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The DIII-D tokamak has elucidated crucial physics and developed projectable solutions for ITER and fusion power plants in the key areas of core performance, boundary heat and particle transport, and integrated scenario operation, with closing the core-edge integration knowledge gap being the overarching mission. New experimental validation of high-fidelity, multi-channel, non-linear gyrokinetic turbulent transport models for ITER provides strong confidence it will achieve Q ⩾ 10 operation. Experiments identify options for easing H-mode access in hydrogen, and give new insight into the isotopic dependence of transport and confinement. Analysis of 2,1 islands in unoptimized low-torque IBS demonstration discharges suggests their onset time occurs randomly in the constant β phase, most often triggered by non-linear 3-wave coupling, thus identifying an NTM seeding mechanism to avoid. Pure deuterium SPI for disruption mitigation is shown to provide favorable slow cooling, but poor core assimilation, suggesting paths for improved SPI on ITER. At the boundary, measured neutral density and ionization source fluxes are strongly poloidally asymmetric, implying a 2D treatment is needed to model pedestal fuelling. Detailed measurements of pedestal and SOL quantities and impurity charge state radiation in detached divertors has validated edge fluid modelling and new self-consistent ‘pedestal-to-divertor’ integrated modeling that can be used to optimize reactors. New feedback adaptive ELM control minimizes confinement reduction, and RMP ELM suppression with sustained high core performance was obtained for the first time with the outer strike point in a W-coated, compact and unpumped small-angle slot divertor. Advances have been made in integrated operational scenarios for ITER and power plants. Wide pedestal intrinsically ELM-free QH-modes are produced with more reactor-relevant conditions, Low torque IBS with W-equivalent radiators can exhibit predator-prey oscillations in T _e and radiation which need control. High- β _P scenarios with q _min > 2, q _95 –7.9, β _N > 4, β _T –3.3% and H _98y2 > 1.5 are sustained with high density ( $\bar n$ = 7E19 m ^−3 , f _G –1) for 6 τ _E , improving confidence in steady-state tokamak reactors. Diverted NT plasmas achieve high core performance with a non-ELMing edge, offering a possible highly attractive core-edge integration solution for reactors.

Abstract Background The Healthy, Hunger-Free Kids Act of 2010 (P.L. 111-296) prompted the expansion of federal requirements for local school wellness policies, which aim to improve health promoting practices across school districts in the USA. This qualitative study examined how school district superintendents—as key school leaders who are often listed as the district accountability figure for wellness policies applicable to kindergarten through 12th grade—engaged with wellness policy implementation. The inquiry was guided by evidence-informed implementation and leadership frameworks, including the Consolidated Framework for Implementation Research (CFIR) and “bridging, buffering, and brokering” strategies from education leadership theory. Methods We conducted focus groups and interviews with superintendents (n = 39) from 23 states. Interviews were recorded and professionally transcribed; transcripts were team-coded in Atlas.ti v8 using an iteratively revised coding guide that was informed by CFIR, pilot testing, and during weekly analyst meetings. Principles of constant comparative analysis were employed to develop themes. Results Most superintendents’ reported positive perspectives and personal motivations to engage with wellness policy implementation. Within the CFIR process domain, superintendents demonstrated adaptive leadership traits and employed a combination of “bridging, buffering, and brokering” strategies to lead implementation activities. Rather than focus on personal traits, an emphasis on specific strategies highlights actions that may be applied. Conclusions The findings offer practical strategies to support superintendents with implementation, as well as a formative contribution to the dearth of theoretical frameworks in school wellness literature, particularly by advancing the specific understanding of leadership roles within a broader implementation framework. The application of education theory allowed for a deeper inquiry into the potential ways that leaders’ strategies and engagement influences implementation more broadly.

Abstract To protect against the constant threat of inhaled pathogens, the lung is equipped with cellular defenders. In coordination with resident and recruited immune cells, this defence is initiated by the airway and alveolar epithelium following their infection with respiratory viruses. Further support for viral clearance and infection resolution is provided by adjacent endothelial and stromal cells. However, even with these defence mechanisms, respiratory viral infections are a significant global health concern, causing substantial morbidity, socioeconomic losses, and mortality, underlining the need to develop effective vaccines and antiviral medications. In turn, the identification of new treatment options for respiratory infections is critically dependent on the availability of tractable in vitro experimental models that faithfully recapitulate key aspects of lung physiology. For such models to be informative, it is important these models incorporate human-derived, physiologically relevant versions of all cell types that normally form part of the lungs anti-viral response. This review proposes a guideline using human induced pluripotent stem cells (iPSCs) to create all the disease-relevant cell types. iPSCs can be differentiated into lung epithelium, innate immune cells, endothelial cells, and fibroblasts at a large scale, recapitulating in vivo functions and providing genetic tractability. We advocate for building comprehensive iPSC-derived in vitro models of both proximal and distal lung regions to better understand and model respiratory infections, including interactions with chronic lung diseases.

Abstract This article examines whether the patterns of urbanization in China over the past twenty years have resulted in a more balanced or increasingly polarized city size distribution. China is an important study area due to the immense scale of its urbanization and the substantial role of its planners in coordinating and striving for more balanced development patterns. This study utilizes measures of the spatial and temporal characteristics of built-up area (BUA) expansion across 23 urban agglomerations in China, focusing on size dynamics through the urban primacy index and Pareto exponent. The BUA within these 23 UAs increased by 280.90% in the study period. Coastal urban agglomerations were larger in size at baseline and maintained relatively high annual growth rates compared to inland agglomerations, indicating rising polarization. Changes within agglomerations were indicative of declining polarization, as evidenced by the reduction in the urban primacy index and the increase of Pareto exponent. Policies implemented to achieve enhanced urbanization coordination in China appear to be partially successful, but the growth of urban regions with existing large size continues to fuel uneven urban development and polarization.

Acute calcific longus colli tendinitis is a differential diagnosis of neck pain. Typical presentation consists in a triad of symptoms including acute onset neck pain, neck stiffness and odynophagia. Computed tomography (CT) is the gold standard for acute calcific longus colli tendinitis diagnosis and the main radiological findings include prevertebral soft tissue swelling and the presence of amorphous calcifications. The case involves a 39-year-old female who presented to the emergency department with acute unilateral cervical pain that resulted in acute calcific longus colli tendinitis.

