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ContextRotenone is a toxic chemical found in various plants, including some used as food. Rotenone poisoning can be fatal and there is no antidote. Mechanistically, rotenone inhibits mitochondrial complex I, leading to reduced ATP production, compensatory glycolytic upregulation and secondary lactate production, and oxidative stress. Our literature review examined acute rotenone poisoning in humans, including exposure scenarios, clinical presentations, and treatments.MethodsWe searched five databases for relevant literature from database inception through the search date: July 12, 2022, pairing controlled vocabulary and keywords for "rotenone" with terms relating to human exposures and outcomes, such as "ingestion," "exposure," and "poisoning." We included all peer-reviewed reports found using the search terms where the full English text was available. Data abstracted included the number, age, weight, and sex of the exposed person(s), country where exposure happened, exposure scenario, ingestion context, estimated dose, clinical features, whether hospitalization occurred, treatments, and outcomes.ResultsAfter removing non-qualifying sources from 2,631 publications, we identified 11 case reports describing 18 victims, 15 of whom were hospitalized and five died. Most cases occurred in private quarters where victims unknowingly consumed rotenone-containing plants. Vomiting and metabolic acidosis occurred most commonly. Some patients exhibited impaired cardiopulmonary function. Supportive treatment addressed symptoms and included gastric lavage and/or activated charcoal to remove rotenone from the stomach, vasopressors for hypotension, mechanical ventilation for respiratory insufficiency, and sodium bicarbonate for acidosis. Some patients received N-acetylcysteine to counter oxidative stress.ConclusionsRotenone poisoning, though rare, can be fatal. Exposure prevention is impractical since rotenone is found in some plants used as food or pesticides. Cases may be under-diagnosed because symptoms are non-specific and under-reported in English-language journals since most cases occurred in non-English speaking countries. Treatments are supportive. Exploring antioxidant therapy in animal models of rotenone poisoning may be indicated considering rotenone's mechanism of toxicity.

BackgroundHydrogen sulfide is a highly toxic, flammable, and colorless gas. Hydrogen sulfide has been identified as a potential terrorist chemical threat agent in mass-casualty events. Our previous studies showed that cobinamide, a vitamin B12 analog, effectively reverses the toxicity from hydrogen sulfide poisoning. In this study, we investigate the effectiveness of intratracheally administered cobinamide in treating a lethal dose hydrogen sulfide gas inhalation and compare its performance to saline control administration.MethodsA total of 53 pathogen-free New Zealand White rabbits were used for this study. Four groups were compared: (i) received no saline solution or drug intratracheally (n = 15), (ii) slow drip saline intratracheally (n = 15), (iii) fast drip saline intratracheally (n = 15), and (iv) slow drip cobinamide intratracheally (n = 8). Blood pressure was continuously monitored, and deoxy- and oxyhemoglobin concentration changes were monitored in real-time in vivo using continuous wave near-infrared spectroscopy.ResultsThe mean (± standard deviation) weight for all animals (n = 53) was 3.87 ± 0.10 kg. The survival rates of the slow cobinamide and the fast saline groups were 75 percent and 60 percent, respectively, while the survival rates in the slow saline and control groups were 26.7 percent and 20 percent, respectively. A log-rank (Mantel-Cox) test showed that survival in fast saline and slow cobinamide groups were significantly greater than those of no saline control and slow saline groups (P

Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane-associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane-associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser515 by ERK increased the nuclear accumulation and binding of AR to the promoter of Ctnnb1, which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of Ctnnb1 and CTNN1B, respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer.

The sensitivity and responsiveness of living cells to environmental changes are enabled by dynamic protein structures, inspiring efforts to construct artificial supramolecular protein assemblies. However, despite their sophisticated structures, designed protein assemblies have yet to be incorporated into macroscale devices for real-life applications. We report a 2D crystalline protein assembly of C98/E57/E66L-rhamnulose-1-phosphate aldolase (CEERhuA) that selectively blocks or passes molecular species when exposed to a chemical trigger. CEERhuA crystals are engineered via cobalt(II) coordination bonds to undergo a coherent conformational change from a closed state (pore dimensions

