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BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Introduction: Athletic trainers are trained to recognize exertional heat stroke (EHS), which is critical to implementing lifesaving measures. Rectal thermometry is the best practice for recognizing EHS, and the Commission on Accreditation of Athletic Training Education (CAATE) requires students to learn rectal thermometry. Rooted in transformative learning theory, this study explored the perceptions and experiences of athletic training students following simulated EHS encounters with either high-fidelity (HF) simulators or standardized patients (SPs). Methods: This was a qualitative study using phenomenological theory. Through semi-structured qualitative interviews, we explored participants' personal experiences and perceptions following their simulation interventions. Participants included sixteen first-year Master of Athletic Training students (HF=8, SP=8; 4 males and 4 females in each group) ages 21-38 (23.69±4.48) who were enrolled in a course discussing exertional heat illnesses. Data Analysis: We recorded and transcribed the interviews verbatim. We used qualitative software, Nvivo (Denver, CO), to categorize the data into themes and codes. To ensure trustworthiness, we used member checking and investigator triangulation. Results: Three themes emerged from the data: 1) Simulation environment, 2) Mindset shifts, and 3) Perceptions of other simulation types. Participants from both groups described positive learning experiences in a foreign yet low stakes learning environment emphasizing repetition for learning the skill. The HF group shared beneficial aspects of patient-history-taking opportunities. The SP group shared the benefits and applicability of developing a patient-provider relationship through communicating with their SP. Most participants from both groups could immerse themselves in the encounter for a realistic experience. Both groups discussed how their mindset towards EHS and rectal thermometry changed after their encounter. Lastly, both groups agreed their simulation intervention was superior to practicing on a task trainer. Conclusions: Instructors of athletic training programs should strive to implement realistic simulated encounters for emergency skills training of athletic training students. A safe space for learning in a low-stakes environment should be fostered. Based on the shared perceived benefits of SP encounters for building provider-patient rapport and feedback opportunities, instructors should consider implementing SPs throughout their curriculum.

Introduction. Low-cost, accurate high-risk HPV tests are needed for cervical cancer screening in limited-resource settings. Objective. To compare the performance of the low-cost Hybribio-H13 test with the Hybrid Capture® 2 to detect cervical intraepithelial neoplasia grade 2 or 3 (CIN2 and CIN3). Materials and methods. Archived baseline samples tested by the Hybrid Capture® 2 from women of the ASCUS-COL trial, aged 20 to 69 years, with biopsy-colposcopy directed diagnosis of CIN2+ (n = 143), CIN3+ (n = 51), and < CIN2 (n = 632) were blindly tested by the Hybribio-H13 test. Results. The relative sensitivity of the Hybribio-H13 test versus the Hybrid Capture® 2 for detecting CIN2+ was 0.89 (90% CI = 0,80-0,98; NIT = 0,66), and for CIN3+ was 0,92 (90% CI = 0,85-0,98; NIT = 0,35). Relative specificity was 1.19 (90% CI = 1.05-1.33; NIT

Often, research on the efficacy of postsecondary workforce programs does not convey their impact on true social mobility. The purpose of this study is to investigate project-based Career and Technical Education (CTE) workforce pathways in Silicon Valley. This study takes a step towards better understanding what constitutes the metrics that explain functioning pathways. In contributing to Project-Based Learning (PBL) theory, Amaral et al. (2015) found that seven PBL essentials form good learning outcomes; Creghan and Adair-Creghan (2015) then showed a measurable outcome of PBL is higher attendance, to which Plasman and Gottfried (2020), using a case of Applied STEM CTE (AS-CTE), framed attendance as a predictor of the efficacy of a workforce pathway. Recommendation: Through ethnography, the investigators observed that when social mobility was added as a metric of high quality PBL with AS-CTE in a predictive ontology framework of education success, an improved level of attendance was observed. The authors conclude that using the seven essentials and social mobility as a metric of PBL helps explain the observation of PBL's improved efficacy. Hence, social mobility should be a metric of PBL AS-CTE program outcomes.

