Identifying patients at risk of anaphylaxis.

Anaphylaxis is an acute, potentially fatal, systemic hypersensitivity reaction that warrants prompt diagnosis and management. It continues to be challenging to anticipate who may be at risk of a severe, life-threatening allergic reaction. Anaphylaxis can be caused by a range of allergens, such as certain foods, medications, latex, insect stings, etc. Cofactors that augment the severity of clinical symptoms and increase the risk of poor outcomes include exercise, stress, infectious diseases, underlying mast cell disease, active allergic disease such as asthma, advanced age, intake of certain medications, history of previous anaphylaxis, and delayed or missed administration of adrenaline. According to the European Anaphylaxis Registry, food is the major elicitor of anaphylaxis, especially eggs, cow milk, and nuts, in children and adolescents. Reaction to insect venom has also been noted in young adulthood. Early recognition of signs and symptoms and prompt treatment are crucial in anaphylaxis management to avoid serious and even fatal outcomes. It is crucial for both individuals and clinicians to identify the cause of anaphylaxis. Biomarkers of anaphylaxis, such as histamine, tryptase, platelet activation factor (PAF), chymase, carboxypeptidase A3, dipeptidyl peptidase I (DPPI), basogranulin, CCL-2, hsa-miR-451a, may be useful in diagnosis and management. The purpose of this review article is to present a comprehensive overview of current evidence and expert opinions regarding the risk factors that predispose individuals to anaphylaxis. Additionally, it provides insights into potential biomarkers and genetic markers for accurate diagnosis and management. This review underscores the significance of expert guidance in enhancing patient outcomes and enabling self-management of anaphylactic episodes.

Orientation and Onboarding Experiences of Internationally Educated Nurses Transitioning to U.S. Nursing Practice.

Nursing professional development practitioners are faced with meeting the onboarding needs of internationally educated nurses (IENs) recruited to work in the United States. The purpose of this secondary data analysis study was to assess differences between demographic characteristics, orientation, and onboarding variables and IEN's length of orientation and retention to a healthcare system. A significant difference in the length of orientation by unit assigned, degree type, and retention were discovered.

Observation of oxygenated intermediates in functional mimics of aminophenol dioxygenase.

Aminophenol dioxygenases (APDO) are mononuclear nonheme iron enzymes that utilize dioxygen (O2) to catalyze the conversion of o-aminophenols to 2-picolinic acid derivatives in metabolic pathways. This study describes the synthesis and O2 reactivity of two synthetic models of substrate-bound APDO: [FeII(TpMe2)(tBu2APH)] (1) and [FeII(TpMe2)(tBuAPH)] (2), where TpMe2 = hydrotris(3,5-dimethylpyrazole-1-yl)borate, tBu2APH = 4,6-di-tert-butyl-2-aminophenolate, and tBuAPH2 = 4-tert-butyl-2-aminophenolate. Both Fe(II) complexes behave as functional APDO mimics, as exposure to O2 results in oxidative CC bond cleavage of the o-aminophenolate ligand. The ring-cleaved products undergo spontaneous cyclization to give substituted 2-picolinic acids, as verified by 1H NMR spectroscopy, mass spectrometry, and X-ray crystallography. Reaction of the APDO models with O2 at low temperature reveals multiple intermediates, which were probed with UV-vis absorption, electron paramagnetic resonance (EPR), Mössbauer (MB), and resonance Raman (rRaman) spectroscopies. The most stable intermediate at -70 °C in THF exhibits multiple isotopically-sensitive features in rRaman samples prepared with 16O2 and 18O2, confirming incorporation of O2-derived atom(s) into its molecular structure. Insights into the geometric structures, electronic properties, and spectroscopic features of the observed intermediates were obtained from density functional theory (DFT) calculations. Although functional APDO models have been previously reported, this is the first time that an oxygenated ligand-based radical has been detected and spectroscopically characterized in the ring-cleaving mechanism of a relevant synthetic system.

Spinal Cord Stimulator Inequities Within the US Military Health System.

