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Abstract Within the thymus, thymic epithelial cells (TECs) create dedicated microenvironments for T cell development and selection. Considering that TECs are sensitive to distinct pathophysiological conditions, uncovering the molecular elements that coordinate their thymopoietic role has important fundamental and clinical implications. Particularly, medullary thymic epithelial cells (mTECs) play a crucial role in central tolerance. Our previous studies, along with others, suggest that mTECs depend on molecular factors linked to genome-protecting pathways, but the precise mechanisms underlying their function remain unknown. These observations led us to examine the role of Foxo3, as it is expressed in TECs and involved in DNA damage response. Our findings show that mice with TEC-specific deletion of Foxo3 (Foxo3cKO) displayed a disrupted mTEC compartment, with a more profound impact on the numbers of CCL21+ and thymic tuft mTEClo subsets. At the molecular level, Foxo3 controls distinct functional modules in the transcriptome of cTECs and mTECs under normal conditions, which includes the regulation of ribosomal biogenesis and DNA damage response, respectively. These changes in the TEC compartment resulted in a reduced total thymocyte cellularity and specific changes in regulatory T cell and iNKT cell development in the Foxo3cKO thymus. Lastly, the thymic defects observed in adulthood correlated with mild signs of altered peripheral immunotolerance in aged Foxo3cKO mice. Moreover, the deficiency in Foxo3 moderately aggravated the autoimmune predisposition observed in Aire-deficient mice. Our findings highlight the importance of Foxo3 in preserving the homeostasis of TECs and in supporting their role in T cell development and tolerance.

Abstract Objectives The use of hemoadsorption (HA) has become popular in the treatment of vasoplegic states associated with massive cytokine release, including septic shock. However, this approach does not seem to be based on robust evidence, and it does not follow international guidelines. To understand the pathophysiological rationale and timing of HA, we conducted a large animal septic shock experiment. Design Prospective randomized large-animal peritoneal septic shock experiment. Setting Laboratory investigation. Subjects Twenty-six anesthetized, mechanically ventilated, and instrumented pigs randomly assigned into (1) sham-operated group with HA (SHAM, n = 5); (2) sepsis animals without HA (SEPSIS, n = 5); (3) sepsis group with HA at norepinephrine initiation (EARLY, n = 8); and (4) sepsis group with HA initiated at norepinephrine rate reaching 0.5 μg/kg/min (LATE, n = 8). Interventions Peritoneal sepsis was induced by cultivated autologous feces inoculation. A CytoSorb cartridge (200 g) with a blood flow rate of 200 mL/min and heparin anticoagulation was used to perform HA. The animals received sedation and intensive organ support up to 48 h or until they experienced cardiovascular collapse. Measurements and main results Systemic hemodynamics, multiple-organ functions, and immune-inflammatory response were measured at predefined periods. The HA treatment was not associated with any measurable benefit in terms of systemic hemodynamics and organ support. The systemic inflammatory markers were unaffected by any of the treatment timings. In contrast, the HA resulted in higher vasopressor load and decreased 36-h survival (5 animals in SHAM (100%), 4 (80%) in SEPSIS, 4 (57%) in EARLY, and 2 (25%) in LATE; p = 0.041). The HA exposure in healthy animals was associated with hemodynamic deterioration, systemic inflammatory response, and cytopenia. Conclusions In this large-animal-controlled fulminant sepsis study, the HA was unable to counteract the disease progression in the early or advanced septic shock phase. However, findings from the HA-exposed sham animals suggest potential safety concerns.

Abstract Aims The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. Methods and results A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single‐photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P

Growth is an important marker of child health and development. It is related to aspects such as social-economic conditions, being affected by social inequalities. Race is a social construct that functions as an essential tool of racism. It creates social hierarchy, resulting in segregation, different quality and access to health care, and unequal distributions of social determinants on health. Understanding the effects of ethno-racial inequalities on growth trajectories is essential to improve children development and well-being. In the study we investigated child growth according to maternal ethno-racial group using a nationwide Brazilian database. Data were obtained via linkage of the CIDACS Birth Cohort and the Brazilian Food the Nutrition Surveillance System. It included 4,090,271 children under 5 years old, born at term, followed-up between 2008 and 2017. We used mixed-effects model to estimate both original and standardized forms of length/height and weight trajectories. Results pointed out to growth differences among the racial groups, concerning both markers. Children born to Indigenous mothers presented the most critical situation, followed by those born to Parda, Asian-descent, and Black mothers. The strengthening of policies aimed at protecting Indigenous children should be urgently undertaken to address systematic ethno-racial health inequalities. Additionally, these findings may help policymakers to achieve the United Nation’s 2030 Sustainable Development Goals (eradication of hunger and all forms of malnutrition).