Much work has been done to understand and improve soil and water conservation where agriculture has driven land use intensification. Less is known about soil- and water-related impacts from intensification driven by solar farming, especially at watershed-scales. Here we employed Hydrologic Engineering Center's Hydrologic Modeling System (HEC-HMS) to model Pond Creek, a rural watershed in Texas, USA. Land use is primarily crop cultivation and secondarily pasture for cattle grazing. Presently, several industrial-scale projects are planned to convert ≈15–30% of Pond Creek from agriculture to solar farms. The model was parameterized using public data sources and information from local stakeholders, then calibrated to several historical precipitation events. Experiments were conducted by varying precipitation depth, duration, and land uses: native vegetation pre-cultivation (control), cultivation (current), current conditions with 15% solar farm conversion (solar), and current conditions with 30% solar farm conversion (solar x2). Shifting to solar farming led to significant increases in cumulative sediment load (+12%–30%), with no significant differences in peak discharge rate changes (+0.38%–4%). Comparison to soil loss tolerance values showed current and solar treatment erosion rates exceeded tolerance values between 0.17 and 2.29 tons per hectare and all treatments were significantly different than the native treatment. We discuss high leverage strategies applicable to solar farm development sites as well as watersheds where they reside. Accelerating demand for land for renewable energy such as solar farming warrants greater attention from the soil and water conservation community to anticipate and mitigate impacts across landscapes.

IntroductionCancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management.ObjectivesThe main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS).Materials and methodsA population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations.ResultsCC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS.ConclusionsUsing clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

BackgroundSignificant funding and attention are directed toward school-based health and nutrition interventions. Less attention is given to the potential unintended consequences of these policies, especially those that target children and adolescents. This systematic review aimed to elucidate the unintended consequences of school-based health and nutrition policies in the United States.MethodsWe conducted a systematic review, adhering to PRISMA guidelines, to analyze quantitative, qualitative, and mixed methods research conducted between January 2013 and September 2023. The search strategy encompassed three databases, identifying 11 articles that met the inclusion criteria.ResultsUnintended consequences were organized into four themes: disordered weight control behaviors, parental discomfort or encouragement of disordered weight control behaviors, eating disorder triggers, and financial losses. The analysis of disordered weight control behaviors indicates limited impact on youth, and we noted limited consensus in the assessment of these behaviors. We observed parent concerns about BMI screening and reporting as well as apprehensions about privacy and efficacy. There were fewer articles addressing eating disorder antecedents, although there was evidence that some youths with eating disorders considered school health class a trigger of their disorder. One study was identified that found an increase in food waste following replacement of sugar-sweetened beverages.ImplicationsFindings underscore the importance of comprehensive evaluation and consideration of unintended consequences in the development and implementation of school-based health policies. Recommendations include further longitudinal research, integrating obesity prevention with eating disorder prevention, and de-implementation when unintended consequences potentially outweigh benefits, such as in BMI screening and surveillance.Systematic Review Registration: Identifier CRD42023467355. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=467355

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Adoptive immunotherapy with Epstein–Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus. We have developed a peptide-based, virus-free, serum-free closed system to manufacture a bank of virus-specific T cells (VST) for clinical use. We compared these with standard LCL-derived VST using comprehensive characterization and potency assays to determine differences that might influence clinical benefits. Multi-parameter flow cytometry revealed that peptide-derived VST had an expanded central memory population and less exhaustion marker expression than LCL-derived VST. A quantitative HLA-matched allogeneic cytotoxicity assay demonstrated similar specific killing of EBV-infected targets, though peptide-derived EBV T cells had a significantly higher expression of antiviral cytokines and degranulation markers after antigen recall. High-throughput T cell receptor-beta (TCRβ) sequencing demonstrated oligoclonal repertoires, with more matches to known EBV-binding complementary determining region 3 (CDR3) sequences in peptide-derived EBV T cells. Peptide-derived products showed broader and enhanced specificities to EBV nuclear antigens (EBNAs) in both CD8 and CD4 compartments, which may improve the targeting of highly expressed latency antigens in PTLD. Importantly, peptide-based isolation and expansion allows rapid manufacture and significantly increased product yield over conventional LCL-based approaches.

Abstract Background The Interrupted Time Series (ITS) is a robust design for evaluating public health and policy interventions or exposures when randomisation may be infeasible. Several statistical methods are available for the analysis and meta-analysis of ITS studies. We sought to empirically compare available methods when applied to real-world ITS data. Methods We sourced ITS data from published meta-analyses to create an online data repository. Each dataset was re-analysed using two ITS estimation methods. The level- and slope-change effect estimates (and standard errors) were calculated and combined using fixed-effect and four random-effects meta-analysis methods. We examined differences in meta-analytic level- and slope-change estimates, their 95% confidence intervals, p-values, and estimates of heterogeneity across the statistical methods. Results Of 40 eligible meta-analyses, data from 17 meta-analyses including 282 ITS studies were obtained (predominantly investigating the effects of public health interruptions (88%)) and analysed. We found that on average, the meta-analytic effect estimates, their standard errors and between-study variances were not sensitive to meta-analysis method choice, irrespective of the ITS analysis method. However, across ITS analysis methods, for any given meta-analysis, there could be small to moderate differences in meta-analytic effect estimates, and important differences in the meta-analytic standard errors. Furthermore, the confidence interval widths and p-values for the meta-analytic effect estimates varied depending on the choice of confidence interval method and ITS analysis method. Conclusions Our empirical study showed that meta-analysis effect estimates, their standard errors, confidence interval widths and p-values can be affected by statistical method choice. These differences may importantly impact interpretations and conclusions of a meta-analysis and suggest that the statistical methods are not interchangeable in practice.