Major pathologic changes in the proximal aorta underlie the life-threatening aortic aneurysms and dissections in Marfan Syndrome; current treatments delay aneurysm development without addressing the primary pathology. Because excess oxidative stress and nitric oxide/protein kinase G signaling likely contribute to the aortopathy, we hypothesized that cobinamide, a strong antioxidant that can attenuate nitric oxide signaling, could be uniquely suited to prevent aortic disease. In a well-characterized mouse model of Marfan Syndrome, cobinamide dramatically reduced elastin breaks, prevented excess collagen deposition and smooth muscle cell apoptosis, and blocked DNA, lipid, and protein oxidation and excess nitric oxide/protein kinase G signaling in the ascending aorta. Consistent with preventing pathologic changes, cobinamide diminished aortic root dilation without affecting blood pressure. Cobinamide exhibited excellent safety and pharmacokinetic profiles indicating it could be a practical treatment. We conclude that cobinamide deserves further study as a disease-modifying treatment of Marfan Syndrome.

Purpose To describe the design, conduct, and results of the Breast Multiparametric MRI for prediction of neoadjuvant chemotherapy Response (BMMR2) challenge. Materials and Methods The BMMR2 computational challenge opened on May 28, 2021, and closed on December 21, 2021. The goal of the challenge was to identify image-based markers derived from multiparametric breast MRI, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI, along with clinical data for predicting pathologic complete response (pCR) following neoadjuvant treatment. Data included 573 breast MRI studies from 191 women (mean age [±SD], 48.9 years ± 10.56) in the I-SPY 2/American College of Radiology Imaging Network (ACRIN) 6698 trial (ClinicalTrials.gov: NCT01042379). The challenge cohort was split into training (60%) and test (40%) sets, with teams blinded to test set pCR outcomes. Prediction performance was evaluated by area under the receiver operating characteristic curve (AUC) and compared with the benchmark established from the ACRIN 6698 primary analysis. Results Eight teams submitted final predictions. Entries from three teams had point estimators of AUC that were higher than the benchmark performance (AUC, 0.782 [95% CI: 0.670, 0.893], with AUCs of 0.803 [95% CI: 0.702, 0.904], 0.838 [95% CI: 0.748, 0.928], and 0.840 [95% CI: 0.748, 0.932]). A variety of approaches were used, ranging from extraction of individual features to deep learning and artificial intelligence methods, incorporating DCE and DWI alone or in combination. Conclusion The BMMR2 challenge identified several models with high predictive performance, which may further expand the value of multiparametric breast MRI as an early marker of treatment response. Clinical trial registration no. NCT01042379 Keywords: MRI, Breast, Tumor Response Supplemental material is available for this article. © RSNA, 2024.

Social and emotional learning (SEL) has been increasingly emphasized in educational research and practice for promoting children's wellbeing. Perhaps the most well-known SEL framework is the model provided by the Collaborative for Academic, Social, and Emotional Learning (CASEL). This framework has become the dominant framework informing state SEL standards, which guide educators' SEL related practice. Yet, the content of these standards has not been formally examined for alignment with the CASEL framework. The purpose of this exploratory study was to evaluate the content of CASEL-based state standards to explore how the CASEL framework is translated into school-based practice and to understand what SEL skills are valued by states. Using text mining and network analysis, we identified SEL standard content that was consistent across nine states and examined relationships within and across CASEL domains. Implications of these findings for research and practice are discussed.

Much has been written on tenure status among librarians due to the unique work responsibilities they have in comparison to other faculty across campus. This study explores one facet of work often unique to tenure-track librarians--long-term or permanent management responsibilities. In addition to gathering descriptive data about what type of managing work is being done on the tenure track, by whom and where, this study also analyzes how these roles and responsibilities impact one's success on the tenure track and vice versa, and how tenure-track work influences one's ability to manage. Eighty-seven librarians completed an online survey and the results show that, while there are some positives to being a manager while on the tenure track, including demonstrable leadership opportunities, most noted a lack of time to perform all required responsibilities in both areas. Other findings that emerged included a belief that managing did not count towards earning tenure and that other faculty colleagues, both in and out of the library, did not understand the full scope of managers' work. Recommendations include that library leaders consider if job roles with a heavy management focus should be tenure-track and if so, how tenure-track managers can be better supported and include their management responsibilities in promotion and tenure documentation.

