Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity.

BACKGROUND: Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS: Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS: After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS: There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

An observational study of therapeutic procedures and in-hospital outcomes among patients admitted for acute myocardial infarction in Spain, 2016-2022: the role of diabetes mellitus.

BACKGROUND: We used the Spanish national hospital discharge data from 2016 to 2022 to analyze procedures and hospital outcomes among patients aged ≥ 18 years admitted for ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) according to diabetes mellitus (DM) status (non-diabetic, type 1-DM or type 2-DM). METHODS: We built logistic regression models for STEMI/NSTEMI stratified by DM status to identify variables associated with in-hospital mortality (IHM). We analyzed the effect of DM on IHM. RESULTS: Spanish hospitals reported 201,950 STEMIs (72.7% non-diabetic, 0.5% type 1-DM, and 26.8% type 2-DM; 26.3% female) and 167,285 NSTEMIs (61.6% non-diabetic, 0.6% type 1-DM, and 37.8% type 2-DM; 30.9% female). In STEMI, the frequency of percutaneous coronary intervention (PCI) increased among non-diabetic people (60.4% vs. 68.6%; p < 0.001) and people with type 2-DM (53.6% vs. 66.1%; p < 0.001). In NSTEMI, the frequency of PCI increased among non-diabetic people (43.7% vs. 45.7%; p < 0.001) and people with type 2-DM (39.1% vs. 42.8%; p < 0.001). In NSTEMI, the frequency of coronary artery by-pass grafting (CABG) increased among non-diabetic people (2.8% vs. 3.5%; p < 0.001) and people with type 2-DM (3.7% vs. 5.0%; p < 0.001). In the entire population, lower IHM was associated with undergoing PCI (odds ratio [OR] [95% confidence interval] = 0.34 [0.32-0.35] in STEMI; 0.24 [0.23-0.26] in NSTEMI) or CABG (0.33 [0.27-0.40] in STEMI; 0.45 [0.38-0.53] in NSTEMI). IHM decreased over time in STEMI (OR = 0.86 [0.80-0.93]). Type 2-DM was associated with higher IHM in STEMI (OR = 1.06 [1.01-1.11]). CONCLUSIONS: PCI and CABG were associated with lower IHM in people admitted for STEMI/NSTEMI. Type 2-DM was associated with IHM in STEMI.

Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

PURPOSE/BACKGROUND: The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. METHODS: Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. FINDINGS/RESULTS: An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. IMPLICATIONS/CONCLUSIONS: Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

A Systematic Review of Clozapine Concentration-Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders.

BACKGROUND: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance. METHODS: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. RESULTS: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). CONCLUSIONS: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.

Relationship Maintenance Scale in Young Couples: Validity Evidence and Reliability of a Short Scale in Peru.

Relationship maintenance has shifted from understudied to extensively researched in the past two decades due to its close association with satisfaction. This study aimed to validate the Relationship Maintenance Scale (EMP) in a sample of young adults in Lima. The sample included 899 participants aged 18-25 (Mean = 20.67, SD = 2.54); 690 females (76.80%) and 209 males (23.20%), all in relationships of at least three months (Mean = 22.05, SD = 19.95). Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were used to determine the EMP's structure, with Omega coefficient (ω) estimating reliability. Results indicated a four-factor structure for EMP, removing items 8, 9, 12, and 14, demonstrating good fit (SRMR = .043; CFI = .977; TLI = .971; RMSEA = .058). EMP showed acceptable reliability across factors: Companionship (ω = .78), Affectivity (ω = .83), Complementarity (ω = .77), and Shared interaction (ω = .70), with the latter being less stable. EMP correlated as expected with relationship satisfaction (r ≥ .50). In conclusion, EMP is a valid and reliable instrument for future Spanish studies, with further research on psychometric properties recommended.

The Power of Puppetry as an Arts-Based Tool for Health and Disability Communication Research.