Tropical cyclones (TCs) produce strong winds and heavy rains accompanied by consecutive events such as landslides and storm surges, resulting in losses of lives and livelihoods, particularly in regions with high socioeconomic vulnerability. To proactively mitigate the impacts of TCs, humanitarian actors implement anticipatory action. In this work, we build upon such an existing anticipatory action for the Philippines, which uses an impact-based forecasting model for housing damage based on eXtreme Gradient Boosting (XGBoost) to release funding and trigger early action. We improve it in three ways. First, we perform a correlation and selection analysis to understand if Philippines-specific features can be left out or replaced with features from open global data sources. Secondly, we transform the target variable (percentage of completely damaged houses) and not yet grid-based global features to a 0.1∘ grid resolution by de-aggregation using Google Open Buildings data. Thirdly, we evaluate XGBoost regression models using different combinations of global and local features at grid and municipality spatial levels. We first introduce a two-stage model to predict if the damage is above 10 % and then use a regression model trained on all or only high-damage data. All experiments use data from 39 typhoons that impacted the Philippines between 2006–2020. Due to the scarcity and skewness of the training data, specific attention is paid to data stratification, sampling, and validation techniques. We demonstrate that employing only the global features does not significantly influence model performance. Despite excluding local data on physical vulnerability and storm surge susceptibility, the two-stage model improves upon the municipality-based model with local features. When applied to anticipatory action, our two-stage model would show a higher true-positive rate, a lower false-negative rate, and an improved false-positive rate, implying that fewer resources would be wasted in anticipatory action. We conclude that relying on globally available data sources and working at the grid level holds the potential to render a machine-learning-based impact model generalizable and transferable to locations outside of the Philippines impacted by TCs. Also, a grid-based model increases the resolution of the predictions, which may allow for a more targeted implementation of anticipatory action. However, it should be noted that an impact-based forecasting model can only be as good as the forecast skill of the TC forecast that goes into it. Future research will focus on replicating and testing the approach in other TC-prone countries. Ultimately, a transferable model will facilitate the scaling up of anticipatory action for TCs.

Abstract Energetic electron precipitation (EEP) from the radiation belts into Earth's atmosphere leads to several profound effects (e.g., enhancement of ionospheric conductivity, possible acceleration of ozone destruction processes). An accurate quantification of the energy input and ionization due to EEP is still lacking due to instrument limitations of low‐Earth‐orbit satellites capable of detecting EEP. The deployment of the Electron Losses and Fields InvestigatioN (ELFIN) CubeSats marks a new era of observations of EEP with an improved pitch‐angle (0°–180°) and energy (50 keV–6 MeV) resolution. Here, we focus on the EEP recorded by ELFIN coincident with electromagnetic ion cyclotron (EMIC) waves, which play a major role in radiation belt electron losses. The EMIC‐driven EEP (∼200 keV–∼2 MeV) exhibits a pitch‐angle distribution (PAD) that flattens with increasing energy, indicating more efficient high‐energy precipitation. Leveraging the combination of unique electron measurements from ELFIN and a comprehensive ionization model known as Boulder Electron Radiation to Ionization (BERI), we quantify the energy input of EMIC‐driven precipitation (on average, ∼3.3 × 10−2 erg/cm2/s), identify its location (any longitude, 50°–70° latitude), and provide the expected range of ion‐electron production rate (on average, 100–200 pairs/cm3/s), peaking in the mesosphere—a region often overlooked. Our findings are crucial for improving our understanding of the magnetosphere‐ionosphere‐atmosphere system as they accurately specify the contribution of EMIC‐driven EEP, which serves as a crucial input to state‐of‐the‐art atmospheric models (e.g., WACCM) to quantify the accurate impact of EMIC waves on both the atmospheric chemistry and dynamics.

IntroductionMyoelectric pattern recognition systems have shown promising control of upper limb powered prostheses and are now commercially available. These pattern recognition systems typically record from up to 8 muscle sites, whereas other control systems use two-site control. While previous offline studies have shown 8 or fewer sites to be optimal, real-time control was not evaluated.MethodsSix individuals with no limb absence and four individuals with a transradial amputation controlled a virtual upper limb prosthesis using pattern recognition control with 8 and 16 channels of EMG. Additionally, two of the individuals with a transradial amputation performed the Assessment for Capacity of Myoelectric Control (ACMC) with a multi-articulating hand and wrist prosthesis with the same channel count conditions.ResultsUsers had significant improvements in control when using 16 compared to 8 EMG channels including decreased classification error (p = 0.006), decreased completion time (p = 0.019), and increased path efficiency (p = 0.013) when controlling a virtual prosthesis. ACMC scores increased by more than three times the minimal detectable change from the 8 to the 16-channel condition.DiscussionThe results of this study indicate that increasing EMG channel count beyond the clinical standard of 8 channels can benefit myoelectric pattern recognition users.

Determining the magnitude and direction of the interstellar magnetic field ( B _ISM ) is a long-standing problem. To date, some methods to infer the direction and magnitude have utilized best-fit models to the positions of the termination shock and heliopause measured by Voyager 1 and 2. Other models use the circularity of the Interstellar Boundary Explorer (IBEX) ribbon assuming a secondary energetic neutral atom (ENA) mechanism. Previous studies have revealed that the B _ISM organizes the orientation of the heliotail with respect to the solar meridian. Here we propose a new way to infer the direction of the B _ISM based on ENA observations of the heliotail. IBEX observations of the heliotail have revealed high-latitude lobes of enhanced ENA flux at energies >2 keV. Analyses showed that the high-latitude lobes are nearly aligned with the solar meridian, while also exhibiting a rotation with solar cycle. We show, using steady-state solar wind conditions, that the inclination of the lobes reproduced with commonly used values for the angle ( α _BV ) between B _ISM and the interstellar flow in the hydrogen deflection plane (40° < α _BV < 60°) is inconsistent with the IBEX ENA observations. We report that 0° < α _BV < 20° best replicates the heliotail lobe inclinations observed by IBEX. Additionally, our model results indicate that the variation of the solar magnetic field magnitude with solar cycle causes the longitudinal rotation of the lobes observed by IBEX by affecting the inclination of the lobes.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years, made possible by publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to overconsumption. We test an innovative, scalable strategy to target ACT-subsidies to clients with a confirmatory diagnosis. We supported malaria testing(mRDTs) in 39 medicine outlets in western Kenya, randomized to three study arms; control arm offering subsidized mRDT testing (0.4USD), client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully-subsidized) ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions, resulting in targeting of ACTs to confirmed malaria cases- 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates(RD = 0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients(RD = 0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. This uncertainty undermines our ability to definitively conclude that client-directed subsidies are not effective for improving testing and appropriate treatment. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain. Trial registration: ClinicalTrials.gov NCT04428307.

