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K-12 schools are a major sector for efforts to prevent and treat student mental health problems. In the United States, these efforts have led to the emergence of the MultiTiered System of Supports (MTSS) universal prevention, early intervention, and treatment policy framework. With a major focus on behavioral and mental health, MTSS has been adopted by all fifty state education departments. However, multi-level complexities of addressing student mental health within and across organizational structures complicate MTSS and broader policy development, implementation, and evaluation; disconnects between policy writers and practitioners obstruct progress, limiting positive outcomes. To bridge these policy-to-practice gaps, a multi-component solution is needed. The authors propose integrating the following elements: the Massachusetts School Mental Health Consortium's Five Guiding Principles for Building a Coordinated School Mental Health System, the comprehensive school improvement methodology Evolutionary Systems Improvement (ESI); and the ontological framework of BioPsychoSocioTechnical Systems Theory (BPST). Individual application of these components has already yielded systems-level improvements outperforming compliance-driven procedures. Used together, these components offer a multi-level solution for establishing conceptually-guided, measurement-based loops that transcend the restrictions of uninformed policy, supporting stakeholders as they work to systematically eliminate barriers and improve student mental health.

This study explores the lived experience of both in-service and pre-service apprentices studying Level 7 apprenticeship programmes. Using qualitative questionnaires, this article facilitates a thematic analysis exploring how aspects such as: rationale for enrolment; study habits; prioritisation of workload; resilience and wellbeing are experienced by educators studying either an Academic Professional Apprenticeship or a Senior Leaders Apprenticeship programme. Results demonstrate a mixed landscape is apparent for Level 7 apprentices, with tangible differences, both within and between groups, exhibited regarding reason for enrolment and study habits. The challenge around balancing work-life priorities and the encroachment of work commitments on study time (and vice versa) are a common theme for both cohorts, with those who have better established working patterns and relationships more resilient to the challenges of Level 7 apprenticeship study.

How do we teach for human dignity in a context where life is, generally speaking, not treated as precious? How do we carve spaces for humanity amidst inhumane contexts? In this paper, five experienced teachers share how they work from the cracks to expand spaces for human dignity in their schools. They write and act as teacher-philosophers, dually considering it means to teach for human dignity and practically speaking how it can be done.

A newly available radiative flux dataset specifically designed to enable the evaluation of the diurnal cycle in top-of-atmosphere (TOA) fluxes as captured by climate and Earth system models is presented. Observations over the period 2007–2012 made by the Geostationary Earth Radiation Budget (GERB) instrument are used to derive monthly hourly mean outgoing longwave radiation (OLR) and reflected shortwave (RSW) fluxes on a regular 1° latitude–longitude grid covering approximately 60° N–60° S and 60° E–60° W. The impact of missing data is evaluated in detail, and a data-filling solution is implemented using estimates of broadband fluxes from the Spinning Enhanced Visible and Infrared Imager flying on the same Meteosat platform, scaled to the GERB observations. This relatively simple approach is shown to deliver an approximate improvement by a factor of 10 in both the bias caused by missing data and the associated variability in the error. To demonstrate the utility of this V1.1 filled GERB Observations for Climate Model Intercomparison Projects (Obs4MIPs) dataset, comparisons are made to radiative fluxes from two climate configurations of the Hadley Centre's Global Environmental Model: HadGEM3-GC3.1 and HadGEM3-GC5.0. Focusing on marine stratocumulus and deep convective cloud regimes, diurnally resolved comparisons between the models and observations highlight discrepancies between the model configurations in terms of their ability to capture the diurnal amplitude and the phase in TOA fluxes, details that cannot be diagnosed by comparisons at lower temporal resolutions. For these cloud regimes the GC5.0 configuration shows improved fidelity to the observations relative to GC3.1, although notable differences remain. The V1.1 filled GERB Obs4MIPs monthly hourly TOA fluxes are available from the Centre for Environmental Data Analysis, with the OLR fluxes accessible at https://doi.org/10.5285/90148d9b1f1c40f1ac40152957e25467 (Bantges et al., 2023a) and the RSW fluxes accessible at https://doi.org/10.5285/57821b58804945deaf4cdde278563ec2 (Bantges et al., 2023b).

