Shifting fire regimes cause continent-wide transformation of threatened species habitat.

Human actions are causing widespread increases in fire size, frequency, and severity in diverse ecosystems globally. This alteration of fire regimes is considered a threat to numerous animal species, but empirical evidence of how fire regimes are shifting within both threatened species' ranges and protected areas is scarce, particularly at large spatial and temporal scales. We used a big data approach to quantify multidecadal changes in fire regimes in southern Australia from 1980 to 2021, spanning 415 reserves (21.5 million ha) and 129 threatened species' ranges including birds, mammals, reptiles, invertebrates, and frogs. Most reserves and threatened species' ranges within the region have experienced declines in unburnt vegetation (≥30 y without fire), increases in recently burnt vegetation (≤5 y since fire), and increases in fire frequency. The mean percentage of unburnt vegetation within reserves declined from 61 to 36% (1980 to 2021), whereas the mean percentage of recently burnt vegetation increased from 20 to 35%, and mean fire frequency increased by 32%, with the latter two trends primarily driven by the record-breaking 2019 to 2020 fire season. The strongest changes occurred for high-elevation threatened species, and reserves of high elevation, high productivity, and strong rainfall decline, particularly in the southeast of the continent. Our results provide evidence for the widely held but poorly tested assumption that threatened species are experiencing widespread declines in unburnt habitat and increases in fire frequency. This underscores the imperative for developing management strategies that conserve fire-threatened species in an increasingly fiery future.

Bone Health ECHO Case Report: Fractures and Hypercalcemia in a Patient with Stage 5 Chronic Kidney Disease.

Bone Health ECHO (Extension for Community Healthcare Outcomes) is a virtual community of practice with the aim of enhancing global capacity to deliver best practice skeletal healthcare. The prototype program, established at the University of New Mexico, has been meeting online weekly since 2015, focusing on presentation and discussion of patient cases. These discussions commonly cover issues that are relevant to a broad range of patients, thereby serving as a force multiplier to improve the care of many patients. This is a case report from Bone Health ECHO about a patient with stage 5 chronic kidney disease, hypercalcemia, and low bone density, and the discussion that followed.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy.

Paramedic Education and Training for the Management of Patients Presenting with Low-Acuity Clinical Conditions: A Scoping Review.

Ambulance services around the world are increasingly attending to calls for non-emergency conditions. These lower-acuity conditions do not always require patients to be transported to the emergency department. Consequently, over the past two decades, ambulance services have implemented strategies to support paramedics in diverting non-urgent patients to alternative care pathways. However, assessing and managing low-acuity conditions can be challenging for paramedics, especially when education and training has traditionally focussed on emergency care. This scoping review explores the education and training provided to paramedics on low-acuity clinical conditions and the use of alternative care pathways. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews was applied. The databases searched included Scopus, CINAHL, Embase, Emcare, and MEDLINE (PubMed). The search identified one-hundred sixty-six records, with a total of nine articles reviewed after the removal of duplicates and the screening process. The articles were diverse, with education and training ranging from university degrees for extended care practitioners to short in-service-based training for a suite of protocols or assessment tools. However, the literature addressing education and training on low-acuity conditions and alternative care pathways is limited, with the type and length of education programs appearing to influence practice. There is a need for further research to establish a low acuity education model.

Extinction risk of the world's freshwater mammals.

The continued loss of freshwater habitats poses a significant threat to global biodiversity. We reviewed the extinction risk of 166 freshwater aquatic and semiaquatic mammals-a group rarely documented as a collective. We used the International Union for the Conservation of Nature Red List of Threatened Species categories as of December 2021 to determine extinction risk. Extinction risk was then compared among taxonomic groups, geographic areas, and biological traits. Thirty percent of all freshwater mammals were listed as threatened. Decreasing population trends were common (44.0%), including a greater rate of decline (3.6% in 20 years) than for mammals or freshwater species as a whole. Aquatic freshwater mammals were at a greater risk of extinction than semiaquatic freshwater mammals (95% CI -7.20 to -1.11). Twenty-nine species were data deficient or not evaluated. Large species (95% CI 0.01 to 0.03) with large dispersal distances (95% CI 0.03 to 0.15) had a higher risk of extinction than small species with small dispersal distances. The number of threatening processes associated with a species compounded their risk of extinction (95% CI 0.28 to 0.77). Hunting, land clearing for logging and agriculture, pollution, residential development, and habitat modification or destruction from dams and water management posed the greatest threats to these species. The basic life-history traits of many species were poorly known, highlighting the need for more research. Conservation of freshwater mammals requires a host of management actions centered around increased protection of riparian areas and more conscientious water management to aid the recovery of threatened species.

