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Michael Bogart,1 Lindsay GS Bengtson,2 Mary G Johnson,2 Scott H Bunner,2 Noelle N Gronroos,2 Kristi K DiRocco3 1US Value Evidence & Outcomes, R&D US, GSK, Research Triangle Park, NC, USA; 2Health Economics and Outcomes Research, Optum, Eden Prairie, MN, USA; 3USA, Medical Affairs, GSK, Collegeville, PA, USACorrespondence: Kristi K DiRocco, US Medical Affairs, GSK, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA, Tel +1 610-412-7175, Email kristi.k.dirocco@gsk.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) have been shown to benefit from triple therapy commonly delivered by multiple-inhaler triple therapy (MITT); however, the complexity of MITT regimens may decrease patient adherence. Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), a once-daily single-inhaler triple therapy (SITT), became available in the United States (US) in 2017, but real-world data comparing outcomes for SITT versus MITT are currently limited. This study compared outcomes among patients with COPD initiating MITT versus SITT with FF/UMEC/VI who were either Medicare Advantage with Part D (MAPD) beneficiaries or commercial enrollees in the US.Methods: Retrospective study using administrative claims data from the Optum Research Database for patients with COPD who initiated FF/UMEC/VI or MITT between September 1, 2017, and March 31, 2019 (index date: first pharmacy claim for FF/UMEC/VI cohort; earliest day of ≥ 30 consecutive days-long period of overlap in the day’s supply of all triple therapy components for MITT cohort). COPD exacerbations, adherence to triple therapy, and all-cause and COPD-related health care resource utilization (HCRU) and costs were compared between FF/UMEC/VI and MITT initiators.Results: In total, 4659 FF/UMEC/VI initiators and 9845 MITT initiators for the MAPD population, and 821 FF/UMEC/VI initiators and 1893 MITT initiators for the commercial population were included in the study. MAPD beneficiaries initiating FF/UMEC/VI had a significantly lower annual rate of severe exacerbations compared to MITT initiators (0.26 vs 0.29; p=0.014). They also had a significantly higher mean adherence (proportion of days covered) (0.51 vs 0.37; p< 0.001) and significantly lower all-cause and COPD-related inpatient stays compared to MITT initiators ([32.02% vs 34.27%; p=0.017], [16.09% vs 17.72%; p=0.037]). Trends were similar among the commercial population, but the results were not statistically significant.Conclusion: FF/UMEC/VI initiators had significantly fewer severe exacerbations, higher triple therapy adherence, and lower HCRU costs compared to MITT initiators for MAPD beneficiaries.Plain language summary: Triple therapy for chronic obstructive pulmonary disease (COPD) includes the use of several inhalers daily in a respiratory therapy combination known as multiple-inhaler triple therapy (MITT), which can be challenging for patients. However, treatment can be simplified by combining these therapies into just one inhaler, in a respiratory therapy combination known as single-inhaler triple therapy (SITT). As there is currently limited information comparing treatment outcomes in patients using SITT versus those using MITT in the real world, in this study we included Medicare Advantage with Part D (MAPD) beneficiaries and commercial enrollees with COPD who started using either an SITT combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) or MITT. More specifically, we looked at flare-ups in COPD symptoms (known as exacerbations), percentage of days that a patient had their medication on hand (known as treatment adherence), and health care utilization and costs. The study was conducted using administrative claims data between September 1, 2016, and March 31, 2020 from the Optum Research Database. For patients who had MAPD insurance, individuals who started FF/UMEC/VI experienced fewer severe exacerbations and increased treatment adherence, as compared to those who started MITT. They also had lower health care utilization and costs compared to those using MITT. Similar results were observed for patients who were commercially enrolled, albeit lacking statistical significance. Overall, the findings of this study indicate that triple therapy with FF/UMEC/VI can improve exacerbations and treatment adherence in patients with COPD and decrease health care utilization and associated costs.Keywords: chronic obstructive pulmonary disease, triple therapy, multiple-inhaler triple therapy, single-inhaler triple therapy, adherence, exacerbations

