New Advances in Attention-Deficit/Hyperactivity Disorder-like Dogs.

Similar to humans, dogs could suffer an Attention-Deficit/Hyperactivity Disorder-like syndrome (ADHD-like). In fact, several studies highlight the use of dogs as a model for studying ADHD. This condition entails behavioral problems expressed through impulsivity, attention issues, hyperactivity, and/or aggression, compromising the quality of life for both the caregiver and the dog. The pathophysiology of ADHD-like is complex and is associated with dysregulation of various neurotransmitters such as serotonin and dopamine. The expression of ADHD-like behavior in dogs would appear to depend on a classical gene-environment interaction as is the case with many neurological disorders in humans. In addition to the described symptomatology, ADHD-like dogs can exhibit strong comorbidities with compulsive behaviors, aggressiveness, inappropriate elimination and fearfulness, in addition to epilepsy, foreign body ingestion, and pruritus. In spite of the fact that there is no veterinary consensus about the diagnosis of ADHD-like, some validated questionnaires could be helpful, but these cannot be used as a unique diagnostic tool. The use of drugs, such as fluoxetine, in addition to an adequate environmental enrichment, relaxation protocols, and behavior modification can achieve an adequate quality of life for both the dog and caregivers.

Pilot study of an online brief mindfulness-based intervention to improve the well-being of managers and reduce their stress at work.

Objectives. The COVID-19 pandemic, remote work and new technologies have heightened workplace pressures. Effective response and essential organizational changes require business leaders to be more adaptable, with managers' presence playing a pivotal role in successful implementation. The study assesses a brief mindfulness-based emotional regulation for managers (MBERM) intervention, to reduce workplace stress and enhance managerial well-being. Methods. An 8-week non-randomized controlled trial was conducted with a waiting list control group and an intervention group. Pre-post differences were measured by Student's t test or Wilcoxon test, and effect size calculated using the Hedge's g formula. The sample included 23 managers (17 men and six women) with average age 50 years. The study assessed anxiety and depressive symptoms, psychological flexibility, perceived self-efficacy, general work-related well-being, perceived stress and mindfulness. Results. Statistically significant changes were observed in the intervention group in depression, anxiety, work-related acceptance and action, general self-efficacy, exhaustion, alienation, stress and non-reactivity. The control group showed no statistically significant changes in any of the variables. Conclusion. The MBERM intervention could improve the emotional and work-related well-being of managers and reduce stress levels and burnout. Further study of this intervention is needed to promote adherence and ensure a long-term improvement.

Factors related to mortality in patients with chronic obstructive pulmonary disease in Colombian population / Factores relacionados con la mortalidad en pacientes con enfermedad pulmonar obstructiva crónica en población colombiana

Introduction. Data in low- and middle-income countries on mortality and its related risk factors in patients with chronic obstructive pulmonary disease are limited. Objective. To identify the incidence of death and its relationship with variables in a Colombian population during 12 months of follow-up. Materials and methods. We carried out a retrospective study in subjects diagnosed with chronic obstructive pulmonary disease in a third-level hospital in Colombia. Odds ratios were calculated using multivariable logistic regression analysis with the outcome variable "mortality at 12 months". Results. We included 524 patients, 18.1% (95 / 524) died. The average age was 69.7 (SD = 8.92), and 59.2% (310 / 524) were women. The variables associated with mortality were age (OR = 6.54; 95% CI = 3.65-11.36; p < 0.001), years of exposure to wood smoke (OR = 4.59; 95% CI = 1.64-2.82; p = 0.002), chronic heart failure (OR = 1.81; 95% CI = 1.13-2.91; p = 0.014), cerebrovascular disease (OR = 3.35; 95% CI = 1.04-10.75; p = 0.032), and chronic kidney disease (OR = 6.96; 95% CI = 1.15-41.67; p=0.015). When adjusting the variables in the multivariate analysis, only an association was found for sex (OR = 1.55; 95% CI = 0.95-2.54; p = 0.008) and age (OR = 5.94; 95% CI = 3.3-10.69; p < 0.001). Conclusion. Age, years of exposure to wood smoke, chronic heart failure, and cerebrovascular and chronic kidney disease were the clinical variables associated with a fatal outcome. However, age and sex were the only variables related to mortality when adjusted for confounding factors.

