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Abstract Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.

Abstract Background Preterm birth is a major cause of infant mortality and morbidity and accounts for 7–8% of births in the UK. It is more common in women from socially deprived areas and from minority ethnic groups, but the reasons for this disparity are poorly understood. To inform interventions to improve child survival and their quality of life, this study examined the socioeconomic and ethnic inequalities in preterm births (

Abstract Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Abstract Globally, catadromous freshwater eels of the genus Anguilla are of conservation concern, including critically endangered European eel (Anguilla anguilla). Pumping stations that move river water to a higher elevation severely impact eels during their seaward spawning migration. Fish-friendly pumps can mitigate fish injury and mortality but here we uniquely rethink a fish-friendly pump as a fish passage solution. In this pluriannual study, the seasonal timing of pump operation was misaligned with the typical silver eel migration period. Eels were almost exclusively nocturnal but night-time pumping represented as little as 5.6% a year. Night-time eel approaches were primarily influenced by pump duration and temperature, but did not align with lunar phase, unlike in unregulated rivers. After reaching the pumping station, eel passage was influenced by weedscreen aperture and increased when the aperture was increased. Passive sensor collision suggested non-pump infrastructure could cause injury and mortality to eels. It is therefore recommended pump operation should align with the timing of silver eel migration, weedscreen and pump entrance efficiencies should be maximised, and non-pump infrastructure must have low fish injury risk. Ultimately, considering the entire structure a fish passage solution will help ensure fish-friendly pumps have high conservation value for anguillid eels globally.

Abstract Compact, high-precision inertial sensors are needed in the control schemes of many modern physics experiments to isolate them from disturbances caused by seismic motion. We present an inertial sensor whose mechanical oscillator fits on a one-inch diameter optic. The oscillators achieve a mechanical Quality factor of a fundamental oscillation mode of 600,000 and a resonance frequency of 50 Hz, giving them a suspension thermal noise floor lower than all commercially available inertial sensors. The motion of this fundamental mode is suitable to encode inertial motion into the sensor readout. The oscillator is combined with an optical resonator readout scheme that achieves a displacement noise of 100 fm/ $$\sqrt{\text{Hz}}$$ Hz above 0.2 Hz. We validate the sensors’ noise floor using a huddle test. Below 20 Hz, the sensor offers comparable performance to the best inertial sensors available today while being a fraction of the size. Above 20 Hz, the sensor is, to the author’s knowledge, the best demonstrated in the literature to date for such a sensor, with a self-noise floor of 0.1 ng/ $$\sqrt{\text{Hz}}$$ Hz . The excellent performance of the sensors across seismically relevant frequencies, vacuum compatibility, and compact size make it a prime candidate for integration into sophisticated seismic isolation schemes, such as those used by gravitational wave detectors.

ABSTRACT Students with strong metacognitive skills are positioned to learn and achieve more than peers who are still developing their metacognition. Yet, many students come to college without well-developed metacognitive skills. As part of a longitudinal study on metacognitive development, we asked when, why, and how first-year life science majors use metacognitive skills of planning, monitoring, and evaluating. Guided by the metacognition framework, we collected data from 52 undergraduates at three institutions using semi-structured interviews. We found that first-year students seek study recommendations from instructors, peers, and online resources when they plan their study strategies. First-year students struggle to accurately monitor their understanding and benefit when instructors help them confront what they do not yet know. First-year students evaluate the effectiveness of their study plans at two specific points: immediately after taking an exam and/or after receiving their grade on an exam. While first-year students may be particularly open to suggestions on how to learn, they may need help debunking myths about learning. First-year students acknowledge they are still learning to monitor and welcome formative assessments that help them improve the accuracy of their monitoring. First-year students may be primed to receive guidance on their metacognition at the points when they are most likely to evaluate the effectiveness of their study strategies and plans. Based on our results, we offer suggestions for instructors who want to support first-year students to further develop their metacognition.

The self-association of therapeutic antibodies can result in elevated viscosity and create problems in manufacturing and formulation, as well as limit delivery by subcutaneous injection. The high concentration viscosity of some antibodies has been reduced by variable domain mutations or by the addition of formulation excipients. In contrast, the impact of Fc mutations on antibody viscosity has been minimally explored. Here, we studied the effect of a panel of common and clinically validated Fc mutations on the viscosity of two closely related humanized IgG1, κ antibodies, omalizumab (anti-IgE) and trastuzumab (anti-HER2). Data presented here suggest that both Fab-Fab and Fab-Fc interactions contribute to the high viscosity of omalizumab, in a four-contact model of self-association. Most strikingly, the high viscosity of omalizumab (176 cP) was reduced 10.7- and 2.2-fold by Fc modifications for half-life extension (M252Y:S254T:T256E) and aglycosylation (N297G), respectively. Related single mutations (S254T and T256E) each reduced the viscosity of omalizumab by ~6-fold. An alternative half-life extension Fc mutant (M428L:N434S) had the opposite effect in increasing the viscosity of omalizumab by 1.5-fold. The low viscosity of trastuzumab (8.6 cP) was unchanged or increased by [Formula: see text]2-fold by the different Fc variants. Molecular dynamics simulations provided mechanistic insight into the impact of Fc mutations in modulating electrostatic and hydrophobic surface properties as well as conformational stability of the Fc. This study demonstrates that high viscosity of some IgG1 antibodies can be mitigated by Fc mutations, and thereby offers an additional tool to help design future antibody therapeutics potentially suitable for subcutaneous delivery.