In January 2021, Germany commenced surveillance of SARS-CoV-2 variants under the Corona Surveillance Act, which ceased in July 2023. The objective was to bolster pandemic control, as specific alterations in amino acids, particularly within the spike protein, were linked to heightened transmission and decreased vaccine effectiveness.Consequently, our team conducted whole genome sequencing using the commercially accessible ARTIC protocol on Illumina's NextSeq500 platform and MiSeq for SARS-CoV-2 positive samples obtained from patients at Heidelberg University Hospital, affiliated hospitals, and the public health office in the Rhine-Neckar/Heidelberg region. Throughout the pandemic, we refined the existing ARTIC V4 protocol as well as our bioinformatics pipeline, the details of which are outlined in this report. This report reflects the protocol for the MiSeq analysis, the protocol for the NextSeq500 can be found in our previous publication.

Introduction: This study aimed to develop, implement, and test a visuo-haptic simulator designed to explore the buoyancy phenomenon for freshman engineering students enrolled in physics courses. The primary goal was to enhance students’ understanding of physical concepts through an immersive learning tool.Methods: The visuo-haptic simulator was created using the VIS-HAPT methodology, which provides high-quality visualization and reduces development time. A total of 182 undergraduate students were randomly assigned to either an experimental group that used the simulator or a control group that received an equivalent learning experience in terms of duration and content. Data were collected through pre- and post-tests and an exit-perception questionnaire.Results: Data analysis revealed that the experimental group achieved higher learning gains than the control group (p = 0.079). Additionally, students in the experimental group expressed strong enthusiasm for the simulator, noting its positive impact on their understanding of physical concepts. The VIS-HAPT methodology also reduced the average development time compared to similar visuo-haptic simulators.Discussion: The results demonstrate the efficacy of the buoyancy visuo-haptic simulator in improving students’ learning experiences and validate the utility of the VIS-HAPT method for creating immersive educational tools in physics.

Teaching interdisciplinary research methods to honors students across disciplines is complex. A pre-capstone seminar, The Art of Inquiry, centers ethical considerations within and beyond individual research interests, helping junior and senior students of all majors prepare for ethical, scholarly projects.

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.

Abstract In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3–31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target.

During food quality control, NIR technology enables the rapid and non-destructive determination of the typical quality characteristics of food categories, their origin, and the detection of potential counterfeits. Over the past 20 years, the NIR results for a variety of food groups—including meat and meat products, milk and milk products, baked goods, pasta, honey, vegetables, fruits, and luxury items like coffee, tea, and chocolate—have been compiled. This review aims to give a broad overview of the NIRS processes that have been used thus far to assist researchers employing non-destructive techniques in comparing their findings with earlier data and determining new research directions.

Background: As health coaching is becoming more popular as a health promotion intervention tool, there is a lack of empirical evidence to understand the clients' experience in the peer health coaching program among college students. Purpose: This qualitative study explored the experiences and perceptions of the health coaching clients following an 8-week peer health coaching intervention in college. Method: A total of 14 student clients (female, n = 9, 57% White) from the health coaching program participated in the focus group, following an 8-week peer health coaching program. The semistructured focus group guide was developed to understand their experience. Results: Clients' positive experience in the health coaching program contributed to transformative outcomes, including behavioral outcomes and goal achievement, well-being and personal growth, and self-empowerment, with the coaching relationship mediating the relationship and the coaching modality moderating the relationship. Discussion: The health coaching experience facilitated lifestyle changes, helped clients gain self-efficacy and confidence to manage their health and wellbeing and provided an overall caring, enjoyable, supportive experience. The bonding with the peer health coaches provided important social support for the student clients. Translation to Health Education Practice: A peer health coaching program can be a cost-effective option for health promotion on college campuses.