Abstract Lung cancer is the leading cause of cancer deaths in the United States and worldwide. While influenza illness is known to be particularly dangerous for frail and elderly patients, the relationship between influenza illness and outcomes in patients with cancer remains largely unknown. The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with non-small cell lung cancer (NSCLC) diagnosed between 2009 and 2015. Influenza-like illness (ILI) activity, provided by the Outpatient Influenza-like Illness Surveillance Network of the Center of Disease for Control and Prevention, was merged with the SEER dataset on the state-month level. Regional monthly mortality rates were compared during low versus high flu months in this ecological cohort study. 202,485 patients with NSCLC from 13 SEER-reporting states were included in the analysis. 53 of 1049 state-months (5.1%) had high flu activity. Monthly mortality rates during low and high flu months were 0.041 (95% CI 0.041–0.042) and 0.051 (95% CI 0.050–0.053), respectively (RR 1.24 [95% CI 1.21–1.27]). The association between ILI activity and mortality was observed at the individual state level and in all clinical and regional subgroups. Increased regional influenza activity is associated with higher mortality rates for patients with NSCLC. Vaccine-directed initiatives and increased awareness amongst providers will be necessary to address the growing but potentially preventable burden of influenza-related lung cancer deaths in the U.S.

Fire has been a significant part of southeastern American forests for thousands of years. Prescribed fire is an effective method to achieve some land management goals, but sometimes it is not possible to use this tool. Fortunately, there are alternative treatment options that land managers can consider. Although none of these surrogate treatments will produce the same suite of benefits as prescribed fire, they can mimic some of the benefits that prescribed fire creates and are better than applying no treatments. This publication provides an overview for landowners and land managers that want to understand surrogate treatments and the economic and ecological tradeoffs associated with each treatment.

BackgroundFood insecurity is associated with increased morbidity and mortality in people with human immunodeficiency virus (HIV) on antiretroviral therapy, but its relationship with immune dysregulation, a hallmark of HIV infection and comorbidity, is unknown.MethodsIn 241 women participating in the Women's Interagency HIV Study, peripheral blood mononuclear cells were characterized by flow cytometry to identify cell subsets, comprising surface markers of activation (%CD38+HLADR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and co-stimulation (%CD57- CD28+) on CD4+ and CD8+ T cells. Mixed-effects linear regression models were used to assess the relationships of food insecurity with immune outcomes, accounting for repeated measures at ≤3 study visits and adjusting for sociodemographic and clinical factors.ResultsAt the baseline study visit, 71% of participants identified as non-Hispanic Black, 75% were virally suppressed, and 43% experienced food insecurity. Food insecurity was associated with increased activation of CD4+ and CD8+ T cells, increased senescence of CD8+ T cells, and decreased co-stimulation of CD4+ and CD8+ T cells (all P 40 copies/mL and CD4

Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.

Abstract Lung cancer has been the most common cancer worldwide for several decades. The outcomes of patients with locally advanced lung cancer remain dismal, and only a minority of patients survive more than 5 years. However, tumor therapeutic resistance mechanisms are poorly studied. Identification of therapeutic resistance pathways in lung cancer in order to increase the sensitivity of lung tumor cells to therapeutic agents is a crucial but challenging need. To identify novel genes that modulate the response to platinum-based therapy, we performed a genome-wide high-throughput ribonucleic acid interference (RNAi) screen via transfection of human lung cancer (PC9) cells with a viral short hairpin RNA (shRNA) library. We further validated a potential target via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic survival assays on PC9 and A549 lung tumor cells transfected with small interfering RNAs (siRNAs) to successfully downregulate protein expression and then treated with increasing doses of cisplatin or X-ray radiation. We determined protein expression by immunohistochemistry (IHC) after chemoradiotherapy and analyzed gene expression-based survival outcomes in two cohorts of human non-small-cell lung cancer (NSCLC) patients. The screen identified several targets involved in epithelial-to-mesenchymal transition (EMT), including Smurf1, Smurf2, YAP1, and CEBPZ, and glycolytic pathway proteins, including PFKFB3. Furthermore, we found that the small molecule proteasome inhibitor bortezomib significantly downregulated Smurf2 in lung cancer cells. The addition of bortezomib in combination with cisplatin and radiation therapy in PC9 and A549 cells led to an increase in deoxyribonucleic acid (DNA) double-strand breaks with increased numbers of γ-H2AX-positive cells and upregulation of apoptosis. Finally, we found that Smurf2 protein expression was upregulated in situ after treatment with cisplatin and radiation therapy in a relevant cohort of patients with stage III NSCLC. Additionally, Smurf2 gene expression was the strongest predictor of survival in patients with squamous NSCLC after chemotherapy or chemoradiotherapy. We successfully identified and validated Smurf2 as both a common modulator of resistance and an actionable target in lung cancer. These results suggest the urgent need to investigate clinical Smurf2 inhibition via bortezomib in combination with cisplatin and radiation for patients with locally advanced NSCLC.