BackgroundWhile early autism intervention can significantly improve outcomes, gaps in implementation exist globally. These gaps are clearest in Africa, where forty percent of the world's children will live by 2050. Task-sharing early intervention to non-specialists is a key implementation strategy, given the lack of specialists in Africa. Naturalistic Developmental Behavioral Interventions (NDBI) are a class of early autism intervention that can be delivered by caregivers. As a foundational step to address the early autism intervention gap, we adapted a non-specialist delivered caregiver coaching NDBI for the South African context, and pre-piloted this cascaded task-sharing approach in an existing system of care.ObjectivesFirst, we will test the effectiveness of the caregiver coaching NDBI compared to usual care. Second, we will describe coaching implementation factors within the Western Cape Department of Education in South Africa.MethodsThis is a type 1 effectiveness-implementation hybrid design; assessor-blinded, group randomized controlled trial. Participants include 150 autistic children (18-72 months) and their caregivers who live in Cape Town, South Africa, and those involved in intervention implementation. Early Childhood Development practitioners, employed by the Department of Education, will deliver 12, one hour, coaching sessions to the intervention group. The control group will receive usual care. Distal co-primary outcomes include the Communication Domain Standard Score (Vineland Adaptive Behavior Scales, Third Edition) and the Language and Communication Developmental Quotient (Griffiths Scales of Child Development, Third Edition). Proximal secondary outcome include caregiver strategies measured by the sum of five items from the Joint Engagement Rating Inventory. We will describe key implementation determinants.ResultsParticipant enrolment started in April 2023. Estimated primary completion date is March 2027.ConclusionThe ACACIA trial will determine whether a cascaded task-sharing intervention delivered in an educational setting leads to meaningful improvements in communication abilities of autistic children, and identify implementation barriers and facilitators.Trial registrationNCT05551728 in Clinical Trial Registry (https://clinicaltrials.gov).

Background: Ventriculoperitoneal shunt (VPS) can be placed solely by a neurosurgeon often via an open-laparotomy approach, or laparoscopically as a collaborative effort between a neurosurgeon and a general surgeon. Prior studies have shown conflicting results when examining outcomes regarding infection, revision rate, hospital charges, length of stay, and mortality between the open mini-laparotomy and the laparoscopic approaches. Objective: The current study uses the National Inpatient Sample (NIS) to compare outcomes of open mini-laparotomy vs. laparoscopic collaborative approach in VPS placement. Methods: We performed a retrospective database study of the NIS from October 2015-December 2017 utilizing International Classification of Diseases, 10th Revision coding to identify all cases of VPS placement. All analyses accounted for the sampling design of the NIS. Results: A total of 6580 cases (4969 with open mini-laparotomy approach and 1611 with laparoscopic collaborative approach) met inclusion criteria. Hospital charges, infection rates, and revision rates were similar between approaches. There were no significant differences in length of stay, mortality, or complication rates between the two approaches. Conclusion: The collaborative, laparoscopic approach to VPS placement has similar outcomes and is non-inferior to the traditional open mini-laparotomy approach.

Abstract In the adult sensory cortex, increases in neural activity elicited by sensory stimulation usually drive vasodilation mediated by neurovascular coupling. However, whether neurovascular coupling is the same in neonatal animals as adults is controversial, as both canonical and inverted responses have been observed. We investigated the nature of neurovascular coupling in unanesthetized neonatal mice using optical imaging, electrophysiology, and BOLD fMRI. We find in neonatal (postnatal day 15, P15) mice, sensory stimulation induces a small increase in blood volume/BOLD signal, often followed by a large decrease in blood volume. An examination of arousal state of the mice revealed that neonatal mice were asleep a substantial fraction of the time, and that stimulation caused the animal to awaken. As cortical blood volume is much higher during REM and NREM sleep than the awake state, awakening occludes any sensory-evoked neurovascular coupling. When neonatal mice are stimulated during an awake period, they showed relatively normal (but slowed) neurovascular coupling, showing that that the typically observed constriction is due to arousal state changes. These result show that sleep-related vascular changes dominate over any sensory-evoked changes, and hemodynamic measures need to be considered in the context of arousal state changes.

Abstract Background Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers. Methods The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50–69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation. Results In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million. Conclusions Introducing a single PSA screening test for men aged 50–69 across England and Wales could lead to very high initial secondary-care costs.

Abstract Recyclable and biodegradable microelectronics, i.e., “green” electronics, are emerging as a viable solution to the global challenge of electronic waste. Specifically, flexible circuit boards represent a prime target for materials development and increasing the utility of green electronics in biomedical applications. Circuit board substrates and packaging are good dielectrics, mechanically and thermally robust, and are compatible with microfabrication processes. Poly(octamethylene maleate (anhydride) citrate) (POMaC) – a citric acid-based elastomer with tunable degradation and mechanical properties – presents a promising alternative for circuit board substrates and packaging. Here, we report the characterization of Elastomeric Circuit Boards (ECBs). Synthesis and processing conditions were optimized to achieve desired degradation and mechanical properties for production of stretchable circuits. ECB traces were characterized and exhibited sheet resistance of 0.599 Ω cm−2, crosstalk distance of

Abstract Background Despite the high number of children living with neurodevelopmental disabilities in sub–Saharan Africa, access to early intervention is almost non-existent. It is therefore important to develop feasible, scalable early autism intervention that can be integrated into systems of care. While Naturalistic Developmental Behavioural Intervention (NDBI) has emerged as an evidence-based intervention approach, implementation gaps exist globally, and task-sharing approaches may address access gaps. In this South African proof-of-principle pilot study, we set out to answer two questions about a 12-session cascaded task-sharing NDBI—whether the approach could be delivered with fidelity, and whether we could identify signals of change in child and caregiver outcomes. Methods We utilized a single-arm pre-post design. Fidelity (non-specialists, caregivers), caregiver outcomes (stress, sense of competence), and child outcomes (developmental, adaptive) were measured at baseline (T1) and follow-up (T2). Ten caregiver-child dyads and four non-specialists participated. Pre-to-post summary statistics were presented alongside individual trajectories. Non-parametric Wilcoxon signed rank test for paired samples was used to compare group medians between T1 and T2. Results Caregiver implementation fidelity increased in 10/10 participants. Non-specialists demonstrated a significant increase in coaching fidelity (increases in 7/10 dyads). Significant gains were seen on two Griffiths-III subscales (Language/Communication—9/10 improved, Foundations of Learning—10/10 improved) and on the General Developmental Quotient (9/10 improved). Significant gains were also seen on two Vineland Adaptive Behaviour Scales (Third Edition) subscales (Communication—9/10 improved, Socialization—6/10 improved) and in the Adaptive Behaviour Standard Score (9/10 improved). Caregiver sense of competence improved in 7/10 caregivers and caregiver stress in 6/10 caregivers. Conclusions This proof-of-principle pilot study of the first cascaded task-sharing NDBI in Sub-Saharan Africa provided fidelity and intervention outcome data which supported the potential of such approaches in low-resource contexts. Larger studies are needed to expand on the evidence-base and answer questions on intervention effectiveness and implementation outcomes.