Introducción. En los países de medianos y bajos ingresos, los datos sobre la mortalidad y los factores de riesgo en pacientes con enfermedad pulmonar obstructiva crónica son limitados. Objetivo. Identificar la incidencia de muerte y sus variables relacionadas en una población colombiana durante 12 meses de seguimiento. Materiales y métodos. Se llevó a cabo un estudio retrospectivo de sujetos con diagnóstico de enfermedad pulmonar obstructiva crónica en una clínica de tercer nivel en Colombia. Los cocientes de probabilidades se calcularon mediante un análisis de regresión logística multivariable con la variable de resultado "mortalidad a los 12 meses". Resultados. Ingresaron 524 pacientes, de los cuales el 18,1 % (95 / 524) murió. La edad promedio fue de 69,7 (DE = 8,92) y el 59,2 % (310 / 524) eran mujeres. Las variables asociadas con la mortalidad fueron la edad (OR = 6,54; IC95%: 3,65-11,36; p < 0,001), años de exposición al humo de leña (OR = 4,59; IC95%: 1,64-12,82; p = 0,002), insuficiencia cardiaca crónica (OR = 1,81; IC95%: 1,13-2,91; p = 0,014), enfermedad cerebrovascular (OR = 3,35; IC95%: 1,04-10,75; p = 0,032) y enfermedad renal crónica (OR=6,96; IC 95%:1,15-41,67; p = 0,015). Al ajustar las variables en el análisis multivariado únicamente se mostró asociación entre el sexo (OR = 1,55; IC95%: 0,95-2,54; p = 0,008) y la edad (OR = 5,94; IC95%: 3,3-10,69; p < 0,001). Conclusión. La edad, los años de exposición al humo de leña, la insuficiencia cardiaca crónica, la enfermedad cerebrovascular y la renal crónica fueron variables clínicas asociadas a un desenlace fatal. Sin embargo, la edad y el sexo fueron las únicas relacionadas con la mortalidad al ajustarlas por factores de confusión.

Automated free speech analysis reveals distinct markers of Alzheimer's and frontotemporal dementia.

Dementia can disrupt how people experience and describe events as well as their own role in them. Alzheimer's disease (AD) compromises the processing of entities expressed by nouns, while behavioral variant frontotemporal dementia (bvFTD) entails a depersonalized perspective with increased third-person references. Yet, no study has examined whether these patterns can be captured in connected speech via natural language processing tools. To tackle such gaps, we asked 96 participants (32 AD patients, 32 bvFTD patients, 32 healthy controls) to narrate a typical day of their lives and calculated the proportion of nouns, verbs, and first- or third-person markers (via part-of-speech and morphological tagging). We also extracted objective properties (frequency, phonological neighborhood, length, semantic variability) from each content word. In our main study (with 21 AD patients, 21 bvFTD patients, and 21 healthy controls), we used inferential statistics and machine learning for group-level and subject-level discrimination. The above linguistic features were correlated with patients' scores in tests of general cognitive status and executive functions. We found that, compared with HCs, (i) AD (but not bvFTD) patients produced significantly fewer nouns, (ii) bvFTD (but not AD) patients used significantly more third-person markers, and (iii) both patient groups produced more frequent words. Machine learning analyses showed that these features identified individuals with AD and bvFTD (AUC = 0.71). A generalizability test, with a model trained on the entire main study sample and tested on hold-out samples (11 AD patients, 11 bvFTD patients, 11 healthy controls), showed even better performance, with AUCs of 0.76 and 0.83 for AD and bvFTD, respectively. No linguistic feature was significantly correlated with cognitive test scores in either patient group. These results suggest that specific cognitive traits of each disorder can be captured automatically in connected speech, favoring interpretability for enhanced syndrome characterization, diagnosis, and monitoring.

Examining the source and composition of organic matter through saturated hydrocarbons, δ13C, and δ15N in a subtropical water reservoir.