Purpose: Adaptive magnetic resonance imaging–guided linear accelerators (aMRI-LINACs) are an emerging technology with the potential to improve radiation treatment for cancer through improved visualization and adaptive treatment. Given the competing forces of the increased cost, knowledge, and staff required for aMRI-LINAC therapy, it is unpredictable how rapidly and for whom aMRI-LINAC therapy is being adopted. Therefore, given that aMRI-LINAC therapy was granted approval from the Food and Drug Administration in late 2017, we evaluated the National Cancer Database (NCDB) to obtain a nationwide view of early aMRI-LINAC adoption in 2018 to 2019. Methods and Materials: Forty-three disease sites were aggregated. A sample of patients who underwent intensity modulated radiation therapy (IMRT) from 2018 to 2019 were matched 1:1 by stage for the top 4 cancer sites. We then compared 9 characteristics of interest (age, % White [vs non-White], % residing in metro areas, % living in the greatest income quartile, % insured by Medicare, % uninsured or unknown insurance status, % treated at a comprehensive cancer center or academic center, % with no recorded Charlson-Deyo comorbidities, and % residing in an area with highest educational) between the 2 samples (aMRI-LINAC and matched IMRT). Results: Only 171 patients were recorded as having been treated with aMRI-LINACs in the NCDB in 2018 to 2019. Fifty-six percent were male, 89% White, and 54% enrolled in Medicare. The most common sites of disease treated were lung (33 patients), pancreas (30 patients), prostate (29 patients), and breast (23 patients). There were no significant differences between aMRI-LINAC- and IMRT-matched patients except that patients with lung or breast cancer treated with aMRI-LINAC were significantly more likely to be treated at a comprehensive cancer center or academic center. Conclusions: aMRI-LINAC adoption recorded in the NCDB after Food and Drug Administration approval was potentially underreported, slow, and attributed to academic sites of practice. Further longitudinal study will be needed to assess how practice patterns evolve with greater adoption.

Introduction: Athletic trainers are trained to recognize exertional heat stroke (EHS), which is critical to implementing lifesaving measures. Rectal thermometry is the best practice for recognizing EHS, and the Commission on Accreditation of Athletic Training Education (CAATE) requires students to learn rectal thermometry. Rooted in transformative learning theory, this study explored the perceptions and experiences of athletic training students following simulated EHS encounters with either high-fidelity (HF) simulators or standardized patients (SPs). Methods: This was a qualitative study using phenomenological theory. Through semi-structured qualitative interviews, we explored participants' personal experiences and perceptions following their simulation interventions. Participants included sixteen first-year Master of Athletic Training students (HF=8, SP=8; 4 males and 4 females in each group) ages 21-38 (23.69±4.48) who were enrolled in a course discussing exertional heat illnesses. Data Analysis: We recorded and transcribed the interviews verbatim. We used qualitative software, Nvivo (Denver, CO), to categorize the data into themes and codes. To ensure trustworthiness, we used member checking and investigator triangulation. Results: Three themes emerged from the data: 1) Simulation environment, 2) Mindset shifts, and 3) Perceptions of other simulation types. Participants from both groups described positive learning experiences in a foreign yet low stakes learning environment emphasizing repetition for learning the skill. The HF group shared beneficial aspects of patienthistory-taking opportunities. The SP group shared the benefits and applicability of developing a patient-provider relationship through communicating with their SP. Most participants from both groups could immerse themselves in the encounter for a realistic experience. Both groups discussed how their mindset towards EHS and rectal thermometry changed after their encounter. Lastly, both groups agreed their simulation intervention was superior to practicing on a task trainer. Conclusions: Instructors of athletic training programs should strive to implement realistic simulated encounters for emergency skills training of athletic training students. A safe space for learning in a low-stakes environment should be fostered. Based on the shared perceived benefits of SP encounters for building provider-patient rapport and feedback opportunities, instructors should consider implementing SPs throughout their curriculum. [ABSTRACT FROM AUTHOR]