Abstract Background COVID-19 led to a rapid acceleration in the number of systematic reviews. Readers need to know how up to date evidence is when selecting reviews to inform decisions. This cross-sectional study aimed to evaluate how easily the currency of COVID-19 systematic reviews published early in the pandemic could be determined and how up to date these reviews were at the time of publication. Methods We searched for systematic reviews and meta-analyses relevant to COVID-19 added to PubMed in July 2020 and January 2021, including any that were first published as preprints. We extracted data on the date of search, number of included studies, and date first published online. For the search date, we noted the format of the date and where in the review this was reported. A sample of non-COVID-19 systematic reviews from November 2020 served as a comparator. Results We identified 246 systematic reviews on COVID-19. In the abstract of these reviews, just over half (57%) reported the search date (day/month/year or month/year) while 43% failed to report any date. When the full text was considered, the search date was missing from 6% of reviews. The median time from last search to publication online was 91 days (IQR 63–130). Time from search to publication was similar for the subset of 15 rapid or living reviews (92 days) but shorter for the 29 reviews published as preprints (37 days). The median number of studies or publications included per review was 23 (IQR 12–40). In the sample of 290 non-COVID SRs, around two-thirds (65%) reported the search date while a third (34%) did not include any date in the abstract. The median time from search to publication online was 253 days (IQR 153–381) and each review included a median of 12 studies (IQR 8–21). Conclusions Despite the context of the pandemic and the need to easily ascertain the currency of systematic reviews, reporting of the search date information for COVID-19 reviews was inadequate. Adherence to reporting guidelines would improve the transparency and usefulness of systematic reviews to users.

Betatron acceleration is commonly cited as a primary accelerator of energetic electrons at dipolarization fronts, and many case studies compare observed energetic electrons measurements to a betatron model. In this work, we extend this to a statistical study. We identified 168 dipolarizations with an enhanced flux of energetic electrons at Magnetospheric Multiscale (MMS). We compared the observed flux of energetic electrons above 1 keV to a betatron acceleration model assuming a source population similar to the population in the quiet plasma sheet and found that, on average, the model slightly overestimated the observation, but there was a wide spread of errors. We then tested characteristics such as position, change in and strength of magnetic field, and wave power to determine if any of these characteristics affected the accuracy of the model; the only clear correlations were that the model was less accurate when the initial total magnetic field was smaller and when there was a higher Ey during the dipolarization. Since the betatron model did not explain our observations very well, we repeated with a full adiabatic model that included a Fermi acceleration component as well. We found that the adiabatic model slightly underestimated the observations, but with a smaller error than the betatron model under the same assumptions. Testing the same parameters, we found that the adiabatic model also did not strongly rely on any of the parameters except the initial magnetic field, and the anti-correlation with Ey was no longer present. The fact that neither model was generally applicable means that either adiabatic processes alone are not enough to explain electron acceleration at dipolarization fronts in general, or the common assumption we used, that the source population has the same phase space density as the cold pre-existing population, is not valid.

ABSTRACT In an attempt to identify novel bacterial species, microbiologists have examined a wide range of environmental niches. We describe the serendipitous discovery of a novel gram-negative bacterial species from a different type of extreme niche: a purchased vial of antibiotic. The vial of antibiotic hygromycin B was found to be factory contaminated with a bacterial species, which we designate Pseudomonas hygromyciniae sp. nov. The proposed novel species belongs to the P. fluorescens complex and is most closely related to P. brenneri, P. proteolytica, and P. fluorescens. The type strain Pseudomonas hygromyciniae sp. nov. strain SDM007T (SDM007T) harbors a novel 250 kb megaplasmid which confers resistance to hygromycin B and contains numerous other genes predicted to encode replication and conjugation machinery. SDM007T grows in hygromycin concentrations of up to 5 mg/mL but does not use the antibiotic as a carbon or nitrogen source. While unable to grow at 37°C ruling out its ability to infect humans, it grows and survives at temperatures between 4 and 30°C. SDM007T can infect plants, as demonstrated by the lettuce leaf model, and is highly virulent in the Galleria mellonella infection model but is unable to infect mammalian A549 cells. These findings indicate that commercially manufactured antibiotics represent another extreme environment that may support the growth of novel bacterial species. IMPORTANCE Physical and biological stresses in extreme environments may select for bacteria not found in conventional environments providing researchers with the opportunity to not only discover novel species but to uncover new enzymes, biomolecules, and biochemical pathways. This strategy has been successful in harsh niches such as hot springs, deep ocean trenches, and hypersaline brine pools. Bacteria belonging to the Pseudomonas species are often found to survive in these unusual environments, making them relevant to healthcare, food, and manufacturing industries. Their ability to survive in a variety of environments is mainly due to the high genotypic and phenotypic diversity displayed by this genus. In this study, we discovered a novel Pseudomonas sp. from a desiccated environment of a sealed antibiotic bottle that was considered sterile. A close genetic relationship with its phylogenetic neighbors reiterated the need to use not just DNA-based tools but also biochemical characteristics to accurately classify this organism.

Summary: Kinases are important therapeutic targets, and their inhibitors are classified according to their mechanism of action, which range from blocking ATP binding to covalent inhibition. Here, a mechanism of inhibition is highlighted by capturing p21-activated kinase 5 (PAK5) in an intermediate state of activation using an Affimer reagent that binds in the P+1 pocket. PAK5 was identified from a non-hypothesis-driven high-content imaging RNAi screen in urothelial cancer cells. Silencing of PAK5 resulted in reduced cell number, G1/S arrest, and enlargement of cells, suggesting it to be important in urothelial cancer cell line survival and proliferation. Affimer reagents were isolated to identify mechanisms of inhibition. The Affimer PAK5-Af17 recapitulated the phenotype seen with siRNA. Co-crystallization revealed that PAK5-Af17 bound in the P+1 pocket of PAK5, locking the kinase into a partial activation state. This mechanism of inhibition indicates that another class of kinase inhibitors is possible.

Treating cell lines with glucocorticoids offers protection against the damage caused by subsequent exposure to selected bacterial pore-forming toxins, and is dependent on the glucocorticoid receptor.