Riesgo de extinción de los mamíferos de agua dulce Resumen La pérdida continua de hábitats de agua dulce representa una amenaza importante para la biodiversidad mundial. Analizamos el riesgo de extinción de 166 especies de mamíferos acuáticos y semiacuáticos de agua dulce-un grupo que se documenta pocas veces como colectivo. Usamos las categorías de la Lista Roja de Especies Amenazadas de la Unión Internacional para la Conservación de la Naturaleza de diciembre 2021 para determinar el riesgo de extinción. Después comparamos este riesgo entre grupos taxonómicos, áreas geográficas y caracteres biológicos. El 30% de los mamíferos de agua dulce están categorizados como amenazados. La declinación de las tendencias poblacionales fue común (44.0%), incluyendo una mayor tasa de declinación (3.6% en 20 años) que para los mamíferos o las especies de agua dulce como conjunto. Los mamíferos acuáticos de agua dulce se encuentran en mayor riesgo de extinción que los mamíferos semiacuáticos (95% IC -7.20 a -1.11). Veintinueve especies no contaban con suficientes datos o no estaban evaluadas. Las especies grandes (95% IC 0.01 a 0.03) con distancias de dispersión amplias (95% IC 0.03 a 0.15) tuvieron un mayor riesgo de extinción que las especies pequeñas con menores distancias de dispersión. El número de procesos amenazantes asociados a alguna especie agravó su riesgo de extinción (95% CI 0.28 a 0.77). Las principales amenazas para estas especies fueron la cacería, el desmonte de tierras para tala y agricultura, la contaminación, los desarrollos residenciales y la destrucción o modificación del hábitat causados por presas o manejo hidrológico. Se sabe poco sobre los caracteres básicos de la historia de vida de muchas especies, lo que destaca la necesidad de más investigación al respecto. La conservación de mamíferos de agua dulce requiere una serie de acciones gestoras centradas en el incremento de la protección de las áreas ribereñas y una gestión hidrológica más consciente para ayudar a la recuperación de las especies amenazadas.

Tropical cyclone winds and precipitation stimulate cone production in the masting species longleaf pine (Pinus palustris).

Many trees exhibit masting - where reproduction is temporally variable and synchronous over large areas. Several dominant masting species occur in tropical cyclone (TC)-prone regions, but it is unknown whether TCs correlate with mast seeding. We analyzed long-term data (1958-2022) to test the hypothesis that TCs influence cone production in longleaf pine (Pinus palustris). We integrate field observations, weather data, satellite imagery, and hurricane models to test whether TCs influence cone production via: increased precipitation; canopy density reduction; and/or mechanical stress from wind. Cone production was 31% higher 1 yr after hurricanes and 71% higher after 2 yr, before returning to baseline levels. Cyclone-associated precipitation was correlated with increased cone production in wet years and cone production increased after low-intensity winds (≤ 25 m s-1 ) but not with high-intensity winds (> 25 m s-1 ). Tropical cyclones may stimulate cone production via precipitation addition, but high-intensity winds may offset any gains. Our study is the first to support the direct influence of TCs on reproduction, suggesting a previously unknown environmental correlate of masting, which may occur in hurricane-prone forests world-wide.

Fire shapes fungal guild diversity and composition through direct and indirect pathways.

