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The ever-increasing importance of irrigation monitoring and water-use optimization in agriculture calls for new solutions for a more complete understanding of the plant growth dynamic and the agricultural water cycle. In this study, the fitness for use of the Flower Power low-cost sensors, not designed for scientific applications, is evaluated in an integrated agricultural monitoring context in contrast to freely available satellite information from Landsat 8, Sentinel 1 and 2. Measurements of air temperature, solar radiation, leaf area index (LAI) and soil moisture are considered. 456 sensors have been deployed in the Capitanata Irrigation Consortium (Italy) as part of the GROW Observatory project with local farmers collaborating as citizen scientists to either deploy these sensors, monitor the environmental variables and control irrigation management. The main results are: (i) positive agreement between Flower Power sensors and high-quality professional stations for measurements of meteorological variables (5.6°C RMSE for Air Temperature); (ii) acceptable estimates of crops LAI (RMSE = 0.55 m2 m−2) and mixed ones of Surface Soil Moisture (m = 0.75, R2 = 0.23) from Flower Power sensors in respect to different satellite data; (iii) potentiality of these sensors combined with remote sensing in providing suitable tools for irrigation management.

In response to the adoption of Agile practices and processes by businesses, IT/IS educators are working to add Agile content to their courses. Teaching students about Agile involves teaching them about the history, mindset, and values of Agile, along with an introduction to the practices and processes used in an Agile product. Along with this, it is essential that students gain experience using Agile in a project setting. This paper discusses an Agile practice project where students use all aspects of Agile to address a problem and build a solution using Legos. The use of Legos, along with a project that students can easily see themselves using, the practice project allows students to focus on developing their Agile skills and mindset. The project serves as a useful transition from traditional classroom instruction about Agile to a project for a real-world client.

In 2009, the International Soil Moisture Network (ISMN) was initiated as a community effort, funded by the European Space Agency, to serve as a centralised data hosting facility for globally available in situ soil moisture measurements (Dorigo et al., 2011b, a). The ISMN brings together in situ soil moisture measurements collected and freely shared by a multitude of organisations, harmonises them in terms of units and sampling rates, applies advanced quality control, and stores them in a database. Users can freely retrieve the data from this database through an online web portal (https://ismn.earth/en/, last access: 28 October 2021). Meanwhile, the ISMN has evolved into the primary in situ soil moisture reference database worldwide, as evidenced by more than 3000 active users and over 1000 scientific publications referencing the data sets provided by the network. As of July 2021, the ISMN now contains the data of 71 networks and 2842 stations located all over the globe, with a time period spanning from 1952 to the present. The number of networks and stations covered by the ISMN is still growing, and approximately 70 % of the data sets contained in the database continue to be updated on a regular or irregular basis. The main scope of this paper is to inform readers about the evolution of the ISMN over the past decade, including a description of network and data set updates and quality control procedures. A comprehensive review of the existing literature making use of ISMN data is also provided in order to identify current limitations in functionality and data usage and to shape priorities for the next decade of operations of this unique community-based data repository.

First-year teachers often experience tensions between their visions of high-quality and equitable mathematics instruction and the realities of school culture and politics. Subsequently, first-year teachers need a professional learning space where they can be supported in enacting their instructional visions while developing their professional voices. In this paper, we share the voices of four first-year teachers and how a community of practice supported them to navigate the individual challenges of their classroom practices. Findings from this study yielded two major themes: 1) the community of practice supported them to reflect, envision, and articulate alternative realities; and 2) instructional visions were filters that empowered them to strengthen their professional voices while developing as equitable mathematics teachers.

In the United States, 16.6 million adults are unable to comprehend sentences or read common documents, thereby limiting their ability to participate in a literate society. Given the consequences of low literacy, we conducted a single-case study with adult multilingual learners to test the effectiveness of a game app, Codex: The Lost Words of Atlantis, on word decoding. The analyses of the pilot study showed moderate to large effect sizes on phonological decoding of taught and untaught words and large and statistically significant increases from pre-test to post-test on five distal reading measures. These results suggest the app may support adult multilingual learners in learning to decode common English words.

