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School readiness assessments in South Africa still predominantly focus on the assessment of cognitive skills. The Emotional Social Screening Tool for School Readiness (E3SR) was developed to bridge the perceived gap in assessing emotional-social skills as a domain of school readiness. An emerging body of research reports exists on the psychometric properties and factor structure of the E3SR. An initial validation study recommended a 6-factor solution instead of the theoretical 9-factor model that was proposed in the development of the E3SR. The E3SR (Revised) was also reduced in length. We report here on a pilot study of which the aim was to establish the reliability and construct validity of the E3SR (Revised). A cross-sectional survey design was used to gather data from 9 pre-schools in Cape Town, South Africa. Pre-school teachers (n = 24) constituted the respondent group who completed the E3SR (Revised) screening questionnaires on Grade R learners (n = 394). Analysis was conducted on 321 completed screening questionnaires. With the data analysis we aimed to: a) summarise sample characteristics of teachers and children; b) establish reliability estimates; and c) establish construct validity and confirming the factor structure. Ethics clearance was given by the Humanities and Social Science Research Ethics Committee (HSSREC) of the University of the Western Cape. The study adhered to stipulated ethics requirements. Data failed to show multivariate normality; however, this violation of normality was expected and was theoretically supported. The sample size (n = 321) was sufficient for factor analysis of a 36-item scale. All subscales showed excellent reliability: Cronbach's alphas ranged between 0.939 and 0.971. CFA results demonstrated a good model fit. The E3SR (Revised) was found to be reliable and valid for use. The use of a rigorous methodological process including the decision-making matrix represent good research practice that can be used in instrument development across cultures.

Abstract White blood cell (WBC) ratios are used as diagnostic markers for various inflammatory or tumor diseases as well as stress in a broad range of species. The aim of this work was to provide data on five WBC ratios (neutrophil-to-lymphocyte ratio [NLR], band neutrophil-to-lymphocyte ratio [BLR], band neutrophil-to-neutrophil-to-lymphocyte ratio [BNLR], band neutrophil-to-neutrophil ratio [BNR] and lymphocyte-to-monocyte ratio [LMR]) in South American camelids (SAC) and characterize their association with demographic and important diagnostic parameters. Medical records of 307 SAC (275 alpacas, 32 llamas) that were presented at a veterinary teaching hospital were evaluated retrospectively. WBC ratios were calculated based on hematologic results of the initial blood samples. The influence of species, sex, age, body condition score, WBC count, and anemia on those ratios was investigated using descriptive statistics and generalized linear models. NLR, BLR and LMR were found to be significantly influenced by age and WBC count. Associations of individual WBC ratios with species, nutritional status or an anemic condition could be detected. NLR was 4.32; 2.31–7.81 (median; IQR), BLR 0.24; 0.07–0.87, BNLR 3.66 × 10–3; 1.17 × 10–3 − 14.20 × 10–3, BNR 0.06; 0.02–0.15 and LMR was 7; 3.54–14.67. Our data might serve as a basis for further studies on WBC ratios in SAC. The animals in this study showed a variety of underlying diseases. It should hence be noted that these values are orientation values and provide a representative overview of conditions in a clinic, but are not suitable as reference values for healthy animals.

Abstract Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS SMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS Smarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS SMARCB1- within the TME.

Abstract This study assesses the use of fructosamine as a diagnostic tool for hyperglycemia in alpacas in view of their sensitivity to stress and susceptibility to conditions like lipid mobilization syndrome. Plasma fructosamine, like in diagnosing diabetes in cats and dogs, can reveal long-term blood glucose trends, differentiating stress-induced spikes from persistent diabetic hyperglycemia. In 125 alpacas presented as patients of a veterinary clinic, plasma glucose and fructosamine concentrations were compared for correlations with findings of the general clinical examination, laboratory parameters, demographic data, and a behavioral stress assessment processed by using principal component analysis. Hyperglycemia was observed on admission of 71% (89/125) of the animals. This was significantly associated with a higher concentration of serum cortisol and a higher behavioral stress scoring. Fructosamine above the reference limit was detected in only 15% (13/89) of the hyperglycemic individuals. In addition to a positive correlation of fructosamine to glucose concentration, positive relationships with different plasma proteins were detected. A relationship to stress parameters was not observed. These findings underscore stress as a significant trigger for hyperglycemia in alpacas and suggest fructosamine as a valuable parameter for distinguishing between stress-induced and diabetic hyperglycemia. However, the dependence of fructosamine formation on total plasma protein concentration should be considered to avoid misinterpretation.