In this article, we argue that using puppetry as a tool for arts-based research can enhance existing health and disability communication scholarship. We position interdisciplinary puppetry research alongside concepts and theories of interest to communication scholars, including entertainment education, embodiment and performance, communicated narrative sense-making, and dialogue. Then, we share an illustrative case study from our research with the nonprofit organization, MicheLee Puppets. Drawing from interviews with five puppeteers, we describe how the Live Puppet Chat program created unexpected opportunities to connect with neurodiverse spectators during the COVID-19 pandemic. Our "crystalized" narrative and thematic analysis demonstrates how puppeteers used puppet-objects to facilitate dialogue with chat participants. This involved (a) suspending disbelief, (b) suspending judgment, (c) communicating through the lens of (neurodiverse) empowerment, and (c) improvising for empowerment.

New Psychometric Evidence of the Grief Impairment Scale (GIS) in People Who Have Experienced the Death of a Loved One From a Network Psychometric Approach in Two Latin American Countries.

This study aimed to evaluate the psychometric properties of the Grief Impairment Scale (GIS) using a network psychometric model. A total of 1048 individuals from Peru and El Salvador participated. A network psychometric model was used to determine internal structure, reliability, and cross-country invariance. The results indicate that the GIS items were grouped into a single network structure through Exploratory Graph Analysis. Reliability was estimated by structural consistency, and it was found that when replicating the network structure within an empirical dimension, a single network structure was consistently obtained, and all items remained stable. Furthermore, the network structure was invariant, thus functioning similarly across the different country groups. In conclusion, the GIS presented solid psychometric evidence of validity based on its internal structure, reliability, and cross-country invariance. Therefore, the GIS is a psychometrically sound measure of functional impairment symptoms due to grief for Peruvian and Salvadoran individuals.

Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism.

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential "hypo-priors" theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

Enhanced meristem development, tolerance to oxidative stress and hyposensitivity to nitric oxide in the hypermorphic vq10-H mutant in AtVQ10 gene.

Nitric oxide (NO) and reactive oxygen are common factors in multiple plant responses to stress, and their involvement in hypoxia-triggered responses is key to ensure growth under adverse environmental conditions. Here, we analyse the regulatory functions exerted by hypoxia-, NO- and oxidative stress-inducible Arabidopsis gene coding for the VQ motif-containing protein 10 (VQ10). A hypermorphic vq10-H mutant allowed identifying VQ10-exerted regulation on root and shoot development as well as its role in regulating responses to NO and oxidative stress. Enhanced VQ10 expression in vq10-H plants led to enhanced elongation of the primary root, and increased root cell division and meristem size during early postgermination development. In shoots, VQ10 activation of cell division was counteracted by WRKY33-exerted repression, thus leading to a dwarf bushy phenotype in plants with enhanced VQ10 expression in a wrky33 knock-out background. Low number of differentially expressed genes were identified when vq10-H versus Col-0 plants were compared either under normoxia or hypoxia. vq10-H and VQ10ox plants displayed less tolerance to submergence but, in turn, were more tolerant to oxidative stress and less sensitive to NO than wild-type plants. VQ10 could be a node integrating redox-related regulation on development and stress responses.

Temporal trends and outcomes of heart transplantation in Spain (2002-2021): propensity score matching analysis to compare patients with and without type 2 diabetes.

BACKGROUND: The impact of Type 2 Diabetes (T2D) on the outcomes of heart transplantation (HT) has not yet been clearly established. The objectives of this study were to examine the trends in the prevalence of T2D among individuals who underwent a HT in Spain from 2002 to 2021, and to compare the clinical characteristics and hospitalization outcomes between HT recipients with and without T2D. METHODS: We used the national hospital discharge database to select HT recipients aged 35 and older. The International Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10) were used to identify patients with and without T2D. We also recorded comorbidities, complications of HT, and procedures. Propensity score matching (PSM) and Cox regression were used to analyze the effect of T2D on in-hospital mortality (IHM). RESULTS: Between 2002 and 2021, a total of 4429 HTs (T2D, 19.14%) were performed in Spain. The number of HTs in patients with T2D decreased from 2002 to 2005 (n = 171) to 2014-2017 (n = 154), then rose during 2018-2021 (n = 186). Complications of HT increased in patients with and without T2D over the study period (26.9% and 31.31% in 2002-2005 vs. 42.47% and 45.01% in 2018-2021, respectively). The results of the PSM showed that pneumonia and Gram-negative bacterial infections were less frequent in patients with T2D and that these patients less frequently required hemodialysis, extracorporeal membrane oxygenation (ECMO), and tracheostomy. They also had a shorter hospital stay and lower IHM than patients without diabetes. The variables associated with IHM in patients with T2D were hemodialysis and ECMO. IHM decreased over time in people with and without T2D. The Cox regression analysis showed that T2D was associated with lower IHM (HR 0.77; 95% CI 0.63-0.98). CONCLUSIONS: The number of HTs increased in the period 2018-2021 compared with 2002-2005 in patients with and without T2D. Over time, complications of HT increased in both groups studied, whereas IHM decreased. The presence of T2D is associated with lower IHM.