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

Subcutaneous injection is the preferred route of administration for many antibody therapeutics for reasons that include its speed and convenience. However, the small volume limit (typically [Formula: see text]2 mL) for subcutaneous delivery often necessitates antibody formulations at high concentrations (commonly ≥100 mg/mL), which may lead to physicochemical problems. For example, antibodies with large hydrophobic or charged patches can be prone to self-interaction giving rise to high viscosity. Here, we combined X-ray crystallography with computational modeling to predict regions of an anti-glucagon receptor (GCGR) IgG1 antibody prone to self-interaction. An extensive mutational analysis was undertaken of the complementarity-determining region residues residing in hydrophobic surface patches predicted by spatial aggregation propensity, in conjunction with residue-level solvent accessibility, averaged over conformational ensembles from molecular dynamics simulations. Dynamic light scattering (DLS) was used as a medium throughput screen for self-interaction of ~ 200 anti-GCGR IgG1 variants. A negative correlation was found between the viscosity determined at high concentration (180 mg/mL) and the DLS interaction parameter measured at low concentration (2–10 mg/mL). Additionally, anti-GCGR variants were readily identified with reduced viscosity and antigen-binding affinity within a few fold of the parent antibody, with no identified impact on overall developability. The methods described here may be useful in the optimization of other antibodies to facilitate their therapeutic administration at high concentration.

Climate models, derived from process understanding, are essential tools in the study of climate change and its wide-ranging impacts. Hindcast and future simulations provide comprehensive spatiotemporal estimates of climatology that are frequently employed within the environmental sciences community, although the output can be afflicted with bias that impedes direct interpretation. Post-processing bias correction approaches utilise observational data to address this challenge, although they are typically criticised for not being physically justified and not considering uncertainty in the correction. This paper proposes a novel Bayesian bias correction framework that robustly propagates uncertainty and models underlying spatial covariance patterns. Shared latent Gaussian processes are assumed between the in situ observations and climate model output, with the aim of partially preserving the covariance structure from the climate model after bias correction, which is based on well-established physical laws. Results demonstrate added value in modelling shared generating processes under several simulated scenarios, with the most value added for the case of sparse in situ observations and smooth underlying bias. Additionally, the propagation of uncertainty to a simulated final bias-corrected time series is illustrated, which is of key importance to a range of stakeholders, such as climate scientists engaged in impact studies, decision-makers trying to understand the likelihood of particular scenarios and individuals involved in climate change adaption strategies where accurate risk assessment is required for optimal resource allocation. This paper focuses on one-dimensional simulated examples for clarity, although the code implementation is developed to also work on multi-dimensional input data, encouraging follow-on real-world application studies that will further validate performance and remaining limitations. The Bayesian framework supports uncertainty propagation under model adaptations required for specific applications, providing a flexible approach that increases the scope of data assimilation tasks more generally.

Nonhuman primates demonstrate great behavioral diversity in their responses to death, yet the most prevalent of these—infant corpse carrying—remains poorly understood. While mothers are the most frequent carriers, corpse carrying can be performed by non-mothers, and heterospecifics’ corpses are also carried. We propose a new hypothesis to explain, in part, non-maternal corpse carrying, the ‘mammalian cues hypothesis,’ and experimentally test it in a population of wild baboons. The mammalian-cues hypothesis argues that evolutionary pressures on maternal responsiveness have created a generalized attraction towards mammalian-typical traits in mammals of both sexes. This attraction may drive interest in inanimate objects (including corpses) that display mammalian cues. To test this, we presented objects that varied in mammalian traits to wild chacma baboons (Papio ursinus) and recorded their behavioral responses. Contrary to our hypothesis, baboons handled all objects (i.e., with or without mammalian traits) for similar lengths of time. However, in partial support of our hypothesis, baboons groomed the objects with fur—even those without any other mammalian traits—and explored them in a less destructive manner. We caution that infant corpse grooming by non-mothers in primates may be indicative of the visual and tactile stimuli the corpse presents rather than an interest in death or a reflection of social bonds.