Designing machine learning hardware on flexible substrates is promising for several applications. Here, the authors propose an integrated smart system built with low-cost flexible electronics components for classifying human malodour, and demonstrates that the proposed system scores malodour as good as expert human assessors.

With the increasing availability of more advanced prostheses individuals with a transradial amputation can now be fit with single to multi-degree of freedom hands. Reliable and accurate control of these multi-grip hands still remains challenging. This is the first multi-user study to investigate at-home control and use of a multi-grip hand prosthesis under pattern recognition and direct control. Individuals with a transradial amputation were fitted with and trained to use an OSSUR i-Limb Ultra Revolution with Coapt COMPLETE CONTROL system. They participated in two 8-week home trials using the hand under myoelectric direct and pattern recognition control in a randomized order. While at home, participants demonstrated broader usage of grips in pattern recognition compared to direct control. After the home trial, they showed significant improvements in the Assessment of Capacity for Myoelectric Control (ACMC) outcome measure while using pattern recognition control compared to direct control; other outcome measures showed no differences between control styles. Additionally, this study provided a unique opportunity to evaluate EMG signals during home use. Offline analysis of calibration data showed that users were 81.5% [7.1] accurate across a range of three to five grips. Although EMG signal noise was identified during some calibrations, overall EMG quality was sufficient to provide users with control performance at or better than direct control.

Soil phosphorus (P) partitioning could contribute to species diversity and structure in plant communities, but field-scale evidence for P partitioning remains scarce. We hypothesized that the presence of P partitioning could be inferred from statistical associations between the spatial distributions of plants and chemical forms of bioavailable soil P. We investigated this in a diverse tropical tree community on Barro Colorado Island, Panama. We quantified potentially bioavailable forms of soil P by extraction in 2 mM citric acid followed by treatment with phosphatase enzymes. We then linked these P forms to the distribution of 189 tree species in a 50 ha forest dynamics plot by testing species–P associations against null models of random dispersal. We found that 20% of tree species were significantly (α = 0.05) associated with the depletion of at least one soil organic P fraction, although around half of these associations might be false rejections of the null hypothesis due to type I error. Species in the Fabaceae (legumes), which are known to express high rates of phosphatase in their roots, were most frequently associated with soil P fractions. We interpret our findings as evidence of widespread P partitioning at the community scale, affecting a relatively small proportion of tree species in this moderately fertile forest. We predict that stronger evidence of partitioning will be found at sites with lower P availability.

Voyager 1 and 2 data from the vicinity of the heliopause and very local interstellar medium are reexamined to better understand the confounding lack of rotation in the magnetic field ( B -field) across the heliopause observed by both Voyagers, despite their very large spatial separations (>100 au). Using three estimates for the orientation of the B -field in the pristine interstellar medium and four models of the heliosphere, we calculate draped interstellar B -field orientations along the model heliopauses and compare those estimates to the Voyager observations. At both Voyagers, expected draped B -fields are inconsistent with the observed B -field orientations after the boundary crossings. Furthermore, we show how the longer-term trends of the observed B -fields at both Voyagers after the crossings actually rotated away from both the expected draped B -field and the pristine interstellar B -field directions. We develop evidence, including an illustrative and analogous set of observations from Magnetospheric Multiscale spacecraft along Earth’s magnetopause, in support of a hypothesis that both Voyagers transited a thick boundary layer of reconnected magnetic flux along the heliopause surface. We estimate that Voyager 1 has not yet fully transited this boundary layer, the radial thickness of which at the Voyager 1 crossing location may be >18 au and likely much thicker. Meanwhile, at Voyager 2's crossing location, the boundary layer is likely much thinner, and for Voyager 2, we present evidence that Voyager 2 might already have transited the boundary layer and entered a region of fields and plasma that were never connected to the Sun—the very local interstellar medium.

Summary: Electron microscopy-based polyclonal epitope mapping (EMPEM) can delineate epitope specificities of serum antibodies to a given antigen following vaccination or infection. Here, we present a protocol for the EMPEM method for rapid high-throughput assessment of antibody responses to glycoprotein antigens in vaccination and infection studies. We describe steps for antibody isolation and digestion, antigen complex and purification, and electron microscope imaging. We then detail procedures for processing and analysis of EMPEM data.For complete details on the use and execution of this protocol, please refer to Bianchi et al. (2018).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The first vulnerability framework for sustainability science was published about two decades ago. It embedded vulnerability analysis into the foundational lens of sustainability and resilience research – the social-environmental system (SES) – and called for an integration of the vulnerabilities of the social and environmental subsystems as opposed to the dominating attention given at the time to societal vulnerability. The framework recognised that the environment itself is vulnerable to disturbances and that the interactions of the two subsystems create a system-wide vulnerability central to questions of sustainability or sustainable development. It also provided multiple components of analysis that should be considered if vulnerability research and assessments were to contribute more fully to sustainability themes. Using bibliometric analysis and attention to subsequent vulnerability publications, various impacts of this original framework on vulnerability studies were examined in the study, including its recognition by citations, citation pathways and fields of study, and the degree to which its various dimensions were employed. It was found that its large citation recognition was not necessarily matched by attention to the dimensions the framework proposed, noting several exceptions. Contribution: The authors interpreted this discrepancy to have followed from the analytical complexity fostered by the framework and to the significant proportion of vulnerability interests that was and remains focused on societal vulnerability as opposed to the social-environmental one, even in this moment in which sustainability in the Anthropocene has become a paramount query.

Summary: Background: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. Methods: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. Findings: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. Interpretation: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. Funding: LSHTM COVID-19 Response Grant (DONAT15912).

Antibodies that broadly inhibit influenza virus neuraminidase by binding to its active site could be therapeutic candidates, but circulating viruses have acquired a glycosylation site in that region. Here, the authors show that, while the S245N glycosylation site affects binding of tested monoclonal antibodies, protective activity in a mouse model is maintained.