OBJECTIVES: Although studies have described inequities in spinal cord stimulation (SCS) receipt, there is a lack of information to inform system-level changes to support health care equity. This study evaluated whether Black patients exhaust more treatment options than do White patients, before receiving SCS. MATERIALS AND METHODS: This retrospective cohort study included claims data of Black and non-Latinx White patients who were active-duty service members or military retirees who received a persistent spinal pain syndrome (PSPS) diagnosis associated with back surgery within the US Military Health System, January 2017 to January 2020 (N = 8753). A generalized linear model examined predictors of SCS receipt within two years of diagnosis, including the interaction between race and number of pain-treatment types received. RESULTS: In the generalized linear model, Black patients (10.3% [8.7%, 12.0%]) were less likely to receive SCS than were White patients (13.6% [12.7%, 14.6%]) The interaction term was significant; White patients who received zero to three different types of treatments were more likely to receive SCS than were Black patients who received zero to three treatments, whereas Black and White patients who received >three treatments had similar likelihoods of receiving a SCS. CONCLUSIONS: In a health care system with intended universal access, White patients diagnosed with PSPS tried fewer treatment types before receiving SCS, whereas the number of treatment types tried was not significantly related to SCS receipt in Black patients. Overall, Black patients received SCS less often than did White patients. Findings indicate the need for structured referral pathways, provider evaluation on equity metrics, and top-down support.

Sustainable and Biomimetic Methodology for Extraction of High-Value-Added Compounds in Almond Hulls.

Almond trees are the most cultivated nut tree in the world. The production of almonds generates large amounts of by-products, much of which goes unused. Herein, this study aimed to develop a green chemistry approach to identify and extract potentially valuable compounds from almond by-products. Initially, a screening was performed with 10 different Natural Deep Eutectic Solvents (NADESs). The mixture lactic acid/glycerol, with a molar ratio 1:1 (1:50 plant material to NADES (w/v) with 20% v/v of water) was identified as the best extraction solvent for catechin, caffeoylquinic acid, and condensed tannins in almond hulls. Subsequently, a method was optimized by a Design of Experiment (DoE) protocol using a miniaturized extraction technique, Microwave-Assisted Extraction (MAE), in conjunction with the chosen NADESs. The optimal conditions were found to be 70 °C with 15 min irradiation time. The optimal extraction conditions determined by the DoE were confirmed experimentally and compared to methods already established in the literature. With these conditions, the extraction of metabolites was 2.4 times higher, according to the increase in total peak area, than the established literature methods used. Additionally, by applying the multiparameter Analytical Greenness Metric (AGREE) and Green Analytical Process Index (GAPI) metrics, it was possible to conclude that the developed method was greener than the established literature methods as it includes various principles of green analytical chemistry.

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines.

Following metastatic spread, many hormone receptor positive (HR+) patients develop a more aggressive phenotype with an observed loss of the HRs estrogen receptor (ER) and progesterone receptor (PR). During metastasis, breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS). Unfortunately, the role for FSS on the regulation of HR expression and function during metastasis is not fully understood. This study was designed to elucidate the impact of FSS on HR+ breast cancer. Utilizing a microfluidic platform capable of exposing breast cancer cells to FSS that mimics in situ conditions, we demonstrate the impact of FSS exposure on representative HR+ breast cancer cell lines through protein and gene expression analysis. Proteomics results demonstrated that 540 total proteins and 1473 phospho-proteins significantly changed due to FSS exposure and pathways of interest included early and late estrogen response. The impact of FSS on response to 17ß-estradiol (E2) was next evaluated and gene expression analysis revealed repression of ER and E2-mediated genes (PR and SDF1) following exposure to FSS. Western blot demonstrated enhanced phosphorylation of mTOR following exposure to FSS. Taken together, these studies provide initial insight into the effects of FSS on HR signaling in metastatic breast cancer.

Recovery kinetics of dual AAV-mediated human otoferlin expression.

Deafness-causing deficiencies in otoferlin (OTOF) have been addressed preclinically using dual adeno-associated virus (AAV)-based approaches. However, timing of transduction, recombination of mRNA, and protein expression with dual hybrid AAV methods methods have not previously been characterized. Here, we have established an ex vivo assay to determine the kinetics of dual-AAV mediated expression of OTOF in hair cells of the mouse utricle. We utilized two different recombinant vectors that comprise DB-OTO, one containing the 5' portion of OTOF under the control of the hair cell-specific Myo15 promoter, and the other the 3' portion of OTOF. We explored specificity of the Myo15 promoter in hair cells of the mouse utricle, established dose response characteristics of DB-OTO ex vivo in an OTOF-deficient mouse model, and demonstrated tolerability of AAV1 in utricular hair cells. Furthermore, we established deviations from a one-to-one ratio of 5' to 3' vectors with little impact on recombined OTOF. Finally, we established a plateau in quantity of recombined OTOF mRNA and protein expression by 14 to 21 days ex vivo with comparable recovery timing to that in vivo model. These findings demonstrate the utility of an ex vivo model system for exploring expression kinetics and establish in vivo and ex vivo recovery timing of dual AAV-mediated OTOF expression.