The decline of the woodland caribou population is a result of their habitat loss. To conserve the habitat of the woodland caribou and protect it from extinction, it is critical to accurately characterize and monitor its habitat. Conventionally, products derived from low to medium spatial resolution remote sensing data, such as land cover classification and vegetation indices are used for wildlife habitat assessment. These products fail to provide information on the structure complexities of forest canopies which reflect important characteristics of caribou’s habitats. Recent studies have employed the LiDAR system (Light Detection And Ranging) to directly retrieve the three dimensional forest attributes. Although promising results have been achieved, the acquisition cost of LiDAR data is very high. In this study, utilizing the very high spatial resolution imagery in characterizing the structural development the of forest canopies was exploited. A stand based image texture analysis was performed to predict forest succession stages. The results were demonstrated to be consistent with those derived from LiDAR data.

This study aimed to investigate the effects of Storytelling Narrated Videos (SNV) on students’ knowledge retention and transferability. A total of 56 students from a university in Indonesia were randomly assigned to a quasi-experimental research design exposed to SNV and to Lecture Narrated Videos (LNV). Two videos were created to deliver content on Bloom’s Taxonomy, one using a lecture-style format and the other adopting a storytelling approach. Data were collected through tests, questionnaires, and essays. The findings revealed that participants exposed to SNV had higher retention memory scores, indicating a positive impact on knowledge retention compared to those who watched LNV. Moreover, the storytelling videos facilitated cognitive skill progression, enhanced understanding through engaging visuals, and fostered a strong connection with a familiar narrator, resulting in a more dynamic and memorable learning experience. The study also examined knowledge transfer and found that participants who watched the storytelling videos performed better in applying Bloom’s Taxonomy concepts to planning teaching objectives in the essay test. This suggests that the incorporation of storytelling narration and promoting transfer knowledge activities can enhance students’ understanding, retention, and practical application of the learned material. Overall, the findings highlight the potential of incorporating storytelling in narrated videos to improve students’ knowledge retention, transferability, and engagement in educational settings.

Recent reports of upconversion and white light emission from graphitic particles warrant an explanation of the physics behind the process. A model is offered, wherein the upconversion is facilitated by photoinduced electronic structure modification allowing for multiphoton processes. As per the prediction of the model, it is experimentally shown that graphite upconverts infrared light centered around 1.31 μm (0.95 eV) to broadband white light centered around 0.85 μm (1.46 eV). The results suggest that upconversion from shortwave infrared (≈3 μm, 0.45 eV) to visible region may be possible. The experiments show that the population dynamics of the electronic states involved in this upconversion process occur in the timescale of milliseconds.

Summary: Triple-negative breast cancer (TNBC) is characterized by lack of the estrogen (ER) receptor, progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), and standard receptor-targeted therapies are ineffective. FOXC1, a transcription factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are regulated in parallel by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER + breast cancer.

This qualitative study investigated how mixed-reality simulations supported the development of justice-oriented core teaching practices within a large elementary education program. Told from the point-of-view of two methods instructors, using candidates' written and oral reflections, the authors examined the use of Mursion[R] mixed reality simulation software as a tool for rehearsing to teach content through a justice-oriented lens. Three themes emerged from the words of the teacher candidates in the focus group, as well as in their written reflections after completing each of the simulation cycles during their coursework: (a) simulations provided a safety net for students (and their teachers) in PK-12 schools; (b) simulations made the learning of these core practices focused on skill development (versus classroom management) and thus less messy; and (c) simulations provided a safe space to apply justice-oriented lenses while engaging students in content. Simulations augmented the candidates' field experience, while providing a window on their development as teachers committed to becoming change agents enacting just and equitable learning. Implications and the limitations of using simulations to support teacher candidate learning are discussed, particularly when the goal is teaching for equity.