Abstract Scanning laser ophthalmoscopes (SLOs) are used widely for reflectance, fluorescence or autofluorescence photography and less commonly for retroillumination imaging. SLOs scan a visible light or near-infrared radiation laser beam across the retina, collecting light from each retinal spot as it’s illuminated. An SLO’s clinical applications, image contrast and axial resolution are largely determined by an aperture overlying its photodetector. High contrast, reflectance images are produced using small diameter, centered apertures (confocal apertures) that collect retroreflections and reject side-scattered veiling light returned from the fundus. Retroillumination images are acquired with annular on-axis or laterally-displaced off-axis apertures that capture scattered light and reject the retroreflected light used for reflectance imaging. SLO axial resolution is roughly 300 μm, comparable to macular thickness, so SLOs cannot provide the depth-resolved chorioretinal information obtainable with optical coherence tomography’s (OCT’s) 3 μm axial resolution. Retroillumination highlights and shades the boundaries of chorioretinal tissues and abnormalities, facilitating detection of small drusen, subretinal drusenoid deposits and subthreshold laser lesions. It also facilitates screening for large-area chorioretinal irregularities not readily identified with other en face retinal imaging modalities. Shaded boundaries create the perception of lesion elevation or depression, a characteristic of retroillumination but not reflectance SLO images. These illusions are not reliable representations of three-dimensional chorioretinal anatomy and they differ from objective OCT en face topography. SLO retroillumination has been a useful but not indispensable retinal imaging modality for over 30 years. Continuing investigation is needed to determine its most appropriate clinical roles in multimodal retinal imaging.

HIV-1 vaccine design aims to induce broadly neutralizing antibodies such as IOMA, the only described antibody in its class. Here, the authors present the isolation, characterisation and structure of three additional antibodies within the IOMA class

Abstract In situ exploration of Uranus has been limited to a single flyby encounter by the Voyager 2 spacecraft in January 1986. Nonetheless, new investigation has led to significant questions about the origin of energetic ions observed in the region between its moons Miranda and Ariel. Radial and pitch angle diffusion modeling suggests that typical magnetospheric sources cannot explain the observed characteristics of these energetic ions. We suggest that these are likely being introduced by a source from one of these moons and give rise to waves that could result in the observed particle distribution characteristics. This may reveal that internal plasma sources in the system may be important for Uranus' magnetospheric dynamics and may contribute to its unexpectedly strong radiation belts.

Abstract On 7 January 2014, a solar storm erupted, which eventually compressed the Earth's magnetosphere leading to the generation of chorus waves. These waves enhanced local wave‐particle interactions and led to the precipitation of electrons from 10 s eV to 100 s keV. This paper shows observations of a low energy cutoff in the precipitation spectrum from Van Allen Probe B Helium Oxygen Proton Electron measurements. This low energy cutoff is well replicated by the predicted loss calculated from pitch angle diffusion coefficients from wave and plasma observations on Probe B. To our knowledge, this is the first time a single spacecraft has been used to demonstrate an accurate theoretical prediction for chorus wave‐induced precipitation and its low energy cutoff. The specific properties of the precipitating soft electron spectrum have implications for ionospheric activity, with the lowest energies mainly contributing to thermospheric and ionospheric upwelling, which influences satellite drag and ionospheric outflow.

The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.

An important question that is being increasingly studied across subdisciplines of Heliophysics is “how do mesoscale phenomena contribute to the global response of the system?” This review paper focuses on this question within two specific but interlinked regions in Near-Earth space: the magnetotail’s transition region to the inner magnetosphere and the ionosphere. There is a concerted effort within the Geospace Environment Modeling (GEM) community to understand the degree to which mesoscale transport in the magnetotail contributes to the global dynamics of magnetic flux transport and dipolarization, particle transport and injections contributing to the storm-time ring current development, and the substorm current wedge. Because the magnetosphere-ionosphere is a tightly coupled system, it is also important to understand how mesoscale transport in the magnetotail impacts auroral precipitation and the global ionospheric system response. Groups within the Coupling, Energetics and Dynamics of Atmospheric Regions Program (CEDAR) community have also been studying how the ionosphere-thermosphere responds to these mesoscale drivers. These specific open questions are part of a larger need to better characterize and quantify mesoscale “messengers” or “conduits” of information—magnetic flux, particle flux, current, and energy—which are key to understanding the global system. After reviewing recent progress and open questions, we suggest datasets that, if developed in the future, will help answer these questions.

Background: Necrotizing soft-tissue infection (NSTI) is a medical emergency. We investigated the impact of racial, socioeconomic disparities, and comorbidities on mortality, complications, length of stay, and charges in patients with NSTI. Methods: Data were acquired from the National Inpatient Sample from Q4 2015 to 2017. ICD-10, Clinical Modification codes were utilized to identify relevant cases. Logistic regression was used to assess socioeconomic, racial, and health risk factors for adverse outcomes in NSTI patients. Results: Of 16,071,053 cases identified during the study period, 15,078 (0.094%) NSTI cases were recognized. Black patients had increased odds of amputation (OR 1.40 95% CI 1.24–1.58, p

Abstract Background There are increasing efforts for the integration of mental health services into primary care settings in low- and middle-income countries. However, commonly used approaches to train primary care providers (PCPs) may not achieve the expected outcomes for improved service delivery, as evidenced by low detection rates of mental illnesses after training. One contributor to this shortcoming is the stigma among PCPs. Implementation strategies for training PCPs that reduce stigma have the potential to improve the quality of services. Design In Nepal, a type 3 hybrid implementation-effectiveness cluster randomized controlled trial will evaluate the implementation-as-usual training for PCPs compared to an alternative implementation strategy to train PCPs, entitled Reducing Stigma among Healthcare Providers (RESHAPE). In implementation-as-usual, PCPs are trained on the World Health Organization Mental Health Gap Action Program Intervention Guide (mhGAP-IG) with trainings conducted by mental health specialists. In RESHAPE, mhGAP-IG training includes the added component of facilitation by people with lived experience of mental illness (PWLE) and their caregivers using PhotoVoice, as well as aspirational figures. The duration of PCP training is the same in both arms. Co-primary outcomes of the study are stigma among PCPs, as measured with the Social Distance Scale at 6 months post-training, and reach, a domain from the RE-AIM implementation science framework. Reach is operationalized as the accuracy of detection of mental illness in primary care facilities and will be determined by psychiatrists at 3 months after PCPs diagnose the patients. Stigma will be evaluated as a mediator of reach. Cost-effectiveness and other RE-AIM outcomes will be assessed. Twenty-four municipalities, the unit of clustering, will be randomized to either mhGAP-IG implementation-as-usual or RESHAPE arms, with approximately 76 health facilities and 216 PCPs divided equally between arms. An estimated 1100 patients will be enrolled for the evaluation of accurate diagnosis of depression, generalized anxiety disorder, psychosis, or alcohol use disorder. Masking will include PCPs, patients, and psychiatrists. Discussion This study will advance the knowledge of stigma reduction for training PCPs in partnership with PWLE. This collaborative approach to training has the potential to improve diagnostic competencies. If successful, this implementation strategy could be scaled up throughout low-resource settings to reduce the global treatment gap for mental illness. Trial registration ClinicalTrials.gov, NCT04282915 . Date of registration: February 25, 2020.