Nicole M Engel-Nitz,1 Mary G Johnson,1 Michael P Johnson,1 Ashley S Cha-Silva,2 Samantha K Kurosky,2 Xianchen Liu2 1Optum, Eden Prairie, MN, 55344, USA; 2Pfizer Inc, New York, NY, 10017, USACorrespondence: Nicole M Engel-Nitz, HEOR | Optum Life Sciences, MN950-1000, 11000 Optum Circle, Eden Prairie, MN, 55344, USA, Tel +1 952-205-7770, Email Nicole.engel-nitz@optum.comPurpose: To assess adherence and persistence with palbociclib therapy in patients with HR+/HER2- metastatic breast cancer (mBC) in a US real-world setting.Methods: This retrospective study evaluated palbociclib dosing, adherence, and persistence using commercial and Medicare Advantage with Part D claims data from the Optum Research Database. Adult patients with mBC who had continuous enrollment 12 months prior to mBC diagnosis and initiated first-line palbociclib with aromatase inhibitor (AI) or fulvestrant between 02/03/2015 and 12/31/2019 were included. Demographic and clinical characteristics, palbociclib dosing and dose changes, adherence (medication possession ratio [MPR]), and persistence were measured. Adjusted logistic and Cox regression models were used to examine demographic and clinical factors associated with adherence and discontinuation.Results: Patients (n = 1066) with a mean age of 66 years were included; 76.1% received first-line palbociclib+AI and 23.9% palbociclib+fulvestrant. Most patients (85.7%) initiated palbociclib at 125 mg/day. Of the 34.0% of patients with a dose reduction, 82.6% reduced from 125 to 100 mg/day. Overall, 80.0% of patients were adherent (MPR), and 38.3% discontinued palbociclib during a mean (SD) follow-up of 16.0 (11.2) and 17.4 (13.4) months, for palbociclib+fulvestrant and palbociclib+AI, respectively. Annual income below &dollar;75,000 was significantly associated with poor adherence. Older age (age 65– 74 years (hazard ratio [HR] 1.57, 95% CI, 1.06, 2.33), age ≥ 75 years (HR 1.61, 95% CI: 1.08, 2.41)) and bone-only metastatic disease (HR 1.37, 95% CI, 1.06, 1.76) were significantly associated with palbociclib discontinuation.Conclusion: In this real-world study, > 85% of patients started palbociclib at 125 mg/day and 1 in 3 had dose reductions during the follow-up. Patients were generally adherent and persistent with palbociclib. Older age, bone-only disease, and low-income levels were associated with early discontinuation or non-adherence. Further studies are needed to understand the associations of clinical and economic outcomes with palbociclib adherence and persistence.Keywords: breast cancer, palbociclib, adherence, persistence, metastatic

Background: It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients.Objective: To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management.Design: A randomized, open-label, controlled trial with blinded end point assessment.Setting: Tertiary care center.Patients: Adults with and without diabetes who were undergoing on-pump cardiac surgery.Measurements: The primary outcome was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital.Intervention: Patients were randomly assigned to receive continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) or conventional treatment (n = 201). Patients in the conventional treatment group were not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). Both groups were treated with insulin infusion to maintain normoglycemia after surgery.Results: Mean glucose concentrations were statistically significantly lower in the intensive treatment group at the end of surgery (6.3 mmol/L [SD, 1.6] [114 mg/dL {SD, 29}] in the intensive treatment group vs. 8.7 mmol/L [SD, 2.3] [157 mg/dL {SD, 42}] in the conventional treatment group; difference, -2.4 mmol/L [95% CI, -2.8 to -1.9 mmol/L] [-43 mg/dL {CI, -50 to -35 mg/dL}]). Eighty two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, -1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, -1 to 0 days]) was similar for both groups.Limitations: This single-center study used a composite end point and could not examine whether outcomes differed by diabetes status.Conclusions: Intensive insulin therapy during cardiac surgery does not reduce perioperative death or morbidity. The increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention. [ABSTRACT FROM AUTHOR]

Objective: To determine whether some adverse outcomes of hemodialysis could be explained by subclinical heparin-induced thrombocytopenia (HIT).Patients and Methods: Platelet factor 4 (PF4)-heparin antibodies were measured by enzyme-linked immunosorbent assay In a population-based cohort of hemodlalysis patients. Participants were then followed up prospectively for thromboembollc events, cardiovascular events, or death.Results: Of the 59 hemodialysis patients residing In Olmsted County, Minnesota, 57 (97%) agreed to study participation. The mean +/- SD age of the patients was 64 +/- 17 years (median hemodialysis duration, 23 months), and 27 (47%) were women. The enzyme-linked Immunosorbent assay was positive for PF4-heparin