Abstract The growing field of quantum information technology requires propagation of information over long distances with efficient readout mechanisms. Excitonic quantum fluids have emerged as a powerful platform for this task due to their straightforward electro-optical conversion. In two-dimensional transition metal dichalcogenides, the coupling between spin and valley provides exciting opportunities for harnessing, manipulating, and storing bits of information. However, the large inhomogeneity of single layers cannot be overcome by the properties of bright excitons, hindering spin-valley transport. Nonetheless, the rich band structure supports dark excitonic states with strong binding energy and longer lifetime, ideally suited for long-range transport. Here we show that dark excitons can diffuse over several micrometers and prove that this repulsion-driven propagation is robust across non-uniform samples. The long-range propagation of dark states with an optical readout mediated by chiral phonons provides a new concept of excitonic devices for applications in both classical and quantum information technology.

This scoping review identifies the mechanistic pathways of metformin when used to treat head and neck cancer cells, in the pre-clinical setting. Understanding the underlying mechanisms will inform future experimental designs exploring metformin as a potential adjuvant for head and neck cancer. This scoping review was conducted according to the Joanna-Briggs Institute framework. A structured search identified 1288 studies, of which 52 studies fulfilled the eligibility screen. The studies are presented in themes addressing hallmarks of cancer. Most of the studies demonstrated encouraging anti-proliferative effects in vitro and reduced tumor weight and volume in animal models. However, a few studies have cautioned the use of metformin which supported cancer cell growth under certain conditions.

Abstract Objectives To analyze and synthesize the reported psychometric properties of the Fertility Quality of Life (FertiQoL) instrument and describe its implications for use in practice and research in men and women with infertility. Methods A systematic literature search was performed to identify all articles using the FertiQoL tool. PubMed, CINAHL, and PsycINFO were searched from September 2006 through May 2022. Studies were eligible for inclusion if they reported psychometric data on the original FertiQoL tool using a sample population of individuals with infertility. Sample size, country of origin, and psychometric data were documented for each study. Results The initial search revealed 153 articles that had utilized the FertiQoL. Following abstract, title, and full-text screenings, 53 articles reported psychometric data and met criteria for inclusion. The FertiQoL is a sound measurement with satisfactory reliability and validity. Studies indicated adequate reliability in the overall scale ( $$\alpha=0.43-0.92$$ α = 0.43 - 0.92 ), as well as the core Emotional, Mind/Body, Social, and Relational scales ( $$\alpha=0.43-0.92$$ α = 0.43 - 0.92 ) and two optional Tolerability and Environment fertility treatment subscales ( $$\alpha=0.67-0.91$$ α = 0.67 - 0.91 ). Although the Relational subscale exhibited slightly lower reliability in several studies, the internal consistency for the measurement as a whole was satisfactory. Results also indicate adequate: 1) face and content validity with extensive professional and patient feedback during development; 2) convergent validity with general quality of life, depression, and anxiety measurements; and 3) structural validity using both confirmatory and exploratory factor analyses. Conclusion The FertiQoL tool is the most commonly used instrument to measure the impact of fertility issues on quality of life in men and women with infertility. Understanding the impact of infertility on quality of life provides valuable insight into the areas of infertility-related care that need to be prioritized, such as mental health or relational stressors. While the instrument has been used in different patient populations with infertility and available in multiple translations, it is necessary to understand the updated psychometric properties and the implications for its use. This review shows that the FertiQoL is reliable and valid for cross-cultural use among individuals with various etiologies of infertility.

Abstract Bilayer materials made of 2D monolayers are emerging as new systems creating diverse opportunities for basic research and applications in optoelectronics, thermoelectrics, and topological science among others. Herein, we present a computational bilayer materials dataset containing 760 structures with their structural, electronic, and transport properties. Different stacking patterns of each bilayer have been framed by analyzing their monolayer symmetries. Density functional theory calculations including van der Waals interactions are carried out for each stacking pattern to evaluate the corresponding ground states, which are correctly identified for experimentally synthesized transition metal dichalcogenides, graphene, boron nitride, and silicene. Binding energies and interlayer charge transfer are evaluated to analyze the interlayer coupling strength. Our dataset can be used for materials screening and data-assisted modeling for desired thermoelectric or optoelectronic applications.