Background: Nearly one-half of patients admitted with acute decompensated heart failure (ADHF) are discharged with unresolved congestion, elevating rehospitalization risk. This may be due to suboptimal intravenous (IV) loop diuretic dosing, which may be influenced by home oral diuretic dose. Objectives: The objective of this study was to determine the association between: 1) home oral loop diuretic dose and optimal initial IV loop diuretic dosing in ADHF; and 2)receiving optimal initial IV loop diuretic dosing and length of stay and 30-day readmission. Methods: Retrospective analysis of adults admitted to a large U.S. hospital for ADHF on home oral loop diuretics from 1 January 2014 to 21 December 2021. Patients were categorized by home dose: low (≤40 mg furosemide equivalents), medium (>40-80 mg furosemide equivalents), and high (>80 mg furosemide equivalents). Optimal initial IV dosing was considered ≥2 times home oral dosing. Poisson regression models estimated prevalence ratios (CIs) for optimal initial IV loop diuretic dosing. Results: Among 3,269 adults admitted for ADHF (mean age 63 years, 62% male), optimal initial IV dosing occurred in 2,218 (67.9%). The prevalence of optimal initial IV dosing among low, medium, and high home dosing was 95.5%, 59.9%, and 4.0%, respectively. Adjusted prevalence ratios for optimal IV dosing with high and medium home dosing, compared to low, were 0.05 (95% CI: 0.03-0.07) and 0.66 (95% CI: 0.62-0.70), respectively. There was no difference in length of stay or 30-day readmission between optimal and suboptimal initial IV diuretic dosing. Conclusions: Among patients with ADHF, higher home loop diuretic dose was strongly associated with a substantially lower likelihood of optimal initial IV diuretic dosing.

The Blackfeet Nation in northwestern Montana, United States, is implementing its Agriculture Resource Management Plan (ARMP), an Indigenous-led, sustainable agriculture plan prioritizing economic development for Indigenous producers, intergenerational health and well-being of Amskapi Piikani Blackfeet people, and ecological and cultural sensitivities within this sovereign nation and its traditional territories. Since the passage of the American Indian Agricultural Resource Management Act of 1993, only three Tribes have drafted and finalized Agricultural Resource Management Plans (ARMPs). The Blackfeet ARMP is now being held up as a national model of Tribal sovereignty. “Blackfeet Innovation Pathways to Food Sovereignty,” an Indigenous-led research project, emerged from the Blackfeet Nation’s community-based strategic planning process identifying gaps, systemic barriers and impactful solutions for achieving Blackfeet food sovereignty through the implementation of the Blackfeet Nation ARMP, along with research influenced by the ARMP. This paper provides a community case study of the ongoing process and offers a translational model of sustainable agriculture and food sovereignty within Indigenous lands to improve the economic futures of producers and their families, as well as health outcomes for Native communities.

Introduction Breast cancer survivors have an increased risk for chronic fatigue and altered gut microbiota composition, both with negative health and quality of life affects. Exercise modestly improves fatigue and is linked to gut microbial diversity and production of beneficial metabolites. Studies suggest that gut microbiota composition is a potential mechanism underlying fatigue response to exercise. Randomised controlled trials testing the effects of exercise on the gut microbiome are limited and there is a scarcity of findings specific to breast cancer survivors. The objective of this study is to determine if fitness-related modifications to gut microbiota occur and, if so, mediate the effects of aerobic exercise on fatigue response.Methods and analysis The research is a randomised controlled trial among breast cancer survivors aged 18–74 with fatigue. The primary aim is to determine the effects of aerobic exercise training compared with an attention control on gut microbiota composition. The secondary study aims are to test if exercise training (1) affects the gut microbiota composition directly and/or indirectly through inflammation (serum cytokines), autonomic nervous system (heart rate variability) or hypothalamic-pituitary-adrenal axis mediators (hair cortisol assays), and (2) effects on fatigue are direct and/or indirect through changes in the gut microbiota composition. All participants receive a standardised controlled diet. Assessments occur at baseline, 5 weeks, 10 weeks and 15 weeks (5 weeks post intervention completion). Faecal samples collect the gut microbiome and 16S gene sequencing will identify the microbiome. Fatigue is measured by a 13-item multidimensional fatigue scale.Ethics and dissemination The University of Alabama at Birmingham Institutional Review Board (IRB) approved this study on 15 May 2019, UAB IRB#30000320. A Data and Safety Monitoring Board convenes annually or more often if indicated. Findings will be disseminated in peer-reviewed journals and conference presentations.Trial registration number ClinicalTrials.gov, NCT04088708.

This research used three scales to explore ethnicity and other variables' effects on university students' self-assessed academic help-seeking. The scores from each respective scale were regressed onto academic and demographic variables. In two of the three regression models, Age was the only significant factor, older students self-assessing as less avoidant and more persuaded of the benefits of help-seeking. However, investigating an interaction in one model revealed that older Pacific Islanders followed an opposite pattern, self-assessing as "more" avoidant of help-seeking with increased age, and significantly "more" avoidant than same-age peers of other ethnicities. Pacific Islanders also self-assessed significantly higher in instrumental help-seeking. In summary, except for Pacific Islanders, ethnic background had surprisingly little effect on academic help-seeking, a finding which may be attributable to the highly multicultural research setting. These findings suggest that younger students and older Pacific Islanders may benefit from focused efforts to facilitate their receiving academic help.

The National Marine Fisheries Service listed 5 distinct population segments (DPSs) of Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) under the Endangered Species Act in 2012 (Federal Register, 2012a 2012b). Since this [...]