The sources of organic matter in the sediments of the Passaúna reservoir, an important water supply for the local population, were thoroughly investigated. The objective was to identify the origins of organic matter through the analysis of saturated hydrocarbons, elemental composition (total organic carbon and total nitrogen), and the content of δ13C and δ15N isotopes. This comprehensive approach allowed us to trace the sources of organic matter and discerns indicating heightened primary productivity within the reservoir. To achieve this, two sediment cores spanning a 140-year interval (1880-2020) were retrieved from the reservoir. Core 2 accumulates the majority of sediments, particularly near the dam area. In these parts, sediment deposits can reach up to 1 m above the pre-impoundment soil. Sediments near the area where core 1 was collected contain more sand, resulting in lower thickness compared to core 2. Sediment core 1 primarily reflects terrestrial sources of organic matter, as supported by stable isotope values of δ13C and δ15N. The δ13C values ranged from -23.0 ‰ to -25.7 ‰ in core 1 and from -28.4 ‰ to -29.2 ‰ in core 2. Meanwhile, the δ15N values ranged from 6.6 ‰ to 10.8 ‰ in core 1 and from 3.8 ‰ to 7.6 ‰ in core 2. The distribution of saturated hydrocarbons revealed that organic matter originates from both allochthonous and autochthonous sources. Periods of intense primary productivity were indicated by the presence of n-C16, n-C17, n-C18, and n-C19 alkanes. Additionally, we observed periods characterized by high primary productivity, indicative of elevated nutrient input likely resulting from increased urbanization and industrial activity in the area.

Understanding consumer food choices & promotion of healthy and sustainable Mediterranean diet and lifestyle in children and adolescents through behavioural change actions: the DELICIOUS project.

Over the last decades, the abandonment of traditional dietary patterns, such as the Mediterranean diet, represents an important threat for human health and environmental safeguard. The DELICIOUS project aims to promote healthy lifestyles among children and adolescents by implementing activities and tools to increase the adherence to the Mediterranean Diet with an attention to the environmental impacts of the diet. This study protocol describes the DELICIOUS project as a single-arm, uncontrolled behavioural intervention providing formal and non-formal education activities, development of new snacks and recipe reformulation, web/mobile app development, and physical activities to school children and adolescents in five European countries. The project aims to increase awareness of the nutritional benefits and the sustainability aspects of the Mediterranean Diet and to promote consumers' empowerment through an online platform for sustainable and healthy meal planning in the school canteen.

A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

Secukinumab in patients with moderate-to-severe hidradenitis suppurativa based on prior biologic exposure: an efficacy and safety analysis from the SUNSHINE and SUNRISE phase III trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate-to-severe HS. It is unknown whether prior biologic exposure affects the efficacy and safety of secukinumab. OBJECTIVES: To investigate the efficacy and safety of secukinumab in patients with moderate-to-severe HS based on prior exposure to -biologics. METHODS: This was an analysis of the SUNSHINE and SUNRISE phase III trials of secukinumab in patients with moderate-to-severe HS. Patients were randomized at baseline to receive secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo for 16 weeks. After week 16, patients on the SECQ2W and SECQ4W schedules remained on the same treatment regimen, while patients randomized to placebo were switched to either SECQ2W or SECQ4W up to week 52. Assessments based on prior exposure to biologics included Hidradenitis Suppurativa Clinical Response (HiSCR), abscess and inflammatory nodule (AN) count, flare rates, HS-related pain [numerical rating scale 30 (NRS30)], 55% reduction in the International Hidradenitis Suppurativa Severity Score System (IHS4-55), Dermatology Life Quality Index, EuroQol-5D and safety. RESULTS: Overall, 1084 patients were randomized in the SUNSHINE and SUNRISE trials and included in this analysis; 255 (23.5%) were biologic-experienced [SECQ2W (n = 80); SECQ4W (n = 81); placebo (n = 94)] and 829 (76.5%) were biologic-naïve [SECQ2W (n = 281); SECQ4W (n = 279); placebo (n = 269)]. At week 16, responses were more efficacious for secukinumab than for placebo with regard to HiSCR in patients who were biologic-experienced {SECQ2W 37.0% [odds ratio (OR) 1.60, 95% confidence interval (CI) 0.83-3.08]; SECQ4W 38.8% [OR 1.67, 95% CI 0.86-3.22]; placebo 27.3%} and biologic-naïve [SECQ2W 45.6% (OR 1.64, 95% CI 1.15-2.33); SECQ4W 45.4% (OR 1.61, 95% CI 1.13-2.29); placebo 34.2%]. Similar results were observed for AN count, NRS30 and IHS4-55. The higher response seen at week 16 with secukinumab was sustained, with a trend toward improvement over time, through to week 52 in both subgroups. Additional efficacy was observed for quality-of-life assessments, and no differences in safety between subgroups were observed. CONCLUSIONS: Regardless of prior biologic exposure, secukinumab was efficacious in improving the signs and symptoms of HS. This finding positions secukinumab as the first option in patients who are biologic-naïve, as well as in patients who have previously been treated with other biologic therapy, based on individual patient needs.

