Sex matters: Differences in prodromes, clinical and neuropsychological features in individuals with a first episode mania or psychosis.

OBJECTIVE: This study was aimed at identifying sex differences in patients presenting a first episode mania (FEM) or psychosis (FEP) to help shaping early treatment strategies focused on sex differences. METHODS: Patients with a FEM or FEP underwent a clinical, neuropsychological (neurocognitive functions and emotional intelligence) and functional assessment. Performance on those variables was compared between groups through general linear model, with sex and group (FEM vs FEP) as main effects and group by sex interactions. RESULTS: The total sample included 113 patients: FEM = 72 (45.83 % females) and FEP = 41 (46.34 % females). There were significant main effects for group (not for sex) for most of the clinical features (depressive, negative and positive symptoms) and psychosocial functioning (χ2 = 8.815, p = 0.003). As for neuropsychological performance, there were significant main effects for sex and group. Females performed better than males in verbal memory (χ2 = 9.038, p = 0.003) and obtained a higher emotional intelligence quotient (χ2 = 13.20, p < 0.001). On the contrary, males obtained better results in working memory (χ2 = 7.627, p = 0.006). FEP patients significantly underperformed FEM patients in most cognitive domains. There were significant group by sex interactions for few neuropsychological variables, namely processing speed (χ2 = 4.559, p = 0.033) and verbal fluency (χ2 = 8.913, p = 0.003). LIMITATIONS: Differences between sexes were evaluated, but the influence of gender was not considered. Retrospective evaluation of prodromes and substance use. No healthy control group comparator. CONCLUSION: The main finding is the presence of significant sex effect and group by sex interaction on specific neurocognitive cognition and emotional intelligence measures. Tailored sex-based early treatment strategies might be implemented.

The impact of sex in the effectiveness of functional remediation in bipolar disorder.

BACKGROUND: Functional recovery remains a core clinical objective for patients with bipolar disorder (BD). Sociodemographic, clinical, and neurocognitive variables are associated with long-term functional impairment, yet the impact of sex differences is unclear. Functional remediation (FR) is a validated intervention aimed at achieving functional recovery in BD. The present study assessed the effect of sex differences of FR on psychosocial functioning at post-treatment (6-months) and 12-month follow-up (FUP). To the best of our knowledge, this is the first study to explore the role of sex as a factor in the efficacy of FR. METHODS: 157 participants with BD were randomly assigned to either FR (N = 77) or treatment as usual group (80). Clinical, sociodemographic, neuropsychological, and functional data were obtained using a comprehensive assessment battery. Sex differences were explored via a general linear model (GLM) for repeated measures to compare the effect of sex on the intervention over time (6 months and FUP). RESULTS: Results demonstrated that FR benefits both sexes, males (p = 0.001; d' = 0.88) and females (p = 0.04; d' = 0.57), at 6 months suggesting a generalized functional improvement. Conversely, at 12-month FUP sex differences were observed only in males (p = 0.005; d' = 0.68). CONCLUSIONS: FR is a beneficial intervention for males and females after treatment, suggesting that there are no relevant distinct needs. Females may benefit from ongoing psychosocial functioning booster sessions after the intervention to maintain original improvements. Future research exploring sex differences could help to identify strategies to offer personalized FR intervention approaches in individuals with BD.

Diagnostic potential of combining plasma biomarkers of tissue damage and inflammation in pediatric TB.

