ABSTRACT
NT-0796 is an ester prodrug which is metabolized by carboxylesterase-1 (CES1) to yield the carboxylic acid NDT-19795, an inhibitor of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome. When applied to human monocytes/macrophages which express CES1, however, NT-0796 is much more potent at inhibiting NLRP3 inflammasome activation than is NDT-19795. Comparison of the binding of NDT-19795 and NT-0796 in a cell-based NLRP3 target engagement assay confirms that NDT-19795 is the active species. Moreover, microsomes expressing CES1 efficiently convert NT-0796 to NDT-19795, confirming CES1-dependent activation. To understand the basis for the enhanced potency of the ester prodrug species in human monocytes, we analyzed the accumulation and de-esterification of NT-0796 in cultured cells. Our studies reveal NT-0796 rapidly accumulates in cells, achieving estimated cellular concentrations above those applied to the medium, with concomitant metabolism to NDT-19795 in CES1-expressing cells. Using cells lacking CES1 or a poorly hydrolysable NT-0796 analog demonstrated that de-esterification is not required for NT-0796 to achieve high cellular levels. As a result of a dynamic equilibrium whereby NDT-19795 formed intracellularly is subsequently released to the medium, concentrations of NT-0796 sufficient to inhibit NLRP3 can be completely metabolized to NDT-19795 resulting in a transient pharmacodynamic response. In contrast, when NDT-19795 is applied directly to cells, observed cell-associated levels are below those present in the medium and remain stable over time. Dynamics observed within the context of a closed tissue culture system highlight the utility of NT-0796 as a vehicle for delivering the NDT-19795 acid payload to CES1 expressing cells.
Subject(s)
Carboxylesterase , Carboxylic Ester Hydrolases , Inflammasomes , Monocytes , NLR Family, Pyrin Domain-Containing 3 Protein , Prodrugs , Humans , Prodrugs/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Monocytes/metabolism , Monocytes/drug effects , Inflammasomes/metabolism , Carboxylesterase/metabolism , Carboxylesterase/antagonists & inhibitors , Carboxylic Ester Hydrolases/metabolism , Carboxylic Ester Hydrolases/antagonists & inhibitors , Esters/chemistry , THP-1 CellsABSTRACT
Aim: To evaluate the effects of double (axillary and femoral) vs. single (axillary) cannulation on early outcomes of acute type A aortic dissection (ATAAD). Materials & methods: Meta-analysis using PubMed/MEDLINE, Scopus, and Cochrane databases through August 23, 2023. Focused on operative mortality, postoperative stroke, re-exploration for bleeding, spinal cord injury, and renal replacement therapy. Results: Among 5 propensity score-matched studies with 2127 patients, double cannulation showed comparable mortality and higher rates of postoperative stroke (pooled odds ratio: 1.69, 95% confidence interval: 1.19-2.39) and need for renal replacement therapy (pooled odds ratio: 1.35, 95% confidence interval: 1.13-1.60) compared with single cannulation. Conclusion: Double arterial cannulation in ATAAD surgery is associated with increased postoperative stroke and renal replacement therapy than single cannulation.
What is this summary about? We studied the optimal way to maintain blood flow during surgery for acute aortic dissection. We focused on comparing the use of one tube placement site in the axillary artery with two sites, both in the axillary and femoral arteries, in five previous studies.What were the results? Using two sites was associated with a higher risk of stroke and need for dialysis after surgery than using only one site.What do the results mean? Adding a tube in the femoral artery for blood flow may increase the risk of complications. It appears that placing the tube only in the axillary artery may be a safer choice for appropriately selected patients having this surgery.
Subject(s)
Aortic Dissection , Axillary Artery , Humans , Aortic Dissection/surgery , Acute Disease , Catheterization/methods , Catheterization, Peripheral/methods , Femoral Artery , Postoperative Complications/epidemiology , Postoperative Complications/prevention & controlABSTRACT
Black soils, which play an important role in agricultural production and food security, are well known for their relatively high content of soil organic matter (SOM). SOM has a significant impact on the sustainability of farmland and provides nutrients for plants. Hyperspectral imaging (HSI) in the visible and near-infrared region has shown the potential to detect soil nutrient levels in the laboratory. However, using portable spectrometers directly in the field remains challenging due to variations in soil moisture (SM). The current study used spectral data captured by a handheld spectrometer outdoors to predict SOM, available nitrogen (AN), available phosphorus (AP) and available potassium (AK) with different SM levels. Partial least squares regression (PLSR) models were established to compare the predictive performance of air-dried soil samples with SMs around 20%, 30% and 40%. The results showed that the model established using dry sample data had the best performance (RMSE = 4.47 g/kg) for the prediction of SOM, followed by AN (RMSE = 20.92 mg/kg) and AK (RMSE = 22.67 mg/kg). The AP was better predicted by the model based on 30% SM (RMSE = 8.04 mg/kg). In general, model performance deteriorated with an increase in SM, except for the case of AP. Feature wavelengths for predicting four kinds of soil properties were recommended based on variable importance in the projection (VIP), which offered useful guidance for the development of portable hyperspectral sensors based on discrete wavebands to reduce cost and save time for on-site data collection.
