NEUROBEACHIN regulates hematopoietic progenitor differentiation and survival by modulating NOTCH activity.

Hematopoietic stem cells (HSCs) can generate all blood cells. This ability is exploited in HSC transplantation (HSCT) to treat hematologic disease. A clear understanding of the molecular mechanisms that regulate HSCT is necessary to continue improving transplant protocols. We identified the BEACH-domain containing protein (BDCP), NEUROBEACHIN (NBEA), as a putative regulator of HSCT. Here, we demonstrated that NBEA and related BDCPs, including LRBA, NBEAL1 and LYST, are required during HSCT to efficiently reconstitute the hematopoietic system of lethally irradiated mice. Nbea knockdown in mouse HSCs induced apoptosis and a differentiation block post-transplantation. Nbea deficiency in hematopoietic progenitor cells perturbed the expression of genes implicated in vesicle trafficking and led to changes in NOTCH receptor localization. This resulted in perturbation of the NOTCH transcriptional program, which is required for efficient HSC engraftment. In sum, our findings reveal a novel role for NBEA in the control of NOTCH receptor turnover in hematopoietic cells and supports a model where BDCP regulated vesicle trafficking is required for efficient HSCT.

Differences between Patients with Sporadic and Familial Pheochromocytoma-Is It Possible to Avoid Genetic Testing in Certain Patients?

BACKGROUND: Pheochromocytoma (PHEO) is a rare neuroendocrine tumour with a strong genetic link, which therefore may modify its clinical behaviour and prognosis. The aim of the study is to evaluate the epidemiological and clinical differences between patients with sporadic and familial PHEO, as well as the specific differences in the index cases. METHODS: A retrospective analysis of 136 patients in a tertiary hospital (1984-2021). Epidemiological, clinical, and histological variables were analysed. STATISTICS: SPSS 28.0 software was used. Univariate and multivariate logistic regression analyses were performed. p < 0.05 was considered statistically significant. RESULTS: 64.71% of the cases (n = 88) presented a genetic mutation (familial cases). Additionally, 32.39% (n = 23) corresponded to index cases and the rest to screening cases. The main differences between patients with familial and sporadic PHEO were age (OR = 0.93 (0.89-0.97)), blood pressure-related symptoms (OR = 0.22 (0.06-0.89)), bilaterality (OR = 15.49 (3.76-63.84)), and size (OR = 0.70 (0.54-0.92)). Among patients with sporadic PHEO and index cases, only bilaterality was significant (OR = 13.53 (1.24-144.34)). CONCLUSIONS: Patients with familial PHEO diagnosed by screening differ from sporadic cases in terms of age, clinical features, and size. However, patients with sporadic PHEO only differ from index cases by a lower presence of bilaterality, which reaffirms the importance of genetic screening of patients with PHEO and their relatives.

Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction.

Introduction: Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods: In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results: Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and µCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion: In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.

Prevalence and prognostic significance of malnutrition in patients with secondary mitral regurgitation undergoing transcatheter edge-to-edge repair.

BACKGROUND: Malnutrition is associated with poor prognosis in several cardiovascular diseases; however, its role in patients with secondary mitral regurgitation (SMR) is poorly known. AIMS: To evaluate the impact of nutritional status, assessed using different scores, on clinical outcomes in patients with SMR undergoing transcatheter edge-to-edge repair (TEER) in a real-world setting. METHODS: A total of 658 patients with SMR and complete nutritional data were identified from the MIVNUT registry. Nutritional status has been assessed using controlling nutritional status index (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) scores. Outcomes of interest were all-cause mortality and all-cause mortality or heart failure (HF) hospitalization. RESULTS: Any malnutrition grade was observed in 79.4%, 16.7%, and 47.9% of patients by using CONUT, PNI, and GNRI, respectively, while moderate to severe malnutrition was noted in 24.7%, 16.7%, and 25.6% of patients, respectively. At a median follow-up of 2.2 years, 212 patients (32.2%) died. Moderate-severe malnutrition was associated with a higher rate of all-cause mortality (HR: 2.46 [95% CI: 1.69-3.58], HR: 2.18 [95% CI: 1.46-3.26], HR: 1.97 [95% CI: 1.41-2.74] for CONUT, PNI, and GNRI scores, respectively). The combined secondary endpoint of all-cause mortality and HF rehospitalization occurred in 306 patients (46.5%). Patients with moderate-severe malnutrition had a higher risk of the composite endpoint (HR: 1.56 [95% CI: 1.20-2.28], HR: 1.55 [95% CI: 1.01-2.19], HR: 1.36 [95% CI: 1.02-1.80] for CONUT, PNI, and GNRI scores, respectively). After adjustment for multiple confounders, moderate-severe malnutrition remained independently associated with clinical outcomes. CONCLUSIONS: Moderate-severe malnutrition was common in patients with SMR undergoing TEER. It was independently associated with poor prognosis regardless of the different scores used.