Reactive oxygen species- and nitric oxide-dependent regulation of ion and metal homeostasis in plants.

Deterioration and impoverishment of soil, caused by environmental pollution and climate change, result in reduced crop productivity. To adapt to hostile soils, plants have developed a complex network of factors involved in stress sensing, signal transduction, and adaptive responses. The chemical properties of reactive oxygen species (ROS) and reactive nitrogen species (RNS) allow them to participate in integrating the perception of external signals by fine-tuning protein redox regulation and signal transduction, triggering specific gene expression. Here, we update and summarize progress in understanding the mechanistic basis of ROS and RNS production at the subcellular level in plants and their role in the regulation of ion channels/transporters at both transcriptional and post-translational levels. We have also carried out an in silico analysis of different redox-dependent modifications of ion channels/transporters and identified cysteine and tyrosine targets of nitric oxide in metal transporters. Further, we summarize possible ROS- and RNS-dependent sensors involved in metal stress sensing, such as kinases and phosphatases, as well as some ROS/RNS-regulated transcription factors that could be involved in metal homeostasis. Understanding ROS- and RNS-dependent signaling events is crucial to designing new strategies to fortify crops and improve plant tolerance of nutritional imbalance and metal toxicity.

Will ChatGPT3 Substitute for us as Clozapine Experts?

BACKGROUND: ChatGPT3 is a new artificial intelligence program released on February 13, 2023. METHOD: The authors tested ChatGPT3 on February 18, 2023, and repeated the test a week later. They used their expertise on the effects of ethnic ancestry in the stratification of clozapine dosing and the new idea that they published in March 2022 that African-Americans need higher clozapine doses because they have higher clozapine clearance. RESULTS: In the first interaction on February 18, ChatGPT3 provided reasonable and very up-to-date information, which included a comment that patients of African ancestry have higher clozapine metabolism. The other 4 interactions became progressively more concerning as we asked ChatGPT3 to provide references to justify the latter statement. ChatGPT3 provided non-existent "references" using articles from real journals, with real authors, false PubMed identifiers, and false titles. Moreover, ChatGPT3 said that the first author wrote in 2003 that African-Americans had higher CYP1A2 activity when that did not happen until 2022. One week later, the second author repeated the same set of questions. This time ChatGPT3 described the opposite, that African-Americans have "lower" CYP1A2 activity and "slower" metabolism. ChatGPT3 provided another set of articles to justify the information; some were real but did not comment on clozapine metabolism in African-Americans while others did not exist. CONCLUSIONS: ChatGPT3 provided a mixture of truth, twisted reality, and non-existent "facts." Within one week it defended opposite positions regarding a clinically relevant issue such as using higher or lower clozapine doses in African-Americans.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Relationship Satisfaction in Young Couples: Evidence for Validity of Short Scale Combining CFA and IRT.