INTRODUCTION: Immune-based diagnostic tests for tuberculosis (TB) have suboptimal sensitivity in children and cannot differentiate between latent infection (LTBI) and active disease. This study evaluated the diagnostic potential of a broad range of biomarkers of tissue damage and inflammation in unstimulated plasma in children. METHODS: We analyzed 17 biomarkers in 15 non-M. tuberculosis (MTB)-infected controls and 33 children with TB infection (LTBI, n = 8; probable TB, n = 19; confirmed TB, n = 6). Biomarker concentrations were measured using a Luminex magnetic bead-based platform and multiplex sandwich immunoassays. Concentrations, correlations and diagnostic accuracy assessments were conducted among patient groups. RESULTS: Confirmed TB cases had significantly higher concentrations of IFN-γ and IL-2 and higher IFN-γ/MCP-1 and IL-2/MCP-1 ratios compared to LTBI and non-MTB-infected children. Among children with confirmed TB, there was a strong correlation between IFN-γ and IL-10 (r = 0.95; p < 0.001) and a significant correlation between IL-2 and IL-1ra (r = 0.92), IL-21 (r = 0.91), MCP-3 (r = 0.84), and MMP-1 (r = 0.85). The IFN-γ/MCP-1 ratio was the most accurate biomarker combination for differentiating between MTB-infected and non-MTB-infected children (AUC, 0.82; sensitivity, 87.9%; specificity, 66.6%; p < 0.001) and between active TB and non-MTB-infected children (AUC 0.82; sensitivity 88.0%; specificity 60.0%; p < 0.001). None of the biomarkers investigated were able to discriminate between LTBI and active TB. CONCLUSION: Our data suggest that combining the analyses of multiple biomarkers in plasma has the potential to enhance diagnosis of TB in children and, thus, warrants additional investigation. In particular, the diagnostic potential of IFN-γ/MCP-1 ratios should be further explored in larger pediatric cohorts.

Estimation of the difference between peritoneal microenvironment and core body temperature during laparoscopic surgery - a prospective observational study.

Maintaining patients' temperature during surgery is beneficial since hypothermia has been linked with perioperative complications. Laparoscopic surgery involves the insufflation of carbon dioxide (CO2) into the peritoneal cavity and has become the standard in many surgical indications since it is associated with better and faster recovery. However, the use of cold and dry CO2 insufflation can lead to perioperative hypothermia. We aimed to assess the difference between intraperitoneal and core temperatures during laparoscopic surgery and evaluate the influence of duration and CO2 insufflation volume by fitting a mixed generalized additive model. In this prospective observational single-center cohort trial, we included patients aged over 17 with American Society of Anesthesiology risk scores I to III undergoing laparoscopic surgery. Anesthesia, ventilation, and analgesia followed standard protocols, while patients received active warming using blankets and warmed fluids. Temperature data, CO2 ventilation parameters, and intraabdominal pressure were collected. We recruited 51 patients. The core temperature was maintained above 36 °C and progressively raised toward 37 °C as pneumoperitoneum time passed. In contrast, the intraperitoneal temperature decreased, thus creating a widening difference from 0.4 [25th-75th percentile: 0.2-0.8] °C at the beginning to 2.3 [2.1-2.3] °C after 240 min. Pneumoperitoneum duration and CO2 insufflation volume significantly increased this temperature difference (P < 0.001 for both parameters). Core vs. intraperitoneal temperature difference increased linearly by 0.01 T °C per minute of pneumoperitoneum time up to 120 min and then 0.05 T °C per minute. Each insufflated liter per unit of time, i.e. every 10 min, increased the temperature difference by approximately 0.009 T °C. Our findings highlight the impact of pneumoperitoneum duration and CO2 insufflation volume on the difference between core and intraperitoneal temperatures. Implementing adequate external warming during laparoscopic surgery effectively maintains core temperature despite the use of dry and unwarmed CO2 gases, but peritoneal hypothermia remains a concern, suggesting the importance of further research into regional effects.Trial registration: Clinicaltrials.gov: NCT04294758.

Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

Safety of long-term esophageal stent use for multiple indications.

Background: Long-term (>30 days) esophageal stenting is controversial. Previous studies have documented complications associated with long-term esophageal stent use. This study's objective was to investigate complications associated with long-term esophageal stent use. Methods: A retrospective review of stenting done by thoracic surgery for any reason between 2010-2020 was completed. Patients were included if they had at least 30 days of follow-up after their initial stent placement. Outcomes included stent dwell time, patient outcomes, procedural and stent-related complications. Results: Fifty-six patients, with 25 having ≥2 stents placed were included; overall, 90 stents were placed. The median length of initial esophageal stent dwell time was 59 [interquartile range (IQR), 21-119] days. Stent migration was the most common complication and occurred more with benign indications (P=0.12). As the length of dwell time increased, prevalence of any complication decreased. Complication rates between short-term (<30 days) and long-term stents were not significantly different (P=0.39). No instances of esophageal perforation or aortoesophageal fistulas related to stents were identified. There was one instance of post-esophagectomy tracheoesophageal fistula which was managed successfully with prolonged stenting. Conclusions: Over a 10-year period, there were no instances of stent erosion into the aorta or esophageal perforation, and the most frequent stent-related complication was stent migration. Long-term esophageal stenting did not result in increased rates of stent related complications in our cohort. This case series demonstrates that long-term stents may be safely used for many different indications. Randomized controlled studies may be needed to validate these findings.