antibodies in 2 patients (3.5%). The PF4-heparin antibody content varied over a 10-fold range and was not associated with the duration of hemodialysis (P = .99). During a median follow-up of 798 days, 16 thrombotic events, 37 cardiovascular events, and 23 deaths (Including 13 cardiovascular deaths) occurred. After adjusting for the Framingham risk score, the all-cause mortality rate was significantly higher for patients with the highest tertile of PF4-heparln antibody content compared with patients in the lower tertilles (hazard ratio, 2.47; P = .03). Furthermore, 8 (73%) of deaths in this tertile were due to cardiovascular causes (hazard ratio, 4.14; P = .02).Conclusions: Despite repetitive heparin exposure, the prevalence of HIT In patients undergoing maintenance hemodialysis is no greater than that anticipated for other patient populations. However, to our knowledge, this is the first study to show an association between elevated PF4-heparin antibodies and Increased mortality rates in hemodlalysis patients. [ABSTRACT FROM AUTHOR]

Here, we present a Monte Carlo toolkit for validating step range filter (SRF) spectrometer designs. Geant4 is used to transport charged particles through the SRF filters to generate synthetic SRF data that include realistic CR-39 effects. Synthetic SRF spectra generated by this method inherently account for instrument response and allow for the quantification of SRF performance before shots. The usefulness of this toolkit is demonstrated through its application to a number of problems. A new broadband SRF for the ∼10 MeV wide 3He3He proton spectrum is validated, and an analysis method for analyzing 3He3He-p SRF data that accounts for instrument response is put forth. In addition, an SRF design for the compact recoil-proton spectrometer (CRS) on the Z-machine is validated. Finally, a new calibration technique for the DD-p SRF is proposed and validated., (© 2025 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Solar radiation is an important environmental variable for terrestrial animals, but its impact on the heat balance of large flying insects has been poorly studied. Desert bees are critical to ecosystem function through their pollination services, and are exposed to high radiant loads. We assessed the role of solar radiation in the heat balance of flying desert Centris pallida bees by calculating heat budgets for individuals in a respirometer in shaded versus sunny conditions from 16 to 37°C air temperatures, comparing the large and small male morphs and females. Solar radiation was responsible for 43 to 54% of mean total heat gain. Bees flying in the sun had thorax temperatures 1.7°C warmer than bees flying in the shade, storing a very small fraction of incident radiation in body tissues. In most cases, flight metabolic rate was not suppressed for bees flying in the sun, but evaporative water loss rates more than doubled. The most dramatic response to solar radiation was an increase in convection, mediated by a more than doubling of convective conductance, allowing thermoregulation while conserving body water. In large morph males and females, the increased convective conductance in the sun was mediated by increased heat transfer from the thorax to abdomen. Because convection is limited as body temperatures approach air temperatures, solar radiation combined with warming air temperatures may cause endothermic flying bees to reach a tipping point at which increases in non-sustainable evaporation are necessary for survival., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2025. Published by The Company of Biologists.)

The Particle Time of Flight (PTOF) diagnostic is a chemical vapor deposition diamond-based detector and is the only diagnostic for measuring nuclear bang times of low yield (<1013) shots on the National Ignition Facility. Recently, a comprehensive study of detector impulse responses revealed certain detectors with very fast and consistent impulse responses with a rise time of <50 ps, enabling low yield burn history measurements. At the current standoff of 50 cm, this measurement is possible with fast 14 MeV neutrons from deuterium-tritium (DT) fusion plasmas. PTOF-inferred DT burn width numbers compare well with widths inferred from the gamma reaction history diagnostic on mid-yield (1013-1015) shots, where both systems are capable of making this measurement. These new capabilities could be extended to 2.5 MeV deuterium-deuterium neutrons from D plasmas and to even lower yield by reducing the detector standoff distance to 10 cm; a design for this is also presented., (© 2025 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 ( 6 ), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 ( 6 ) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.