Abstract Background Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body’s cellular response to a hot environment. Objective This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. Methods We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. Results At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (β: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. Conclusions These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

The Far-INfrarEd Spectrometer for Surface Emissivity (FINESSE) instrument combines a commercial Bruker EM27 spectrometer with a front-end viewing and calibration rig developed at Imperial College London. FINESSE is specifically designed to enable accurate measurements of surface emissivity, covering the range 400–1600 cm−1, and, as part of this remit, can obtain views over the full 360° angular range. In this part, Part 1, we describe the system configuration, outlining the instrument spectral characteristics, our data acquisition methodology, and the calibration strategy. As part of the process, we evaluate the stability of the system, including the impact of knowledge of blackbody (BB) target emissivity and temperature. We also establish a numerical description of the instrument line shape (ILS), which shows strong frequency-dependent asymmetry. We demonstrate why it is important to account for these effects by assessing their impact on the overall uncertainty budget on the level 1 radiance products from FINESSE. Initial comparisons of observed spectra with simulations show encouraging performance given the uncertainty budget.

In this paper, we describe a method for retrieving the surface emissivity of specular surfaces across the wavenumber range of 400–1600 cm−1 using novel radiance measurements of the Far-INfrarEd Spectrometer for Surface Emissivity (FINESSE) instrument. FINESSE is described in detail in Part 1 (Murray et al., 2024) of this paper. We apply the method to two sets of measurements of distilled water. The first set of emissivity retrievals is of distilled water heated above ambient temperature to enhance the signal-to-noise ratio. The second set of emissivity retrievals is of ambient temperate water at a range of viewing angles. In both cases, the observations agree well with calculations based on compiled refractive indices across the mid- and far-infrared. It is found that the reduced contrast between the up- and downwelling radiation in the ambient temperature case degrades the performance of the retrieval. Therefore, a filter is developed to target regions of high contrast, which improves the agreement between the ambient temperature emissivity retrieval and the predicted emissivity. These retrievals are, to the best of our knowledge, the first published simultaneous retrievals of the surface temperature and emissivity of water that extend into the far-infrared and demonstrate a method that can be used and further developed for the in situ retrieval of the emissivity of other surfaces in the field.

Summary: A thermoradiative diode is a device that can generate power through thermal emission from the warm Earth to the cold night sky. Accurate assessment of the potential power output requires knowledge of the downwelling radiation from the atmosphere. Here, accurate modeling of this radiation is used alongside a detailed balance model of a diode at the Earth’s surface temperature to evaluate its performance under nine different atmospheric conditions. In the radiative limit, these conditions yield power densities between 0.34 and 6.5 W.m−2, with optimal bandgaps near 0.094 eV. Restricting the angles of emission and absorption to less than a full hemisphere can marginally increase the power output. Accounting for non-radiative processes, we suggest that if a 0.094 eV device would have radiative efficiencies more than two orders of magnitude lower than a diode with a bandgap near 0.25 eV, the higher bandgap material is preferred.

Introduction: This study aimed to i) identify the care needs of families experiencing cardiac arrest; and ii) co-identify strategies for meeting the identified care needs. Cardiac arrest survivors and family members (of survivors and non-survivors) were engaged as “experience experts,” collaborators and co-researchers in this study. Methods: A qualitative study using semi-structured interviews of cardiac arrest survivors and family members was conducted. Participants were recruited from the membership of the Family Centred Cardiac Arrest Care Project. Interviews were recorded, transcribed, and analysed using Framework analysis. Results: Twenty-eight participants described 22 unique cardiac arrest events. We identified five primary care need themes: 1) “Help us help our loved one”; 2) “Work with us as a cohesive team”; 3) “See us: treat us with humanity and dignity”; 4) “Address our family’s ongoing emergency”; and 5) “Help us to heal after the cardiac arrest” as well as 29 subordinate care need themes. We performed touchpoint mapping to identify key moments of interaction between patients and families, and the health system to highlight potential areas for improvement, as well as strategies for meeting family care needs. Conclusion: Our participants identified varied family care needs during and long after cardiac arrest. Fortunately, many proposed strategies are inexpensive and have low barriers to adoption. However, some unmet care needs identified suggest larger systemic issues such as service gaps that leave families feeling abandoned and isolated. Overall, our findings suggest that care during and after cardiac arrest are critical components of a comprehensive cardiac arrest care system.