"Forcing" new interpretations of molecular tension sensor studies.

Molecular tension sensors are central tools for mechanobiology studies but have limitations in interpretation. Reporting in Cell Reports Methods, Shoyer et al. discover that fluorescent protein photoswitching in concert with sensor extension may expand the use and interpretation of common force-sensing tools.

Neighborhood Deprivation is Associated With Hospital Length of Stay, Discharge Disposition, and Readmission Rates for Patients Who Survive Hospitalization With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is a leading cause of disability in the United States. Limited research exists on the influence of area-level socioeconomic status and outcomes after TBI. This study investigated the correlation between the Area Deprivation Index (ADI) and (1) 90-day hospital readmission rates, (2) facility discharge, and (3) prolonged (≥5 days) hospital length of stay (LOS). METHODS: Single-center retrospective review of adult (18 years or older) patients who were admitted for TBI during 2018 was performed. Patients were excluded if they were admitted for management of a chronic or subacute hematoma. We extracted relevant clinical and demographic data including sex, comorbidities, age, body mass index, smoking status, TBI mechanism, and national ADI. We categorized national ADI rankings into quartiles for analysis. Univariate, multivariate, and area under the receiver operating characteristic curve (AUROC) analyses were performed to assess the relationship between ADI and 90-day readmission, hospital LOS, and discharge disposition. RESULTS: A total of 523 patients were included in final analysis. Patients from neighborhoods in the fourth ADI quartile were more likely to be Black (P = .007), have a body mass index ≥30 kg/m2 (P = .03), have a Charlson Comorbidity Index ≥5 (P = .004), and have sustained a penetrating TBI (P = .01). After controlling for confounders in multivariate analyses, being from a neighborhood in the fourth ADI quartile was independently predictive of 90-day hospital readmission (odds ratio [OR]: 1.35 [1.12-1.91], P = .011) (model AUROC: 0.82), discharge to a facility (OR: 1.46 [1.09-1.78], P = .03) (model AUROC: 0.79), and prolonged hospital LOS (OR: 1.95 [1.29-2.43], P = .015) (model AUROC: 0.85). CONCLUSION: After adjusting for confounders, including comorbidities, TBI mechanism/severity, and age, higher ADI was independently predictive of longer hospital LOS, increased risk of 90-day readmission, and nonhome discharge. These results may help establish targeted interventions to identify at-risk patients after TBI.

Mortality burden from variation in provision of surgical care in emergency general surgery: a cohort study using the National Inpatient Sample.

Background: The decision to undertake a surgical intervention for an emergency general surgery (EGS) condition (appendicitis, diverticulitis, cholecystitis, hernia, peptic ulcer, bowel obstruction, ischemic bowel) involves a complex consideration of factors, particularly in older adults. We hypothesized that identifying variability in the application of operative management could highlight a potential pathway to improve patient survival and outcomes. Methods: We included adults aged 65+ years with an EGS condition from the 2016-2017 National Inpatient Sample. Operative management was determined from procedure codes. Each patient was assigned a propensity score (PS) for the likelihood of undergoing an operation, modeled from patient and hospital factors: EGS diagnosis, age, gender, race, presence of shock, comorbidities, and hospital EGS volumes. Low and high probability for surgery was defined using a PS cut-off of 0.5. We identified two model-concordant groups (no surgery-low probability, surgery-high probability) and two model-discordant groups (no surgery-high probability, surgery-low probability). Logistic regression estimated the adjusted OR (AOR) of in-hospital mortality for each group. Results: Of 375 546 admissions, 21.2% underwent surgery. Model-discordant care occurred in 14.6%; 5.9% had no surgery despite a high PS and 8.7% received surgery with low PS. In the adjusted regression, model-discordant care was associated with significantly increased mortality: no surgery-high probability AOR 2.06 (1.86 to 2.27), surgery-low probability AOR 1.57 (1.49 to 1.65). Model-concordant care showed a protective effect against mortality (AOR 0.83, 0.74 to 0.92). Conclusions: Nearly one in seven EGS patients received model-discordant care, which was associated with higher mortality. Our study suggests that streamlined treatment protocols can be applied in EGS patients as a means to save lives. Level of evidence: III.