Background: Depression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia., Methods: To this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21)., Results: Our results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior., Conclusion: We interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Adolescent ballet dancers are commonly recognized as aesthetic athletes who are at higher risk for body dissatisfaction, disordered eating, and eating disorders. Although athletic participation can generally protect against negative mental and physical health outcomes, idealization of a body ideal specific to ballet can confer unique vulnerability for eating pathology. Despite this known vulnerability, rigorous efforts to prevent eating pathology among young dancers are lacking. Previously, we reported on a trial of the Female Athlete Body Project adapted for professional female ballet dancers. The current study tested a subsequent adaptation, the Athlete Body Project (ABP), tailored for younger dancers, including a version for boys. This non-randomized, uncontrolled pilot trial tested ABP among boys and girls in two elite ballet schools ( N  = 23), formatted in-person and via video-conferencing. Program delivery met benchmarks for feasibility and acceptability across gender and delivery formats, and dancers provided positive qualitative feedback. Overall results suggest the potential of ABP in intervening on pre-post eating pathology and body appreciation, and significantly decreasing drive for muscularity among young ballet dancers. Taken together, this pilot work addresses a gap in the field and advances the needed development of eating disorder prevention programming for young, high-risk aesthetic athletes.

Objective: Despite efforts toward achieving gender-based equality in clinical trial enrollment, females are frequently underrepresented and gender-specific data analysis is lacking. Identifying and addressing gender bias in medical decision-making and outcome reporting may facilitate more equitable healthcare delivery. This study aimed to determine if gender differences exist in the clinical evaluation and surgical management of patients with degenerative lumbar conditions., Methods: Consecutive adult patients undergoing spinal surgery for degenerative lumbar conditions (disc herniation [DH], spinal canal stenosis [SCS], and degenerative spondylolisthesis [DS]) were prospectively enrolled across 16 tertiary academic centers. Outcome domains included pain, disability, health-related quality of life (HRQOL), expectations of surgery, and satisfaction with surgical outcome. Covariates pertaining to the preoperative use of healthcare resources, diagnostic testing, and visits to healthcare providers were compared between genders before and after propensity score matching for 13 baseline demographic and procedural variables., Results: Data were analyzed for 5038 patients (2396 female, 2642 male) with degenerative spinal pathologies including SCS (40.2%), DS (33.2%), and DH (26.6%). Surgical treatment effect was similar for both genders. For all conditions, female patients had worse pre- and postoperative pain, disability, and HRQOL. Significant gender differences were identified for marital status, education, employment status, exercise activities, and disability claims. Female patients were more likely to use select medications, diagnostic imaging tests, and nonsurgical therapeutic interventions, and access various healthcare providers. Findings were similar following post hoc propensity score matching., Conclusions: In this multicenter, prospective, observational cohort study, male and female patients benefitted similarly from surgery for degenerative lumbar spine disease. However, female patients had worse preoperative clinical assessment scores and were more likely to use select healthcare resources.