Morphological Study before and after Thermal Treatment of Polymer-Polymer Mixed-Matrix Membranes for Gas Separations.

A good integration of the polymer materials that form a mixed-matrix membrane (MMM) for gas separation is essential to reaching interesting permselective properties. In this work, a porous polymer network (PPN), obtained by combining triptycene and trifluoroacetophenone, has been used as a filler, which was blended with two o-hydroxypolyamides (HPAs) that act as polymer matrices. These polymer matrices have been thermally treated to induce a thermal rearrangement (TR) of the HPAs to polybenzoxazoles (ß-TR-PBOs) through a solid-state reaction. For its structural study, various techniques have been proposed that allow us to undertake a morphological investigation into the integration of these materials. To access the internal structure of the MMMs, three different methods were used: a polishing process for the material surface, the partial dissolution of the polymer matrix, or argon plasma etching. The argon plasma technique has not only revealed its potential to visualize the internal structure of these materials; it has also been proven to allow for the transformation of their permselective properties. Force modulation and phase contrast in lift-mode techniques, along with the topographic images obtained via the tapping mode using a scanning probe microscope (SPM), have allowed us to study the distribution of the filler particles and the interaction of the polymer and the filler. The morphological information obtained via SPM, along with that of other more commonly used techniques (SEM, TGA, DSC, FTIR, WASX, gas adsorption, and permeability measurements), has allowed us to postulate the most probable structural configuration in this type of system.

Implementable Prediction of Pressure Injuries in Hospitalized Adults: Model Development and Validation.

Background: Numerous pressure injury prediction models have been developed using electronic health record data, yet hospital-acquired pressure injuries (HAPIs) are increasing, which demonstrates the critical challenge of implementing these models in routine care. Objective: To help bridge the gap between development and implementation, we sought to create a model that was feasible, broadly applicable, dynamic, actionable, and rigorously validated and then compare its performance to usual care (ie, the Braden scale). Methods: We extracted electronic health record data from 197,991 adult hospital admissions with 51 candidate features. For risk prediction and feature selection, we used logistic regression with a least absolute shrinkage and selection operator (LASSO) approach. To compare the model with usual care, we used the area under the receiver operating curve (AUC), Brier score, slope, intercept, and integrated calibration index. The model was validated using a temporally staggered cohort. Results: A total of 5458 HAPIs were identified between January 2018 and July 2022. We determined 22 features were necessary to achieve a parsimonious and highly accurate model. The top 5 features included tracheostomy, edema, central line, first albumin measure, and age. Our model achieved higher discrimination than the Braden scale (AUC 0.897, 95% CI 0.893-0.901 vs AUC 0.798, 95% CI 0.791-0.803). Conclusions: We developed and validated an accurate prediction model for HAPIs that surpassed the standard-of-care risk assessment and fulfilled necessary elements for implementation. Future work includes a pragmatic randomized trial to assess whether our model improves patient outcomes.

Comparison of i-gel® and LMA® Supreme™ for Facilitating Fiberoptic Endotracheal Intubation: A Prospective Randomized Trial.

Supraglottic airway (SGA) is an alternative to endotracheal intubation, however endotracheal intubation is often essential. One method to convert from an SGA to an endotracheal tube (ETT) is utilizing the SGA as a conduit for fiberoptic-guided advancement of an Aintree catheter (airway exchange catheter), and exchange of the SGA for an ETT. In this prospective randomized study, we compared two SGA devices in facilitating this exchange. Subjects were randomized to receive either the i-gel® or LMA® Supreme™ SGA. The SGA was placed and an Aintree intubation catheter was inserted through the SGA over a fiberoptic bronchoscope. Next, the SGA was removed, leaving the Aintree within the trachea, and an ETT was placed over the Aintree catheter and advanced into the trachea. The i-gel group exhibited shorter time to successful intubation (median, 191 vs. 434 seconds; P = .002). The i-gel group also had fewer study subjects requiring more than one attempt for successful Aintree placement (33% vs. 75%, P = .02). The i-gel group showed superior laryngeal view score (LVS) (6 vs. 4; P = .003). The i-gel SGA achieved a faster time to successful intubation, higher rate of first attempt Aintree placement, and superior LVS.