Hidradenitis suppurativa (HS) is a chronic skin disease that causes painful boils. HS is common and affects about 0.4% of the world's population. Treating the condition is difficult, but drugs called 'biologics' can help to improve the symptoms. For example, secukinumab is a biologic drug that has been shown to be effective and well-tolerated for the treatment of HS. In this analysis, we investigated whether previous treatment with biologics could affect the effectiveness and tolerability of secukinumab. This analysis included data from two identical clinical trials (called SUNSHINE and SUNRISE) that recruited adult patients with HS who had moderate-to-severe disease. In these trials, patients took secukinumab 300 mg every 2 weeks or every 4 weeks for 1 year, or a placebo for 4 months and then switched to secukinumab until 1 year. At regular intervals, the effectiveness and tolerability of secukinumab were examined and the results were compared between patients who had previously used another biologic and patients who had never used a biologic before. After 16 weeks, patients who took secukinumab had better results than the patients who took a placebo, independent of previous biologic use. Secukinumab was still effective and had improved results over 1 year of treatment in both subgroups. Regardless of whether patients had previously been taking another biologic, secukinumab was just as tolerable as placebo and there were no new safety risks. Our analysis shows that secukinumab is effective and tolerable, regardless of whether patients have previously used another biologic drug.

Comparisons of lumbosacral kinematics among non-specific chronic low back pain subgroups and healthy during prolonged sitting: A cross-sectional observational study.

BACKGROUND: The literature has suggested a variety of postural changes of the spine that possibly contribute to the increase in back pain during sitting in persons with non-specific chronic low back pain (NS-CLBP). However, the heterogeneity of NS-CLBP persons has made the ability to attribute pain increase to a particular sitting posture very difficult. Therefore, the purpose of this study was to compare lumbosacral kinematics and their roles in pain increase among homogenous NS-CLBP subgroups and healthy controls over a 1-h sitting period. METHODS: Twenty NS-CLBP subjects with motor control impairment [10 classified as having flexion pattern (FP) disorder, and 10 with active extension pattern (AEP) disorder], and 10 healthy controls participated in the study. Subjects underwent a 1-h sitting protocol on a standard office chair. Lumbosacral postures including sacral tilt, third lumbar vertebrae (L3) position, and relative lower lumbar angle were recorded using two-dimensional inclinometers over the 1-h period. Perceived back-pain intensity was measured using a visual analog scale every 10 min throughout the sitting period. RESULTS: All study groups (FP, AEP and healthy controls) significantly differed from each other in the measured lumbosacral kinematics at the beginning as well as at the end of the sitting period (p ≤ 0.05). Only the NS-CLBP subgroups showed significant changes in the lumbosacral kinematics across the 1-h sitting period (p < 0.01), and that the directions of change occurred toward end spinal postures (lumbar kyphosis for FP subgroup and lumbar lordosis for the AEP subgroup). In addition, both NS-CLBP subgroups reported a similarly significant increase in pain through mid-sitting (p < 0.001). However, after mid-sitting, the AEP subgroup reported much less increase in pain level that was accompanied by a significant decrease in the lumbar lordotic postures (p = 0.001) compared to FP subgroup. CONCLUSION: The present study's findings suggest that each NS-CLBP subgroup presented with differently inherent sitting postures. These inherently dysfunctional postures coupled with the directional changes in the lumbosacral kinematics toward the extreme ranges across the 1-h sitting period, might explain the significant increase in pain among subgroups.