Pulmonary microvascular endothelial cells contribute to the integrity of the lung gas exchange interface, and they are highly glycolytic. Although glucose and fructose represent discrete substrates available for glycolysis, pulmonary microvascular endothelial cells prefer glucose over fructose, and the mechanisms involved in this selection are unknown. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is an important glycolytic enzyme that drives glycolytic flux against negative feedback and links glycolytic and fructolytic pathways. We hypothesized that PFKFB3 inhibits fructose metabolism in pulmonary microvascular endothelial cells. We found that PFKFB3 knockout cells survive better than wild-type cells in fructose-rich medium under hypoxia. Seahorse assays, lactate and glucose measurements, and stable isotope tracing showed that PFKFB3 inhibits fructose-hexokinase-mediated glycolysis and oxidative phosphorylation. Microarray analysis revealed that fructose upregulates PFKFB3, and PFKFB3 knockout cells increase fructose-specific GLUT5 (glucose transporter 5) expression. Using conditional endothelial-specific PFKFB3 knockout mice, we demonstrated that endothelial PFKFB3 knockout increases lung tissue lactate production after fructose gavage. Last, we showed that pneumonia increases fructose in BAL fluid in mechanically ventilated ICU patients. Thus, PFKFB3 knockout increases GLUT5 expression and the hexokinase-mediated fructose use in pulmonary microvascular endothelial cells that promotes their survival. Our findings indicate that PFKFB3 is a molecular switch that controls glucose versus fructose use in glycolysis and help better understand lung endothelial cell metabolism during respiratory failure.

The use of standard protocols in studies supports consistent data collection, improves data quality, and facilitates cross-study analyses. Funded by the National Institutes of Health, the PhenX (consensus measures for Phenotypes and eXposures) Toolkit is a catalog of recommended measurement protocols that address a wide range of research topics and are suitable for inclusion in a variety of study designs. In 2020, a PhenX Working Group of smoking cessation experts followed a well-established consensus process to identify and recommend measurement protocols suitable for inclusion in smoking cessation and smoking harm reduction studies. The broader scientific community was invited to review and provide feedback on the preliminary recommendation of the Working Group. Fourteen selected protocols for measuring smoking cessation, harm reduction, and biomarkers research associated with smoking cessation were released in the PhenX Toolkit ( https://www.phenxtoolkit.org) in February 2021. These protocols complement existing PhenX Toolkit content related to tobacco regulatory research, substance use and addiction research, and other measures of smoking-related health outcomes. Adopting well-established protocols enables consistent data collection and facilitates comparing and combining data across studies, potentially increasing the scientific impact of individual studies.

Abstract Anemia is a common problem in South American camelids (SACs). Infections with Candidatus Mycoplasma haemolamae (CMh), a cell-wall free, hemotropic bacterium, are often suspected to be an important cause of anemia, as the pathogen infects the erythrocytes and is found in the blood of up to 30% of SACs. The information on the clinical signs of animals infected with this pathogen vary widely. Most infections are clinically inapparent. Treatment is usually carried out with oxytetracycline. A detailed overview of the clinical and hematological findings in 13 alpacas infected with Candidatus M. haemolamae (CMh+), based on patients from our university clinic and comparing those findings with the results of 22 negative alpacas (CMh−) is provided. Assignment to both groups was based on the PCR result. No relevant clinical or hematological differences between CMh+ and CMh− were found, the clinical signs in CMh+ were usually due to comorbidities. The examination of a blood smear alone proved to be insufficient; a PCR test should be carried out to confirm or rule out an infection. A critical review of the need for antibiotic treatment on the basis of a positive test result alone is recommended.