A Th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides.

Pesticides are chemicals widely used in agriculture to keep crops healthy and prevent them from being destroyed by pests, thus contributing to a sustainable food and feed production. However, long-term exposure to these compounds may be harmful to human health as they can affect the function of various organs systems, including the immune system. There is growing evidence that pesticides may increase the risk of developing immune-based diseases and inflammation. This study assessed whether greenhouse farmers occupationally exposed to pesticides presented alterations in immunoregulatory proteins, used as surrogate biomarkers of immune function. The study population consisted of 175 greenhouse workers occupationally exposed to pesticides and 91 non-exposed controls. Serum levels of 27 cytokines, chemokines and growth factors were measured using a magnetic bead-based immunoassay in a subpopulation of 111 greenhouse workers and 79 non-exposed controls. Since analytical determinations were performed in two periods of the same crop season with different use of pesticides (period of high and low pesticide exposure), linear mixed models for repeated measures were used to optimize statistical inference. The increase in IL-13, IL-4 and IL-6 observed in greenhouse workers compared to controls, and in the period of high exposure to pesticides relative to that of low exposure, suggest an altered Th1/Th2 balance towards the Th2 response. This finding points to a type-2 inflammation commonly presented as allergic inflammation, which has often been reported in farm-workers and in which pesticide exposure is considered a risk factor. Furthermore, the increase in IL-1ß and VEGF, mediators of inflammation and angiogenesis, may suggest a low-grade systemic inflammation that might underlie chronic pathological conditions linked to pesticide exposure.

Genomic insights into the population history and adaptive traits of Latin American Criollo cattle.

Criollo cattle, the descendants of animals brought by Iberian colonists to the Americas, have been the subject of natural and human-mediated selection in novel tropical agroecological zones for centuries. Consequently, these breeds have evolved distinct characteristics such as resistance to diseases and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.

Exposure to environmental pollutants and genetic variants related to oxidative stress and xenobiotic metabolism-Association with prostate cancer.

This study assessed whether genetic variants coding for certain enzymes involved in xenobiotic detoxification, antioxidant defences and DNA repair, along with exposure to environmental chemicals, were associated with an increased prostate cancer (PCa) risk. The study population consisted of 300 men (150 PCa cases and 150 controls) which underwent prostate biopsy as their serum prostate specific antigen (PSA) levels were greater than 4 ng/ml. Genetic variants in GSTM1, GSTP1, SOD2, CAT, GPX1, XRCC1 were determined and data for chemical exposures was obtained through a structured questionnaire and by biomonitoring in a subsample of cases and controls. High serum PSA levels were associated with a greater risk of PCa, while physical exercise appears to exert a protective effect against its development. In addition, elevated urinary levels of certain organic pollutants, such as benzo(a)pyrene (BaP), bisphenol A (BPA), and ethyl-paraben (EPB), were associated with an increased risk of PCa.

Bridging the Gap: Exploring Bronchopulmonary Dysplasia through the Lens of Biomedical Informatics.

Bronchopulmonary dysplasia (BPD), a chronic lung disease predominantly affecting premature infants, poses substantial clinical challenges. This review delves into the promise of biomedical informatics (BMI) in reshaping BPD research and care. We commence by highlighting the escalating prevalence and healthcare impact of BPD, emphasizing the necessity for innovative strategies to comprehend its intricate nature. To this end, we introduce BMI as a potent toolset adept at managing and analyzing extensive, diverse biomedical data. The challenges intrinsic to BPD research are addressed, underscoring the inadequacies of conventional approaches and the compelling need for data-driven solutions. We subsequently explore how BMI can revolutionize BPD research, encompassing genomics and personalized medicine to reveal potential biomarkers and individualized treatment strategies. Predictive analytics emerges as a pivotal facet of BMI, enabling early diagnosis and risk assessment for timely interventions. Moreover, we examine how mobile health technologies facilitate real-time monitoring and enhance patient engagement, ultimately refining BPD management. Ethical and legal considerations surrounding BMI implementation in BPD research are discussed, accentuating issues of privacy, data security, and informed consent. In summation, this review highlights BMI's transformative potential in advancing BPD research, addressing challenges, and opening avenues for personalized medicine and predictive analytics.

The Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation.

Mammalian fertilization initiates the reprogramming of oocytes and sperm, forming a totipotent zygote. During this intricate process, the zygotic genome undergoes a maternal-to-zygotic transition (MZT) and subsequent zygotic genome activation (ZGA), marking the initiation of transcriptional control and gene expression post-fertilization. Histone modifications are pivotal in shaping cellular identity and gene expression in many mammals. Recent advances in chromatin analysis have enabled detailed explorations of histone modifications during ZGA. This review delves into conserved and unique regulatory strategies, providing essential insights into the dynamic changes in histone modifications and their variants during ZGA in mammals. The objective is to explore recent advancements in leading mechanisms related to histone modifications governing this embryonic development phase in depth. These considerations will be useful for informing future therapeutic approaches that target epigenetic regulation in diverse biological contexts. It will also contribute to the extensive areas of evolutionary and developmental biology and possibly lay the foundation for future research and discussion on this seminal topic.

Tumor microenvironment in thyroid cancer: Immune cells, patterns, and novel treatments.

The tumor immune microenvironment of thyroid cancer is the heterogeneous histological space in which tumor cells coexist with host cells. Published data from this review were identified by search and selection database of Pubmed, Elsevier, and Science Direct. Searching was made in two steps using different keywords. In thyroid pathology, the inflammatory response is very important, and might have a key role finding new diagnostic and therapeutic methods, particularly in thyroid cancer. Different immune cells may be more or less present in different types of thyroid cancer and may even have different functions, hence the importance of knowing their presence in different thyroid tumor pathologies. Cancer-related inflammation could be a useful target for new diagnostic and therapeutic strategies by analyzing peritumoral and intratumoral immune cells in different types of thyroid tumors. Moreover, novel strategies for thyroid cancer treatments, such as monoclonal antibodies targeting checkpoint inhibitors, are emerging as promising alternatives.

Bacteria- and fungus-derived PAMPs induce innate immune memory via similar functional, metabolic, and transcriptional adaptations.

Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with ß-glucan, a fungus-derived dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived Toll-like receptor 4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance, and attenuation of cytokine production. Examination of macrophages ex vivo showed amplification of metabolism, phagocytosis, and respiratory burst after treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions, and protein synthesis and suppressed pathways regulating cell division. ß-glucan treatment minimally altered macrophage differential gene expression in response to lipopolysaccharide (LPS) challenge, whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response, especially cytokine gene expression. These results show that ß-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.

Engaging GME Learners in Health System-Aligned Improvement Work in the Clinical Learning Environment.

Alignment between graduate medical education (GME) and health system priorities is foundational to meaningful engagement of residents and fellows in systems improvement work within the clinical learning environment. The Residents and Fellows Leading Interprofessional Continuous Improvement Teams program at the University of California San Francisco was designed over a decade ago to address barriers to trainee participation in health system-based improvement work. The program provides structure and support for health system-aligned trainee-led improvement projects in the clinic learning environment. Project champions (residents/fellows) from GME programs attend workshops where they learn improvement methodologies and develop proposals for health system-based improvement projects for their training programs. Proposals are supported by local faculty mentors and are reviewed and approved by GME and health systems' leaders. During the academic year, teams share their progress using visual management boards and interactive leader rounds. The health system provides a modest financial incentive for successful projects. Since the program's inception, thousands of trainees from 58 residency and fellowship programs have participated either as champions or participants in the program at least once, and in total over 300 projects have been implemented. Approximately three-quarters of the specific improvement goals were met, all projects meaningfully engaged residents and fellows, and many projects continued after the learners graduated. This active partnership between GME and a health system created a symbiotic relationship; trainees received education and support to complete improvement projects, while the health system reaped additional benefits from the alignment and impact of the projects. This partnership continues to grow with steady increases in participating programs, spread to partner health systems, and scholarship for trainees and faculty.