Improving accessibility to radiotherapy services in Cali, Colombia: cross-sectional equity analyses using open data and big data travel times from 2020.

In this study, we evaluated and forecasted the cumulative opportunities for residents to access radiotherapy services in Cali, Colombia, while accounting for traffic congestion, using a new people-centred methodology with an equity focus. Furthermore, we identified 1-2 optimal locations where new services would maximise accessibility. We utilised open data and publicly available big data. Cali is one of South America's cities most impacted by traffic congestion. METHODOLOGY: Using a people-centred approach, we tested a web-based digital platform developed through an iterative participatory design. The platform integrates open data, including the location of radiotherapy services, the disaggregated sociodemographic microdata for the population and places of residence, and big data for travel times from Google Distance Matrix API. We used genetic algorithms to identify optimal locations for new services. We predicted accessibility cumulative opportunities (ACO) for traffic ranging from peak congestion to free-flow conditions with hourly assessments for 6-12 July 2020 and 23-29 November 2020. The interactive digital platform is openly available. PRIMARY AND SECONDARY OUTCOMES: We present descriptive statistics and population distribution heatmaps based on 20-min accessibility cumulative opportunities (ACO) isochrones for car journeys. There is no set national or international standard for these travel time thresholds. Most key informants found the 20-min threshold reasonable. These isochrones connect the population-weighted centroid of the traffic analysis zone at the place of residence to the corresponding zone of the radiotherapy service with the shortest travel time under varying traffic conditions ranging from free-flow to peak-traffic congestion levels. Additionally, we conducted a time-series bivariate analysis to assess geographical accessibility based on economic stratum. We identify 1-2 optimal locations where new services would maximize the 20-min ACO during peak-traffic congestion. RESULTS: Traffic congestion significantly diminished accessibility to radiotherapy services, particularly affecting vulnerable populations. For instance, urban 20-min ACO by car dropped from 91% of Cali's urban population within a 20-min journey to the service during free-flow traffic to 31% during peak traffic for the week of 6-12 July 2020. Percentages represent the population within a 20-min journey by car from their residence to a radiotherapy service. Specific ethnic groups, individuals with lower educational attainment, and residents on the outskirts of Cali experienced disproportionate effects, with accessibility decreasing to 11% during peak traffic compared to 81% during free-flow traffic for low-income households. We predict that strategically adding sufficient services in 1-2 locations in eastern Cali would notably enhance accessibility and reduce inequities. The recommended locations for new services remained consistent in both of our measurements.These findings underscore the significance of prioritising equity and comprehensive care in healthcare accessibility. They also offer a practical approach to optimising service locations to mitigate disparities. Expanding this approach to encompass other transportation modes, services, and cities, or updating measurements, is feasible and affordable. The new approach and data are particularly relevant for planning authorities and urban development actors.

Natural Occurring Terpene Cyclic Anhydrides: Biosynthetic Origin and Biological Activities.

Cyclic acid anhydride is a not very widespread structure in nature, but with a determining role in natural products possessing this functionality in their skeleton. To the best of our knowledge, no revision of terpenes containing cyclic anhydrides has been previously reported. The result was that more than 100 terpenic cyclic anhydrides and related compounds were found to be in need of being reported. This review has been systematically organized by terpene skeletons, from the smallest to largest, describing their sources and bioactivities. In addition, different biosynthetic pathways for their final oxidations, namely, routes A, B and C, leading to the formation of these heterocyclic natural products, have been proposed. We have also included the most plausible precursors of these natural products, which mostly happened to be present in the same natural source. Some molecules derived from terpene cyclic anhydrides, such as their natural imide derivatives, have also been described due to their significant biological activity. In this sense, special attention has been paid to cantharidin because of its historical relevance and its broad bioactivity. A plausible biosynthesis of cantharidin has been proposed for the first time. Finally, cyclic anhydride structures that were firstly assigned as anhydrides and later corrected have been also described.

Prolonged exposure to the synthetic glucocorticoid dexamethasone induces brain damage via oxidative stress and apoptotic response in adult Daniorerio.

