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Background: In the United States, Black and Latino children with asthma are more likely than White children with asthma to require emergency department visits or hospitalizations because of an asthma exacerbation. Although many cite patient-level socioeconomic status and access to health care as primary drivers of disparities, there is an emerging focus on a major root cause of disparities-systemic racism. Current conceptual models of asthma disparities depict the historical and current effects of systemic racism as the foundation for unequal exposures to social determinants of health, environmental exposures, epigenetic factors, and differential healthcare access and quality. These ultimately lead to biologic changes over the life course resulting in asthma morbidity and mortality. Methods: At the 2022 American Thoracic Society International Conference, a diverse panel of experts was assembled to identify gaps and opportunities to address systemic racism in childhood asthma research. Panelists found that to examine and address the impacts of systemic racism on children with asthma, researchers and medical systems that support biomedical research will need to 1) address the current gaps in our understanding of how to conceptualize and characterize the impacts of systemic racism on child health, 2) design research studies that leverage diverse disciplines and engage the communities affected by systemic racism in identifying and designing studies to evaluate interventions that address the racialized system that contributes to disparities in asthma health outcomes, and 3) address funding mechanisms and institutional research practices that will be needed to promote antiracism practices in research and its dissemination. Results: A thorough literature review and expert opinion discussion demonstrated that there are few studies in childhood asthma that identify systemic racism as a root cause of many of the disparities seen in children with asthma. Community engagement and participation in research studies is essential to design interventions to address the racialized system in which patients and families live. Dissemination and implementation studies with an equity lens will provide the multilevel evaluations required to understand the impacts of interventions to address systemic racism and the downstream impacts. To address the impacts of systemic racism and childhood asthma, there needs to be increased training for research teams, funding for studies addressing research that evaluates the impacts of racism, funding for diverse and multidisciplinary research teams including community members, and institutional and financial support of advocating for policy changes based on study findings. Conclusions: Innovative study design, new tools to identify the impacts of systemic racism, community engagement, and improved infrastructure and funding are all needed to support research that will address impacts of systemic racism on childhood asthma outcomes.

PURPOSE: Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. METHODS: Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I-III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal-Wallis rank sum and Fishers exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. RESULTS: Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19-3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013). CONCLUSIONS: Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

Multilevel interventions (MLIs) are appropriate to reduce health disparities among Indigenous peoples because of their ability to address these communities' diverse histories, dynamics, cultures, politics, and environments. Intervention science has highlighted the importance of context-sensitive MLIs in Indigenous communities that can prioritize Indigenous and local knowledge systems and emphasize the collective versus the individual. This paradigm shift away from individual-level focus interventions to community-level focus interventions underscores the need for community engagement and diverse partnerships in MLI design, implementation, and evaluation. In this paper, we discuss three case studies addressing how Indigenous partners collaborated with researchers in each stage of the design, implementation, and evaluation of MLIs to reduce health disparities impacting their communities. We highlight the following: (1) collaborations with multiple, diverse tribal partners to carry out MLIs which require iterative, consistent conversations over time; (2) inclusion of qualitative and Indigenous research methods in MLIs as a way to honor Indigenous and local knowledge systems as well as a way to understand a health disparity phenomenon in a community; and (3) relationship building, maintenance, and mutual respect among MLI partners to reconcile past research abuses, prevent extractive research practices, decolonize research processes, and generate co-created knowledge between Indigenous and academic communities.

Multilevel interventions (MLIs) are appropriate to reduce health disparities among Indigenous peoples because of their ability to address these communities' diverse histories, dynamics, cultures, politics, and environments. Intervention science has highlighted the importance of context-sensitive MLIs in Indigenous communities that can prioritize Indigenous and local knowledge systems and emphasize the collective versus the individual. This paradigm shift away from individual-level focus interventions to community-level focus interventions underscores the need for community engagement and diverse partnerships in MLI design, implementation, and evaluation. In this paper, we discuss three case studies addressing how Indigenous partners collaborated with researchers in each stage of the design, implementation, and evaluation of MLIs to reduce health disparities impacting their communities. We highlight the following: (1) collaborations with multiple, diverse tribal partners to carry out MLIs which require iterative, consistent conversations over time; (2) inclusion of qualitative and Indigenous research methods in MLIs as a way to honor Indigenous and local knowledge systems as well as a way to understand a health disparity phenomenon in a community; and (3) relationship building, maintenance, and mutual respect among MLI partners to reconcile past research abuses, prevent extractive research practices, decolonize research processes, and generate co-created knowledge between Indigenous and academic communities.

Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

Renal angiomyolipoma (AML) is a typically benign renal tumor that is divided into 2 classes, the classical variant and the more aggressive epithelioid variant. It is extremely rare for an AML to exhibit aggressive features such as vascular invasion. We present the case of a 36-year-old female who presented with right lower quadrant pain for 9 months and was found to have an AML with tumor extension into the renal vein and the IVC. Diagnosis was confirmed with histopathology and the patient was treated with a total nephrectomy. The epithelioid subtype of AML is a rare variant that should be considered in the differential of a renal mass with vascular invasion.

Abstract Background Keratoconus in children is often more severe and rapidly progressive compared to adults. While Scheimpflug imaging (Pentacam) improves screening, there are no established pediatric guidelines. Due to challenges in diagnosis, we aimed to correlate clinical factors with abnormal imaging results to aid in the development of screening protocols. Methods A single-center retrospective cohort analysis of patients 3–18 years screened for keratoconus with ophthalmic examination and initial Scheimpflug imaging between 2021 to 2023. Scheimpflug indices including final D, ART max, and calculated CAIRO 8, which is a corneal metric combining pachymetry, ART max, and elevation, were compared to published pediatric ranges for normal and keratoconus corneas. Results Seventy-eight patients (11.8 ± 3.9 years) were screened with the majority referred due to high and/or progressive astigmatism (74 patients, 94%). Forty-nine patients (63%) were male and 48 (62%) self-reported Hispanic ethnicity. Average astigmatism was 4.9 ± 1.8 D and 86% had with-the-rule astigmatism. Fourteen patients (18%) had corneal findings on slit lamp. Average LogMAR CDVA was 0.243 ± 0.274 D. By Pentacam, 55 (70%) patients had ≥ 1 indeterminate or keratoconus value. Patients stratified as keratoconus by all parameters were older (15 vs. 11 years, p = 0.015–0.02), had worse visual acuity (p

Abstract Cancer staging is an essential clinical attribute informing patient prognosis and clinical trial eligibility. However, it is not routinely recorded in structured electronic health records. Here, we present BB-TEN: Big Bird – TNM staging Extracted from Notes, a generalizable method for the automated classification of TNM stage directly from pathology report text. We train a BERT-based model using publicly available pathology reports across approximately 7000 patients and 23 cancer types. We explore the use of different model types, with differing input sizes, parameters, and model architectures. Our final model goes beyond term-extraction, inferring TNM stage from context when it is not included in the report text explicitly. As external validation, we test our model on almost 8000 pathology reports from Columbia University Medical Center, finding that our trained model achieved an AU-ROC of 0.815–0.942. This suggests that our model can be applied broadly to other institutions without additional institution-specific fine-tuning.

Abstract The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies.

Abstract Purpose Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. Methods Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I–III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal–Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. Results Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19–3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013). Conclusions Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

