of S1415CD, a prospective, pragmatic trial evaluating the impact of automated orders to improve PP-CSF prescribing, we evaluated patients' baseline knowledge of PP-CSF and whether that knowledge improved following the first cycle of chemotherapy. METHODS: Adult patients with breast, colorectal, or non-small-cell lung cancer initiating chemotherapy were enrolled in S1415CD between January 2016 and April 2020. Eight questions assessing knowledge of CSF indications, risks, benefits, and out-of-pocket costs were included in a baseline survey and in a follow-up survey at the end of the first cycle of chemotherapy. Responses were stratified by the trial arm and whether chemotherapy was low, intermediate, or high FN risk. RESULTS: Of the 3605 eligible patients, 3580 (99.3%) completed the baseline survey, and 3420 (95.5%) completed the follow-up survey. At baseline, 803 (22.4%) patients responded "Don't know" to all 8 questions, and all patients averaged 2.75 correct questions. At follow-up, knowledge increased by 0.34 in the high-FN-risk group (p < 0.001) but declined for the other FN-risk groups. In multivariate analysis, receiving a high-FN-risk regimen and younger age were significantly associated with knowledge improvement. CONCLUSION: Chemotherapy patients had poor knowledge of PP-CSF that improved only modestly among recipients of high-FN-risk chemotherapy. Further efforts to inform patients about the risks, benefits, and costs of PP-CSF may be warranted, particularly for those in whom prophylaxis is indicated. TRIAL REGISTRATION: NCT02728596, April 6, 2016.

Comparing effects and application of telemedicine for different specialties in emergency medicine using the Emergency Talk Application (U-Sim ETA Trial).

Telemedicine as a technology can support processes in the field of emergency medicine (EM) including therapies and diagnostics, but technically is often based on hardware solutions for local EM structures, especially when involving the field of pre-hospital EM. By developing an open-source, data protection compliant solution (EU GDPR and HIPAA) as well as using standardized web and open-source based technology the Emergency Talk Application (ETA) can be used as a technology that can connect emergency medical providers and include already available regional structures. By actively involving patients and connecting these with emergency or urgent care physicians ETA can be used not only as a teleconsultation system for paramedics and physicians, but in a wider network. Randomised simulation trial, comparing EM scenarios from the field of internal medicine, trauma and neurology. Participants were qualified as certified paramedics or emergency physicians (EP). Paramedics performed as ambulances crews and involved an EP if needed via ETA as Tele-Emergency Physicians (TEP). EP participated from a device of their choice, while being able to stay within their clinical workspace. From 141 scenarios 129 used ETA. Significant differences were found for the length of scenarios, duration of time the TEP was on scene, TEP arrival after scenario start, duration until TEP was called and the duration until a diagnosis was made. Also a strong positive and significant correlation between duration of the scenario and the time a TEP was bound could be described. Telemedicine is a technology that is increasingly used in the field of EM. Improving the use of telemedicine by using up-to date technology while allowing an integration of available technical and human resources is a challenge in the field of emergency medicine especially with its regional but also broad medical variety. When using one technical solution, understanding that different cases need a different medical and also telemedical approach can help in the understanding and improving therapies, diagnostics but also the involved processes and solutions. Such results are not only relevant for healthcare providers but especially by law and decision makers as to which type of solution could be introduced in each regional setting.