Abstract The sensitivity and responsiveness of living cells to environmental changes are enabled by dynamic protein structures, inspiring efforts to construct artificial supramolecular protein assemblies. However, despite their sophisticated structures, designed protein assemblies have yet to be incorporated into macroscale devices for real-life applications. We report a 2D crystalline protein assembly of C98/E57/E66L-rhamnulose-1-phosphate aldolase (CEERhuA) that selectively blocks or passes molecular species when exposed to a chemical trigger. CEERhuA crystals are engineered via cobalt(II) coordination bonds to undergo a coherent conformational change from a closed state (pore dimensions

Abstract Objective To examine the unique contribution of patient reported experiences of compassion to overall patient quality care ratings. Additionally, we assess whether patients’ reported experiences of compassion in the emergency department differed between sociodemographic groups. Methods Provincial data for this cross-sectional study were collected from 03/01/2022 to 09/05/2022 from 14 emergency departments in Alberta, Canada. Data from 4501 emergency department patients (53.6% women, 77.1% White/European) were analyzed. The primary outcome was patients’ overall quality care ratings during their most recent ED visit. Measures included in the hierarchical stepwise regression included demographics, and those drawn from the Emergency Department Patient Experience of Care (EDPEC) questionnaire: single and multi-item measures of patient information (e.g., patient perceptions health) and patient experience (e.g., physician communication), and compassion (e.g., Sinclair Compassion Questionnaire; SCQ-ED). Results Data from 4501 ED patients were analysed. Stepwise hierarchical linear multiple regression indicated that of 21 included variables, compassion most strongly predicted overall quality care ratings (b=1.61, 95% CI 1.53-1.69, p

This study examines land use transformations and their impact on groundwater quality fluctuations in Chengalpattu district, Tamil Nadu. Chengalpattu is a rapidly urbanizing coastal region in South India. Landsat 5 and 9 satellite imagery were utilized to create land use land cover (LULC) maps for 2011 and 2021, with overall accuracies of 82.20% and 85.71%, respectively. The analysis showed significant growth in built-up and fallow lands due to urbanization, which has altered LULC. Groundwater Quality Index (GQI) was generated using seven groundwater quality parameters, adhering to World Health Organization (WHO) standards. The mean GQI showed slight fluctuations during pre- and post-monsoon periods, with a declining trend in pre-monsoon seasons. The study area predominantly experiences moderate groundwater quality, with fewer areas of low and high quality. The findings indicate that land use transformation significantly impacts groundwater quality, emphasizing the need for sustainable urban planning and water resource management in the region.

In marine ecosystems, most physiological, ecological, or physical processes are size dependent. These include metabolic rates, the uptake of carbon and other nutrients, swimming and sinking velocities, and trophic interactions, which eventually determine the stocks of commercial species, as well as biogeochemical cycles and carbon sequestration. As such, broad-scale observations of plankton size distribution are important indicators of the general functioning and state of pelagic ecosystems under anthropogenic pressures. Here, we present the first global datasets of the Pelagic Size Structure database (PSSdb), generated from plankton imaging devices. This release includes the bulk particle normalized biovolume size spectrum (NBSS) and the bulk particle size distribution (PSD), along with their related parameters (slope, intercept, and R2) measured within the epipelagic layer (0–200 m) by three imaging sensors: the Imaging FlowCytobot (IFCB), the Underwater Vision Profiler (UVP), and benchtop scanners. Collectively, these instruments effectively image organisms and detrital material in the 7–10 000 µm size range. A total of 92 472 IFCB samples, 3068 UVP profiles, and 2411 scans passed our quality control and were standardized to produce consistent instrument-specific size spectra averaged to 1° × 1° latitude and longitude and by year and month. Our instrument-specific datasets span most major ocean basins, except for the IFCB datasets we have ingested, which were exclusively collected in northern latitudes, and cover decadal time periods (2013–2022 for IFCB, 2008–2021 for UVP, and 1996–2022 for scanners), allowing for a further assessment of the pelagic size spectrum in space and time. The datasets that constitute PSSdb's first release are available at https://doi.org/10.5281/zenodo.11050013 (Dugenne et al., 2024b). In addition, future updates to these data products can be accessed at https://doi.org/10.5281/zenodo.7998799.