TERT activation targets DNA methylation and multiple aging hallmarks.

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

NR0B2 re-educates myeloid immune cells to reduce regulatory T cell expansion and progression of breast and other solid tumors.

Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (Tregs); Tregs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1ß; IL1ß driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing Treg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2.

Natural language processing pipeline to extract prostate cancer-related information from clinical notes.

OBJECTIVES: To develop an automated pipeline for extracting prostate cancer-related information from clinical notes. MATERIALS AND METHODS: This retrospective study included 23,225 patients who underwent prostate MRI between 2017 and 2022. Cancer risk factors (family history of cancer and digital rectal exam findings), pre-MRI prostate pathology, and treatment history of prostate cancer were extracted from free-text clinical notes in English as binary or multi-class classification tasks. Any sentence containing pre-defined keywords was extracted from clinical notes within one year before the MRI. After manually creating sentence-level datasets with ground truth, Bidirectional Encoder Representations from Transformers (BERT)-based sentence-level models were fine-tuned using the extracted sentence as input and the category as output. The patient-level output was determined by compilation of multiple sentence-level outputs using tree-based models. Sentence-level classification performance was evaluated using the area under the receiver operating characteristic curve (AUC) on 15% of the sentence-level dataset (sentence-level test set). The patient-level classification performance was evaluated on the patient-level test set created by radiologists by reviewing the clinical notes of 603 patients. Accuracy and sensitivity were compared between the pipeline and radiologists. RESULTS: Sentence-level AUCs were ≥ 0.94. The pipeline showed higher patient-level sensitivity for extracting cancer risk factors (e.g., family history of prostate cancer, 96.5% vs. 77.9%, p < 0.001), but lower accuracy in classifying pre-MRI prostate pathology (92.5% vs. 95.9%, p = 0.002) and treatment history of prostate cancer (95.5% vs. 97.7%, p = 0.03) than radiologists, respectively. CONCLUSION: The proposed pipeline showed promising performance, especially for extracting cancer risk factors from patient's clinical notes. CLINICAL RELEVANCE STATEMENT: The natural language processing pipeline showed a higher sensitivity for extracting prostate cancer risk factors than radiologists and may help efficiently gather relevant text information when interpreting prostate MRI. KEY POINTS: When interpreting prostate MRI, it is necessary to extract prostate cancer-related information from clinical notes. This pipeline extracted the presence of prostate cancer risk factors with higher sensitivity than radiologists. Natural language processing may help radiologists efficiently gather relevant prostate cancer-related text information.

The continuous flow synthesis of azos.

Azo compounds find use in many areas of science, displaying crucial properties for important applications as photoconductive organic pigments, fluorescent quenchers, paints, cosmetics, inks, and in the large and valuable dye industry. Due to the unstable intermediates, and the exothermic and fast reactions used in their synthesis, high value azo compounds are excellent candidates for continuous flow manufacturing. This comprehensive review covers the progress made to date on developing continuous flow systems for azo synthesis and reflects on the main challenges still to be addressed, including scale up, conversion, product purity, and environmental impact. The further development of integrated continuous flow processes has the potential to help tackle these challenges and deliver improved methods for azo compound generation.

Paradoxical gender effects in meat consumption across cultures.

Men tend to eat more meat than women, but it is not clear why. We tested three hypotheses in a cross-cultural design (20,802 individuals in 23 countries across four continents): that gender differences are (a) universal, (b) related to gender roles and thus weaker in countries with higher gender equality and human development, or (c) related to opportunities to express gender roles and thus stronger in countries with higher gender equality and human development. Across all countries, men tended to consume more meat than women. However, this difference increased significantly in countries with greater human development and gender equality. The paradoxical gender gap in meat consumption aligns with previous research that suggests greater differences in behavior across genders in contexts that are more developed and gender equal. We discuss implications for theories of culture and gender as well as practical implications for global meat reduction.