Due to its extensive use as a painkiller, anti-inflammatory, and immune modulatory agent, as well as its effectiveness in treating severe COVID-19, dexamethasone, a synthetic glucocorticoid, has gained attention not only for its impact on public health but also for its environmental implications. Various studies have reported its presence in aquatic environments, including urban waters, surface samples, sediments, drinking water, and wastewater effluents. However, limited information is available regarding its toxic effects on nontarget aquatic organisms. Therefore, this study aimed to investigate the mechanism of toxicity underlying dexamethasone-induced brain damage in the bioindicator Danio rerio following long-term exposure. Adult zebrafish were treated with environmentally relevant concentrations of dexamethasone (20, 40, and 60 ng L-1) for 28 days. To elucidate the possible mechanisms involved in the toxicity of the pharmaceutical compound, we conducted a behavioral test battery (Novel Tank and Light and Dark tests), oxidative stress biomarkers, acetylcholinesterase enzyme activity quantification, histopathological analysis, and gene expression analysis using qRT-PCR (p53, bcl-2, bax, caspase-3, nrf1, and nrf2).The results revealed that the pharmaceutical compound could produce anxiety-like symptoms, increase the oxidative-induced stress response, decrease the activity of acetylcholinesterase enzyme, and cause histopathological alterations, including perineuronal vacuolization, granular and molecular layers deterioration, cell swallowing and intracellular spaces. The expression of genes involved in the apoptotic process (p53, bax, and casp-3) and antioxidant defense (nrf1 and nrf2) was upregulated in response to oxidative damage, while the expression of the anti-apoptotic gene bcl-2 was down-regulated indicating that the environmental presence of dexamethasone may pose a threat to wildlife and human health.

Emotional intelligence and neurocognition profiles in first-episode psychosis: A two-year follow-up study.

Emotional intelligence (EI) and neurocognition (NC) impairments are common in first-episode psychosis (FEP), yet their evolution over time remains unclear. This study identified patient profiles in EI and NC performance in FEP. 98 adult FEP patients and 128 healthy controls (HCs) were tested on clinical, functional, EI, and NC variables at baseline and two-year follow-up (FUP). A repeated-measures ANOVA compared the effects of group (patients and HCs) and time on EI. Significant EI improvements were observed in both groups. Four groups were created based on NC and EI performance at baseline and FUP in patients: impairment in NC and EI, impairment in NC only, impairment in EI only, and no impairment. At FUP, patients impaired in NC and EI showed less cognitive reserve (CR), greater negative and positive symptoms, and poorer functional outcomes. At FUP, three group trajectories were identified: (I) maintain dual impairment (II) maintain no impairment or improve, (III) maintain sole impairment or worsen. The maintain dual impairment group had the lowest levels of CR. EI and NC impairments progress differently in FEP. Greater CR may protect against comorbid EI/NC impairment. Identifying these patient characteristics could contribute to the development of personalised interventions.

TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by a number of variables, including endoplasmic reticulum stress (ER). Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade.

Effect of lung volume preservation during spontaneous breathing trial on successful extubation in patients receiving mechanical ventilation: protocol for a multicenter clinical trial.

BACKGROUND: In standard weaning from mechanical ventilation, a successful spontaneous breathing test (SBT) consisting of 30 min 8 cmH2O pressure-support ventilation (PSV8) without positive end-expiratory pressure (PEEP) is followed by extubation with continuous suctioning; however, these practices might promote derecruitment. Evidence supports the feasibility and safety of extubation without suctioning. Ultrasound can assess lung aeration and respiratory muscles. We hypothesize that weaning aiming to preserve lung volume can yield higher rates of successful extubation. METHODS: This multicenter superiority trial will randomly assign eligible patients to receive either standard weaning [SBT: 30-min PSV8 without PEEP followed by extubation with continuous suctioning] or lung-volume-preservation weaning [SBT: 30-min PSV8 + 5 cmH2O PEEP followed by extubation with positive pressure without suctioning]. We will compare the rates of successful extubation and reintubation, ICU and hospital stays, and ultrasound measurements of the volume of aerated lung (modified lung ultrasound score), diaphragm and intercostal muscle thickness, and thickening fraction before and after successful or failed SBT. Patients will be followed for 90 days after randomization. DISCUSSION: We aim to recruit a large sample of representative patients (N = 1600). Our study cannot elucidate the specific effects of PEEP during SBT and of positive pressure during extubation; the results will show the joint effects derived from the synergy of these two factors. Although universal ultrasound monitoring of lungs, diaphragm, and intercostal muscles throughout weaning is unfeasible, if derecruitment is a major cause of weaning failure, ultrasound may help clinicians decide about extubation in high-risk and borderline patients. TRIAL REGISTRATION: The Research Ethics Committee (CEIm) of the Fundació Unió Catalana d'Hospitals approved the study (CEI 22/67 and 23/26). Registered at ClinicalTrials.gov in August 2023. Identifier: NCT05526053.