The Indoor CHEMical model in Python, INCHEM-Py, is an open-source and accessible box model for the simulation of the indoor atmosphere and is a refactor (rewrite of source code) and significant development of the INdoor Detailed Chemical Model (INDCM). INCHEM-Py creates and solves a system of coupled ordinary differential equations that include gas-phase chemistry, surface deposition, indoor–outdoor air change, indoor photolysis processes and gas-to-particle partitioning for three common terpenes. It is optimised for ease of installation and simple modification for inexperienced users, while also providing unfettered access to customise the physical and chemical processes for more advanced users. A detailed user manual is included with the model and updated with each version release. In this paper, INCHEM-Py v1.2 is introduced, and the modelled processes are described in detail, with benchmarking between simulated data and published experimental results presented, alongside discussion of the parameters and assumptions used. It is shown that INCHEM-Py achieves excellent agreement with measurements from an experimental campaign which investigate the effects of different surfaces on the concentrations of different indoor air pollutants. In addition, INCHEM-Py shows closer agreement to experimental data than INDCM. This is due to the increased functionality of INCHEM-Py to model additional processes, such as deposition-induced surface emissions. A comparative analysis with a similar zero-dimensional model, AtChem2, verifies the solution of the gas-phase chemistry. Published community use cases of INCHEM-Py are also presented to show the variety of applications for which this model is valuable to further our understanding of indoor air chemistry.

Abstract Background The global mining industry is an important partner in advancing the 2030 Agenda for Sustainable Development. In 2018, Anglo American plc published their Sustainable Mining Plan, containing a goal for improving health and wellbeing aligned with the Sustainable Development Goal 3 (SDG3) targets. Having formed an independent multidisciplinary research consortium, we designed and implemented a mixed-methods approach to attain a deeper understanding of SDG3 priorities within the local context of communities hosting Anglo American mining operations located in Latin America. Methods In 2019, within the host communities of three mining operations in Chile, three in Brazil, and one in Peru, we conducted a qualitative study which included stakeholder workshops and key informant interviews. We also quantitatively appraised existing health data. Findings emerging from the qualitative and quantitative assessments were compared to identify health and wellbeing priority areas for action relevant to each community. Results Across the three countries, 120 people took part in workshops and 35 in interviews. In these workshops and interviews, non-communicable diseases (SDG3.4), harmful alcohol consumption (SDG3.5), and pollution, particularly air pollution (SDG3.9), were consistently identified as areas for priority action. There were similarities in the reporting of individual, interpersonal, community, societal, and structural factors underlying these priority areas across the different communities. The availability of quantitative data was generally good at the state level, becoming increasing sparse as we focused on smaller geographies. The priorities identified in the quantitative assessments generally aligned with those highlighted in the qualitative data. Conclusions We highlight the importance of engaging with local populations to understand and address health needs. To address the priorities identified, intervention packages tailored to the specific needs of host communities, that tackle associated upstream societal level factors, are required. To facilitate this, appropriate monitoring systems and epidemiological investigations should be implemented to better understand the local context and quantify health issues. In the host communities, it is essential for the mining sector to be a key health partner in promoting integrated programmes that contribute to achieving the priority objectives and targets aligned with the SDG3 agenda.

Abstract Objective Use of computational fluid dynamic (CFD) simulations to measure the changes in upper airway geometry and aerodynamics during (a) an episode of Exercise‐Induced Laryngeal Obstruction (EILO) and (b) speech therapy exercises commonly employed for patients with EILO. Methods Magnetic resonance imaging stills of the upper airway including the nasal and oral cavities from an adult female were used to re‐construct three‐dimensional geometries of the upper airway. The CFD simulations were used to compute the maximum volume flow rate (l/s), pressure (Pa), airflow velocity (m/s) and area of cross‐section opening in eight planes along the vocal tract, separately for inhalation and exhalation. Results Numerical predictions from three‐dimensional geometrical modeling of the upper airway suggest that the technique of nose breathing for inhalation and pursed lip breathing for exhalation show most promising pressure conditions and cross‐sectional diameters for rescue breathing exercises. Also, if EILO is due to the constriction at the vocal fold level, then a quick sniff may also be a proper rescue inhalation exercise. EILO affects both the inspiratory and the expiratory phases of breathing. Conclusions A prior knowledge of the supraglottal aerodynamics and the corresponding upper airway geometry from CFD analysis has the potential to assist the clinician in choosing the most effective rescue breathing technique for optimal functional outcome of speech therapy intervention in patients with EILO and in understanding the pathophysiology of EILO on a case‐by‐case basis with future studies. Level of Evidence 4

