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With the rise of neoliberal reforms and efforts to privatize education, there is a growing need to examine how actors and groups from the public and private sectors influence educational policy change together. In this article, we advance a critical approach to understanding the changing discursive space of educational politics by following discourses through an expansive policy network that goes beyond its traditional boundaries. Specifically, we draw on argumentative discourse analysis (ADA), which allows for the analysis of how and why various actors and groups come together to assign certain meanings to educational phenomena or problems, leading to policy responses or changes. Rooted in Foucault's notions of discourse and power, ADA offers a unique approach to discourse analysis that can illuminate policy change through discourse coalitions. Three case studies from educational policy scholarship are discussed to illustrate the value and utility of ADA in future critical education policy studies.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.

Mosquito-borne illnesses represent a significant global health peril, resulting in approximately one million fatalities annually. West Nile, dengue, Zika, and malaria are continuously expanding their global reach, driven by factors that escalate mosquito populations and pathogen transmission. Innovative control measures are imperative to combat these catastrophic ailments. Conventional approaches, such as eliminating breeding sites and using insecticides, have been helpful, but they face challenges such as insecticide resistance and environmental harm. Given the mounting severity of mosquito-borne diseases, there is promise in exploring innovative approaches using synthetic biology to bolster mosquitoes' resistance to pathogens, or even eliminate the mosquito vectors, as a means of control. This review outlines current strategies, future goals, and the importance of gene editing for global health defenses against mosquito-borne diseases.

This study develops a thermal homogenization model for an aluminum honeycomb panel using the representative volume element (RVE) concept, considering the orthotropic nature of the structure. The RVE thermal homogenization method is a numerical approach for analyzing heterogeneous materials. It employs a constitutive model based on RVE performance to represent thermal behavior. Effective parameters are determined through averaging techniques, and the finite element method solves the thermal problem, accounting for structure topology and material behavior. The resulting heat conduction problem is solved using the finite element method (FEM) to evaluate the effective thermal characteristics. A 3D RVE is generated based on the honeycomb panel's geometry, evaluating thermal conductivity tensor and describing the medium's thermal performance. Numerical tests validate the model by comparing it with the real honeycomb structure under sinusoidal heat flux. Results show good correlation, with maximum temperatures of 1101.9 °C in the real structure and 1096.4 °C in the medium. The homogeneous medium is further used to investigate thermal performance under convective conditions with varying panel thicknesses, achieving over 77 °C temperature reduction with the thickest panel. Natural vibration behavior is considered, demonstrating strong correlation between modal responses and natural frequencies. This modeling approach efficiently analyzes thermal behavior in large honeycomb structures, reducing computational time significantly.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

The current study examined a unique uninational intervention program, conducted separately for Jewish and Arab adolescents, with the aim of cultivating emotional intelligence skills and empathy. 287 adolescents aged 16-17 (115 Jews and 172 Arabs) participated in the program and the study to assess its initial effects. All participants completed self-administered questionnaires; the researcher conducted observations and focus groups. For the Arab participants, the findings showed an improvement in emotional intelligence, empathy towards Arabs and Jews, and relationships with Israeli Jews. Among the Jewish participants, although no statistically significant change in emotional intelligence was observed, there were positive changes in empathy, as well as relationships with Israeli Arabs. The degree of improvement was stronger among Arab participants.

Escalating vector disease burdens pose significant global health risks, as such innovative tools for targeting mosquitoes are critical. CRISPR-Cas technologies have played a crucial role in developing powerful tools for genome manipulation in various eukaryotic organisms. Although considerable efforts have focused on utilizing class II type II CRISPR-Cas9 systems for DNA targeting, these modalities are unable to target RNA molecules, limiting their utility against RNA viruses. Recently, the Cas13 family has emerged as an efficient tool for RNA targeting; however, the application of this technique in mosquitoes, particularly Aedes aegypti, has yet to be fully realized. In this study, we engineered an antiviral strategy termed REAPER (vRNA Expression Activates Poisonous Effector Ribonuclease) that leverages the programmable RNA-targeting capabilities of CRISPR-Cas13 and its potent collateral activity. REAPER remains concealed within the mosquito until an infectious blood meal is uptaken. Upon target viral RNA infection, REAPER activates, triggering programmed destruction of its target arbovirus such as chikungunya. Consequently, Cas13-mediated RNA targeting significantly reduces viral replication and viral prevalence of infection, and its promiscuous collateral activity can even kill infected mosquitoes within a few days. This innovative REAPER technology adds to an arsenal of effective molecular genetic tools to combat mosquito virus transmission.