Aims & Objectives The purpose of this study was to identify patient characteristics associated with engagement and completion of physical therapy (PT) following total knee arthroplasty (TKA) and examine the relationship between number of PT sessions attended and outcomes during the first 12 weeks after surgery. Methods Patients underwent unilateral primary TKA by a single surgeon and were advised to complete 17 PT sessions over 6 weeks at a hospital-affiliated facility. Analyses examined predictors of PT engagement (attendance of ≥2 sessions) and completion (attendance of 17 ± 1 sessions) within 6 weeks and associations between number of PT sessions attended and changes in range of motion (ROM) and Knee Injury and Osteoarthritis Outcome Score (KOOS) values. Results Patients living

Abstract The impacts of global change—from shifts in climate to overfishing to land use change—can depend heavily on local abiotic context. Building an understanding of how to downscale global change scenarios to local impacts is often difficult, however, and requires historical data across large gradients of variability. Such data are often not available—particularly in peer reviewed or gray literature. However, these data can sometimes be gleaned from casual records of natural history—field notebooks, data sheet marginalia, course notes, and more. Here, we provide an example of one such approach for the Gulf of Maine, as we seek to understand how environmental context can influence local outcomes of region‐wide shifts in subtidal community structure. We explore a decade of hand‐drawn algal cover maps around Appledore Island made by Dr. Art Borror while teaching at the Shoals Marine Lab. Appledore's steep wave exposure gradient—from exposed to the open ocean to fully protected—provides a living laboratory to test interactions between global change and local conditions. We then recreate Borror's methods two and a half decades later. We show that overfishing‐driven urchin outbreaks in the 1980s were slowed or stopped by wave exposure and benthic topography. Similarly, local variation appears to have curtailed current invasions by filamentous red algae. Last, some formerly dominant kelps have disappeared over the past 40 years—an observation verified by subtidal surveys. Global change is altering life in the seas around us. While underutilized, solid natural history observations stand as a key resource for us to begin to understand how global change will translate to the heterogeneous mosaic of life in a future Gulf of Maine and other ecosystems around the world.

Purpose: To determine the rate of and risk factors for failure of tibial spine fracture (TSF) repair. Methods: This was a retrospective review of patients aged 18 years or younger with TSF who underwent arthroscopic repair performed by a single orthopaedic surgeon at a large tertiary academic hospital between 2015 and 2022. Demographic, clinical, injury, fracture, and surgical characteristics were collected. Coronal length and sagittal length and height of the fracture fragment were measured on preoperative plain radiographs and magnetic resonance imaging of the knee. Results: Of 25 patients who underwent arthroscopic reduction with internal fixation of TSFs, 2 (8%) experienced fixation failure. In 16 (64%), internal fixation was performed with suture anchors, whereas 8 (32%) underwent internal fixation with screws. There were 19 male patients (76%). There were no differences in demographic factors (age, race, sex, and body mass index), injury characteristics (laterality, mechanism of injury, and activity causing injury), modified Meyers-McKeever fracture classification, or method of internal fixation between the group with fixation failure and the group without failure. Coronal length (14.2 mm vs 18 mm, P = .17) and sagittal length (13.9 mm vs 18.7 mm, P = .17) of the fracture fragment also did not differ significantly between groups. Sagittal height of the fracture fragment was thinner in patients with failure of fixation (4.3 mm) than in those without failure (8 mm) (P = .02). Conclusions: Decreased bone thickness of the displaced fragment was associated with an increased likelihood of fixation failure. Level of Evidence: Level III, retrospective cohort study.

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma.SignificanceWe demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.

The application of extended reality (XR) technology in education has been growing for the last two decades. XR offers immersive and interactive visualization experiences that can enhance learning by making it engaging. Recent technological advances have led to the availability of high-quality and affordable XR headsets. These advancements have spurred a wave of research focused on designing, implementing, and validating XR educational interventions. Limited literature focuses on the recent trends of XR within science, technology, engineering, and mathematics (STEM) education. Thus, this paper presents an umbrella review that explores the exploding field of XR and its transformative potential in STEM education. Using six online databases, the review zoomed in on 17 out of 1972 papers on XR for STEM education, published between 2020 and 2023, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The results highlighted the types of XR technology applied (i.e., virtual reality and augmented reality), the specific STEM disciplines involved, the focus of each study reviewed, and the major findings from recent reviews. Overall, the educational benefits of using XR technology in STEM education are apparent: XR boosts student motivation, facilitates learning engagement, and improves skills, for example. However, using XR in education still has challenges that must be addressed, such as the physical discomfort of the learner wearing the XR headset and technical glitches. Besides revealing trends of using XR in STEM education, this umbrella review encourages reflection on current practices and suggests ways to apply XR to STEM education effectively.