Abstract The T2K experiment presents new measurements of neutrino oscillation parameters using $$19.7(16.3)\times 10^{20}$$ 19.7 ( 16.3 ) × 10 20 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional $$4.7\times 10^{20}$$ 4.7 × 10 20 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on $$\sin ^2\theta _{13}$$ sin 2 θ 13 and the impact of priors on the $$\delta _{\textrm{CP}}$$ δ CP measurement. Both analyses prefer the normal mass ordering and upper octant of $$\sin ^2\theta _{23}$$ sin 2 θ 23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on $$\sin ^2\theta _{13}$$ sin 2 θ 13 from reactors, $$\sin ^2\theta _{23}=0.561^{+0.021}_{-0.032}$$ sin 2 θ 23 = 0 . 561 - 0.032 + 0.021 using Feldman–Cousins corrected intervals, and $$\varDelta {}m^2_{32}=2.494_{-0.058}^{+0.041}\times 10^{-3}~\text {eV}^2$$ Δ m 32 2 = 2 . 494 - 0.058 + 0.041 × 10 - 3 eV 2 using constant $$\varDelta \chi ^{2}$$ Δ χ 2 intervals. The CP-violating phase is constrained to $$\delta _{\textrm{CP}}=-1.97_{-0.70}^{+0.97}$$ δ CP = - 1 . 97 - 0.70 + 0.97 using Feldman–Cousins corrected intervals, and $$\delta _{\textrm{CP}}=0,\pi $$ δ CP = 0 , π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than $$2\sigma $$ 2 σ credible level using a flat prior in $$\delta _{\textrm{CP}},$$ δ CP , and just below $$2\sigma $$ 2 σ using a flat prior in $$\sin \delta _{\textrm{CP}}.$$ sin δ CP . When the external constraint on $$\sin ^2\theta _{13}$$ sin 2 θ 13 is removed, $$\sin ^2\theta _{13}=28.0^{+2.8}_{-6.5}\times 10^{-3},$$ sin 2 θ 13 = 28 . 0 - 6.5 + 2.8 × 10 - 3 , in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Aim: Posterior cranial fossa (PCF) surgery is associated with complications, including cerebrospinal fluid (CSF) leakage. Dural sealants such as polyethylene glycol (PEG)-based hydrogels and fibrin glue can prevent CSF leaks, with evidence suggesting PEG hydrogels may outperform fibrin glue. However, the budget impact of using PEG hydrogels in PCF surgeries in Europe is unclear. Materials & methods: A decision tree was developed based on a previous US model, to assess the budget impact of switching from fibrin glue to PEG hydrogel in PCF surgery across five European countries. Input costs were derived from published sources for the financial year 2022/2023. Health outcomes, including CSF leaks, were considered. Results: The model predicted that using PEG hydrogel instead of fibrin glue in PCF surgery can lead to cost savings in five European countries. Cost savings per patient ranged from EUR 419 to EUR 1279, depending on the country. Sensitivity analysis showed that the incidence of CSF leaks and pseudomeningoceles had a substantial impact on the model’s results. Conclusion: PEG hydrogels may be a cost-effective alternative to fibrin glue in PCF surgery. The model predicted that cost savings would be mainly driven by a reduction in the incidence of postoperative CSF leaks, resulting in reduced reliance on lumbar drains, reparative surgery and shortened hospital stays.

IntroductionIt is often assumed that the ability to recognize the emotions of others is reflexive and automatic, driven only by observable facial muscle configurations. However, research suggests that accumulated emotion concept knowledge shapes the way people perceive the emotional meaning of others’ facial muscle movements. Cultural upbringing can shape an individual’s concept knowledge, such as expectations about which facial muscle configurations convey anger, disgust, or sadness. Additionally, growing evidence suggests that access to emotion category words, such as “anger,” facilitates access to such emotion concept knowledge and in turn facilitates emotion perception.MethodsTo investigate the impact of cultural influence and emotion concept accessibility on emotion perception, participants from two cultural groups (Chinese and White Americans) completed a functional magnetic resonance imaging scanning session to assess functional connectivity between brain regions during emotion perception. Across four blocks, participants were primed with either English emotion category words (“anger,” “disgust”) or control text (XXXXXX) before viewing images of White American actors posing facial muscle configurations that are stereotypical of anger and disgust in the United States.ResultsWe found that when primed with “disgust” versus control text prior to seeing disgusted facial expressions, Chinese participants showed a significant decrease in functional connectivity between a region associated with semantic retrieval (the inferior frontal gyrus) and regions associated with semantic processing, visual perception, and social cognition. Priming the word “anger” did not impact functional connectivity for Chinese participants relative to control text, and priming neither “disgust” nor “anger” impacted functional connectivity for White American participants.DiscussionThese findings provide preliminary evidence that emotion concept accessibility differentially impacts perception based on participants’ cultural background.

Abstract This study describes “lobular-like invasive mammary carcinomas” (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management.

Multiple factors may influence parental vaccine hesitancy towards pediatric COVID-19 vaccines and routine childhood immunizations (RCIs). Using the United States National Immunization Survey—Child COVID Module data collected from parents/guardians of children aged 5–11 years, this cross-sectional study (1) identified the trends and prevalence estimates of parental hesitancy towards pediatric COVID-19 vaccines and RCIs, (2) examined the relationship between hesitancy towards pediatric COVID-19 vaccines and RCIs, and (3) assessed trends in parental hesitancy towards RCIs by sociodemographic characteristics and behavioral and social drivers of COVID-19 vaccination. From November 2021 to July 2022, 54,329 parents or guardians were interviewed. During this 9-month period, the proportion of parents hesitant about pediatric COVID-19 vaccines increased by 15.8 percentage points (24.8% to 40.6%). Additionally, the proportion of parents who reported RCIs hesitancy increased by 4.7 percentage points from November 2021 to May 2022 but returned to baseline by July 2022. Over nine months, parents’ concerns about pediatric COVID-19 infections declined; however, parents were increasingly worried about pediatric COVID-19 vaccine safety and overall importance. Furthermore, pediatric COVID-19 vaccine hesitancy was more prevalent among parents of children who were White (43.2%) versus Black (29.3%) or Hispanic (26.9%) and those residing in rural (51.3%) compared to urban (28.9%) areas. In contrast, RCIs hesitancy was higher among parents of children who were Black (32.0%) versus Hispanic (24.5%) or White (23.6%). Pediatric COVID-19 vaccine hesitancy was 2–6 times as prevalent among parents who were RCIs hesitant compared to those who were RCIs non-hesitant. This positive correlation between parental hesitancy towards pediatric COVID-19 vaccines and RCIs was observed for all demographic and psychosocial factors for unadjusted and adjusted prevalence ratios. Parent–provider interactions should increase vaccine confidence, shape social norms, and facilitate behavior change to promote pediatric vaccination rates.