Abstract While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

This paper presents a study of EFL classroom talk with the focus on how teachers successfully encourage and elicit student dialogic talk through questioning. It is based on observation data from forty-nine classes involving eleven teaching staff in a university in central China. The findings reveal the difficulty of engaging students to be the first to participate in dialogic interactions in a culture where deeply engrained reserve is the accepted norm. Two teacher questioning patterns are identified that are effective in eliciting students' first dialogic contribution in each interaction. These patterns can also serve as a profitable investment to elicit subsequent productive talk from students. This study also argues for a situated, contextualized analysis of classroom talk.

Background Tumor-associated macrophages (TAMs) play a critical function in the development of tumors and are associated with protumor M2 phenotypes. Shifting TAMs towards antitumor M1 phenotypes holds promise for tumor immunotherapy. Oleamide, a primary fatty acid amide, has emerged as a potent anticancer and immunomodulatory compound. However, the regulatory effects of oleamide on TAM phenotypes remain unclear. Methods We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques to study the influence of oleamide on primary human monocyte-derived TAM phenotypes, and we investigated the protein expression profiles based on mass spectrometry to analyze the effect of oleamide on macrophage polarization. Moreover, the advantageous binding scores between oleamide and these target candidate proteins are examined using molecular docking. Results Our study revealed that oleamide effectively suppressed the M2-like TAM phenotype by reducing interleukin (IL)-10 production and downregulating M2-like markers, including vascular endothelial growth factor A (VEGFA), MYC proto-oncogene, bHLH transcription factor (c-Myc), and mannose receptor C-type 1 (CD206). Moreover, the conditioned medium derived from oleamide-treated TAMs induces apoptosis of MDA-MB-231 breast cancer cells. Proteomic analysis identified 20 candidate up- and down-regulation proteins targeted by oleamide, showing modulation activity associated with the promotion of the M1-like phenotype. Furthermore, molecular docking demonstrated favorable binding scores between oleamide and these candidate proteins. Collectively, our findings suggest that oleamide exerts a potent antitumor effect by promoting the antitumor M1-like TAM phenotype. These novel insights provide valuable resources for further investigations into oleamide and macrophage polarization which inhibit the progression of breast cancer, which may provide insight into immunotherapeutic approaches for cancer.

Abstract A new ice refractive index compilation is reported for a broad spectrum ranging from 0.0443 to 106 μm, focusing on the pronounced temperature‐dependence of ice optical properties in the far‐infrared (far‐IR) segment (15–100 μm). A sensitivity study assuming spherical particles shows that selecting ice refractive indices at 12 temperatures and 215 wavelengths in the far‐IR region gives sufficient accuracy in interpolated refractive indices for developing a new ice crystal optical property database. Furthermore, we demonstrate the differences between the bulk single‐scattering properties computed for hexagonal ice particles with this new compilation compared to a previous iteration at three far‐IR wavelengths where substantial differences are noticed between the two ice refractive index compilations. We suggest that our new ice refractive index data set will improve downstream light‐scattering applications for upcoming far‐IR satellite missions and allow robust modeling of outgoing longwave radiation under ice cloud conditions.

The relation of the private life to the public is perplexing when thinking about the role of the public and private in public schooling, particularly as students learn to distinguish and navigate the private and public space of school. Learning to attend to the nuances between private and public and encountering documents that indicate such distinctions exist, such as student conduct codes, sets teachers up for a particular set of expectations when engaging in classroom discourse or other deliberative actions. Learning what constitutes the "privateness" or "publicness" of something is both an outcome and a process of learning the very conception of "what" is the private and "what" is the public. This Deweyan insight presents specific problems to schools and teachers. In this article, the author explores factors that impact teachers' mediation of the private and public within the classroom: ideological separation, confrontational staging, and "enactedness." Ideological separation presents the notion of being able to distinguish publicness and privateness based on the perceived capacity to ideologically separate private and public without overlap. Confrontational staging suggests that by ascribing to ideological separation, the classroom forces teachers to unexpectedly confront the clash of the publicness and privateness of students' lives within the classroom at any moment. Lastly, leveled implications or "enactedness" addresses the conflict between separating out the private and public on paper versus when distinguishing between the two is enacted in a particular classroom context in the moment.