A Benchtop Round Window Model for Studying Magnetic Nanoparticle Transport to the Inner Ear.

INTRODUCTION: The round window membrane (RWM) presents a significant barrier to the local application of therapeutics to the inner ear. We demonstrate a benchtop preclinical RWM model and evaluate superparamagnetic iron oxide nanoparticles (SPIONs) as vehicles for magnetically assisted drug delivery. METHODS: Guinea pig RWM explants were inset into a 3D-printed dual chamber benchtop device. Custom-synthesized 7-nm iron core nanoparticles were modified with different polyethylene glycol chains to yield two sizes of SPIONs (NP-PEG600 and NP-PEG3000) and applied to the benchtop model with and without a magnetic field. Histologic analysis of the RWM was performed using transmission electron microscopy (TEM) and confocal microscopy. RESULTS: Over a 4-h period, 19.5 ± 1.9% of NP-PEG3000 and 14.6 ± 1.9% of NP-PEG600 were transported across the guinea pig RWM. The overall transport increased by 1.45× to 28.4 ± 5.8% and 21.0 ± 2.0%, respectively, when a magnetic field was applied. Paraformaldehyde fixation of the RWM decreased transport significantly (NP-PEG3000: 7.6 ± 1.5%; NP-PEG600: 7.0 ± 1.6%). Confocal and electron microscopy analysis demonstrated nanoparticle localization throughout all cellular layers and layer-specific transport characteristics within RWM. CONCLUSION: The guinea pig RWM explant benchtop model allows for targeted and practical investigations of transmembrane transport in the development of nanoparticle drug delivery vehicles. The presence of a magnetic field increases SPION delivery by 45%-50% in a nanoparticle size- and cellular layer-dependent manner. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3355-3362, 2024.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Changes in Treg and Breg cells in a healthy pediatric population.

The interpretation of clinical diagnostic results in suspected inborn errors of immunity, including Tregopathies, is hampered by the lack of age-stratified reference values for regulatory T cells (Treg) in the pediatric population and a consensus on which Treg immunophenotype to use. Regulatory B cells (Breg) are an important component of the regulatory system that have been poorly studied in the pediatric population. We analyzed (1) the correlation between the three immunophenotypic definitions of Treg (CD4+CD25hiCD127low, CD4+CD25hiCD127lowFoxP3+, CD4+CD25hiFoxP3+), and with CD4+CD25hi and (2) the changes in Treg and Breg frequencies and their maturation status with age. We performed peripheral blood immunophenotyping of Treg and Breg (CD19+CD24hiCD38hi) by flow cytometry in 55 healthy pediatric controls. We observed that Treg numbers varied depending on the definition used, and the frequency ranged between 3.3-9.7% for CD4+CD25hiCD127low, 0.07-1.6% for CD4+CD25hiCD127lowFoxP3+, and 0.24-2.83% for CD4+CD25hiFoxP3+. The correlation between the three definitions of Treg was positive for most age ranges, especially between the two intracellular panels and with CD4+CD25hi vs CD4+CD25hiCD127low. Treg and Breg frequencies tended to decline after 7 and 3 years onwards, respectively. Treg's maturation status increased with age, with a decline of naïve Treg and an increase in memory/effector Treg from age 7 onwards. Memory Breg increased progressively from age 3 onwards. In conclusion, the number of Treg frequencies spans a wide range depending on the immunophenotypic definition used despite a good level of correlation exists between them. The decline in numbers and maturation process with age occurs earlier in Breg than in Treg.

Mycophenolate mofetil for autoimmune cytopenias in children: high rates of response in inborn errors of immunity.