The reuse of wastewater to meet irrigation requirements and slurries, sludges and manures as fertilisers to meet crop nutrient demands inadvertently introduces human and veterinary-use pharmaceuticals into the agro-ecosystem. This review synthesises recent research, which has observed sub-lethal effects, following pharmaceutical uptake by plants. Potential links between pharmaceutical mode of action and observed sub-lethal effects in the plant were then examined. Common receptors and biological pathways across species suggests a clear need to integrate plant cellular biology into our understanding of the impacts of pharmaceuticals on important plant functions and processes. To help prioritise future research efforts an analysis of shared mammalian and plant biochemical pathways was undertaken to identify classes of pharmaceuticals which may present a greater risk to key plant functions. These included sulfonylurea antihyperglycemics, steroids, opiods, antipsychotic phenothiazines and pharmaceuticals targeting several neurotransmitters shared between mammals and plants (including beta-blockers, antihistamines and benzodiazepines). Whilst a number of pharmaceutical induced sub-lethal effects have been observed, this review highlights the clear need to study a wider range of pharmaceuticals on a broader range of plant species, including cover crops and wild plants, under realistic exposure scenarios, to fully understand the wider implications of pharmaceutical exposure in agro-ecosystems. State-of-the art omics-techniques offer great potential to understand the mode of action of pharmaceuticals in plants and elucidate links between the pharmaceutical intended mode of action and observed plant effects. In addition, studies under co-stress from pharmaceutical exposure and other stressors such as increased temperatures, drought or pests are lacking and present an urgent research need in the face of feeding a growing population under the threats of climate change.

Novel metal ceramic multilayer composites with the ability to phase transform into a single phase ultra-high temperature ceramic are described. These materials offer enhanced low-temperature fracture toughness and reliability without sacrificing high-temperature mechanical properties by eliminating the metal reinforcement layers upon reaching temperatures sufficient for the activation of carbon diffusion. At low temperatures, these materials are practically indefinitely stable because of the high activation energy for carbon diffusion in the carbide layers that control the phase transformation kinetics. Here, knowledge of the overall thermodynamics, i.e., carbon content, is combined with prediction of phase transformation kinetics and toughening in the limit of small-scale yielding to characterize the design space of these novel composites. It is proposed that the ability to control thermodynamic and mechanical properties of the post-transformation ceramic via selection of metal-to-ceramic layer ratios makes these novel composites an excellent alternative to current methods for reinforcement of ultra-high temperature ceramics.

Research in social mammals has revealed the complexity of strategies females use in response to female-female reproductive competition and sexual conflict. One point at which competition and conflict manifests acutely is during sexual receptivity, indicated by swellings in some primates. Whether females can adjust their sexual receptivity from cycle to cycle to decrease reproductive competition and sexual conflict in response to social pressures has not been tested. As a first step, this study explores whether sexual receptivity duration is predicted by social pressures in wild female chacma baboons (Papio ursinus). Given that female baboons face intense reproductive competition and sexual coercion, we predicted that: females could shorten the duration of their sexual receptive period to reduce female–female aggression and male coercion or increase it to access multiple or their preferred male(s). We quantified 157 ovulatory cycles from 46 wild females living in central Namibia recorded over 15 years. We found no support for our hypothesis; however, our analyses revealed a negative correlation between maximal-swelling duration and group size, a proxy of within-group competition. This study provides further evidence that swelling is costly as well as a testable framework for future investigations of ‘cycle length manipulation’.

ObjectiveWe conducted a systematic review and appraisal of the cross-cultural adaptation and cross-cultural validity of the Health Assessment Questionnaire (HAQ) and its derivatives, and of the more recent Patient-Reported Outcomes Measurement Information System (PROMIS) functional status assessment measures (FSAMs) in rheumatoid arthritis.MethodsFour electronic medical databases were searched from inception until April 4, 2018 according to the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) group search strategy. Included studies were evaluated using the COSMIN tool for cross-cultural validity and were scored as excellent, good, fair, or poor.ResultsOf 58 articles identified by our search strategy and 3 by manual search, 39 were included: 29 described the translation, cultural adaptation, or cross-cultural validity of the HAQ disability index, 8 other HAQ derivatives, and 2 PROMIS measures, representing 22 languages. Of the 39 articles reviewed, 3 examined the cross-cultural validity of translated versions. These studies were rated as follows: 2 as excellent, 3 good, 13 fair, and 21 poor. Two studies examining cross-cultural validity noted differential item functioning (DIF) between Dutch and US populations for the HAQ-II and PROMIS measures, and a third study found DIF between Turkish and UK populations on the HAQ, indicating cultural differences in questionnaire response.ConclusionThis review highlights a paucity of data on the cross-cultural validity of FSAMs and the mostly poor- or fair-quality methods by which they were translated and adapted, which needs to be considered when using these measures for multinational clinical trials and for day-to-day use in clinical practice.