Coherent Smith-Purcell (SP) radiation originating from three different gratings has been measured at End Station A, SLAC, and has been used to reconstruct the time profile of the electron bunches. The beam energy during these experiments was 28.5 GeV (γ≅55 773) and the number of electrons in the bunch was 0.9–1.4×10^{10}. The spectral distribution of the radiated energy was measured by means of an array of 11 pyroelectric detectors. Typical values of the FWHM of the bunch length are about 2.5 ps, but sharper peaks with FWHM less than 2.0 ps have also been observed. The longitudinal profile also varies with accelerator conditions and can best be approximated by a superposition of 3–4 Gaussian curves. Some typical profiles are presented, together with a discussion of the limitations and strengths of coherent SP radiation as a diagnostic tool. It is concluded that SP radiation offers excellent prospects in this respect, not only in the picosecond range, but potentially in the femtosecond range as well.

BackgroundStroke is a common cause of mortality and morbidity. Insufficient and untimely rehabilitation has been associated with inadequate recovery. Telerehabilitation provides an opportunity for timely and accessible services for individuals with stroke, especially in remote areas. Telerehabilitation is defined as a health care team's use of a communication mode (eg, videoconferencing) to remotely provide rehabilitation services. Telerehabilitation is as effective as facility-based rehabilitation; however, it is infrequently used due to implementation barriers. ObjectiveThe aim of the study is to explore the interaction between the implementation strategies, context, and outcomes of telerehabilitation of patients with stroke. MethodsThis review will follow four steps: (1) defining the review scope, (2) literature search and quality appraisal, (3) data extraction and evidence synthesis, and (4) narrative development. PubMed via MEDLINE, the PEDro database, and CINAHL will be queried till June 2023 and supplemented with citation tracking and a gray literature search. The relevance and rigor of papers will be appraised using the TAPUPAS (Transparency, Accuracy, Purposivity, Utility, Propriety, Accessibility, and Specificity) and Weight of Evidence frameworks. The reviewers will extract and synthesize data iteratively and develop explanatory links between contexts, mechanisms, and outcomes. The results will be reported according to the Realist Synthesis publication standards set by Wong and colleagues in 2013. ResultsThe literature search and screening will be completed in July 2023. Data extraction and analysis will be completed in August 2023, and findings will be synthesized and reported in October 2023. ConclusionsThis will be the first realist synthesis, uncovering the causal mechanisms to explain how, why, and to what extent implementation strategies impact telerehabilitation adoption and implementation. International Registered Report Identifier (IRRID)PRR1-10.2196/47009

Abstract High catalytic efficiency and long‐term stability are two main components for the performance assessment of an electrocatalyst. Previous attention has been paid more to efficiency other than stability. The present work is focused on the study of the stability processed on the FeCoNiRu high‐entropy alloy (HEA) in correlation with its catalytic efficiency. This catalyst has demonstrated not only performing the simultaneous hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) with high efficiency but also sustaining long‐term stability upon HER and OER. The study reveals that the outstanding stability is attributed to the spinel oxide surface layer developed during evolution reactions. The spinel structure preserves the active sites that are inherited from the HEA's intrinsic structure. This work will provide an insightful direction/pathway for the design and manufacturing activities of other metallic electrocatalysts and a benchmark for the assessment of their efficiency–stability relationship.

Animal welfare is a priority across accredited zoological institutions; however, historically, research has been prioritized for mammals. Bird-focused studies accounted for less than 10% of welfare research in zoos and aquariums over the last ten years. Due to the lack of scientific publications on bird welfare, zoo scientists and animal practitioners can look to other industries such as agriculture, laboratories, and companion animal research for insight. This qualitative review highlights findings across industries to inform animal care staff and scientists on the welfare needs of birds within zoos and aquariums. Specifically, the review includes an overview of research on different topics and a summary of key findings across nine resources that affect bird welfare. We also highlight areas where additional research is necessary. Future welfare research in zoos and aquariums should prioritize studies that consider a diversity of bird species across topics and work to identify animal-based measures with empirical evidence. Moving forward, research from other industries can help develop innovative research on bird welfare within zoos and aquariums.