Abstract Background Structural and behavioral interventions to manage work-related stress are effective in employees. Nonetheless, they have been implemented insufficiently, particularly in micro- and small-sized enterprises (MSE). Main barriers include a lack of knowledge and limited resources, which could potentially be overcome with simplified web-based alternatives for occupational stress prevention. However, there is a lack of implementation research about web-based prevention in realistic settings of MSE. Objective The aim of this study is to evaluate the implementation process and success of an integrated web-based platform for occupational stress prevention (“System P”) and to identify potential barriers for its uptake and use in MSE in Germany. Methods This study with a mixed-methods approach investigates eight process-related outcomes in a quantitative part I (adoption, reach, penetration, fidelity/dose, costs, acceptability) and a qualitative part II (acceptability, appropriateness and feasibility). Part I has a pre-post design with two measurements (6 months apart) with 98 individual participants and part II consists of 12 semi-structured interviews with managers and intercorporate stakeholders. Results Part I revealed shortcomings in the implementation process. Adoption/Reach: Despite extensive marketing efforts, less than 1% of the contacted MSE responded to the offer of System P. A total of 40 MSE registered, 24 of which, characterized by good psychosocial safety climate, adopted System P. Penetration: Within these 24 MSE, 15% of the employees used the system. Fidelity/Dose: 11 MSE started a psychosocial risk-assessment (PRA), and no MSE finished it. The stress-management training (SMT) was started by 25 users and completed by 8. Costs: The use of System P was free of charge, but the time required to engage with was an indirect cost. Part II added insights on the perception of the web-based intervention: Acceptance of System P by users and stakeholders was good and it was assessed as appropriate for MSE. Results for feasibility were mixed. Conclusions Although System P was generally perceived as useful and appropriate, only a small number of contacted MSE implemented it as intended. Prior experience and sensitivity for occupational (stress) prevention were mentioned as key facilitators, while (perceived) indirect costs were a key barrier. Enabling MSE to independently manage stress prevention online did not result in successful implementation. Increasing external support could be a solution. ⁺ Full project name “PragmatiKK – Pragmatische Lösungen für die Implementation von Maßnahmen zur Stressprävention in Kleinst- und Kleinbetrieben” (= Pragmatic solutions for the implementation of stress prevention interventions in micro and small-sized enterprises). Trial registration German Register of Clinical Studies (DRKS) DRKS00026154, date of registration 2021-09-16.

Introduction Human cytomegalovirus (CMV) is one of the most encountered opportunistic viral pathogens in kidney transplant recipients (KTRs) (1). Although major advances in the treatment and prophylaxis of CMV-associated complications [...], Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in people who are immunocompromised, such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in people who are immunosuppressed have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific [CD8.sup.+] T cells in patients who are immunocompromised and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific [CD8.sup.+] T cells in KTRs with noncontrolled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific [CD8.sup.+] T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of [CD8.sup.+] T cells could be targeted by inhibiting CD38 to reverse hyporesponsiveness in individuals who fail to control chronic viral infection.

Summary: Enormous efforts have been made to understand the functions of bioluminescence; however, its relevance in soil ecosystems has barely been investigated. In addition, our understanding of the biological relevance of bioluminescence is hampered by the scarcity of tools to genetically manipulate this trait. Using the symbionts of entomopathogenic nematodes, Photorhabdus bacteria, we show that bioluminescence plays important regulatory roles in multitrophic interactions in the soil. Through genetic modifications and exploiting natural variability, we provide direct evidence for the multifunctional nature of bioluminescence. It regulates abiotic and biotic stress resistance, impacts other trophic levels, including nematodes, insects, and plants, and contributes to symbiosis. Our study contributes to understanding the factors that have driven the evolution and maintenance of this trait in belowground ecosystems.

Ocean color satellites require a procedure known as System Vicarious Calibration (SVC) after launch as the pre-launch and on-orbit calibration accuracy is insufficient. The current approach for determination of post-launch SVC uses a single fixed measurement location and may be susceptible to unexpected biases in satellite processing algorithms. Here we describe a novel SVC program which is based on a high resolution and high accuracy radiometric system integrated with an autonomous profiling float (providing a buoyancy engine, physical observations, and communication). This float + radiometer (HyperNav) system can be shipped via air, land, ocean and is deployable from small boats. This SVC program relies on multiple deployment sites with associated facilities to collect a significant amount of SVC quality data in a relatively short time. It has centralized logistics and command-and-control centers ensuring easy access to information regarding the status of each asset and to ensure floats stay within a certain ocean area. The development of the program has been associated with the launch of NASA’s PACE satellite and has been executed by academic institutions in collaboration with an industrial partner. Other approaches for a future float-based operational SVC program are discussed.