Abstract The purpose was to examine patient-centered outcomes and the occurrence of lung fibrotic changes on Chest computed tomography (CT) imaging following pneumonia-related acute respiratory distress syndrome (ARDS). We sought to investigate outpatient clinic chest CT imaging in survivors of COVID19-related ARDS and non-COVID-related ARDS, to determine group differences and explore relationships between lung fibrotic changes and functional outcomes. A retrospective practice analysis of electronic health records at an ICU Recovery Clinic in a tertiary academic medical center was performed in adult patients surviving ARDS due to COVID-19 and non-COVID etiologies. Ninety-four patients with mean age 53 ± 13 and 51% male were included (n = 64 COVID-19 and n = 30 non-COVID groups). There were no differences for age, sex, hospital length of stay, ICU length of stay, mechanical ventilation duration, or sequential organ failure assessment (SOFA) scores between the two groups. Fibrotic changes visualized on CT imaging occurred in a higher proportion of COVID-19 survivors (70%) compared to the non-COVID group (43%, p

Abstract Correctional officers are critical members of the prison community. However, scholarship rarely considers how correctional officers contribute to prison outcomes instead largely focusing on importation (individual) and deprivation (organizational) factors related to the incarcerated population. This is also true regarding how scholars and practitioners approach suicide committed by incarcerated people, one of the leading causes of death in US carceral institutions. Using quantitative data from confinement facilities across the United States, this study answers the research question: What is the relationship between prison suicide rates and correctional officer gender? Results show that deprivation factors (variables related to the carceral environment) influence prison suicide. Additionally, gender diversity among correctional officers reduces the rate of prison suicide. Implications for future research and practice and limitations of the study are also discussed.

Abstract Background Accelerating declines in tuberculosis (TB) incidence is paramount for achieving global goals set for 2030 by the Sustainable Development Goals and the End TB Strategy. The aim of this study was to identify key country-level social determinants of national TB incidence trends. Methods This longitudinal ecological study used country-level data extracted from online databases from the period 2005–2015. We used multivariable Poisson regression models allowing for distinct within- and between-country effects to estimate associations between national TB incidence rates and 13 social determinants of health. The analysis was stratified by country income status. Results The study sample included 48 low- and lower-middle-income countries (LLMICs) and 68 high- and upper-middle income countries (HUMICs), with a total of 528 and 748 observations between 2005–2015, respectively. National TB incidence rates declined in 108/116 countries between 2005–2015, with an average drop of 12.95% in LLMICs and 14.09% in HUMICs. Between LLMICs, higher Human Development Index (HDI), social protection spending, TB case detection, and TB treatment success were associated with lower TB incidence. Higher prevalence of HIV/AIDS was associated with higher TB incidence. Within LLMICs, increases in HDI over time were associated with lower TB incidence rates. Between HUMICs, higher HDI, health spending, and diabetes prevalence were associated with lower TB incidence, whereas higher prevalence of HIV/AIDS and alcohol-use were associated with higher TB incidence. Within HUMICs, increases in HIV/AIDS and diabetes prevalence over time were associated with higher TB incidence. Conclusions In LLMICs, TB incidence rates remain highest in countries with low human development, social protection spending and TB programme performance, and high rates of HIV/AIDS. Strengthening human development is likely to accelerate declines in TB incidence. In HUMICs, TB incidence rates remain highest in countries with low human development, health spending and diabetes prevalence, and high rates of HIV/AIDS and alcohol use. Here, slowing rising rates of HIV/AIDS and diabetes is likely to accelerate declines in TB incidence.