The Particle Time of Flight (PTOF) detector is a chemical vapor deposition diamond-based detector used to measure bang times in low-yield (≲ 1015 neutrons) experiments at the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory (LLNL). Historically, the impulse response for PTOF diamond detectors has been obtained from x-ray timing shots on the NIF and shots on the MegaRay pulsed electron accelerator at LLNL. The impulse response may alternatively be obtained using single particle interactions with the detector, at substantially less cost and higher frequency compared to NIF timing shots, which typically occur months apart. Here, the response of a PTOF detector setup is characterized by statistically averaging a large number of single particle waveforms. A high fidelity instrument response function can be constructed in this way. This is confirmed by comparison of the single particle counting-constructed response to the impulse response function measured for the same detector at LLNL's MegaRay facility., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Neutron measurement is the primary tool in the SPARC tokamak for fusion power (Pfus) monitoring, research on the physics of burning plasmas, validation of the neutronics simulation workflows, and providing feedback for machine protection. A demanding target uncertainty (10% for Pfus) and coverage of a wide dynamic range (>8 orders of magnitude going up to 5 × 1019 n/s), coupled with a fast-track timeline for design and deployment, make the development of the SPARC neutron diagnostics challenging. Four subsystems are under design that exploit the high flux of direct DT and DD plasma neutrons emanating from a shielded opening in a midplane diagnostic port. The systems comprise a set of ∼15 flux monitors, mainly ionization chambers and proportional counters for measurement of the neutron yield rate, two independent foil activation systems for measurement of the neutron fluence, a spectrometric radial neutron camera for poloidal profiling of the plasma emissivity, and a high-resolution magnetic proton recoil spectrometer for measurement of the core neutron spectrum. Together, the four systems ensure redundancy of sensors and methods and aim to provide high resolutions of time (10 ms), space (∼7 cm), and energy (<2% at 14 MeV). This paper presents the broader objectives behind the preliminary design of the SPARC neutron diagnostics and discusses the ongoing studies on neutronics, detector comparisons, prototyping, and integration with the unique infrastructure of SPARC. Engineering details of the four subsystems and the concepts for in situ neutron calibration are also highlighted., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

CR-39 proton radiography is an experimental charged-particle backlighter platform fielded and used at OMEGA and the NIF to image electric and magnetic fields in a subject plasma. Processing a piece of CR-39 involves etching it in hot NaOH, and the etch time can greatly impact the background-to-signal ratio (BSR) in low-fluence (≲4 × 104 cm-2) regions and detection efficiency in high-fluence regions (≳7 × 105 cm-2). For CR-39 data with high fluence variation, these effects mean that any single etch time will result in ≳15% error in the measured signal in either the high- or low-fluence regions. This study aims to quantify the impact of the etch time on the BSR and efficiency losses and how these affect the field reconstruction. Experiments at the MIT Linear Electrostatic Ion Accelerator provided empirical values of the BSR and efficiency losses as a function of the fluence and etch time for fluences ranging from 3 × 103 to 7 × 105 cm-2. Synthetic radiographs were generated with known fields and modulated based on empirical values of BSR and efficiency losses. The fields were reconstructed using a Monge-Ampère code with the modulated radiographs as input. The results indicate that combining short and long etches allows for more accurate analysis of radiographs with high fluence variation, with the mean squared error of the reconstructed fields decreasing by factors of 1.2-7 compared to the reconstructions using only one etch time., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

While mining provides valuable metals and minerals to meet societal demands, it can cause environmental contamination from the residuals (i.e., tailings) of mining. Tailings are often acidic, laden with heavy metals, and lacking adequate nutrients and physical conditions for plant growth, precluding the establishment of plant cover to reduce the offsite movement of mining wastes. This paper describes a case study at the Formosa Mine in Douglas County, Oregon, where tailings were amended with a mixture of lime, biosolids, biochar, and microbial inoculum to facilitate establishment of Douglas-fir (Pseudotsuga menziesii [Mirbel] Franco) seedlings. Results show that the tailings pH increased, and Douglas-fir seedlings survived and grew with these amendments. After 2 years, pH did, however, decrease in some downslope locations and was associated with an increase in tree mortality. This suggests that tailings conditions should be monitored, and amendments should be reapplied as needed, particularly in areas receiving acidic runoff from unamended upslope tailings, until the seedlings are fully established. This study not only provides a prescription for the addition of biochar and other amendments to enhance plant growth for revegetation purposes in low-pH, metal-contaminated mine tailings, but it also demonstrates a method that can be used to address similar problems at other mine sites., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Uncertainty exists regarding the effectiveness