Abstract Background Globally, non-communicable diseases (NCDs) are the leading cause of mortality and morbidity placing a huge burden on individuals, families and health systems, especially in low- and middle-income countries (LMICs). This rising disease burden calls for policy responses that engage the entire health care system. This study aims to synthesize evidence on how people with NCDs choose their healthcare providers in LMICs, and the outcomes of these choices, with a focus on private sector delivery. Methods A systematic search for literature following PRISMA guidelines was conducted. We extracted and synthesised data on the determinants and outcomes of private health care utilisation for NCDs in LMICs. A quality and risk of bias assessment was performed using the Mixed Methods Appraisal Tool (MMAT). Results We identified 115 studies for inclusion. Findings on determinants and outcomes were heterogenous, often based on a particular country context, disease, and provider. The most reported determinants of seeking private NCD care were patients having a higher socioeconomic status; greater availability of services, staff and medicines; convenience including proximity and opening hours; shorter waiting times and perceived quality. Transitioning between public and private facilities is common. Costs to patients were usually far higher in the private sector for both inpatient and outpatient settings. The quality of NCD care seems mixed depending on the disease, facility size and location, as well as the aspect of quality assessed. Conclusion Given the limited, mixed and context specific evidence currently available, adapting health service delivery models to respond to NCDs remains a challenge in LMICs. More robust research on health seeking behaviours and outcomes, especially through large multi-country surveys, is needed to inform the effective design of mixed health care systems that effectively engage both public and private providers. Trial registration PROSPERO registration number CRD42022340059 .

This study explores the lived experience of apprentices on a degree-level programme and their perceptions of how elements of apprenticeship study that aren't components of traditional degree study -- i.e. off-the-job training -- impact their learner journey. This article undertakes a thematic analysis following qualitative interviews with eleven apprentices, who are early-career academic professionals nearing the end of their apprenticeships. Key findings offer a mixed picture, and suggest that the study habits and preferences of apprentices are personal to individuals and are impacted on by employment workload and access to off-the-job study time. Apprentices indicate that many factors encroach on their ability to utilise the allocated off-the-job study time, primarily the ability to be released from employed work and conflicting priorities around meeting study, business, and personal needs. Apprentices suggest that in reality it is almost impossible for them to spend 20% of their working time on their studies. Recommendations are offered to both institutions and individuals, regarding the need for sound dialogue and the removal of barriers to ensure that apprentices can meet the contractual requirements of apprenticeship study.

High temperatures and air pollution exposure are individually known risks to human health, with amplifying adverse health effects during periods of co-exposure. This study compared co-occurring individual-level exposures to particulate matter (PM5, aerodynamic diameter of ≤5 μm) and heat among women in residential and agricultural settings in Guatemala. We measured personal and ambient exposure to PM5, temperature, and humidity among 21 female sugarcane workers in the fields and on their off days. We measured similar exposures among a group of 30 community members not involved in sugarcane work. We collected 171 personal PM5 measurements across 18 sampling days. The median workday personal PM5 concentration was 271 µg/m3, which was 3.6-fold higher than ambient area levels in the fields. The median personal PM5 concentration was 95.8 µg/m3 for off-work days and 83.5 µg/m3 for community days. The average workday individual-level temperature and humidity were 39.4 °C and 82.4%, respectively, with significantly lower temperatures on off-work and community days. The women workers and community members were exposed to high levels of PM5 and heat in both occupational and residential settings. Research needs to consider individual-level exposures at both work and home to help tailor more effective comprehensive prevention efforts to reduce risks.

The concept of educational questions has often been taken up topically, or as a related component to topics within philosophy of education. The rabbit hole approach provides a new perspective for attempting to discover the characteristics of educational questions and to engage with six authors, Biestra, Bingham, LeGrange, Andreotti, Saeverot and Snir seemingly, six conceptions of educational questions. Schulz suggests that the rabbit hole can operate as iterative, exhaustive, or associative. This paper traces the author's exhaustive and associative "rabbit hole" via questioning and inquiry to reveal the ways in which various conceptions of one single concept are presented when philosophy of education students explore educational questions within the field.