Summary: During chronic infection, virus-specific CD8+ cytotoxic T lymphocytes (CTLs) progressively lose their ability to mount effective antiviral responses. This “exhaustion” is coupled to persistent upregulation of inhibitory receptor programmed death-1 (PD-1) (Pdcd1)—key in suppressing antiviral CTL responses. Here, we investigate allelic Pdcd1 subnuclear localization and transcription during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Pdcd1 alleles dissociate from transcriptionally repressive chromatin domains (lamin B) in virus-specific exhausted CTLs but not in naive or effector CTLs. Relative to naive CTLs, nuclear positioning and Pdcd1-lamina dissociation in exhausted CTLs reflect loss of Pdcd1 promoter methylation and greater PD-1 upregulation, although a direct correlation is not observed in effector cells, 8 days post-infection. Genetic deletion of B lymphocyte-induced maturation protein 1 (Blimp-1) enhances Pdcd1-lamina dissociation in effector CTLs, suggesting that Blimp-1 contributes to maintaining Pdcd1 localization to repressive lamina. Our results identify mechanisms governing Pdcd1 subnuclear localization and the broader role of chromatin dynamics in T cell exhaustion.

A novel ocean profiling float system for calibrating and validating satellite-based ocean color observations has been developed and tested. The float-based radiometric sampling system, herein referred to as HyperNav, is complementary to traditional moored in-situ observing systems and provides additional capability due to the relatively small platform size and high radiometric accuracy that allows for opportunistic deployments at locations during seasons and conditions that are best for ocean color observations. The purpose of this study is to optimize the deployment locations of an array of HyperNav systems to support the Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission by performing System Vicarious Calibration (SVC) observations. Specifically, we present the development of logistical and scientific criteria for selecting suitable sites for developing an SVC network of profiling-float-based radiometric systems capable of calibrating and validating ocean color observations. As part of the analyses described in this paper, we have synthetically deployed HyperNav at potential US-based and international sites, including: north of Crete island; south-east of Bermuda island; south of Puerto Rico island; southwest of Port Hueneme, CA; west of Monterey, CA; west of Kona, HI; and south-west of Tahiti island. The synthetic analyses identified Kona, Puerto Rico, Crete, and Tahiti as promising SVC sites. All sites considered are suitable for generating a significant number of validation match-ups. Optimally deploying HyperNav systems at these sites during the PACE post-launch SVC campaign is expected to cost-effectively provide a large number of SVC match-ups to fulfill the PACE calibration requirements.

Study-specific data quality testing is an essential part of minimizing analytic errors, particularly for studies making secondary use of clinical data. We applied a systematic and reproducible approach for study-specific data quality testing to the analysis plan for PRESERVE, a 15-site, EHR-based observational study of chronic kidney disease in children. This approach integrated widely adopted data quality concepts with healthcare-specific evaluation methods. We implemented two rounds of data quality assessment. The first produced high-level evaluation using aggregate results from a distributed query, focused on cohort identification and main analytic requirements. The second focused on extended testing of row-level data centralized for analysis. We systematized reporting and cataloguing of data quality issues, providing institutional teams with prioritized issues for resolution. We tracked improvements and documented anomalous data for consideration during analyses. The checks we developed identified 115 and 157 data quality issues in the two rounds, involving completeness, data model conformance, cross-variable concordance, consistency, and plausibility, extending traditional data quality approaches to address more complex stratification and temporal patterns. Resolution efforts focused on higher priority issues, given finite study resources. In many cases, institutional teams were able to correct data extraction errors or obtain additional data, avoiding exclusion of 2 institutions entirely and resolving 123 other gaps. Other results identified complexities in measures of kidney function, bearing on the study's outcome definition. Where limitations such as these are intrinsic to clinical data, the study team must account for them in conducting analyses. This study rigorously evaluated fitness of data for intended use. The framework is reusable and built on a strong theoretical underpinning. Significant data quality issues that would have otherwise delayed analyses or made data unusable were addressed. This study highlights the need for teams combining subject-matter and informatics expertise to address data quality when working with real world data.

