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Abstract Lymphedema is a progressive lymphatic disease that potentiates physical and psychosocial distress. Despite its impact, patients reportedly encounter lymphatic ignorance throughout the healthcare system. This cross-sectional study aims to summarize clinical characteristics and interactions of lymphedema patients within the healthcare system. Two lymphedema patient cohorts were included: The Global Registry Analysis Cohort included lymphedema patients who contributed to an international digital lymphatic registry and the Interactions Cohort included patients who initiated a questionnaire about interactions with the medical system. The global registry was used to obtain demographic and clinical characteristics from affiliated lymphedema patients. A 23-item online questionnaire on healthcare experiences and satisfaction with lymphatic healthcare was then distributed to the Interactions Cohort. Complete responses were obtained from 2474 participants. Participants were a mean age of 57.5 ± 16.1 years and 51.4% had a cancer history. Participants reported substantial delays in diagnosis and treatment. Cancer-related and non-cancer-related lymphedema patients reported similar levels of perceived physician disinterest in their lymphedema; however, non-cancer-related lymphedema patients reported more care dissatisfaction. Ultimately, patients continue to face delays in lymphedema diagnosis and treatment. We developed an evidence-based model highlighting areas of reform needed to improve lymphatic education and healthcare.

Abstract Background Breast cancer-related lymphedema (BCRL) imposes a significant economic burden on patients, providers, and society. There is no curative therapy for BCRL, but management through self-care can reduce symptoms and lower the risk of adverse events. Main body The economic burden of BCRL stems from related adverse events, reductions in productivity and employment, and the burden placed on non-medical caregivers. Self-care regimens often include manual lymphatic drainage, compression garments, and meticulous skin care, and may incorporate pneumatic compression devices. These regimens can be effective in managing BCRL, but patients cite inconvenience and interference with daily activities as potential barriers to self-care adherence. As a result, adherence is generally poor and often worsens with time. Because self-care is on-going, poor adherence reduces the effectiveness of regimens and leads to costly treatment of BCRL complications. Conclusion Novel self-care solutions that are more convenient and that interfere less with daily activities could increase self-care adherence and ultimately reduce complication-related costs of BCRL.

Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

Abstract Background The development of tyrosine kinase inhibitors (TKIs) has significantly improved survival rates among patients with Philadelphia chromosome (Ph+) B cell acute lymphoblastic leukemia (B‐ALL). Ph‐like B‐ALL patients lack the BCR::ABL1 translocation but share gene expression profiles with Ph+ B‐ALL. The role of TKIs for Ph‐like patients pre‐ and post‐hematopoietic stem cell transplantation (HSCT) is not yet clear. Case Here we present five cases of pediatric, adolescent, and young adult patients who presented with Ph‐like B‐ALL or CML in B‐ALL blast phase who were treated with personalized TKI regimens pre‐ and post‐HSCT. Conclusion This report describes several novel Ph‐like fusions as well as combinations of TKIs with chemotherapy or immunotherapy not yet reported in the pediatric population. This case series provides real‐world experience highlighting the potential application of pre‐ and post‐HSCT use of TKIs in a subset of patients with targetable fusions.

Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.

Abstract West Nile virus (WNV) is the leading cause of mosquito‐borne illness in the continental United States (CONUS). Spatial heterogeneity in historical incidence, environmental factors, and complex ecology make prediction of spatiotemporal variation in WNV transmission challenging. Machine learning provides promising tools for identification of important variables in such situations. To predict annual WNV neuroinvasive disease (WNND) cases in CONUS (2015–2021), we fitted 10 probabilistic models with variation in complexity from naïve to machine learning algorithm and an ensemble. We made predictions in each of nine climate regions on a hexagonal grid and evaluated each model's predictive accuracy. Using the machine learning models (random forest and neural network), we identified the relative importance and variation in ranking of predictors (historical WNND cases, climate anomalies, human demographics, and land use) across regions. We found that historical WNND cases and population density were among the most important factors while anomalies in temperature and precipitation often had relatively low importance. While the relative performance of each model varied across climatic regions, the magnitude of difference between models was small. All models except the naïve model had non‐significant differences in performance relative to the baseline model (negative binomial model fit per hexagon). No model, including the ensemble or more complex machine learning models, outperformed models based on historical case counts on the hexagon or region level; these models are good forecasting benchmarks. Further work is needed to assess if predictive capacity can be improved beyond that of these historical baselines.