Purpose: Infections caused by non-tuberculous mycobacterium (NTM) are increasing, less well-known by health care clinicians, and usually require long term treatment with multiple antimicrobials. There is no existing evidence on clinical pharmacists’ involvement in the care of patients with NTM infections. We sought to characterize pharmacists’ interventions in providing medication management for patients with NTM infections. Methods: A retrospective review of patients aged 18 years or older seen by a pharmacist specializing in NTM from January 1, 2018 through June 1, 2020 was performed. Charts were reviewed for drug therapy problems identified by a pharmacist. Details regarding therapeutic drug monitoring (TDM) and subsequent dose adjustments were obtained. Results: Seventy-seven patients were included. Median age was 68.5 years, and most patients were female. The most common mycobacterium species treated was Mycobacterium avium/intracellulare complex. Majority of pharmacist consults (63.6%) were referred by Pulmonology physicians, with remainder by Infectious Diseases clinicians. Identified drug therapy problems included: needs additional therapy (23%), unnecessary therapy (24.3%), different drug needed (6.8%), dose too low (75.7%), dose too high (20.3%), adverse drug reaction (31.1%), and adherence (8.1%). Fifteen patients had TDM performed during treatment. A clinical pharmacist was involved in evaluation of all TDM results. Over half of patients with TDM levels had at least 1 dose change made. A minority of patients (16.9%) experienced clinical failure. Conclusion: Clinical pharmacists should be involved in this complex care to optimize medication management through identification of drug interactions, tailoring antimicrobial dosing, managing TDM results, and providing adherence counseling.

Background Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies.Methods Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers.Results High rates of grade 3–4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127−GARP− T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse.Conclusions Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3–4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation.Trial registration number NCT01176474 and NCT02970981.

Cell penetrating peptides (CPPs) are a promising technology for therapeutic delivery of macromolecular cargos. CPPs have generally used covalent linkages to cargo, ensuring a common fate as one molecule. Conversely, our CPP-adaptor, TAT-CaM, noncovalently binds calmodulin binding sequence (CBS)-containing cargos in calcium rich media then dissociates in the calcium-poor endosomal environment following internalization, enhancing endosomal escape relative to standard CPPs. In this study, we report cell entry of positively charged protein cargos that were not increased by TAT-CaM while cargos based on the negatively charged maltose binding protein (MBP) displayed little intrinsic internalization but were internalized by TAT-CaM. In addition, association of positively charged proteins with negatively charged nucleic acids reduced internalization. This evidence points to the dominant role cargo charge plays in apparent CPP effectiveness. There has been little systematic investigation as to how interaction between CPPs and cargos impacts internalization efficiency. Our adaptors provide a tool that allows combinatorial assays to detect emergent properties. Toward this end we added 4 endolytic peptide (EP) sequences between cargo CBS and MBP moieties to create 4 new cargos and between TAT and CaM to create 4 new adaptors. The new cargos were assayed for internalization alone and with a panel of CPP-adaptors to identify combinations that displayed increased internalization efficiency or other properties. Among the most important results, addition of the EP LAH4 improved adaptor performance and provided some CPP capability to cargos. MBP-LAH4-CBS was internalized more effectively by most adaptors, suggesting this sequence has general stimulatory ability. Two other EPs, Aurein 1.2 and HA2, also provided some CPP capability to their MBP cargos but were unexpectedly antagonistic to internalization by most adaptors due to retention of adaptor/cargo complexes on the cell surface. We thus identified LAH4 as stimulator of internalization in both adaptors and cargos and uncovered new functionality for Aurein 1.2 and HA2, which may be related to their identification as EPs. Future experiments will test new endolytic capabilities made possible with combinatorial approaches.

MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4+ T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.