Transforming neonatal care with artificial intelligence: challenges, ethical consideration, and opportunities.

Artificial intelligence (AI) offers tremendous potential to transform neonatology through improved diagnostics, personalized treatments, and earlier prevention of complications. However, there are many challenges to address before AI is ready for clinical practice. This review defines key AI concepts and discusses ethical considerations and implicit biases associated with AI. Next we will review literature examples of AI already being explored in neonatology research and we will suggest future potentials for AI work. Examples discussed in this article include predicting outcomes such as sepsis, optimizing oxygen therapy, and image analysis to detect brain injury and retinopathy of prematurity. Realizing AI's potential necessitates collaboration between diverse stakeholders across the entire process of incorporating AI tools in the NICU to address testability, usability, bias, and transparency. With multi-center and multi-disciplinary collaboration, AI holds tremendous potential to transform the future of neonatology.

Supramolecular Nature of Multicomponent Crystals Formed from 2,2'-Thiodiacetic Acid with 2,6-Diaminopurine or N9-(2-Hydroxyethyl)adenine.

The synthesis and characterization of the multicomponent crystals formed by 2,2'-thiodiacetic acid (H2tda) and 2,6-diaminopurine (Hdap) or N9-(2-hydroxyethyl)adenine (9heade) are detailed in this report. These crystals exist in a salt rather than a co-crystal form, as confirmed by single crystal X-ray diffractometry, which reflects their ionic nature. This analysis confirmed proton transfer from the 2,2'-thiodiacetic acid to the basic groups of the coformers. The new multicomponent crystals have molecular formulas [(H9heade+)(Htda-)] 1 and [(H2dap+)2(tda2-)]·2H2O 2. These were also characterized using FTIR, 1H and 13C NMR and mass spectroscopies, elemental analysis, and thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. In the crystal packing the ions interact with each other via O-H⋯N, O-H⋯O, N-H⋯O, and N-H⋯N hydrogen bonds, generating cyclic hydrogen-bonded motifs with graph-set notation of R22(16), R22(10), R32(10), R33(10), R22(9), R32(8), and R42(8), to form different supramolecular homo- and hetero-synthons. In addition, in the crystal packing of 2, pairs of diaminopurinium ions display a strong anti-parallel π,π-stacking interaction, characterized by short inter-centroids and interplanar distances (3.39 and 3.24 Å, respectively) and a fairly tight angle (17.5°). These assemblies were further analyzed energetically using DFT calculations, MEP surface analysis, and QTAIM characterization.

Angiotensin-II for vasoplegia following cardiac surgery.

INTRODUCTION: The objective of this study was to describe the implementation and outcomes of a protocol outlining angiotensin-II utilization for vasoplegia following cardiac surgery. METHODS: This was a retrospective chart review at a single-center university hospital. Included patients received angiotensin-II for vasoplegia refractory to standard interventions, including norepinephrine 20 mcg/min and vasopressin 0.04 units/min, following cardiac surgery between April 2021 and April 2022. RESULTS: 30 patients received angiotensin-II for refractory vasoplegia. Adjunctive agents at angiotensin-II initiation included corticosteroids (26 patients; 87%), epinephrine (26 patients; 87%), dobutamine (17 patients; 57%), dopamine (9 patients; 30%), milrinone (2 patients; 7%), and hydroxocobalamin (4 patients; 13%). At 3 hours, the median mean arterial pressure increased from baseline (70 vs 61.5 mmHg, p = .0006). Median norepinephrine doses at angiotensin-II initiation, 1 hour, 3 hours, and angiotensin-II discontinuation were 0.22, 0.16 (p = .0023), 0.10 (p < .0001), and 0.07 (p < .0001) mcg/kg/min. Median dobutamine doses decreased throughout angiotensin-II infusion from eight to six mcg/kg/min (p = .0313). Other vasoactive medication doses were unchanged. Three patients (10%) subsequently received hydroxocobalamin. Thirteen (43.3%) and five (16.7%) patients experienced mortality by day 28 and venous or arterial thrombosis events, respectively. CONCLUSIONS: The administration of angiotensin-II to vasoplegic patients following cardiac surgery was associated with increased mean arterial pressure, reduced norepinephrine dosages, and reduced dobutamine dosages.