Background: Little is known about trends in implementing skills-based instruction in US schools, specifically for sexual and reproductive health (SRH). We examined state-level trends in the percentage of US secondary schools teaching SRH skills in a required course in grades 6 to 8 and 9 to 12. Methods: Representative data from 35 states participating across 6 cycles of School Health Profiles (2008-2018) was analyzed. The prevalence of teaching four SRH skills was assessed through lead health education teacher self-administered questionnaires. Logistic regression models examined linear trends in the percentages of schools teaching SRH skills in grades 6 to 8 and 9 to 12. Trends were calculated for states with weighted data (response rates [greater than or equal to] 70%) for at least 3 cycles, including 2018. Results: During 2008 to 2018, the median percentage of schools addressing each SRH skill ranged from 63.5% to 69.7% (grades 6-8) and 88.2% to 92.0% (grades 9-12). Linear decreases in SRH skills instruction were more common for grades 6 to 8 than grades 9 to 12; linear increases were comparable for both groups. Most states demonstrated no change in the percentage of schools teaching SRH skills in grades 6 to 8 and 9 to 12. Conclusions: Limited changes and decreases in SRH skills instruction in US secondary schools suggest efforts to strengthen SRH education are needed.

The purpose of this study was to use a grounded theory, qualitative approach to gain a deeper understanding of students' self-regulated learning processes in a required first-year gateway Anatomy and Physiology (A&P) course that is critical for success in health care-related academic programs and professions. At the end of a two-semester sequence in A&P, students were recruited to participate in individual 30-minute semi-structured interviews based on questions related to their metacognitive beliefs and behaviors. Investigators reviewed verbatim transcripts from 25 primarily first-year students and identified four major themes: 1) career orientation, 2) relevance of Anatomy and Physiology, 3) success as the ability to earn good grades, as well as retention and ability to apply materials, and 4) student behaviors referring to the learning and metacognitive strategies reported by students. Within the theme of student behaviors, four sub-themes emerged: collaborative work with peers, self-responsibility, self-awareness, and evolution as learners. The results of this study will help investigators to design and implement strategies to improve success in this course for pre-health professional students.

Abstract Background Soil and water salinity are increasing problems worldwide, causing significantly reduced crop yields. Alfalfa (Medicago sativa L.) is often listed as salt‐sensitive, but field testing of improved cultivars is limited. Forage systems and improved high‐quality alfalfa varieties are needed to enable crop production under high salinity (HS) conditions. Methods The objective of this study was to measure the yield and quality response of alfalfa to high saline conditions in the field and to document the relative saline tolerance of its varieties. HS irrigation water (electrical conductivity of water, or ECw 8.0–11.0 dS m−1) was applied to 33 nondormant alfalfa cultivars and were compared with low salinity (LS) treatments (ECw 0.5–1.2 dS m−1) over 4 years in a Mediterranean environment on a clay loam soil utilizing a split‐plot design. Crops were harvested seven to eight times per year, and the forage quality was measured on selected harvests utilizing near‐infrared spectroscopy. Results The average yield loss due to HS treatment was 23.9% compared with LS treatment, but yields averaged 23.4 Mg ha−1 under HS over the 3 full years of production. This level of production is considered to be economically viable in this region. Differences in salinity tolerance between lines were identified in the field; individual cultivars lost 5%–35% of their LS yield when grown under HS conditions. Forage quality was significantly improved under HS versus LS conditions, but improvements were negatively correlated with biomass yield (R2 > 0.81), similar to responses observed in drought‐stressed alfalfa. Conclusions These yield results confirm greenhouse studies, indicating that alfalfa is highly salt tolerant once established in the field, with potential for further improvement with tolerant cultivars. Salinity tolerance should be chosen based on total biomass yield as well as on the salinity tolerance index (HS yield relative to LS yield). Agronomic practices to mitigate salinity and sodicity are critical, along with improved cultivars.