The Bay of Marseille (BoM), located in the northwestern Mediterranean Sea, is affected by various hydrodynamic processes (e.g., Rhône River intrusion and upwelling events) that result in a highly complex local carbonate system. In any complex environment, the use of models is advantageous since it allows us to identify the different environmental forcings, thereby facilitating a better understanding. By combining approaches from two biogeochemical ocean models and improving the formulation of total alkalinity, we develop a more realistic representation of the carbonate system variables at high temporal resolution, which enables us to study air–sea CO2 fluxes and seawater pCO2 variations more reliably. We apply this new formulation to two particular scenarios that are typical for the BoM: (i) summer upwelling and (ii) Rhône River intrusion events. In both scenarios, our model was able to correctly reproduce the observed patterns of pCO2 variability. Summer upwelling events are typically associated with a pCO2 decrease that mainly results from decreasing near-surface temperatures. Furthermore, Rhône River intrusion events are typically associated with a pCO2 decrease, although, in this case, the pCO2 decrease results from a decrease in salinity and an overall increase in total alkalinity. While we were able to correctly represent the daily range of air–sea CO2 fluxes, the present configuration of Eco3M_MIX-CarbOx does not allow us to correctly reproduce the annual cycle of air–sea CO2 fluxes observed in the area. This pattern directly impacts our estimates of the overall yearly air–sea CO2 flux as, even if the model clearly identifies the bay as a CO2 sink, its magnitude was underestimated, which may be an indication of the limitations inherent in dimensionless models for representing air–sea CO2 fluxes.

Abstract Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the “toxic diol” responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly “toxic diol”. We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation.

Abstract Background Diabetes is the eighth leading cause of death in the USA. Inequities driven by structural racism and systemic oppression have led to racial/ethnic disparities in diabetes prevalence, diagnosis, and treatment. Diabetes-self management training (DSMT), remote glucose monitoring (RGM), and tailored support from a community health worker (CHW) have the potential to improve outcomes. This study will examine the implementation of these interventions in a safety-net healthcare setting. Methods Using implementation science and racial equity principles, this study aims to (1) evaluate the appropriateness; (2) measure fidelity; and (3) compare the effectiveness of varying the combination and sequence of three interventions. An exploratory aim will measure sustainability of intervention adherence and uptake. This mixed-methods trial employs a sequential, multiple assignment randomized trial (SMART) design, patient focus group discussions, and staff interviews. Eligible Black/Latine patients will be recruited using patient lists extracted from the electronic medical record system. After a detailed screening process, eligible patients will be invited to attend an in-person enrollment appointment. Informed consent will be obtained and patients will be randomized to either DSMT or RGM. At 6 months, patients will complete two assessments (diabetes empowerment and diabetes-related distress), and HbA1c values will be reviewed. “Responders” will be considered those who have an HbA1c that has improved by at least one percentage point. “Responders” remain in their first assigned study arm. “Nonresponders” will be randomized to either switch study arms or be paired with a CHW. At 6 months participants will complete two assessments again, and their HbA1c will be reviewed. Twelve patient focus groups, two for each intervention paths, will be conducted along with staff interviews. Discussion This study is the first, to our knowledge, that seeks to fill critical gaps in our knowledge of optimal sequence and combinations of interventions to support diabetes management among Black and Latine patients receiving care at a safety-net hospital. By achieving the study aims, we will build the evidence for optimizing equitable diabetes management and ultimately reducing racial and ethnic healthcare disparities for patients living in disinvested urban settings. Trial registration ClinicalTrials.gov: NCT06040463. Registered on September 7, 2023.