Social Determinants and Consequences of Pain: Toward Multilevel, Intersectional, and Life Course Perspectives.

Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain remain rarely addressed in the context of pain prevention and management. In this review, we aim to 1) examine the broad scope of social determinants and consequences of pain and their interactions across multiple levels of organization, and 2) provide a framework synthesizing existing concepts and potential areas for future work on social aspects of pain, drawing upon socioecological, intersectional, and life course approaches. Integrating interdisciplinary theory and evidence, we outline pathways through which multilevel social factors and pain may affect each other over time. We also provide a brief summary of intrapersonal aspects of pain, which are thought to operate at the interface between individuals and the social context. Progressing from micro- to macrolevel factors, we illustrate how social determinants of pain can directly or indirectly contribute to pain experiences, expression, risk, prognosis, and impact across populations. We consider 1) at the interpersonal level, the roles of social comparison, social relatedness, social support, social exclusion, empathy, and interpersonal conflict; 2) at the group or community level, the roles of intimacy groups, task groups, social categories, and loose associations; and 3) at the societal level, the roles of political, economic, and cultural systems, as well as their policies and practices. We present examples of multilevel consequences of pain across these levels and discuss opportunities to reduce the burden and inequities of pain by expanding multilevel social approaches in pain research and practice. PERSPECTIVE: Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain are often unclearly defined, hindering their use in pain prevention, management, and research. We summarize the scope of social aspects of pain and provide a framework synthesizing existing concepts and potential areas for future work.

DNA-Templated Nanofabrication of CdS-Au Nanoscale Schottky Contacts and Electrical Characterization.

DNA-templated nanofabrication presents an innovative approach to creating self-assembled nanoscale metal-semiconductor-based Schottky contacts, which can advance nanoelectronics. Herein, we report the successful fabrication of metal-semiconductor Schottky contacts using a DNA origami scaffold. The scaffold, consisting of DNA strands organized into a specific linear architecture, facilitates the competitive arrangement of Au and CdS nanorods, forming heterojunctions, and addresses previous limitations in low electrical conductance making DNA-templated electronics with semiconductor nanomaterials. Electroless gold plating extends the Au nanorods and makes the necessary electrical contacts. Tungsten electrical connection lines are further created by electron beam-induced deposition. Electrical characterization reveals nonlinear Schottky barrier behavior, with electrical conductance ranging from 0.5 × 10-4 to 1.7 × 10-4 S. The conductance of these DNA-templated junctions is several million times higher than with our prior Schottky contacts. Our research establishes an innovative self-assembly approach with applicable metal and semiconductor materials for making highly conductive nanoscale Schottky contacts, paving the way for the future development of DNA-based nanoscale electronics.

Anisotropic Icephobic Mechanisms of Textured Surface: Barrier or Accelerator?

Icing has been seen as an economic and safety hazard due to its threats to aviation, power generation, offshore platforms, etc., where passive icephobic surfaces with a surface texturing design have the potential to address this problem. However, the intrinsic icephobic principles associated with the surface textures, energy, elasticity, and hybrid effects are still unclear. To explore the anisotropic wettability, ice nucleation, and ice detaching behaviors, a series of textured poly(dimethylsiloxane) (PDMS)-based coatings with various texture orientations were proposed through a simple stamping method with surface functionalization. The anisotropic hydrophobic/icephobic phenomena and mechanisms were discovered from wettability evaluation, experimentally studied by icing/deicing experiments, and finally verified by microscopic numerical simulations. One-way analysis of variance (one-way ANOVA analysis) was used to analyze the effect of surface textures on hydrophobic/icephobic properties, which assisted in understanding anisotropic phenomena. Typical anisotropic ice nucleation and growth on the textured coatings were clarified using in situ environmental scanning electron microscope (ESEM) characterization. The ice/coating interfacial stress responses were studied by numerical stimulation at the microscopic level, further verifying the localized, amplified, and propagated stress at the ice/coating interface. The theoretical anisotropic responses, barrier effect, and accelerating effect were verified to interpret the anisotropic wettability and icephobicity, depending on the specific surface conditions. This study revealed the basics of the anisotropic icephobic mechanisms of textured icephobic surfaces, further facilitating the R&D of passive icephobic surfaces.

Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells.

Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.