of COVID-19 vaccine to prevent postacute sequelae of COVID-19 (PASC) following a breakthrough infection. While most studies based on symptom surveys found an association between preinfection vaccination status and PASC symptoms, studies of medically attended PASC are less common and have reported conflicting findings., Methods: In this retrospective cohort of patients with an initial SARS-CoV-2 infection who were continually empaneled for primary care in a large US health system, the electronic health record was queried for preinfection vaccination status, demographics, comorbidity index, and diagnosed conditions. Multivariable logistic regression was used to model the outcome of a medically attended PASC diagnosis within 6 months of SARS-CoV-2 infection. Likelihood ratio tests were used to assess the interaction between vaccination status and prevalent variant at the time of infection and between vaccination status and hospitalization for SARS-CoV-2 infection., Results: During the observation period, 6.9% of patients experienced medically attended and diagnosed PASC. A diagnosis of PASC was associated with older age, female sex, hospitalization for the initial infection, and an increased severity-weighted comorbidity index and was inversely associated with infection during the Omicron period. No difference in the development of diagnosed PASC was observed between unvaccinated patients and those vaccinated with either 2 doses of an mRNA vaccine or >2 doses., Conclusions: We found no association between vaccination status at the time of infection and development of medically diagnosed PASC. Vaccine remains an important measure to prevent SARS-CoV-2 infection and severity. Further research is needed to identify effective measures to prevent and treat PASC., Competing Interests: Potential conflicts of interest. M. D. S. discloses a current unpaid elected position on the American College of Occupational and Environmental Medicine Board of Directors. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The evolution of flight in an early winged insect ancestral lineage is recognized as a key adaptation explaining the unparalleled success and diversification of insects. Subsequent transitions and modifications to flight machinery, including secondary reductions and losses, also play a central role in shaping the impacts of insects on broadscale geographic and ecological processes and patterns in the present and future. Given the importance of insect flight, there has been a centuries-long history of research and debate on the evolutionary origins and biological mechanisms of flight. Here, we revisit this history from an interdisciplinary perspective, discussing recent discoveries regarding the developmental origins, physiology, biomechanics, and neurobiology and sensory control of flight in a diverse set of insect models. We also identify major outstanding questions yet to be addressed and provide recommendations for overcoming current methodological challenges faced when studying insect flight, which will allow the field to continue to move forward in new and exciting directions. By integrating mechanistic work into ecological and evolutionary contexts, we hope that this synthesis promotes and stimulates new interdisciplinary research efforts necessary to close the many existing gaps about the causes and consequences of insect flight evolution., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Reconstructing evolutionary trajectories and transitions that have shaped floral diversity relies heavily on the phylogenetic framework on which traits are modelled. In this study, we focus on the angiosperm order Ranunculales, sister to all other eudicots, to unravel higher-level relationships, especially those tied to evolutionary transitions in flower symmetry within the family Papaveraceae. This family presents an astonishing array of floral diversity, with actinomorphic, disymmetric (two perpendicular symmetry axes), and zygomorphic flowers. We generated nuclear and plastid datasets using the Angiosperms353 universal probe set for target capture sequencing (of 353 single-copy nuclear ortholog genes), together with publicly available transcriptome and plastome data mined from open-access online repositories. We relied on the fossil record of the order Ranunculales to date our phylogenies and to establish a timeline of events. Our phylogenomic workflow shows that nuclear-plastid incongruence accompanies topological uncertainties in Ranunculales. A cocktail of incomplete lineage sorting, post-hybridization introgression, and extinction following rapid speciation most likely explain the observed knots in the topology. These knots coincide with major floral symmetry transitions and thus obscure the order of evolutionary events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pokorny, Pellicer, Woudstra, Christenhusz, Garnatje, Palazzesi, Johnson, Maurin, Françoso, Roy, Leitch, Forest, Baker and Hidalgo.)

Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed., Experimental Design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition., Results: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition., Conclusions: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO 2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg -1 . Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods 1,2 . A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome 3,4 . Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins 5-7 . However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes 8 . This 15-fold increase in genus-level sampling relative to comparable nuclear studies 9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade., (© 2024. The Author(s).)