This study aimed to validate a short relationship satisfaction scale (RAS) in a sample of young people and adults in the Lima metropolitan area. There were a total of 806 participants aged between 18 and 30 years: 622 females (77.20%) and 184 males (22.80%). Every participant was currently in a love relationship of a minimum of three months. The methodologies of Confirmatory Factor Analysis (CFA) and Item Response Theory (IRT) were combined to determine the structure and assess the reliability of the instrument. The Omega coefficient (ω) was used from CFA, while the test information function and empirical reliability (rxx) were used from IRT. The results showed that the RAS could be interpreted as a one-dimensional scale when eliminating the items 4-7 and joining the items 1-2. This model shows high goodness of fit from a CFA-perspective. A similar situation occurs in IRT, except that error covariance is not considered. Nevertheless, assuming the elimination of items 4-7 is still a good option. The reliability in both CFA (ω = .838) and IRT (rxx = .862) was satisfactory. The evidence of relationship with other variable showed inverse and big relationship with violent spells of tension and difficulty.

Brief report: Revealing the nuance: Examining approaches for research with adolescents who identify with multiple racial/ethnic groups.

INTRODUCTION: Increasing racial/ethnic diversity in the United States calls for methodological approaches that capture participants who identify with multiple racial/ethnic groups. Existing approaches are oriented toward large samples (N > 500); yet, we do not know how effective these approaches are with more common smaller convenience samples. We explored how several approaches were associated with the sample distribution of racial/ethnic groups and ethnic identity using a small convenience sample. METHODS: In 2017, 320 U.S. adolescents (Mage = 16.04 years, SDage = 1.33; 59% female) responded to an open-ended question regarding their racial/ethnic group(s) in a cross-sectional survey. Seventy-five (23%) adolescents identified with multiple racial/ethnic groups. Remaining adolescents identified solely with the Asian/Hawaiian Native/Pacific Islander (19%), Black/African American (3%), European American (21%), Latinx (34%), or Native American/Alaska Native (<1%) group. RESULTS: Three approaches for adolescents with multiple racial/ethnic groups were employed. Findings indicated that the sample distributions differed across the approaches. The greatest differences were shown for Black/African American, Native American/Alaska Native, and Other Race/Ethnicity groups. Descriptively, ethnic identity also differed across the approaches. For example, multiracial/ethnic adolescents reported greater ethnic identity-exploration than their European American counterparts in one approach than in others. CONCLUSIONS: Researchers should carefully consider approaches to research with adolescents who identify with multiple racial/ethnic groups given implications for the literature. This study demonstrates the critical need to further develop approaches for capturing the complexity of race/ethnicity.

Strong versus weak embodiment: Spatial iconicity in physical, abstract, and social semantic categories.

BACKGROUND: Perceptual and action systems seem to be related to complex cognitive processes, but the scope of grounded or embodied cognition has been questioned. Zwaan and Yaxley (2003) proposed that cognitive processes of making semantic relatedness judgments can be facilitated when word pairs are presented in ways that their referents maintain their iconic configuration rather than their reverse-iconic configuration (the spatial iconicity effect). This effect has been observed in different semantic categories using specific experiments, but it is known that embodiment is highly dependent on task demands. METHOD: The present study analyzed the spatial iconicity effect in three semantic categories (physical, abstract, and social) using the same experimental criteria to determine the scope of embodied cognition. In this reaction-time experiment, 75 participants judged the semantic relatedness of 384 word pairs whose experimental items were presented in their iconic or reverse-iconic configurations. RESULTS: Two mixed-effects models with crossed random effects revealed that the interaction between word meaning and spatial position was present only for physical concepts but neither for abstract nor social concepts. CONCLUSIONS: Within the framework of strong and weak embodiment theories, the data support weak embodiment theory as the most explicative one.

NIN-like protein7 and PROTEOLYSIS6 functional interaction enhances tolerance to sucrose, ABA, and submergence.