Secondary lymphedema is a common condition among cancer survivors, and treatment strategies to prevent or treat lymphedema are in high demand. The development of novel strategies to diagnose or treat lymphedema would benefit from a robust experimental animal model of secondary lymphedema. The purpose of this methods paper is to describe and summarize our experience in developing and characterizing a rat hindlimb model of lymphedema. Here we describe a protocol to induce secondary lymphedema that takes advantage of micro computed tomography imaging for limb volume measurements and visualization of lymph drainage with near infrared imaging. To demonstrate the utility of this preclinical model for studying the therapeutic benefit of novel devices, we apply this animal model to test the efficacy of a biomaterials-based implantable medical device.

Abstract Lower extremity lymphedema (LEL) can result in detriments to quality of life (QOL) and impose a significant economic burden on patients and payers. A common component of treatment is pneumatic compression, which requires patients to remain immobile. We investigated a novel non-pneumatic compression device (NPCD) that allows patients to remain active during compression treatment, to see if it reduces swelling and improves QOL. We conducted a non-randomized, open-label, 12-week pilot study of adult patients with primary or secondary unilateral LEL, and measured changes in limb edema and QOL using the Lymphedema Quality of Life Questionnaire (LYMQOL). Twenty-four subjects were enrolled; the majority were female (17) with secondary lymphedema (21). Eighteen completed the study. Statistically significant improvements were observed in overall QOL, aggregated LYMQOL total score, and three of four LYMQOL subscales (Function, Appearance, Mood). The fourth (Symptoms) trended toward significant improvement (p = 0.06). The average reduction in affected limb edema was 39.4%. The novel NPCD produced statistically significant improvements in QOL, functioning, and edema volume of patients with LEL. Innovations in devices to manage LEL can be effective while allowing patients to maintain mobility and physical activity during treatment.

Abstract Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree‐ring fire scars provide valuable perspectives on fire regimes, including centuries‐long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree‐ring fire‐scar network (NAFSN), which contains 2562 sites, >37,000 fire‐scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000‐m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire‐scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under‐sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non‐Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually‐ to sub‐annually‐resolved tree‐ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America.

Histoplasmosis is an endemic infection of Ecuador, its forms of presentation can be varied and florid, especially in immunosuppressed patients, its lethality is high, hence its diagnosis and treatment should be based on both clinical and laboratory results. Cutaneous histoplasmosis is a form of disseminated Histoplasma capsulatum infection rarely described in HIV patients. The following is a description of the diagnosis and treatment of a patient with generalized papular skin lesions, heat stroke, diarrhea, attributed to adverse reaction of gastritis treatment of 10 days of evolution, this was associated with a recent diagnosis of HIV infection following his admission to hospital.

Abstract Background The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well‐delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non‐lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies. Methods We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders. Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non‐lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise co‐occurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease–disease interrelationships. Results Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease–disease interrelationships was noted in all three lymphatic categories when compared to the control population. Conclusions The presence or absence of a lymphatic disease significantly influences disease interrelationships in the study cohorts. As a physiologic substrate, the lymphatic circulation may be an underappreciated participant in disease pathogenesis. These relationships warrant further, prospective scrutiny and study.