Immunoneuroendocrine, Stress, Metabolic, and Behavioural Responses in High-Fat Diet-Induced Obesity.

Obesity has reached global epidemic proportions, and even though its effects are well-documented, studying the interactions among all influencing factors is crucial for a better understanding of its physiopathology. In a high-fat-diet-induced obesity animal model using C57BL/6J mice, behavioural responses were assessed through a battery of tests, while stress biomarkers and systemic inflammatory cytokines were measured using an Enzyme-Linked ImmunoSorbent Assay and a Bio-Plex Multiplex System. The peritoneal macrophage microbicide capacity was analysed via flow cytometry, and crown-like structures (CLSs) in white adipose tissue (WAT) were evaluated through staining techniques. Results indicated that obese mice exhibited increased body weight, hyperglycaemia, and hyperlipidaemia after 18 weeks on a high-fat diet, as well as worse physical conditions, poorer coordination and balance, and anxiety-like behaviour. Differences in corticosterone and noradrenaline concentrations were also found in obese animals, revealing a stress response and noradrenergic dysregulation, along with a weakened innate immune response characterized by a lower microbicide capacity, and the presence of an underlying inflammation evidenced by more CLSs in WAT. Altogether, these findings indicate that obesity deteriorates the entire stress, inflammatory, metabolic, sensorimotor and anxiety-like behavioural axis. This demonstrates that jointly evaluating all these aspects allows for a deeper and better exploration of this disease and its associated comorbidities, emphasizing the need for individualized and context-specific strategies for its management.

Evaluation of a Lung Ultrasound Score in Hospitalized Adult Patients with COVID-19 in Barcelona, Spain.

Background/Objectives: During the COVID-19 pandemic and the burden on hospital resources, the rapid categorization of high-risk COVID-19 patients became essential, and lung ultrasound (LUS) emerged as an alternative to chest computed tomography, offering speed, non-ionizing, repeatable, and bedside assessments. Various LUS score systems have been used, yet there is no consensus on an optimal severity cut-off. We assessed the performance of a 12-zone LUS score to identify adult COVID-19 patients with severe lung involvement using oxygen saturation (SpO2)/fractional inspired oxygen (FiO2) ratio as a reference standard to define the best cut-off for predicting adverse outcomes. Methods: We conducted a single-centre prospective study (August 2020-April 2021) at Hospital del Mar, Barcelona, Spain. Upon admission to the general ward or intensive care unit (ICU), clinicians performed LUS in adult patients with confirmed COVID-19 pneumonia. Severe lung involvement was defined as a SpO2/FiO2 ratio <315. The LUS score ranged from 0 to 36 based on the aeration patterns. Results: 248 patients were included. The admission LUS score showed moderate performance in identifying a SpO2/FiO2 ratio <315 (area under the ROC curve: 0.71; 95%CI 0.64-0.77). After adjustment for COVID-19 risk factors, an admission LUS score ≥17 was associated with an increased risk of in-hospital death (OR 5.31; 95%CI: 1.38-20.4), ICU admission (OR 3.50; 95%CI: 1.37-8.94) and need for IMV (OR 3.31; 95%CI: 1.19-9.13). Conclusions: Although the admission LUS score had limited performance in identifying severe lung involvement, a cut-off ≥17 score was associated with an increased risk of adverse outcomes. and could play a role in the rapid categorization of COVID-19 pneumonia patients, anticipating the need for advanced care.

Correction: Del Valle-Moreno et al. Model-Informed Precision Dosing Software Tools for Dosage Regimen Individualization: A Scoping Review. Pharmaceutics 2023, 15, 1859.