Nitrate (NO3) assimilation and signaling regulate plant growth through the relevant function of the transcription factor NIN-like Protein7 (NLP7). NO3 is also the main source for plants to produce nitric oxide (NO), which regulates growth and stress responses. NO-mediated regulation requires efficient sensing via the PROTEOLYSIS6 (PRT6)-mediated proteasome-triggered degradation of group VII of ethylene response transcription factors through the Cys/Arg N-degron pathway. The convergence of NO3 signaling and N-degron proteolysis on NO-mediated regulation remains largely unknown. Here, we investigated the functional interaction between NLP7 and PRT6 using Arabidopsis (Arabidopsis thaliana) double prt6 nlp7 mutant plants as well as complementation lines overexpressing NLP7 in different mutant genetic backgrounds. prt6 nlp7 mutant plants displayed several potentiated prt6 characteristic phenotypes, including slower vegetative growth, increased NO content, and diminished tolerance to abiotic stresses such as high-sucrose concentration, abscisic acid, and hypoxia-reoxygenation. Although NLP7 has an N-terminus that could be targeted by the N-degron proteolytic pathway, it was not a PRT6 substrate. The potential PRT6- and NO-regulated nucleocytoplasmic translocation of NLP7, which is likely modulated by posttranslational modifications, is proposed to act as a regulatory loop to control NO homeostasis and action.

Insights into ROS-dependent signalling underlying transcriptomic plant responses to the herbicide 2,4-D.

The synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) functions as an agronomic weed control herbicide. High concentrations of 2,4-D induce plant growth defects, particularly leaf epinasty and stem curvature. Although the 2,4-D triggered reactive oxygen species (ROS) production, little is known about its signalling. In this study, by using a null mutant in peroxisomal acyl CoA oxidase 1 (acx1-2), we identified acyl-coenzyme A oxidase 1 (ACX1) as one of the main sources of ROS production and, in part, also causing the epinastic phenotype following 2,4-D application. Transcriptomic analyses of wild type (WT) plants after treatment with 2,4-D revealed a ROS-related peroxisomal footprint in early plant responses, while other organelles, such as mitochondria and chloroplasts, are involved in later responses. Interestingly, a group of 2,4-D-responsive ACX1-dependent transcripts previously associated with epinasty is related to auxin biosynthesis, metabolism, and signalling. We found that the auxin receptor auxin signalling F-box 3 (AFB3), a component of Skp, Cullin, F-box containing complex (SCF) (ASK-cullin-F-box) E3 ubiquitin ligase complexes, which mediates auxin/indole acetic acid (AUX/IAA) degradation by the 26S proteasome, acts downstream of ACX1 and is involved in the epinastic phenotype induced by 2,4-D. We also found that protein degradation associated with ubiquitin E3-RING and E3-SCF-FBOX in ACX1-dependent signalling in plant responses to 2,4-D is significantly regulated over longer treatment periods.

Sex-related disparities in the incidence and outcomes of infective endocarditis according to type 2 diabetes mellitus status in Spain, 2016-2020.

BACKGROUND: We performed a study to assess sex-differences in incidence (2016-2020), clinical characteristics, use of therapeutic procedures, and in-hospital outcomes in patients with infective endocarditis (IE) according to T2DM status. METHODS: Ours was a retrospective cohort study using data from the Spanish National Hospital Discharge Database. We estimated the incidence of hospitalizations for IE in men and women aged ≥ 40 years with and without T2DM. Propensity score matching (PSM) and multivariable logistic regression were used to compare subgroups according to sex and the presence of T2DM. RESULTS: From 2016 to 2020, IE was coded in 9,958 patients (66.79% men). T2DM was diagnosed in 2,668 (26.79%). The incidence of IE increased significantly from 15.29 cases per 100,000 persons with T2DM in 2016 to 17.69 in 2020 (p < 0.001). However, this increment was significant only among men with T2DM (19.47 cases per 100,000 in 2016 vs. 22.84 in 2020; p = 0.003). The age-adjusted incidence of IE was significantly higher in people with T2DM (both sexes) than in those without T2DM (IRR, 2.86; 95% CI, 2.74-2.99). The incidence of IE was higher in men with T2DM than in women with T2DM (adjusted IRR, 1.85; 95% CI, 1.54-3.31). After PSM, in-hospital mortality (IHM) was higher among T2DM women than matched T2DM men (22.65% vs. 18.0%; p = 0.018). The presence of T2DM was not associated with IHM in men or women. CONCLUSIONS: T2DM is associated with a higher incidence of hospitalization for IE. Findings for T2DM patients who had experienced IE differed by sex, with higher incidence rates and lower IHM in men than in women. T2DM was not associated to IHM in IE in men or in women.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.