Abstract/Introduction: Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1–4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population5–9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such asFGF21, ADIPOQ, GCGandIL6showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liverPCSK9) as well as genes encoding enzymes producing metabolites (adiposePNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource asGene-DerivedCorrelationsAcrossTissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

BackgroundArtificial intelligence (AI) applied to 12-lead electrocardiographs (ECGs) can detect hypertrophic cardiomyopathy (HCM).ObjectivesThe purpose of this study was to determine if AI-enhanced ECG (AI-ECG) can track longitudinal therapeutic response and changes in cardiac structure, function, or hemodynamics in obstructive HCM during mavacamten treatment.MethodsWe applied 2 independently developed AI-ECG algorithms (University of California-San Francisco and Mayo Clinic) to serial ECGs (n = 216) from the phase 2 PIONEER-OLE trial of mavacamten for symptomatic obstructive HCM (n = 13 patients, mean age 57.8 years, 69.2% male). Control ECGs from 2,600 age- and sex-matched individuals without HCM were obtained. AI-ECG output was correlated longitudinally to echocardiographic and laboratory metrics of mavacamten treatment response.ResultsIn the validation cohorts, both algorithms exhibited similar performance for HCM diagnosis, and exhibited mean HCM score decreases during mavacamten treatment: patient-level score reduction ranged from approximately 0.80 to 0.45 for Mayo and 0.70 to 0.35 for USCF algorithms; 11 of 13 patients demonstrated absolute score reduction from start to end of follow-up for both algorithms. HCM scores were significantly associated with other HCM-relevant parameters, including left ventricular outflow tract gradient at rest, postexercise, and with Valsalva, and NT-proBNP level, independent of age and sex (all P < 0.01). For both algorithms, the strongest longitudinal correlation was between AI-ECG HCM score and left ventricular outflow tract gradient postexercise (slope estimate: University of California-San Francisco 0.70 [95% CI: 0.45-0.96], P < 0.0001; Mayo 0.40 [95% CI: 0.11-0.68], P = 0.007).ConclusionsAI-ECG analysis longitudinally correlated with changes in echocardiographic and laboratory markers during mavacamten treatment in obstructive HCM. These results provide early evidence for a potential paradigm for monitoring HCM therapeutic response.

Abstract Background Randomised controlled trials (RCTs) are typically designed to determine beneficial intervention effects. In addition, an important aspect of every trial is to collect data on any potential harmful effects, with the aim of ensuring that the benefit-risk balance is appropriate. The language used by trialists to describe these potential harmful effects is inconsistent. In pharmacological trials, researchers collect adverse events; when a causal relationship is suspected adverse events are further classified as adverse reactions. Academic researchers have moved to collectively refer to these as harm outcomes; the pharmaceutical industry refer to these events as safety outcomes. In trials of complex interventions, phrases such as unintended consequences or effects are used. With the inconsistent use of terminology by researchers and the potential benefits to be gained from harmonising communications, we sought public opinion on terminology used to describe harmful effects and how these outcomes are communicated in the scientific literature, as well as in public facing material on medications. Methods We held two in-person public involvement meetings with public partners, in London and Aberdeen in 2023. Both meetings followed a pre-specified format. We provided a background to the topic including the information researchers collect on potential harms in clinical trials and shared examples on how this information gets presented in practice. We then discussed public partners’ perspectives on terminology used and communication of intervention harm in academic journals and in public facing materials. A summary of these discussions and the main topics raised by public partners are presented. Results Public partners endorsed the use of different terms for different situations, preferring the use of ‘side-effect’ across all contexts and reserving the use of ‘harm’ to indicate more severe events. Generally, public partners were happy with the type of information presented in public facing materials but discussions revealed that presentation of information on public NHS websites led to misconceptions about harm. Conclusion This work provides a starting point on preferred terminology by patients and the public to describe potential harmful intervention effects. Whilst researchers have tried to seek agreement, public partners endorsed use of different terms for different situations. We highlight some key areas for improvement in public facing materials that are necessary to avoid miscommunication and incorrect perception of harm.

Abstract Background Without increasing radiation exposure, ultralow-dose computed tomography (CT) of the chest provides improved diagnostic accuracy of radiological pneumonia diagnosis compared to a chest radiograph. Yet, radiologist resources to rapidly report the chest CTs are limited. This study aimed to assess the diagnostic accuracy of emergency clinicians’ assessments of chest ultralow-dose CTs for community-acquired pneumonia using a radiologist’s assessments as reference standard. Methods This was a cross-sectional diagnostic accuracy study. Ten emergency department clinicians (five junior clinicians, five consultants) assessed chest ultralow-dose CTs from acutely hospitalised patients suspected of having community-acquired pneumonia. Before assessments, the clinicians attended a focused training course on assessing ultralow-dose CTs for pneumonia. The reference standard was the assessment by an experienced emergency department radiologist. Primary outcome was the presence or absence of pulmonary opacities consistent with community-acquired pneumonia. Sensitivity, specificity, and predictive values were calculated using generalised estimating equations. Results All clinicians assessed 128 ultralow-dose CTs. The prevalence of findings consistent with community-acquired pneumonia was 56%. Seventy-eight percent of the clinicians’ CT assessments matched the reference assessment. Diagnostic accuracy estimates were: sensitivity = 83% (95%CI: 77–88), specificity = 70% (95%CI: 59–81), positive predictive value = 80% (95%CI: 74–84), negative predictive value = 78% (95%CI: 73–82). Conclusion This study found that clinicians could assess chest ultralow-dose CTs for community-acquired pneumonia with high diagnostic accuracy. A higher level of clinical experience was not associated with better diagnostic accuracy.