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Attitudes, Self-Confidence, and Knowledge of Primary Care Professionals towards School Bullying.

Attitudes, practices, and knowledge about bullying were evaluated in a sample of 274 primary care professionals, including general practitioners, pediatricians, community, pediatric and school nurses, and residents of these specialties. This study was based on a mixed method with a parallel convergent design without dominance between phases, data were collected concurrently, and conversion of the results from both phases was carried out during data interpretation. The quantitative phase had a cross-sectional observational design, using The Healthcare Provider's Practices, Attitudes, Self-confidence, and Knowledge Regarding Bullying Questionnaire as an instrument. Descriptive and bivariate analyses were performed, which showed a positive correlation between higher self-confidence and knowledge scores and a greater predisposition to detect cases. However, although the dimensions of attitudes and knowledge yielded generally high data, low self-confidence was evident in addressing this problem. In addition, a lack of clear guidelines in the workplace was expressed, highlighting the need to create and provide specific resources to intervene in bullying in said context, which could develop an improvement in self-confidence, leading to greater well-being for the educational community regarding bullying.

Gastrointestinal digestion of olive leaf waste from olive mill production chain in a simulator of the gastrointestinal tract.

BACKGROUND: Currently, olive leaves are considered waste, although their high phenolic content makes them a source of antioxidants that could be used directly. The aim of this work was to study the behavior of phenolic compounds contained in olive leaf from the olive mill production chain during their gastrointestinal digestion. RESULTS: Phenolic compounds in the gastric digestion analyzed by high-performance liquid chromatography-diode array detection-mass spectrometry increased by 58% to 314.5% compared to the meal, while in the intestinal stage they ranged from 1.87 to 9.04 times higher. An increase of between 187% and 903% in bioaccessibility of phenolic compounds in the intestinal phase was observed, except for verbascoside. Furthermore, such compounds were fully bioavailable, except for apigenin-7-O-glucoside, which showed a bioavailability of 56%. CONCLUSION: The current study showed that the concentration of oleuropein, apigegin-7-O-glucoside, hydroxytyrosol hexoside and hydroxytyrosol contained in olive leaf continued to be extracted during the gastrointestinal digestion process. Furthermore, the results obtained with respect to their bioaccessibility and bioavailability suggest a good disposition to pass into the bloodstream where they could exert beneficial effects. Therefore, these results are promising for olive leaf becoming a consumable by-product that could be directly ingested through a simple infusion. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Efficacy of clozapine versus standard treatment in adult individuals with intellectual disability and treatment-resistant psychosis (CLOZAID): study protocol of a multicenter randomized clinical trial.

Background: Intellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field. Methods: A Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them. Discussion: The treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials. Trial registration: Clinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37.

Effect of virgin olive oil as spreadable preparation on atherosclerosis compared to dairy butter in Apoe-deficient mice.

Olive oil is the main source of lipid energy in the Mediterranean diet and there is strong evidence of its health benefits. The effect of extra virgin olive oil (EVOO) in the form of a preparation of spreadable virgin olive oil (S-VO) on the progression of atheroma plaques was investigated in Apoe-deficient mice, a model of accelerated atherosclerosis. METHODS: Two isocaloric Western purified diets containing 20% fat, either as S-VO or as dairy butter, were used to feed 28 males and 16 females of two-month-old Apoe-deficient mice for 12 weeks. S-VO was prepared by blending more than 75% virgin olive oil with other vegetal natural fat to obtain a solid fat. Plasma total cholesterol, triglycerides and HDL cholesterol were measured. Hepatic lipid droplets were analyzed. Areas of atherosclerotic aortic lesions were quantified in cross-sectional images of the proximal aorta and en face analysis of the whole aorta. RESULTS: Total plasma cholesterol was increased in mice on the butter-supplemented diet in both female and male mice compared to S-VO, and the ratio of TC/HDL-cholesterol was significantly lower in S-VO than in the butter diet, although only in males, and no differences in plasma triglycerides were observed. No significant differences in hepatic lipid droplets were observed between diets in either sex. Aortic lesion areas were significantly higher in mice consuming the butter versus the S-VO diet in both sexes. CONCLUSION: Extra virgin olive oil prepared in spreadable form maintained the delay in atheroma plaque progression compared to butter.