Abstract SARS-CoV-2 causes the severe respiratory disease COVID-19. Remdesivir (RDV) was the first fast-tracked FDA approved treatment drug for COVID-19. RDV acts as an antiviral ribonucleoside (adenosine) analogue that becomes active once it accumulates intracellularly. It then diffuses into the host cell and terminates viral RNA transcription. Previous studies have shown that certain nucleoside analogues unintentionally inhibit mitochondrial RNA or DNA polymerases or cause mutational changes to mitochondrial DNA (mtDNA). These past findings on the mitochondrial toxicity of ribonucleoside analogues motivated us to investigate what effects RDV may have on mitochondrial function. Using in vitro and in vivo rodent models treated with RDV, we observed increases in mtDNA copy number in Mv1Lu cells (35.26% increase ± 11.33%) and liver (100.27% increase ± 32.73%) upon treatment. However, these increases only resulted in mild changes to mitochondrial function. Surprisingly, skeletal muscle and heart were extremely resistant to RDV treatment, tissues that have preferentially been affected by other nucleoside analogues. Although our data suggest that RDV does not greatly impact mitochondrial function, these data are insightful for the treatment of RDV for individuals with mitochondrial disease.

Summary: Precise, on-target CRISPR-Cas9 genome editing has been shown in Schistosoma mansoni, involving both non-homology end joining and homology-directed repair pathways. Here, we present a multiplexed CRISPR-Cas9 protocol for large transgene integration into the S. mansoni genome. We describe steps for deploying multiplexed ribonucleoprotein complexes (RNPs) and donor DNA preparation. We then detail procedures for introducing RNPs into schistosome eggs by square-wave electroporation in the presence of a 5′ phosphorothioate-modified double-stranded donor transgene.For complete details on the use and execution of this protocol, please refer to Ittiprasert et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

With chronic disease prevalence on the rise globally, surveillance and monitoring are critical to improving health outcomes. Point-of-care (POC) testing can facilitate epidemiological research and enhance surveillance systems in limited resource settings, but previous research has identified bias between POC devices and laboratory testing. We compared the performance of two POC blood analyzers, the iSTAT handheld (Abbott, Princeton, NJ, USA) and the StatSensor Creatinine (Nova Biomedical, Waltham, MA, USA) to concurrent blood samples analyzed at a local laboratory that were collected from 89 agricultural workers in Guatemala. We measured creatinine and other measures of underlying health status with the POC and the lab blood samples. Pearson correlation coefficients, Bland-Altman plots, no intercept linear regression models and two-sample t-tests were used to evaluate the agreement between the POC and lab values collected across three study days and to assess differences by study day in a field setting. On average there was no observed difference between the iSTAT and lab creatinine measurements (p = 0.91), regardless of study day. Using lab creatinine as the gold standard, iSTAT creatinine results were more accurate compared to the Statsensor, which showed some bias, especially at higher values. The iSTAT had good agreement with the lab for sodium and blood urea nitrogen (BUN), but showed differences for potassium, anion gap, bicarbonate (TCO2), glucose, and hematocrit. In this tropical field setting, the research team devised a protocol to prevent the devices from overheating. In limited resource settings, POC devices carry advantages compared to traditional lab analyses, providing timely results to patients, researchers, and healthcare systems to better evaluate chronic health conditions. Technical challenges due to use of POC devices in high heat and humidity environments can be addressed using a standard protocol for transporting and operating the devices.

This paper presents lessons learnt from research on integrating urban nature into university students’ daily lives for wellbeing benefits. It examines the application of traditional and technological interventions as a way of increasing university students’ engagement with urban nature to support their mental health. It focuses on two research questions: (1) How does a walking intervention and a mobile phone app intervention in urban nature compare - in terms of their effect on nature connection and wellbeing measures? (2) How should engagement with the natural environment be encouraged for university students’ wellbeing? The use of two different styles of nature-based interventions demonstrated the implementation opportunities and challenges amongst the student population. Results analysed the extent of changes over time and differences within groups. This confirmed that the relationship between different aspects of an individual’s relationship with nature is complex and dynamic. The experience of conducting this research highlighted the challenges to implementing novel technological interventions - including creating a nature-based intervention scheme at a university. The difference in outcome measures and unexpected direction of change for connection to nature suggests the need for a holistic approach to improve student wellbeing, including different ways to integrate nature into the university experience.

Background/Aims Immune and inflammatory cells respond to multiple pathological hits in the development of nonalcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD. Methods Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples. Results Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease. Conclusions A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application.