Approximately 390,000 abandoned mines across the US pose considerable, pervasive risks to human and environmental health; world-wide the problem is even greater. Lime, organic materials, and other amendments have been used to decrease metal bioavailability (e.g., Cd, Cu, Mn, Ni, Zn) in contaminated mine wastes and to promote plant community establishment for tailings stabilization. Biochar properties (e.g., alkaline pH, metal sorbing capabilities, available nutrients, improved soil water retention) make it a potential amendment for remediating metal contaminated mine tailings. A three-step procedure was developed to identify biochars that were most effective at reducing heavy metal availability, retaining metals, and subsequently selecting biochars for use in a soil amendment laboratory trial to ultimately be utilized in heavy metal contaminated mine land settings: Step (1) a synthetic precipitation leaching procedure extract of mine tailings was produced, representing potentially available metals, and used to identify metal removal properties of 28 different biochars (e.g., made from various feedstocks and pyrolysis or gasification conditions); Step (2) evaluate how well biochars retained previously sorbed metals; and Step (3) laboratory evaluation of the most promising biochars that removed and did not releases metals, applied at 0, 1, 2.5, and 5% (by wt) to mine tailings for reducing metal bioavailability. The reported methodology and results from this study could be used to quickly identify specific biochars and application rates to reduce mine tailings metal availability and aid in future remediation of abandoned mine sites globally., Competing Interests: Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository ( n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This exploratory post hoc analysis assessed the incidence of respiratory viral coinfections and their impact on clinical outcomes in non-hospitalized adults with mild-to-moderate coronavirus disease-2019 (COVID-19) treated with molnupiravir versus placebo for 5 days in the Phase 2/3 MOVe-OUT trial (NCT04575597), which took place in October 2020 to January 2021 (Phase 2, n = 302) and May 2021 to October 2021 (Phase 3, n = 1,433). Among 1,735 total randomized participants, 1,674 had a baseline respiratory pathogen panel (NxTAG Respiratory Pathogen Panel for the Luminex MAGPIX instrument) performed and 69 (4.1%) were coinfected with at least one additional respiratory viral pathogen. Human rhinovirus/enterovirus (39/69, 56.5%) was the most common coinfection detected at baseline. In the modified intention-to-treat population, two participants with coinfecting respiratory RNA viruses were hospitalized and received respiratory interventions through Day 29, and none died; one participant in the molnupiravir group was coinfected with human rhinovirus/enterovirus, and one participant in the placebo group was coinfected with human metapneumovirus. Hospitalization or death occurred in 6.2% and 9.0% of non-coinfected participants in the molnupiravir versus placebo group, respectively, and over 90% did not require respiratory interventions. Most coinfecting respiratory RNA viruses detected at baseline were not detected at the end of therapy in both the molnupiravir and placebo groups. In summary, participants coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to be hospitalized or die, or require respiratory interventions, compared to participants who were not coinfected with another respiratory RNA virus at baseline in both groups., Importance: Respiratory viral coinfections are known to occur with coronavirus disease-2019 (COVID-19). In a cohort of non-hospitalized adults with mild-to-moderate COVID-19 treated with molnupiravir versus placebo in the MOVe-OUT trial during October 2020 to October 2021, 4.1% of participants had a documented viral coinfection; human rhinovirus/enterovirus was the most common pathogen detected with the NxTAG Respiratory Pathogen Panel assay. Participants who had a coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to have worse clinical outcomes compared to those participants without a viral coinfection, and many coinfecting respiratory RNA viruses were no longer detected at the end of the 5-day treatment period in both groups., Competing Interests: Matthew G. Johnson, Julie M. Strizki, Erin Jensen, Dorothy McCoy, Mary Vesnesky, Carmelle T. Norice, Ying Zhang, Angela Williams-Diaz, Michelle L. Brown, Patricia Carmelitano, Jay A. Grobler, Amanda Paschke, and Carisa De Anda are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Jonathan Cohen: no conflicts of interest. Christine Katlama: no conflicts of interest. Roman Fishchuk: no conflicts of interest. Alfredo Ponce-de-León: Grants: NIH ATCC 1-4; Advisory boards: LATAM MSD, Gilead; Speaker: MSD, Gilead, Becton Dickinson, Qiagen. Nyda Fourie: no conflicts of interest. Chien-Yu Cheng: no conflicts of interest.