Abstract Spatial interactions between trees influence forest community succession. The objective of this study was to investigate how shifts in forest composition and proximity between tree species affect stand development over time in mixed forest systems. At six locations across the Fishlake National Forest, Utah, USA, in stands where facilitation has been documented previously, tree‐ring samples were collected from aspen and subalpine fir trees. Basal area increment was calculated to characterize the effects of the proximity of overstory trees on multidecadal growth responses of aspen and subalpine fir in aspen‐dominant and mixed aspen–conifer stands. Subalpine fir seedlings were established next to aspen (within 10 cm) when aspen was between 15 and 120 years old with a mean age of 60 years. Aspen and subalpine fir growth rates were reduced with increasing conifer abundance. Aspen trees growing next to a proximate subalpine fir tree had slower growth rates over time than aspen trees growing independently. Growth rates of subalpine fir in aspen‐dominated stands were similar when growing independently or near aspen trees. However, subalpine fir in conifer‐dominated stands maintained higher growth rates when growing next to an aspen tree than when growing independently. The data suggest that as stand competition increases with conifer abundance, the proximity of overstory trees increases competitive exclusion of aspen while having a beneficial growth effect on subalpine fir. These results underscore the importance of maintaining natural fire regimes in forest systems that keep competitive interactions in balance.

Lymphedema is a chronic inflammatory disorder characterized by edema, fat deposition, and fibrotic tissue remodeling. Despite significant advances in lymphatic biology research, our knowledge of lymphedema pathology is incomplete. Currently, there is no approved pharmacological therapy for this debilitating disease. Hypoxia is a recognized feature of inflammation, obesity, and fibrosis. Understanding hypoxia-regulated pathways in lymphedema may provide new insights into the pathobiology of this chronic disorder and help develop new medicinal treatments.

Abstract Human activities are changing patterns of ecological disturbance globally. In North American deserts, wildfire is increasing in size and frequency due to fuel characteristics of invasive annual grasses. Fire reduces the abundance and cover of native vegetation in desert ecosystems. In this study, we sought to characterize stem growth and reproductive output of a dominant native shrub in the Mojave Desert, creosote bush (Larrea tridentata (DC.) Coville) following wildfires that occurred in 2005. We sampled 55 shrubs along burned and unburned transects 12 years after the fires (2017) and quantified age, stem diameter, stem number, radial and vertical growth rates, and fruit production for each shrub. The shrubs on the burn transects were most likely postfire resprouts based on stem age while stems from unburn transects dated from before the fire. Stem and vertical growth rates for shrubs on burned transects were 2.6 and 1.7 times higher than that observed for shrubs on unburned transects. Fruit production of shrubs along burned transects was 4.7‐fold more than shrubs along paired unburned transects. Growth rates and fruit production of shrubs in burned areas did not differ with increasing distance from the burn perimeter. Positive growth and reproduction responses of creosote following wildfires could be critical for soil stabilization and re‐establishment of native plant communities in this desert system. Additional research is needed to assess if repeat fires that are characteristic of invasive grass‐fire cycles may limit these benefits.

Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.

The efficacy of antibody detection tools for all stages of Ehrlichia canis infections and for various genotypes remains unclear. We produced recombinant gp36 (rgp36) antigens from different isolates of Thai E. canis to confirm the immunoreactivities to these recombinant proteins from naturally infected dogs. Sera and blood samples were taken from 21 dogs naturally infected with E. canis and in the clinical stages of acute phase ehrlichiosis. The expression vectors and competent E. coli produced two isolates of rgp36. These two major rgp36s were recognized by the dogs' sera in Western blotting, with both anti-dog IgM and IgG used as secondary antibodies. The two different genotypes of these local recombinant immunoreactive proteins were gp36 subgroup A (isolate 1055) and subgroup B (isolate 533). The Western blot analyses successfully identified both specific IgM and IgG from the dogs' sera. Of all 21 cases, five dogs presented specific IgM, twenty dogs presented specific IgG, and the commercial test used found fifteen seropositive dogs. There were four dogs that presented both specific IgM and IgG. Only one dog presented specific IgM only. This report is the first identification of a specific IgM in dogs in response to acute infections with E. canis. The recombinant gp36 isolates may be useful as potential antigenic material for subsequent serological tests that have a high possibility for differentiating between acute, chronic, primary, and nonprimary infections with E. canis.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.