Socio-scientific reasoning (SSR) is key to helping students take informed positions around socio-scientific issues (SSI). SSR comprises four competencies: recognising complexity of SSI's, multiple perspectives around SSI's, the need for ongoing inquiry around SSI's, and skepticism around different parties' claims made about SSI's. The Quantitative Assessment of SSR (QuASSR) provides a promising measurement framework, but there are still important questions around the ability of this instrument to measure transfer across different scenarios and change in SSR over an intervention. Further, prior work suggests that the four competencies may constitute a progression. We explored the ability of the QuASSR to measure transfer of SSR across three different SSI's using 2-faceted and multi-faceted Rasch models. We used path analysis to test the hypothesis that competencies associated with SSR formed a progression. We found transfer or neartransfer of SSR across the three scenarios, and that the competencies comprise a unidimensional hierarchy. Perspective-taking is a necessary bridge between students' understanding of complexity and the higher-level competencies of inquiry and skepticism. Inquiry and skepticism were found to be conditionally independent upon accounting for perspective-taking, supporting the idea that seeing multiple perspectives around SSI's is central to development of the other SSR competencies.

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9– NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9– CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.

Currently there is little guidance given to teachers in selecting focal issues for socio-scientific issues (SSI)-based teaching and learning. As a majority of teachers regularly collaborate with other teachers, understanding what factors influence collaborative SSI-based curriculum design is critical. We invited 18 secondary science teachers to participate in a professional development on SSI-based instruction and curriculum design. Through intentional design, we studied how these teachers formed curriculum design teams and how they selected focal issues for SSI-based curriculum units. We developed substantiative grounded theory to explain these processes. Key findings include how teachers' tensions and agential moves worked in tandem in the development of a safe and shared place to share discontentment and generate opportunities to form design teams and select issues. Teacher passion and existing resources are factors as influential as considerations for issue relevance. Implications for teacher professional development and research are included.

The complex environmental challenges humanity faces require citizens who are scientifically and environmentally literate. Many environmental education programs are situated in the field where students are immersed in their learning. These field-based activities are engaging but may lack opportunities for students to develop critical thinking and reasoning skills necessary to be environmentally literate. We suggest a socio-scientific issue (SSI) based teaching approach can increase epistemic engagement and lead to student gains in scientific and environmental literacy. This study describes how we modified an existing field-based ecology course, framing the learning around a local environmental socio-scientific issue. We used a convergent parallel mixed-methods approach to examine the changes in socio-scientific reasoning (SSR) over time for high school students in this course as a measure of scientific and environmental literacy. Results indicate that a focused SSI field-based environmental education curriculum can support development of socio-scientific reasoning and environmental literacy competencies among high school students.

Context: Athletic training education should focus on evidence-based teaching through providing authentic learning opportunities. Objective: To examine the effectiveness of 2 different instructional methods' impact on pre-athletic training students' assessment and treatment of a patient with exertional heat stroke (EHS). Design: A pretest, posttest randomized control trial study design was used. Setting: Five undergraduate athletic training programs. Patients or Other Participants: Thirty-six pre-athletic training students volunteered to participate. Thirty-two participants completed the research interventions (19 = hybrid simulation [HS], 13 = case-based learning [CLB]). Intervention(s): All participants received educational material and classroom presentation regarding EHS. Participants completed the preintervention Knowledge, Preferences, and Practices of Certified Athletic Trainers Regarding Recognition and Treatment of Exertional Heat Stroke (KPP-EHS) survey. Approximately 2 to 3 weeks after receiving the educational material, the participants completed HS or CBL intervention protocol and completed the postintervention KPP-EHS survey. The HS intervention consisted of a clinical scenario using a standardized patient and rectal thermometer task trainer. The CBL intervention involved completing a case-study worksheet regarding a clinical scenario. At the 6-week follow-up time point participants completed the KPP-EHS survey. Main Outcome Measure(s): Composite and subscale scores from the KPP-EHS survey. Results: A factorial repeated measure 2 x 3 (Group x Time) analysis of variance revealed a statistically significant main effect for time of the total composite score of both groups (F = 28.005, P = 0.000, partial n[superscript 2] = 0.659). Bonferroni post hoc testing revealed a statistically significant difference between time points 1 and 2 (mean difference = -25.176, P = 0.000, 95% confidence interval -34.036, -16.317) and time points 1 and 3 (mean difference = -32.842, P = 0.000, 95% confidence interval -44.917, -20.767). Conclusions: Athletic training educators should consider the use of HS and CBL in conjunction with didactic course work to prepare students to appropriately manage EHS.

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