Abstract Vitamin D3 is clinically used for the treatment of vitamin D3 deficiency or osteoporosis, partially because of its role in regulating phosphate (Pi) and calcium (Ca2+) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in Pi homeostasis; however, the role of vitamin D3 in hypophosphatemia has never been investigated. We administered vehicle or vitamin D3 to wild-type (WT) mice or hypophosphatemic Npt2a−/− mice. In contrast to WT mice, vitamin D3 treatment increased plasma Pi levels in Npt2a−/− mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca2+ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary Pi and Ca2+/creatinine ratios, in Npt2a−/− mice, Pi/creatinine was unchanged and Ca2+/creatinine drastically decreased, coinciding with the highest kidney Ca2+ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a−/− mice, vitamin D3 treatment completely diminished Npt2c abundance, so that mice resembled Npt2a/c double knockout mice. Abundance of intestinal Npt2b and claudin-3 (tight junctions protein) were reduced in Npt2a−/− only, the latter might facilitate the increase in plasma Pi in Npt2a−/− mice. Npt2a might function as regulator between renal Ca2+ excretion and reabsorption in response to vitamin D3.

Abstract Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.

Mohammad Al Masri,1 Hala AlOmari,2 Lina AbuKhader3 1Audiology and Speech Pathology Department, Al-Ahliyya Amman University, Amman, Jordan; 2Hearing and Speech Sciences, University of Jordan, Amman, Jordan; 3Middle East Hearing Association, Amman, JordanCorrespondence: Mohammad Al Masri, Head of the Audio-Vestibular Department, Audiology and Speech Pathology Department, Al-Ahliyya Amman University, Amman, Jordan, Tel +962797157576, Email Masri333@gmail.com; masri@ammanu.edu.joObjective: This study aimed to establish and validate a Jordanian Arabic version of the Dizziness Handicap Inventory (DHI-JA) equivalent to the original DHI in English (DHI-E).Methods: The THI-E questionnaires were translated into formal Jordanian Arabic by two bilingual volunteer audiologists. The final version, curated by the author, was administered to 20 participants with normal balance and 64 patients experiencing dizziness at the Middle East Hearing and Balance Centre.Results: The results demonstrated excellent internal consistency and reliability of DHI-JA. A highly significant correlation was observed between the total scores and sub-scores of DHI-JA and DHI-E.Conclusion: This study concludes that the DHI-JA is a valid and reliable tool for assessing the severity of dizziness and balance disorders in the Jordanian Arabic-speaking population.Keywords: dizziness handicap inventory, Arabic dizziness handicap inventory, vertigo, balance disorder

Abstract Background Despite advancements in family planning (FP) services, several barriers persist in the Occupied Palestinian territory (oPt), blocking women’s access to suitable, high-quality and equitable FP services. The aim of this study was to understand how healthcare providers perceive their abilities, barriers and opportunities in providing good quality FP services. Furthermore, it seeks to explore knowledge and training regarding FP among healthcare providers engaged in providing FP services. Methods A qualitative study was undertaken from August to September 2022 in seven Primary Health Care (PHC) clinics distributed in three governorates and operating under the Palestinian Ministry of Health (MoH) in the West Bank. Semi-structured, in-depth face-to-face interviews were conducted with 13 health providers (Physicians, midwives and nurses), using an interview guide in Arabic language. Transcripts were subsequently analyzed using the six phases of reflexive thematic analysis. Results FP services face various challenges, including shortages in resources such as staff, supplies, infrastructures and FP methods. Midwives possess significant potentials to offer accessible, high-quality, efficient and equitable FP services, yet, their capacities remain underutilized, representing a missed opportunity for a country like Palestine. The study provided a current overview of FP services while illustrating the need for quality FP services and the need for an updated continuous education and training, updated standardized guidelines and protocols and supportive supervision are needed across all levels of healthcare providers. Finally, providers reported a wide range of structural barriers to FP services. Conclusions It is crucial to meticulously address both community-related and health system factors to enhance the fulfillment of FP needs and reduce unintended and closely spaced pregnancies. Policymakers should invest in the development of laws and regulations regarding FP services, promoting a comprehensive and holistic approach to FP services. This includes formulating supportive policies, capacity building of human resources and maintaining security of FP commodities.