Second-line treatments of autoimmune cytopenias (AC) are not well-defined in children. Mycophenolate mofetil (MMF) is an immunosuppressant agent that has been demonstrated to be safe and effective in this setting. A retrospective observational study was conducted in 18 children with prolonged AC who received MMF, in order to describe clinical and biological markers of response. The overall response rate of MMF at 20-30 mg/kg per day was 73.3%. All patients with Evans syndrome (n = 9) achieved complete response. Among the patients with monolineage AC (n = 9), those with an underlying inborn errors of immunity (IEI), tended to respond better to MMF. No biological markers related to treatment response were found. Rather, lymphocyte subpopulations proved useful for patient selection as a marker suggestive of IEI along with immunoglobulin-level determination.

Targeting 7KCh-Induced Cell Death Response Mediated by p38, P2X7 and GSDME in Retinal Pigment Epithelium Cells with Sterculic Acid.

Age-related macular degeneration (AMD) is the main cause of blindness in developed countries. AMD is characterized by the formation of drusen, which are lipidic deposits, between retinal pigment epithelium (RPE) and the choroid. One of the main molecules accumulated in drusen is 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative. It is known that 7KCh induces inflammatory and cytotoxic responses in different cell types and the study of its mechanism of action is interesting in order to understand the development of AMD. Sterculic acid (SA) counteracts 7KCh response in RPE cells and could represent an alternative to improve currently used AMD treatments, which are not efficient enough. In the present study, we determine that 7KCh induces a complex cell death signaling characterized by the activation of necrosis and an alternative pyroptosis mediated by P2X7, p38 and GSDME, a new mechanism not yet related to the response to 7KCh until now. On the other hand, SA treatment can successfully attenuate the activation of both necrosis and pyroptosis, highlighting its therapeutic potential for the treatment of AMD.

The influence of alcohol consumption on Self-Rated Health and Mood during the COVID-19 pandemic in Spain.

Introduction: There is evidence of a significant upturn of certain unhealthy lifestyle choices such as Alcohol Consumption during the COVID-19 pandemic. Objective: To analyze whether Alcohol Consumption has increased since the onset of pandemic and whether it affects the relationship between Mood and Self-Rated Health among adult Spanish population. Methodology: Study of two cross-sectional cohorts (1-initial period of confinement COVID-19 pandemic, 2-between fifth and sixth waves of pandemic) to examine Alcohol Consumption in the relationship between Mood and Self-Rated Health using a moderation analysis with PROCESS macro for SPSS. Results: 5,949 people (62.1% women) participated in the study. Alcohol Consumption showed a significant increase, with men consuming more Alcohol than women in both periods (58.6% vs. 44.7% and 72.1% vs. 56.7%, respectively, p < 0.001). The moderation analysis revealed that sex and Alcohol Consumption conditioned the relationship between Mood and Self-Rated Health in the first survey, with a greater effect on women, who stated that not consuming Alcohol had a positive effect on the relationship between Mood and Self-Rated Health (B: -0.530; p < 0.001). Discussion: Currently it is about of implementing strategies to manage the pandemic-some of them aimed at promoting healthy living and stress management as assets that favor healthy lifestyles with fewer risk factors. New studies are needed to address the social thresholds of alcohol consumption, considering different perspectives for understanding variations in the intrapersonal and social perception of drunkenness, as this has been shown to be inconsistent across cultures and time periods.

Social support as a mediator in the relationship between technostress or academic stress and health: analysis by gender among university students.

Introduction: This research aims to study the role of social support as a mediator in the relationship between technostress or academic stress and health in university students. Methods: A descriptive, quantitative cross-sectional study has been carried out through a self-reported survey answered by 389 students during March and April 2022. The current level of health was the outcome variable. Technostress and academic stress were the criterion variables. Perceived social support was the mediator variable. The sociodemographic variables and ICT use at the educational level were the independent variables. Results: Women have higher levels of technostress and academic stress than men. Social support significantly and positively mediates the relationship between academic stress and self-perceived health in men. Discussion: There is a clear need to develop new social management strategies that assist students in developing stable and long-lasting social networks, which can reduce stress during the student period and provide personal tools for later working life.