Hyperspectral optical observations of the Earth’s surface oceans from space offer a means to improve our understanding of ocean biology and biogeochemistry. NASA’s Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) satellite mission, which includes a hyperspectral ocean color instrument (OCI), will provide radiometric observations of surface ocean with near continuous spectral resolution across the near UV to NIR range. Maintaining sufficient accuracy over the lifetime of satellite ocean color missions requires a robust program for system vicarious calibration (SVC) and product validation. The system vicarious calibration process combines satellite sensor data with in-situ radiometric/optical measurements to remove potential biases due to the combined errors from both satellite radiometric sensor calibration and atmospheric correction. As such, high accuracy, high-spectral resolution in-situ radiometric measurements are required to provide a principal source of truth for the satellite-derived products. To meet the requirements, a novel in-situ radiometric system, called HyperNav, has been developed, rigorously characterized and field tested. Key attributes of HyperNav are dual upwelling radiance heads coupled to individual spectrometers, spectral resolution of ∼2.2 nm (full width, half-maximum) across 320–900 nm, integrated shutter systems for dark measurements, and integrated tilt and pressure sensors. The HyperNav operational modes include traditional profiling and surface modes, as well as integration with an autonomous profiling float for unattended deployment, offering a new capability for a network of autonomous platforms to support the long-term needs for hyperspectral ocean color remote sensing observations. This paper describes the HyperNav design, in-situ operational modes, and field verification results.

Background: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53 -mutated AML/HR-MDS is not well defined. Objectives: To define the genetic, epigenetic, and immunologic landscape of TP53- mutant and TP53 wild-type AML and HR-MDS patients. Design: Post hoc analysis of TP53- mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab. Methods: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53- mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial. Results: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53- mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53- mutant samples suggesting a novel therapeutic target. Conclusion: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53- mutant AML/HR-MDS with mono- or multihit TP53 mutation status. Trial registration: FUSION trial (NCT02775903).

In human medicine, hemostatic disorders such as thrombocytopenia, hyperfibrinolysis, and disseminated intravascular coagulopathy (DIC) have been associated with many cancers. Acute hemorrhage secondary to hyperfibrinolysis has been predominantly reported with prostatic adenocarcinoma in human patients. To the author’s knowledge, severe bleeding due to paraneoplastic hyperfibrinolysis has not yet been reported in veterinary medicine. The case involves an 8-year-old neutered male Border Collie who was evaluated for progressive and recurrent epistaxis, having a history of 1 year of treatment for metastatic nasal adenocarcinoma. A progressive and severe coagulopathy thought to be related to the known cancer was diagnosed. Advanced coagulation testing was consistent with a chronic DIC and secondary hyperfibrinolysis. Throughout 1 week of hospitalization, the dog was treated with multiple blood products, vitamin K1, and anti-fibrinolytic medications. While the dog was initially discharged home, the dog re-presented the following day and was humanely euthanized due to a perceived poor quality of life. Post-mortem analysis revealed a histopathologic diagnosis of disseminated adenocarcinoma. In dogs with disseminated nasal adenocarcinoma that are experiencing severe bleeding, paraneoplastic secondary hyperfibrinolysis should be considered as a differential. Knowing this association could help guide treatment recommendations for optimal patient management.

Question Depression is highly prevalent and associated with numerous adverse consequences for both individuals and society. Due to low uptake of direct treatment, interventions that target related, but less stigmatising problems, such as perceived stress, have emerged as a new research paradigm.This individual participant data (IPD) meta-analysis examines if a web-based stress management intervention can be used as an ‘indirect’ treatment of depression.Study selection and analysis Bayesian one-stage models were used to estimate pooled effects on depressive symptom severity, minimally important improvement and reliable deterioration. The dose–response relationship was examined using multilevel additive models, and IPD network meta-analysis was employed to estimate the effect of guidance.Findings In total, N=1235 patients suffering from clinical-level depression from K=6 randomised trials were included. Moderate-to-large effects were found on depressive symptom severity at 7 weeks post-intervention (d=−0.65; 95% credibility interval (CrI): −0.84 to −0.48) as measured with the Center for Epidemiological Studies’ Depression Scale. Effects were sustained at 3-month follow-up (d=−0.74; 95% CrI: −1.01 to −0.48). Post-intervention symptom severity was linearly related to the number of completed sessions. The incremental impact of guidance was estimated at d=−0.25 (95% CrI: −1.30 to 0.82), with a 35% posterior probability that guided and unguided formats produce equivalent effects.Conclusions Our results indicate that web-based stress management can serve as an indirect treatment, yielding effects comparable with direct interventions for depression. Further research is needed to determine if such formats can indeed increase the utilisation of evidence-based treatment, and to corroborate the favourable effects for human guidance.Study registration Open material repository: osf.io/dbjc8, osf.io/3qtbe.Trial registration number German Clinical Trial Registration (DRKS): DRKS00004749, DRKS00005112, DRKS00005384, DRKS00005687, DRKS00005699, DRKS00005990.