Abstract Background Primary prevention of cardiovascular diseases (CVD) increasingly relies on monitoring global CVD risk scores. Lack of evidence on socioeconomic inequality in these scores and the contributions that specific risk factors make to this inequality impedes effective targeting of CVD prevention. We aimed to address this evidence gap by measuring and decomposing socioeconomic inequality in CVD risk in the Philippines. Methods We used data on 8462 individuals aged 40–74 years from the Philippines National Nutrition Survey and the laboratory-based Globorisk equation to predict 10-year risk of a CVD event from sex, age, systolic blood pressure, total cholesterol, high blood glucose, and smoking. We used a household wealth index to proxy socioeconomic status and measured socioeconomic inequality with a concentration index that we decomposed into contributions of the risk factors used to predict CVD risk. We measured socioeconomic inequalities in these risk factors and decomposed them into contributions of more distal risk factors: body mass index, fat share of energy intake, low physical activity, and drinking alcohol. We stratified by sex. Results Wealthier individuals, particularly males, had greater exposure to all risk factors, with the exception of smoking, and had higher CVD risks. Total cholesterol and high blood glucose accounted for 58% and 34%, respectively, of the socioeconomic inequality in CVD risk among males. For females, the respective estimates were 63% and 69%. Systolic blood pressure accounted for 26% of the higher CVD risk of wealthier males but did not contribute to inequality among females. If smoking prevalence had not been higher among poorer individuals, then the inequality in CVD risk would have been 35% higher for males and 75% higher for females. Among distal risk factors, body mass index and fat intake contributed most to inequalities in total cholesterol, high blood sugar, and, for males, systolic blood pressure. Conclusions Wealthier Filipinos have higher predicted CVD risks and greater exposure to all risk factors, except smoking. There is need for a nuanced approach to CVD prevention that targets anti-smoking programmes on the poorer population while targeting diet and exercise interventions on the wealthier.

Background: Anaphylaxis is a life-threatening allergic reaction with significant risk for children with allergies. Access to potentially life-saving medication is critical for these children. This review aims to describe state laws and policies guiding stock epinephrine in schools for allergic or anaphylactic events and detail recommendations for best practices. Methods: This paper is a comprehensive review of the 50 states and the District of Columbia's (DC) laws and policies for stock epinephrine at schools for children in pre-kindergarten through 12th grade. Results: All 50 states and DC allow undesignated epinephrine in schools to use for allergic or anaphylactic reactions. A key difference arises in whether states allow (N = 37) or mandate (N = 14) that schools stock epinephrine. States exhibit differences in the body responsible for developing stock epinephrine policy (N = 48), along with stakeholders responsible for developing procedures (N = 30) and implementing them (N = 19). Differences also exist in state epinephrine procurement, administration, training, and liability. Conclusions: This review of stock epinephrine laws and policies highlights the significant variation in state legislation despite widespread adoption. Only one-quarter of states mandate that schools have stock epinephrine available for emergency use, underscoring need for a more unified approach with consistent guidelines, comprehensive training, and possible funding for implementation.

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be responsible for SER5’s antiviral activity. This and other reports that document modulation of HIV-1 infectivity by viral lipid composition prompted us to investigate the role of PS in regulating SER5-mediated HIV-1 restriction. First, we show that the level of SER5 incorporation into virions correlates with an increase in PS levels in the outer leaflet of the viral membrane. We developed an assay to estimate the PS distribution across the viral membrane and found that SER5, but not SER2, which lacks antiviral activity, abrogates PS asymmetry by externalizing this lipid. Second, SER5 incorporation diminished the infectivity of pseudoviruses produced from cells lacking a flippase subunit CDC50a and, therefore, exhibited a higher baseline level of surface-accessible PS. Finally, exogenous manipulation of the viral PS levels utilizing methyl-alpha-cyclodextrin revealed a lack of correlation between external PS and virion infectivity. Taken together, our study implies that the increased PS exposure to SER5-containing virions itself is not directly linked to HIV-1 restriction.