Abstract Background Individuals facing socioeconomic hardship experience higher than average rates of chronic disease, such as diabetes, with less access to evidence-based treatment. One solution to address these inequities is a team-based care (TBC) model, defined as one in which at least two providers work collaboratively with a patient and their caregiver(s) to make healthcare decisions. This paper seeks to describe the implementation of a TBC model within a safety-net healthcare setting and determine the extent to which it can be an effective, patient-centered approach to treating individuals with diabetes. Methods Semi-structured interviews were conducted with staff (n = 15) and patients (n = 18). Clinical data were extracted from the electronic medical record of patients (n = 1,599) seen at a safety-net health system in Chicago, Illinois, United States. The mixed methods study was guided by implementation science and participatory research principles. Staff interviews were 60 min and covered patient care activities, work flow, perceived patient experience, and facilitators/barriers to care coordination. Patient interviews were 60 min and covered satisfaction, attitudes about diabetes management, quality of life, and technology. Patient interviews were co-analyzed by research staff and members of a patient advisory committee. Clinical data were collected at an index visit, two years prior and at one-year follow up (n = 1,599). Results Four themes emerged from the interviews: (1) patients perceived the TBC model to be patient centered and of high quality; (2) technology can be an innovative tool, but barriers exist; (3) diabetes management is a complex process; and (4) staff communication enhances care coordination, but misinterpreting roles reduces care coordination. From pre-enrollment to the follow-up period, we found a statistically significant increase in missed visits, decrease in hemoglobin A1c (HbA1c), decrease in body mass index, and decrease in the percent of patients with high blood pressure. We found that each medical visit during the follow-up period was associated with an HbA1c decrease of 0.26 points. Conclusions A TBC model is a patient-centered approach to providing care to patients with complex health needs, such as diabetes, patients were satisfied with the care they were receiving, and the model was associated with an improvement in clinical outcomes.

This text explores the impact of social media on interactions and social relationships, highlighting their role as echo chambers and sources of polarization. It emphasizes the unique characteristics of social networks, such as their affordances – meaning the incentives they offer for action – and their influence on user behavior. By leveraging post-digital theory, which removes the distinction between online and offline worlds, the article proposes to examine the diversity of online discourses. This approach aims to better understand the dynamics of discourse fragmentation and their implications for the reconfiguration of social relationships.

Abstract Floods, droughts, and rainfall‐induced landslides are hydro‐hazards that affect millions of people every year. Anticipation, mitigation, and adaptation to these hazards is increasingly outpaced by their changing magnitude and frequency due to climate change. A key question for society is whether the research we pursue has the potential to address knowledge gaps and to reduce potential future hazard impacts where they will be most severe. We use natural language processing, based on a new climate hazard taxonomy, to review, identify, and geolocate out of 100 million abstracts those that deal with hydro‐hazards. We find that the spatial distribution of study areas is mostly defined by human activity, national wealth, data availability, and population distribution. Hydro‐hazard events that impact large numbers of people lead to increased research activity, but with a strong disparity between low‐ and high‐income countries. We find that 100 times more people need to be affected by hazards before low‐income countries reach comparable research activity to high‐income countries. This “Wealth over Woe” bias needs to be addressed by enabling and targeting research on hydro‐hazards in highly impacted and under‐researched regions, or in those sufficiently socio‐hydrologically similar. We urgently need to reduce knowledge base biases to mitigate and adapt to changing hydro‐hazards if we want to achieve a sustainable and equitable future for all global citizens.

Grant writing is a time-consuming and labor-intensive process that is the essential mechanism by which most academic researchers fund their scientific investigations. To support this effort, we present a software application with corresponding source code that provides draft sections of a typical NIH-style grant to expedite the time to a first draft. The software provides draft grant text, affording researchers extra time to optimize the content and improve the probability of an award. There are three main components to the software: 1) a search and compare tool that compares the proposed research to previously funded NIH applications, 2) a specific aims page drafter, and 3) a research strategy section that incorporates significance, innovation, approach, rigor, and preliminary data. Our initial internal software deployment has been well received, and researchers indicate significant perceived time savings when using this tool.

Summary: Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.