Fire has shaped global ecosystems for millennia by directly killing organisms and indirectly altering habitats and resources. All terrestrial ecosystems, including fire-prone ecosystems, rely on soil-inhabiting fungi, where they play vital roles in ecological processes. Yet our understanding of how fire regimes influence soil fungi remains limited and our knowledge of these interactions in semiarid landscapes is virtually absent. We collected soil samples and vegetation measurements from sites across a gradient in time-since-fire ages (0-75 years-since-fire) and fire frequency (burnt 0-5 times during the recent 29-year period) in a semiarid heathland of south-eastern Australia. We characterized fungal communities using ITS amplicon-sequencing and assigned fungi taxonomically to trophic guilds. We used structural equation models to examine direct, indirect and total effects of time-since-fire and fire frequency on total fungal, ectomycorrhizal, saprotrophic and pathogenic richness. We used multivariate analyses to investigate how total fungal, ectomycorrhizal, saprotrophic and pathogenic species composition differed between post-fire successional stages and fire frequency classes. Time-since-fire was an important driver of saprotrophic richness; directly, saprotrophic richness increased with time-since-fire, and indirectly, saprotrophic richness declined with time-since-fire (resulting in a positive total effect), mediated through the impact of fire on substrates. Frequently burnt sites had lower numbers of saprotrophic and pathogenic species. Post-fire successional stages and fire frequency classes were characterized by distinct fungal communities, with large differences in ectomycorrhizal species composition. Understanding the complex responses of fungal communities to fire can be improved by exploring how the effects of fire flow through ecosystems. Diverse fire histories may be important for maintaining the functional diversity of fungi in semiarid regions.

Herbaceous vegetation responses to experimental fire in savannas and forests depend on biome and climate.

Fire-vegetation feedbacks potentially maintain global savanna and forest distributions. Accordingly, vegetation in savanna and forest ecosystems should have differential responses to fire, but fire response data for herbaceous vegetation have yet to be synthesized across biomes. Here, we examined herbaceous vegetation responses to experimental fire at 30 sites spanning four continents. Across a variety of metrics, herbaceous vegetation increased in abundance where fire was applied, with larger responses to fire in wetter and in cooler and/or less seasonal systems. Compared to forests, savannas were associated with a 4.8 (±0.4) times larger difference in herbaceous vegetation abundance for burned versus unburned plots. In particular, grass cover decreased with fire exclusion in savannas, largely via decreases in C4 grass cover, whereas changes in fire frequency had a relatively weak effect on grass cover in forests. These differential responses underscore the importance of fire for maintaining the vegetation structure of savannas and forests.

Identifying historical and future global change drivers that place species recovery at risk.

Ecosystem management in the face of global change requires understanding how co-occurring threats affect species and communities. Such an understanding allows for effective management strategies to be identified and implemented. An important component of this is differentiating between factors that are within (e.g. invasive predators) or outside (e.g. drought, large wildfires) of a local manager's control. In the global biodiversity hotspot of south-western Australia, small- and medium-sized mammal species are severely affected by anthropogenic threats and environmental disturbances, including invasive predators, fire, and declining rainfall. However, the relative importance of different drivers has not been quantified. We used data from a long-term monitoring program to fit Bayesian state-space models that estimated spatial and temporal changes in the relative abundance of four threatened mammal species: the woylie (Bettongia penicillata), chuditch (Dasyurus geoffroii), koomal (Trichosurus vulpecula) and quenda (Isoodon fusciventor). We then use Bayesian structural equation modelling to identify the direct and indirect drivers of population changes, and scenario analysis to forecast population responses to future environmental change. We found that habitat loss or conversion and reduced primary productivity (caused by rainfall declines) had greater effects on species' spatial and temporal population change than the range of fire and invasive predator (the red fox Vulpes vulpes) management actions observed in the study area. Scenario analysis revealed that a greater extent of severe fire and further rainfall declines predicted under climate change, operating in concert are likely to further reduce the abundance of these species, but may be mitigated partially by invasive predator control. Considering both historical and future drivers of population change is necessary to identify the factors that risk species recovery. Given that both anthropogenic pressures and environmental disturbances can undermine conservation efforts, managers must consider how the relative benefit of conservation actions will be shaped by ongoing global change.