Abstract Background There is little evidence of the influence of dietary patterns on mortality risk among adults 80 years or older (“oldest-old”). We evaluated the association between the Simplified Healthy Eating index (SHE-index) and mortality among Chinese oldest-old. Methods Population-based cohort study from the Chinese Longitudinal Healthy Longevity Survey (CLHLS 1998–2014, n = 35 927), conducted in 22 Chinese provinces, were pooled for analysis. The first seven waves of the CLHLS (1998, 2000, 2002, 2005, 2008–09, 2011–12, and 2013–2014) were utilized, with follow-up to the last wave (2018) (range 0–21 years). The SHE-index was collected in each wave, and was constructed from intake frequency of nine dietary variables, with a higher score indicating better diet quality. Cox proportional hazards model with dietary patterns as a time-varying exposure was employed to analyze the relationship between SHE-index and mortality. Results At baseline, the median age of all participants was 92 years (25th percentile, 85 years; 75th percentile, 100 years). In multivariable models, the hazard ratios (95% confidence intervals) for SHE-index quartile 2, quartile 3 and quartile 4 versus quartile1 were 0.91 (0.88, 0.93), 0.89 (0.86, 0.92) and 0.82 (0.78, 0.85), respectively. Results were generally consistent for men and women and in a large number of sensitivity analyses. Conclusions Healthier eating patterns were associated with a significant reduction in the risk of all-cause mortality among Chinese oldest-old, lending support to the importance of life-long adherence to healthy diet into advanced old age.

Rhenium diboride (ReB2) exhibits high differential strain due to its puckered boron sheets that impede shear deformation. Here, we demonstrate the use of solid solution formation to enhance the Vickers hardness and differential strain of ReB2. ReB2-structured solid solutions (Re0.98Os0.02B2 and Re0.98Ru0.02B2, noted as “ReOsB2” and “ReRuB2”) were synthesized via arc-melting from the pure elements. In-situ high-pressure radial x-ray diffraction was performed in the diamond anvil cell to study the incompressibility and lattice strain of ReOsB2 and ReRuB2 up to ∼56 GPa. Both solid solutions exhibit higher incompressibility and differential strain than pure ReB2. However, while all lattice planes are strengthened by doping osmium (Os) into the ReB2 structure, only the weakest ReB2 lattice plane is enhanced with ruthenium (Ru). These results are in agreement with the Vickers hardness measurements of the two systems, where higher hardness was observed in ReOsB2. The combination of high-pressure studies with experimentally observed hardness data provides lattice specific information about the strengthening mechanisms behind the intrinsic hardness enhancement of the ReB2 system.

Visual stimulation-evoked blood-oxygen-level dependent (BOLD) responses can exhibit more complex temporal dynamics than a simple monophasic response. For instance, BOLD responses sometimes include a phase of positive response followed by a phase of post-stimulus undershoot. Whether the BOLD response during these phases reflects the underlying neuronal signal fluctuations or is contributed by non-neuronal physiological factors remains elusive. When presenting blocks of sustained (i.e. DC) light ON-OFF stimulations to unanesthetized rats, we observed that the response following a decrease in illumination (i.e. OFF stimulation-evoked BOLD response) in the visual cortices displayed reproducible multiple phases, including an initial positive BOLD response, followed by an undershoot and then an overshoot before the next ON trial. This multi-phase BOLD response did not result from the entrainment of the periodic stimulation structure. When we measured the neural correlates of these responses, we found that the high-frequency band from the LFP power (300 – 3000 Hz, multi-unit activity (MUA)), but not the power in the gamma band (30 – 100 Hz) exhibited the same multiphasic dynamics as the BOLD signal. This study suggests that the post-stimulus phases of the BOLD response can be better explained by the high-frequency neuronal signal.

Abstract Agyrotropic electron distributions are frequently taken as an indicator of electron diffusion regions of magnetic reconnection. However, they have also been found at electron‐scale boundaries of the non‐reconnecting magnetopause and are generated by the electron finite gyroradius effect. Here, we present magnetospheric multiscale observations of agyrotropic electron distributions in the foreshock region. These distributions are generated by the electron finite gyroradius effect after magnetic curvature scattering at a thin electron‐scale boundary. Meanwhile, the signatures of magnetic reconnection are absent at this boundary. The test‐particle simulation is adopted to verify the generation of the agyrotropic electron distributions by assuming one‐dimensional magnetic geometry. These observations suggest that agyrotropic electron distributions can be more widely formed at electron‐scale boundaries in space plasma environment.

We highlight the importance of magnetic reconnection at the heliopause, both as one of the key processes driving the interaction between solar and interstellar media, but also as an element of the definition of the heliopause itself. We highlight the main observations that have fed the current debates on the definition, location and shape of the heliopause. We explain that discriminating between the current interpretations of plasma and magnetic field structures near the heliopause necessitates appropriate measurements which are lacking on Voyager 1 and 2, and describe some of the ensuing requirements for thermal plasma measurements on a future Interstellar Probe. The content of this article was submitted as a white paper contribution to the Decadal Survey for Solar and Space Physics 2024–2033 of the National Academy of Sciences.

Abstract Accurately mapping the evolving bathymetry under energetic wave breaking is challenging, yet critical for improving our understanding of sandy beach morphodynamics. Though remote sensing is one of the most promising opportunities for reaching this goal, existing depth‐inversion algorithms using linear approaches face major theoretical and/or technical issues in the surf zone, limiting their accuracy over this region. Here, we present a new depth‐inversion approach relying on Boussinesq theory for quantifying nonlinear dispersion effects in nearshore waves. Using high‐resolution datasets collected in the laboratory under diverse wave conditions and beach morphologies, we demonstrate that this approach results in enhanced levels of accuracy in the surf zone (errors typically within 10%) and presents a major improvement over linear methods. The new nonlinear depth‐inversion approach provides significant prospects for future practical applications in the field using existing remote sensing technologies, including continuous lidar scanners and stereo‐imaging systems.