Study Design: Retrospective analysis was performed of a multi-center Canadian Spine Outcomes and Research Network (CSORN) surgical database., Objective: To determine the rate and time to return to work (RTW) based on workload intensity after elective degenerative lumbar spine surgery., Methods: Patients working pre-operatively, aged greater than 18, who underwent a primary one- or two-level elective lumbar spine surgery for degenerative conditions between January 2015 and October 2020 were evaluated. The percentage of patients who returned to work at 1 year and the time to RTW post-operatively were analyzed based on workload intensity., Results: Of the 1290 patients included in the analysis, the overall rate of RTW was 82% at 1 year. Based on workload there was no significant difference in time to RTW after a fusion procedure, with median time to RTW being 10 weeks. For non-fusion procedure, the sedentary group had a statistically significantly quicker time to RTW than the light-moderate ( P < .005) and heavy-very heavy (<.027) groups., Conclusions: The rate of RTW ranged between 84% for patients with sedentary work to 77% for patient with a heavy-very heavy workload. Median time to resumption of work was about 10 weeks following a fusion regardless of work intensity. There was more variability following non-fusion surgeries such as laminectomy and discectomy reflecting the patient's job demands., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Triple therapy (fluticasone furoate/umeclidinium/vilanterol; FF/UMEC/VI) has been shown to improve symptoms and reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. This real-world study compared exacerbation rates and healthcare resource utilization (HCRU) before and after initiation of FF/UMEC/VI in patients with COPD previously treated with inhaled corticosteroid (ICS)/long-acting β 2 -agonist (LABA)., Methods: This retrospective cohort study included commercial and Medicare Advantage with Part D administrative claims data from September 01, 2016, to March 31, 2020, of patients diagnosed with COPD. The index date was the date of the first FF/UMEC/VI claim (September 2017-March 2019). The 12 months prior to index (baseline) were used to assess patient characteristics and outcomes; the 12 months following index (follow-up) were used to assess study outcomes. All patients had ≥ 30 consecutive days' supply of any ICS/LABA dual therapy during the 12 months prior to FF/UMEC/VI initiation. Subgroup analyses included patients with ≥ 30 consecutive days' supply of budesonide/formoterol (BUD/FORM) during baseline. Analyses of patients with ≥ 1 COPD exacerbation during baseline were reported as well., Results: The overall population included 1449 patients (mean age 70.75 years; 54.18% female), of whom 540 were patients in the BUD/FORM subgroup. Significantly fewer patients experienced any exacerbation during follow-up versus baseline (overall population 53.49% vs 62.59%; p < 0.001; BUD/FORM subgroup 55.00% vs 62.41%; p = 0.004). Effects on exacerbation reduction were more pronounced among patients with ≥ 1 exacerbation during baseline. Lower COPD-related HCRU was observed during the follow-up compared with baseline for both the overall population and the BUD/FORM subgroup., Conclusion: Patients with COPD treated with ICS/LABA during baseline, including patients specifically treated with BUD/FORM and those with a history of ≥ 1 exacerbation, had fewer COPD exacerbations and lower COPD-related HCRU after initiating FF/UMEC/VI., (© 2024. The Author(s).)

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries., (© 2024 Merck Sharp and Dohme LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Common isotherm and kinetic models cannot describe the pH-dependent sorption of heavy metal cations by biochar. In this paper, we evaluated a pH-dependent, equilibrium/kinetic model for describing the sorption of cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) by poultry litter-derived biochar (PLB). We performed sorption experiments across a range of solution pH, initial metal concentration, and reaction time. The sorption of all five metals increased with increasing pH. For Cd, Cu, and Pb, kinetics experiments demonstrated that sorption rates were greater at pH 6.5 than at pH 4.5. For each metal, all sorption data were described using single set of four adjustable parameters. Sorption edge and isotherm data were well described with R 2  > 0.93 in all cases. Time-dependent sorption was well described (R 2  ≥ 0.90) for all metals except Pb (R 2  = 0.77). We then used the best-fit model parameters to calculate linear distribution coefficients (K D ) and equilibration times as a function of pH and initial solution concentration. These calculations provide a more robust way of characterizing biochar affinity for metal cations than Freundlich distribution coefficients or Langmuir sorption capacity. Because this model can characterize metal cation sorption by biochar across a wider range of reaction conditions than traditional isotherm or kinetic models, it is better suited for estimating metal cation/biochar interactions in engineered or natural systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)