Blueberries are an important fruit crop in the Ericaceae represented by multiple Vaccinium species and ecotypes. In addition to their economic value, blueberry fruit is known for an abundance of specialized metabolites with known human health benefits. Phenolic compounds, which include flavonoids and anthocyanins, are an important class of compounds found in blueberry that are known to contribute to fruit flavor and quality and for having health-promoting properties. Previous surveys of phenolic compounds in blueberry have demonstrated considerable variability in concentration of these metabolites, which is associated with differences in environmental factors and cultivars surveyed. This study expands this knowledge by surveying total phenolic, flavonoid, and anthocyanin content in ripe fruits of 71 blueberry cultivars from one growing season in Michigan. Included in this diversity panel are three ecotypes of blueberry (northern highbush, southern highbush, and half highbush). Rubel, Legacy, and Friendship were among the seven cultivars with the highest content of each compound. Total phenolic content showed a 5.03-fold difference among the lowest and highest cultivars, and total flavonoid content and total anthocyanin content demonstrated a 2.66-fold and 6.37-fold difference between the lowest and highest content across cultivars, respectively. There was no significant impact of ecotype on phytochemical composition of ripe fruits. This study also represents the first large-scale analysis of total phenolic content using the Fast Blue BB (FBBB) reagent. Data from this study have the potential to aid in future breeding efforts to enhance the human health benefits of this economically important fruit crop.

Abstract Background Patients living in more deprived localities have lower cancer survival in England, but the role of individual health status at diagnosis and the utilisation of primary health care in explaining these differentials has not been widely considered. We set out to evaluate whether pre-existing individual health status at diagnosis and primary care consultation history (peri-diagnostic factors) could explain socio-economic differentials in survival amongst women diagnosed with breast cancer. Methods We conducted a retrospective cohort study of women aged 15–99 years diagnosed in England using linked routine data. Ecologically-derived measures of income deprivation were combined with individually-linked data from the English National Cancer Registry, Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) databases. Smoking status, alcohol consumption, BMI, comorbidity, and consultation histories were derived for all patients. Time to breast surgery was derived for women diagnosed after 2005. We estimated net survival and modelled the excess hazard ratio of breast cancer death using flexible parametric models. We accounted for missing data using multiple imputation. Results Net survival was lower amongst more deprived women, with a single unit increase in deprivation quintile inferring a 4.4% (95% CI 1.4–8.8) increase in excess mortality. Peri-diagnostic co-variables varied by deprivation but did not explain the differentials in multivariable analyses. Conclusions These data show that socio-economic inequalities in survival cannot be explained by consultation history or by pre-existing individual health status, as measured in primary care. Differentials in the effectiveness of treatment, beyond those measuring the inclusion of breast surgery and the timing of surgery, should be considered as part of the wider effort to reduce inequalities in premature mortality.

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.

The magnetic proximity effect (MPE) has recently been explored to manipulate interfacial properties of two-dimensional (2D) transition metal dichalcogenide (TMD)/ferromagnet heterostructures for use in spintronics and valleytronics. However, a full understanding of the MPE and its temperature and magnetic field evolution in these systems is lacking. In this study, the MPE has been probed in Pt/WS2/BPIO (biphase iron oxide, Fe3O4 and α-Fe2O3) heterostructures through a comprehensive investigation of their magnetic and transport properties using magnetometry, four-probe resistivity, and anomalous Hall effect (AHE) measurements. Density functional theory (DFT) calculations are performed to complement the experimental findings. We found that the presence of monolayer WS2 flakes reduces the magnetization of BPIO and hence the total magnetization of Pt/WS2/BPIO at T > ~120 K—the Verwey transition temperature of Fe3O4 (TV). However, an enhanced magnetization is achieved at T < TV. In the latter case, a comparative analysis of the transport properties of Pt/WS2/BPIO and Pt/BPIO from AHE measurements reveals ferromagnetic coupling at the WS2/BPIO interface. Our study forms the foundation for understanding MPE-mediated interfacial properties and paves a new pathway for designing 2D TMD/magnet heterostructures for applications in spintronics, opto-spincaloritronics, and valleytronics.