The discharge measured in karst springs is known to exhibit distinctive long tails during recession times following distinct short-duration discharge peaks. The long-tailed behavior is generally attributed to the occurrence of tortuous, ramified flow paths that develop in the underground structure of karst systems. Modeling the discharge behavior poses unique difficulties because of the poorly delineated flow path geometry and generally scarce information on the hydraulic properties of catchment-scale systems. In a different context, modeling of long-tailed behavior has been addressed in studies of chemical transport. Here, an adaptation of a continuous time random walk–particle tracking (CTRW-PT) framework for anomalous transport is proposed, which offers a robust means to quantify long-tailed breakthrough curves that often arise during the transport of chemical species under various flow scenarios. A theoretical analogy is first established between partially water-saturated karst flow, characterized by temporally varying water storage, and chemical transport involving the accumulation and release of a chemical tracer. This analogy is then used to develop and implement a CTRW-PT model. Application of this numerical model to the examination of 3 years of summer rainfall and discharge data from a karst aquifer system – the Disnergschroef high-alpine site in the Austrian Alps – is shown to yield robust fits between modeled and measured discharge values. In particular, the analysis underscores the predominance of slow diffusive flow over rapid conduit flow. The study affirms the analogy between partially saturated karst flow and chemical transport, exemplifying the compatibility of the CTRW-PT model for this purpose. Within the specific context of the Disnergschroef karst system, these findings highlight the predominance of slow diffusive flow over rapid conduit flow. The agreement between measured and simulated data supports the proposed analogy between partially saturated karst flow and chemical transport; it also highlights the potential ability of the anomalous transport framework to further enhance modeling of flow and transport in karst systems.

Abstract Violence across Latin America is an increasingly important factor influencing migration to the US. A particular form of violence that is experienced by many Latinx migrants is extortion. This research analyzes the extortion experiences of Latinx immigrant adults arriving at the US southern border and the impact these experiences have on mental health. We find that on average, participants paid $804 in extortion during their migration. The most common perpetrators of extortion in our study were police followed by immigration officials throughout Latin America. Pregnant participants were less likely to experience extortion and adults traveling with children were more likely to be extorted. Participants who were extorted for money reported significantly greater severity of post-traumatic stress disorder (PTSD) symptoms compared to those who were not extorted. This research is the first of its kind to analyze extortion experiences among Latinx immigrants to the US, quantifying the prevalence, amounts paid, countries where extortion occurs, and perpetrators of extortion. In addition, extortion experiences are associated with negative effects on the mental health of newly arrived Latinx immigrants to the US. Based upon these findings, we recommend that extortion should be considered a significant stressor in the migrant experience, particularly for those adults traveling with children.

In this introduction to the special issue of M@n@gement for the 30th anniversary of the AIMS, dedicated to complex societal problems, we examine issues of scale and non-scalability, inspired by Tsing’s work and recent calls for an ethics of care and responsiveness, thus highlighting the need to develop more care and relationality in the study of complex problems and grand challenges. This means questioning scale, recognizing the agency and value of human and nonhuman beings, prioritizing local knowledge, mutual respect, solidarity and coexistence.

This paper presents two leadership training programs focused on redesigning schools to promote student character development and advocates for their suitability to promote character education in diverse cultural contexts. This is especially relevant for researchers, practitioners, and policy makers who are searching for replicable interventions to promote character development in schools, particularly in those countries where the character education movement has not arrived yet. It begins with the theoretical framework that lays the groundwork for these kinds of leadership programs. Second, it describes the PRIMED Institute in Character Education (PICE) and the virtual/video-based Leadership Academy in Character Education (vLACE) programs. Finally, it presents seven arguments in favor of these programs responding to the needs of schools in many different countries.

Computational models are employed to study and respond to pressing environmental issues such as groundwater contamination. This use of computational models, which often involves algorithms and uncertainty that are hidden to the public, has implications for environmental science literacy. This study applies a design-based research approach to explore how technology-infused science instruction can scaffold secondary students in developing proficiency with computational modeling of groundwater contamination as a facet of environmental science literacy. Descriptions of research-based, technology-infused learning experiences situated within a groundwater contamination issue-based context are shared, and evidence of students' subsequent learning is presented. Findings suggest that student learning may be supported by enacting instructional experiences that scaffold students in (a) developing first concrete then increasingly abstract understanding of groundwater system structure, function, and dynamics; (b) building conceptual connections between multiple types of models and representations of a system; and (c) explicitly engaging with and judging uncertainties associated with system models, model outputs, and associated arguments. Insights are shared concerning how instructional technologies including physical models, two-dimensional representations (e.g., maps and cross-sections), and computational models may be employed in science teaching to support students in developing computational modeling competencies needed for participating in debates and discussions about socioenvironmental problems like groundwater contamination.