Background/Context: Black people continue to be popularly imagined as lacking humanity and, as such, are often the disproportionate subjects of unceasing racegender terror and state violence. A vast body of scholarship has documented the failure of schools to adequately serve Black youth in general, and Black boys and men in particular. There is compelling evidence, however, that consistently humanizing interactions with adults in school lead to positive relationships that in turn may protect against Black boys' experience of school as fundamentally dehumanizing. Purpose/Objective/Research Question/Focus of Study: This study examined the significance of positive relationships between Black boys and adults in school as they move(d) across the P--16 education pipeline. The study is guided by the following primary research question: How do young Black men and boys describe and understand their interpersonal relationships with adults in P--16 schools? Research Design: A descriptive phenomenological approach was used to understand how 28 Black boys and young men discuss and describe the characteristics of relationships with adults in their school or university. Seven video- and audiorecorded focus groups were conducted. Data analysis occurred in three phases. Video clips from focus groups were analyzed in the first phase of data analysis. During the second phase of our data analysis, researchers employed critical race theory as a key analytic perspective to interpret the data for what they revealed about the ways anti-Black racism and white supremacy structured schooling experiences. The third phase of analysis centered on coding the entire data set, regardless of grade band, for three specific types of interactions: disciplinary/behavioral, social/relational, and academic. Findings/Results: Key findings from the study center on (a) these participants' keen awareness of the ways their words/behavior/actions are generally misread and misunderstood in U.S. society and (b) the significance of educators' race-gender perceptions of them in building positive relationships that establish and sustain authentic human connections. Conclusions/Recommendations: Human connection emerges over time and differentiates what our participants ultimately perceived as "good"/positive relationships from "bad"/negative relationships with educators. Recognition of the residual consequences of U.S. chattel slavery for the ways we see, know, and understand Black people and Black children is essential to cultivating positive relationships with Black boys. Although "bad" relationships are characterized by interactions reflecting racial misandry that Black boys come to expect as a normal, ordinary feature of their schooling experience, positive relationships are evidenced through consistently humanizing interpersonal interactions with adults that actively counter harmful racial scripts.

Background:. Diabetic foot ulcers (DFUs) pose a significant clinical challenge for providers and patients, and often precede devastating complications such as infection, hospitalization, and amputation. Therefore, advanced treatment options are needed to facilitate the healing of chronic DFUs and improve outcomes in this high-risk population. Cryopreserved viable human amnion membrane allograft (vHAMA) has shown great promise in the treatment of recalcitrant DFUs as a supplement to standard of care (SOC). Placental grafts are rich in extracellular matrix proteins, growth factors, and cytokines, which can induce angiogenesis and dermal fibroblast proliferation, resulting in accelerated healing. Methods:. In this prospective, multicenter single arm trial, 20 patients with nonhealing DFUs received weekly application of vHAMA, in addition to SOC, for up to 12 weeks. The primary study endpoint was proportion of healed wounds at 12 weeks. Secondary endpoints included proportion of wounds healed at 6 weeks, time to heal, and percentage area wound reduction. Subjects were evaluated for ulcer healing and assessed for adverse events at every treatment visit. Results:. At study conclusion, 85% of patients receiving vHAMA healed. Ten wounds healed (50%) by 6 weeks, and 17 wounds (85%) healed by 12 weeks. The mean time to heal was 46.6 days (95% CI: 35.1–58.0), and the average number of vHAMAs used was 5.4 (SD: 3.25). The mean PAR was 86.3% (SD: 40.51). Conclusions:. Aseptically processed, cryopreserved vHAMA should be considered as a safe and effective option for DFUs refractory to SOC therapy.

BackgroundDaily stressors are associated with cognitive decline and increased risk of heart disease, depression, and other debilitating chronic illnesses in midlife adults. Daily stressors tend to occur at home or at work and are more frequent in urban versus rural settings. Conversely, spending time in natural environments such as parks or forests, or even viewing nature-themed images in a lab setting, is associated with lower levels of perceived stress and is hypothesized to be a strong stress “buffer,” reducing perceived stress even after leaving the natural setting. However, many studies of daily stress have not captured environmental contexts and relied on end-of-day recall instead of in-the-moment data capture. With new technology, these limitations can be addressed to enhance knowledge of the daily stress experience. ObjectiveWe propose to use our novel custom-built Stress Reports in Variable Environments (STRIVE) ecological momentary assessment mobile phone app to measure the experience of daily stress of midlife adults in free-living conditions. Using our app to capture data in real time will allow us to determine (1) where and when daily stress occurs for midlife adults, (2) whether midlife adults’ daily stressors are linked to certain elements of the built and natural environment, and (3) how ecological momentary assessment measurement of daily stress is similar to and different from a modified version of the popular Daily Inventory of Stressful Events measurement tool that captures end-of-day stress reports (used in the Midlife in the United States [MIDUS] survey). MethodsWe will enroll a total of 150 midlife adults living in greater Indianapolis, Indiana, in this study on a rolling basis for 3-week periods. As those in underrepresented minority groups and low-income areas have previously been found to experience greater levels of stress, we will use stratified sampling to ensure that half of our study sample is composed of underrepresented minorities (eg, Black, American Indian, Hispanic, or Native Pacific Islanders) and approximately one-third of our sample falls within low-, middle-, and high-income brackets. ResultsThis project is funded by the National Institute on Aging from December 2022 to November 2024. Participant enrollment began in August 2023 and is expected to finish in July 2024. Data will be spatiotemporally analyzed to determine where and when stress occurs for midlife adults. Pictures of stressful environments will be qualitatively analyzed to determine the common elements of stressful environments. Data collected by the STRIVE app will be compared with retrospective Daily Inventory of Stressful Events data. ConclusionsCompleting this study will expand our understanding of midlife adults’ experience of stress in free-living conditions and pave the way for data-driven individual and community-based intervention designs to promote health and well-being in midlife adults. International Registered Report Identifier (IRRID)DERR1-10.2196/51845

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

IntroductionMost cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine.MethodsWe designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform.ResultsVaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells’ ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival.ConclusionsThese findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).