People who live in more deprived areas have poorer health outcomes, and this inequality is a major driver of health and social policy. Many interventions targeting these disparities implicitly assume that poorer health is predominantly associated with area-level factors, and that these inequalities are the same for men and women. However, health differentials due to individual socio-economic status (SES) of men and women are less well documented. We used census data linked to the ONS Longitudinal Study to derive individual-level SES in terms of occupation, education and estimated wage, and examined differences in adult mortality and life expectancy. We modelled age-, sex- and SES-specific mortality using Poisson regression, and summarised mortality differences using life expectancy at age 20. We compared the results to those calculated using area-level deprivation metrics. Wide inequalities in life expectancy between SES groups were observed, although differences across SES groups were smaller for women than for men. The widest inequalities were found across men's education (7.2-year (95% CI: 3.0–10.1) difference in life expectancy between groups) and wage (7.0-year (95% CI: 3.5–9.8) difference), and women's education (5.4-year (95% CI: 2.2–8.1) difference). Men with no qualifications had the lowest life expectancy of all groups. In terms of the number of years' difference in life expectancy, the inequalities measured here with individual-level data were of a similar magnitude to inequalities identified previously using area-level deprivation metrics. These data show that health inequalities are as strongly related to individual SES as to area-level deprivation, highlighting the complementary usefulness of these different metrics. Indeed, poor outcomes are likely to be a product of both community and individual influences. Current policy which bases health spending decisions on evidence of inequalities between geographical areas may overlook individual-level SES inequalities for those living in affluent areas, as well as missing important sex differences.

Objectives Most research on health inequalities uses aggregated deprivation scores assigned to the small area where the patient lives; however, the concordance between aggregate area-level deprivation measures and personal deprivation experienced by individuals living in the area is poorly understood. Our objective was to examine the agreement between individual and ecological deprivation. We tested the concordance between metrics of income, occupation and education at individual and area levels, and assessed the reliability of area-based deprivation measures to predict individual deprivation circumstances.Setting England and Wales.Participants A cancer patient cohort of 9547 individuals extracted from the Officefor National Statistics Longitudinal Study.Outcomes We quantified the concordance between measures of income, occupation and education at individual and area level. In addition, we used ROC (receiveroperating characteristic) curves and the area under the curve (AUC) to assess the reliability of area-based deprivation measures to predict individual deprivation circumstances.Results We found low concordance between individual-level and area-level indicators of deprivation (Cramer’s V statistics range between 0.07 and 0.20). The most commonly used indicator in health inequalities research, area-based income deprivation, was a poor predictor of individual income status (AUC between 0.56 and 0.59), whereas education and occupation were slightly better predictors (AUC between 0.62 and 0.65). The results were consistent across sexes and across six major cancer types.Conclusions Our results indicate that ecological deprivation measures capture only part of the relationship between deprivation and health outcomes, especially with respect to income measurement. This has important implications for our understanding of the relationship between deprivation and health, and, as a consequence, healthcare policy. The results have a wide-reaching impact for the way in which we measure and monitor inequalities, and in turn, fund and organise current UK healthcare policy aimed at reducing them.

BackgroundHigh C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma.MethodsThe effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay.ResultsIn vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients.ConclusionsThese findings suggest that high levels of CRP induce an immunosuppressive milieu in melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer.Trial registration numberNCT01783938 and NCT02983006.

The impact of the capitulum weevil Eustenopus villosus on Centaurea solstitialis seed production was examined at two field sites in central California. The study occurred in 1993–1995 during the early phases of the biological control program on C. solstitialis and before the current guild of capitulum insects had become widespread. Results showed that adult feeding on early flower buds resulted in 60–70% of buds failing to develop. Regrowth delayed capitulum production by 9 days and extended production by 4 weeks at season end. Between 69% and 92% of capitula were punctured from feeding or oviposition but the occurrence of larvae in capitula ranged from 27% to 49%. Seed production in C. solstitialis capitula increased linearly with size. The occurrence of larvae was proportionally higher in larger capitula (>8 mm) but the probability of attack for individual capitula did not vary with plant size. Total seed loss from larval feeding ranged from 34 to 47%. It is recommended that another survey be performed to determine if the level of infestation of E. villosus has increased since its initial introduction.