Exercise provides significant health benefits to patients diagnosed with cancer including improved survival outcomes, quality of life and reduced cancer recurrence. Across multiple murine cancer models, aerobic exercise and resistance training has exhibited anti-tumour properties illustrated by inhibited tumour growth, reduced metastatic potential and modulation of the tumour microenvironment to allow the recognition and destruction of cancer cells. Clinical studies have demonstrated the rapid mobilisation and circulatory release of mature lymphoid populations, myokines and cytokines that occurs with exercise along with tumour vasculature normalisation. Tumour microenvironments enriched with immune cells with anti-cancer potential, such as CD8+ T cells, are termed ‘hot’, whilst those favouring an immunosuppressive environment and lacking in effector immune cells are classed as ‘cold’. Pre-clinical evidence suggests exercise training has the potential to reprogramme cold tumours to become hot, although this requires validation in clinical studies. This hot environment could potentiate immunotherapy responsiveness, improving survival outcomes of patients undergoing cancer immunotherapy and allow those with typically cold tumours to benefit from immunotherapy. This review discusses the complex interactions between exercise and cancer, including exercise-induced alterations within the tumour microenvironment and systemic immunity. The potential role exercise may play in improving cancer immunotherapy responsiveness is explored. This review also highlights the need for translational studies exploring the role of exercise in patients with cancer with the potential to widen the spectrum of tumours that derive significant benefit from immunotherapy.

The SARS-CoV-2 betacoronavirus uses its highly glycosylated trimeric Spike protein to bind to the cell surface receptor angiotensin converting enzyme 2 (ACE2) glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatics analyses of natural variants and with existing 3D structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein both alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation. Taken together, these data can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.

Abstract Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180–3000 nm) compared to rock (495–2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p

Abstract Functional connectivity between the amygdala and the medial prefrontal cortex (mPFC) has been identified as a neural substrate of emotion regulation that undergoes changes throughout development, with a mature profile typically emerging at 10 years of age. Maternal bonding in childhood has been shown to buffer amygdala reactivity and to influence the trajectory of amygdala–mPFC coupling. The oxytocinergic system is critical in the development of social behavior and maternal bonding. Early-life parental care influences the methylation status of the oxytocin receptor (OXTRm) in animal models and humans, and higher OXTRm is associated with lower amygdala–PFC functional connectivity in adults. Using a neuroimaging-epigenetic approach, we investigated saliva-derived OXTRm as a biological marker of structural and functional connectivity maturation in 57 typically developing children (P

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.

Introduction The burden of non-communicable diseases (NCDs) has increased substantially in low- and middle-income countries (LMICs), and adapting health service delivery models to address this remains a challenge. Many patients with NCD seek private care at different points in their encounters with the health system, but the determinants and outcomes of these choices are insufficiently understood. The proposed systematic review will help inform the governance of mixed health systems towards achieving the goal of universal health coverage. This protocol details our intended methodological and analytical approaches, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).Methods and analysis Following the PRISMA approach, this systematic review will develop a descriptive synthesis of the determinants and outcomes of private healthcare utilisation for NCDs in LMICs. The databases Embase, Medline, Web of Science Core Collection, EconLit, Global Index Medicus and Google Scholar will be searched for relevant studies published in English between period 1 January 2010 and 30 June 2022 with additional searching of reference lists. The study selection process will involve a title-abstract and full-text review, guided by clearly defined inclusion and exclusion criteria. A quality and risk of bias assessment will be done for each study using the Mixed Methods Appraisal Tool.Ethics and dissemination Ethical approval is not required because this review is based on data collected from publicly available materials. The results will be published in a peer-reviewed journal and presented at related scientific events.PROSPERO registration number CRD42022340059

Many enveloped viruses enter host cells by fusing with acidic endosomes. The fusion activity of multiple viral envelope glycoproteins does not generally affect viral membrane permeability. However, fusion induced by the Lassa virus (LASV) glycoprotein complex (GPc) is always preceded by an increase in viral membrane permeability and the ensuing acidification of the virion interior. Here, systematic investigation of this LASV fusion phenotype using single pseudovirus tracking in live cells reveals that the change in membrane barrier function is associated with the fusogenic conformational reorganization of GPc. We show that a small-molecule fusion inhibitor or mutations that impair viral fusion by interfering with GPc refolding into the post-fusion structure prevent the increase in membrane permeability. We find that the increase in virion membrane permeability occurs early during endosomal maturation and is facilitated by virus-cell contact. This increase is observed using diverse arenavirus glycoproteins, whether presented on lentivirus-based pseudoviruses or arenavirus-like particles, and in multiple different cell types. Collectively, these results suggest that conformational changes in GPc triggered by low pH and cell factor binding are responsible for virion membrane permeabilization and acidification of the virion core prior to fusion. We propose that this viroporin-like activity may augment viral fusion and/or post-fusion steps of infection, including ribonucleoprotein release into the cytoplasm.