ABSTRACT
BACKGROUND: Suicide among male construction workers are reported to be disproportionally high compared to the working age population. However, there is minimal understanding of the prevalence and associated factors for suicidal ideation, non-suicidal self-injury, and suicide attempt among this occupational group globally. METHODS: A cross-sectional study was conducted on a large sample of male construction workers in Ireland (n = 1,585). We investigated the prevalence of suicidal ideation, non-suicidal self-injury and suicide attempts and sociodemographic, occupational, and mental health factors associated with these three outcomes. Multivariable Poisson regression was performed to estimate the prevalence rate ratio of suicidal ideation (model 1 primary outcome), while multivariable logistic regression was used to estimate the odds ratio of non-suicidal self-injury (model 2 primary outcome), and suicide attempt (model 3 primary outcome). RESULTS: The lifetime prevalence rate for suicidal ideation was 22%, 6% for non-suicidal self-injury, and 6% for suicide attempt. In univariate modelling, socio-demographic and occupation-specific factors associated with the three outcomes included younger age (suicidal ideation and non-suicidal self-injury), not being in a relationship (suicide attempt) and working 35-44 h per week (suicidal ideation and suicide attempt). The mental health factors generalized anxiety disorder, depression, and suicide bereavement were significantly associated with increased risk of the three outcomes. In fully adjusted multivariable models, increasing severity of generalized anxiety disorder and depression were associated with an increased prevalence rate ratio of suicidal ideation, and a higher odds ratio of non-suicidal self-injury and suicide attempt. CONCLUSION: Suicidal ideation, non-suicidal self-injury and suicide attempt are significant issues for male construction workers that require specific attention. Findings highlight a need to support younger male construction workers and those bereaved by suicide. They also highlight the need for the early detection and treatment of generalized anxiety disorder and depression in order to intervene in, and potentially prevent, suicidality among male construction workers.
Subject(s)
Self-Injurious Behavior , Suicidal Ideation , Suicide, Attempted , Humans , Male , Suicide, Attempted/statistics & numerical data , Suicide, Attempted/psychology , Adult , Ireland/epidemiology , Self-Injurious Behavior/epidemiology , Self-Injurious Behavior/psychology , Cross-Sectional Studies , Prevalence , Risk Factors , Middle Aged , Young Adult , Construction Industry , AdolescentABSTRACT
PURPOSE: To investigate the impact of direct aortic cannulation (DAC) versus femoral arterial cannulation (FAC) on clinical outcomes of surgery for acute type A aortic dissection. METHODS: PubMed/MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials were searched until August 25, 2023, to conduct a meta-analysis. Primary endpoints of the study were operative mortality and postoperative stroke. Secondary endpoints were cardiopulmonary bypass time, myocardial ischemic time, hypothermic circulatory arrest time, temporary neurological dysfunction (TND), combined stroke and TND, re-exploration for bleeding, and need for renal replacement therapy. A random-effect model was used to estimate the pooled effect size, and a leave-one-out method was used for the primary endpoints for sensitivity analysis. RESULTS: 15 studies met our eligibility criteria, including a total of 7941 samples. Operative mortality was significantly lower in the DAC group with a pooled odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.61-0.85)]. Incidence of postoperative stroke was also lower in the DAC group with a pooled OR of 0.79 (95% CI: 0.66-0.94). However, after excluding one study with the greatest weight, the difference became nonsignificant. DAC was also associated with a lower incidence of postoperative TND, and re-exploration for bleeding with a pooled OR of 0.52 (95% CI: 0.37-0.73), and 0.60 (95% CI: 0.47-0.77), respectively. CONCLUSIONS: This meta-analysis showed that patients who underwent ATAAD repair with DAC had a lower incidence of operative mortality, postoperative stroke, TND, and re-exploration for bleeding compared to those who underwent FAC.
ABSTRACT
Background: Researchers define Emotional Labour (EL) as the effort associated with meeting the emotional requirements of the job, yet nobody has ever directly tested this effort. Building on classic stress and ego depletion theory, this study develops the Emotional Effort Scale (EEF). Methods: In Study 1, exploratory (N = 197) and confirmatory factor analysis (N = 182) were conducted with a British sample. In Study 2, the instrument was adapted to Spanish and measurement invariance was tested (N = 304). In Study 3, (N = 185), we tested convergent and divergent validity with the EL strategies (i.e., surface acting and deep acting) and the relationship between EEF and emotional exhaustion. Results: The final scale is a two-dimensional measure (explicit and implicit emotional effort) with good reliability levels in all samples (N = 818). Additionally, it shows adequate convergent, divergent and nomological validity. Conclusions: The Emotional Effort construct adds unique value to the literature. Thus, explicit effort seems to be the mechanism that explains the association between EL and exhaustion. Additionally, this study adapts and translates the measure to two of the most used languages in the world, enabling the emergence of cross-national studies in the field of emotions at work (AU)
Antecedentes: la literatura define el Trabajo Emocional como el esfuerzo asociado al cumplimiento de las reglas de expresión emocional del puesto; sin embargo, este esfuerzo no ha sido medido aún. Desde la teoría transaccional de estrés y la ego depletion theory desarrollamos la Escala del Esfuerzo Emocional (EEF). Método: en el Estudio 1 se condujeron análisis factoriales exploratorios (N = 197) y confirmatorios (N = 182) en muestras británicas. En el Estudio 2 la escala se adaptó al español y se realizaron análisis de invarianza (N = 304). En el Estudio 3 (N = 185) se examinó la validez convergente y divergente de la escala con las estrategias de trabajo emocional (i.e., actuación superficial y profunda), y se estudió la relación entre el esfuerzo y el cansancio emocional. Resultados: la escala final tiene dos factores (explícito e implícito) y buenos niveles de fiabilidad en todas las muestras (N = 818). Además, presenta adecuada validez convergente, divergente y nomológica. Conclusiones: el constructo del esfuerzo emocional contribuye de manera notable a la literatura, y parece ser el mecanismo que explica la relación entre el trabajo y el cansancio emocional. Además, el instrumento se ha validado en dos de las lenguas más usadas en el mundo, permitiendo el desarrollo de futuros estudios trasnacionales (AU)