Positive Psychological Intervention Delivered Using Virtual Reality in Patients on Hemodialysis With Comorbid Depression: Protocol and Design for the Joviality Randomized Controlled Trial.

BACKGROUND: Depression is highly prevalent in individuals on hemodialysis, but it is infrequently identified and remains undertreated. In this paper, we present details of the methodology of a randomized controlled trial (RCT) aimed at testing the feasibility and preliminary efficacy of a 5-week positive psychological intervention in individuals on hemodialysis with comorbid depression delivered using immersive virtual reality (VR) technology. OBJECTIVE: We aim to describe the protocol and design of the Joviality trial whose main objectives are 2-fold: determine the feasibility of the Joviality VR software through metrics capturing rates of recruitment, refusal, retention, noncompliance, and adherence, as well as end-user feedback; and assess preliminary efficacy for outcomes measures of depressive symptoms, psychological well-being and distress, quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalizations. METHODS: This 2-arm RCT is scheduled to enroll 84 individuals on hemodialysis with comorbid depression from multiple outpatient centers in Chicago, Illinois, United States. Enrollees will be randomized to the following groups: VR-based Joviality positive psychological intervention or sham VR (2D wildlife footage and nature-based settings with inert music presented using a head-mounted display). To be eligible, individuals must be on hemodialysis for at least 3 months, have Beck Depression Inventory-II scores of ≥11 (ie, indicative of mild-to-severe depressive symptoms), be aged ≥21 years, and be fluent in English or Spanish. The Joviality VR software was built using agile design principles and incorporates fully immersive content, digital avatars, and multiplex features of interactability. Targeted skills of the intervention include noticing positive events, positive reappraisal, gratitude, acts of kindness, and mindful or nonjudgmental awareness. The primary outcomes include metrics of feasibility and acceptability, along with preliminary efficacy focused on decreasing symptoms of depression. The secondary and tertiary outcomes include quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalization rates. There are 4 assessment time points: baseline, immediately after the intervention, 3 months after the intervention, and 6 months after the intervention. We hypothesize that depressive symptoms and hemodialysis-related markers of disease will substantially improve in participants randomized to the VR-based Joviality positive psychology treatment arm compared with those in the attention control condition. RESULTS: This RCT is funded by the National Institute of Diabetes and Digestive and Kidney Diseases and is scheduled to commence participant recruitment in June 2023. CONCLUSIONS: This trial will be the first to test custom-built VR software to deliver a positive psychological intervention, chairside, in individuals on hemodialysis to reduce symptoms of depression. Within the context of an RCT using an active control arm, if proven effective, VR technology may become a potent tool to deliver mental health programming in clinical populations during their outpatient treatment sessions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05642364; https://clinicaltrials.gov/ct2/show/NCT05642364. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45100.

Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency.

BACKGROUND: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown. METHODS: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models. RESULTS: We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42. CONCLUSIONS: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).

Identification of 7-Ketocholesterol-Modulated Pathways and Sterculic Acid Protective Effect in Retinal Pigmented Epithelium Cells by Using Genome-Wide Transcriptomic Analysis.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. AMD is characterized by the formation of lipidic deposits between the retinal pigment epithelium (RPE) and the choroid called drusen. 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative, is closely related to AMD as it is one of the main molecules accumulated in drusen. 7KCh induces inflammatory and cytotoxic responses in different cell types, and a better knowledge of the signaling pathways involved in its response would provide a new perspective on the molecular mechanisms that lead to the development of AMD. Furthermore, currently used therapies for AMD are not efficient enough. Sterculic acid (SA) attenuates the 7KCh response in RPE cells and is presented as an alternative to improve these therapies. By using genome-wide transcriptomic analysis in monkey RPE cells, we have provided new insight into 7KCh-induced signaling in RPE cells, as well as the protective capacity of SA. 7KCh modulates the expression of several genes associated with lipid metabolism, endoplasmic reticulum stress, inflammation and cell death and induces a complex response in RPE cells. The addition of SA successfully attenuates the deleterious effect of 7KCh and highlights its potential for the treatment of AMD.