Structure-activity relationships of actively FhuE transported rifabutin derivatives with potent activity against Acinetobacter baumannii.

Hospital-acquired infections are on the rise and represent both, a clinical and financial burden. With resistance emerging and an ever-dwindling armamentarium at hand, infections caused by Acinetobacter baumannii are particularly problematic, since these bacteria have a high level of resistance and resilience to traditional and even last-resort antibiotics. The antibiotic rifabutin was recently found to show potent in vitro and in vivo activity against extensively drug resistant A. baumannii. Building on this discovery, we report on the synthesis and activity of rifabutin analogs, with a focus on N-functionalization of the piperidine ring. The antimicrobial testing uncovered structure activity relationships (SAR) for A. baumannii that were not reflected in Staphylococcus aureus. The cellular activity did not correlate with cell-free transcription inhibition, but with bacterial intracellular compound accumulation. Mass spectrometry-based accumulation studies confirmed the involvement of the siderophore receptor FhuE in active compound translocation at low concentrations, and they showed a strong impact of the culture medium on the accumulation of rifabutin. Overall, the study underlines the structural feature required for strong accumulation of rifabutin in A. baumannii and identifies analogs as or more potent than rifabutin against A. baumannii.

Paramedic Education to Support the Use of Low-Acuity Care Pathways: A Scoping Review Protocol.

Ambulance services worldwide have transformed over time into health care services that not only attend to life-threatening emergencies, but are also increasingly being utilised for patients with low-acuity or non-urgent illness and injury. As a result, there has been a need to adapt and include mechanisms to assist paramedics in the assessment and management of such patients, including alternative pathways of care. However, it has been identified that education and training for paramedics in the care of low-acuity patients is limited. This study aims to identify potential gaps in the literature and inform further research, paramedic education and training, patient care guidelines, and policy. A scoping review will be conducted utilising the Joanna Briggs Institutes methodology. A range of relevant electronic databases will be searched along with the grey literature, using search terms related to paramedic education for low-acuity patient care pathways. The search results will be screened by two authors and presented in the PRISMA-ScR format, with articles presented in tabular format and analysed thematically. The results of this scoping review will inform further research exploring paramedic education, clinical guidelines, policy and experiences in the management of low-acuity patients.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer.

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential of targeting undruggable pathogenic proteins. After the first proof-of-concept proteolysis-targeting chimeric (PROTAC) molecule was reported, the TPD field has entered a new era. In addition to PROTAC, numerous novel TPD strategies have emerged to expand the degradation landscape. However, their physicochemical properties and uncontrolled off-target side effects have limited their therapeutic efficacy, raising concerns regarding TPD delivery system. The combination of TPD and nanotechnology offers great promise in improving safety and therapeutic efficacy. This review provides an overview of novel TPD technologies, discusses their clinical applications, and highlights the trends and perspectives in TPD nanomedicine.

A Community-Engaged Process for Adapting a Proven Community Health Worker Model to Integrate Precision Cancer Care Delivery for Low-income Latinx Adults With Cancer.

INTRODUCTION: Disparities in precision cancer care delivery among low-income Latinx adults are well described. In prior work, we developed a community health worker-led goals of care and cancer symptom assessment intervention. The objective of this study was to adapt this intervention for a community setting, incorporating precision cancer care delivery. METHODS: We used a two-phased systematic approach to adapt an evidence-based intervention for our community. Specifically, we used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to identify barriers and facilitators to precision cancer care delivery via 1-hr interviews with Latinx adults with cancer, Latinx caregivers, community leaders, primary care and oncology clinicians, and community health workers. Interviews were recorded, transcribed, and analyzed using the constant comparative method and grounded theory analysis. Phase 2 involved interviews with key community advisors using the Expert Panels Method to decide on final adaptations. RESULTS: Using this community-engaged approach, we identified specific intervention adaptations to ensure precision cancer care delivery in a community setting, which included: (a) expansion of the intervention inclusion criteria and mode of delivery; (b) integration of low-literacy precision cancer care intervention activities in Spanish in collaboration with community-based organizations; (c) ensuring goals reflective of patient and community priorities. CONCLUSIONS: This systematic and community-engaged approach to adapt an intervention for use in delivering precision cancer care strengthened an evidence-based approach to promote the needs and preferences of patients and key community stakeholders.

Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer.

The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology-based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule-based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC - especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.

A comparison of different methods and materials for establishing maximal intercuspal position: A clinical study.

STATEMENT OF PROBLEM: Which method or material used to record the intercuspal position yields the best accuracy of location of the maxillary and mandibular casts is unclear. PURPOSE: The purpose of this clinical study was to determine the most reliable method of recording a patient's maximal intercuspal position by comparing 2 common methods with 2 popular registration materials. MATERIAL AND METHODS: Complete-arch impressions were made of both jaws with a polyvinyl siloxane impression material in a metal stock tray followed by 4 interocclusal registrations for each of the 17 participants. Two registration techniques were used. More than 1 record was obtained in the first technique, as the participant had to close through a wax sheet or a polyvinyl siloxane material. In the second technique, a polyvinyl siloxane material was injected from the buccal aspect between occluded tooth surfaces. Casts were made from Type 4 stone and vertical measurements of the casts were carried out by using digital vernier calipers, accurate to 100 µm. Hand articulation of the casts was used as the control. Consistency of measurement was assessed by the intraclass correlation coefficient, and comparisons were made by using repeated-measures regression analysis. RESULTS: Statistical analysis showed significant discrepancies when the participant closed through both wax and polyvinyl siloxane material (P<.001). No statistically significant differences to the control group were present when polyvinyl siloxane was injected laterally after closure. CONCLUSIONS: Hand articulation was the most accurate method of reproducing the maximal intercuspal position in a completely dentate individual with horizontal and vertical occlusal stability and was therefore considered the control. Recording the position after the participant had closed by using a polyvinyl siloxane material was the most accurate.

Altruism in Paramedicine: A Scoping Review.

While altruism has been studied in healthcare professions such as nursing and medicine, the exploration of the characteristics of altruism, as related to paramedicine and emergency care in Australia, is limited. This scoping review explores altruism in paramedicine from the perspective of the paramedic as practitioner, learner, and educator as seen through the lens of the paramedic and the patient. Also discussed is the positive impact of altruism on the patient experience of care. A scoping review was used to assess the availability of data related to altruism in paramedicine. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews was used to guide the process. Search categories were orientated around the subject (altruism) and discipline (paramedicine). A total of 27 articles are included in this scoping review. Initial searching identified 742 articles; after duplicate removal, 396 articles were screened with 346 excluded. Fifty articles were full-text reviewed and 23 excluded. The final 27 were extracted following full-text screening. None of the articles are specific to altruism in paramedicine. The data related to the practice of altruism in paramedicine are extremely limited. The preponderance of data arise from Europe and North America which, due to crewing and service differences, may impact the practice of altruism in different regions. Recent changes to the scope of paramedic practice, workload, education, and case acuity may influence behaviour regarding altruism, compassion, caring, and associated caring behaviours. The practice and education of paramedics including altruism, compassion, caring and caring behaviours in the Australasian setting warrants further research.

CD47: Beyond an immune checkpoint in cancer treatment.

The transmembrane protein, CD47, is recognized as an important innate immune checkpoint, and CD47-targeted drugs have been in development with the aim of inhibiting the interaction between CD47 and the regulatory glycoprotein SIRPα, for antitumor immunotherapy. Further, CD47 mediates other essential functions such as cell proliferation, caspase-independent cell death (CICD), angiogenesis and other integrin-activation-dependent cell phenotypic responses when bound to thrombospondin-1 (TSP-1) or other ligands. Mounting strategies that target CD47 have been developed in pre-clinical and clinical trials, including antibodies, small molecules, siRNAs, and peptides, and some of them have shown great promise in cancer treatment. Herein, the authors endeavor to provide a retrospective of ligand-mediated CD47 regulatory mechanisms, their roles in controlling antitumor intercellular and intracellular signal transduction, and an overview of CD47-targetd drug design.