Novel endothelial progenitor cells populations as biomarkers of damage and remission in systemic lupus erythematosus.

INTRODUCTION: Endothelial progenitor cells (EPCs) are essential for maintenance of vascular homeostasis and stability, key processes in the pathogenesis of systemic lupus erythematosus (SLE). However, the role and phenotypic characterization of EPCs populations in SLE have not been completely elucidated. OBJECTIVE: To identify EPCs specific subpopulations in patients with SLE using a novel flow cytometry tool. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SLE and healthy controls (HC). mRNA and surface protein expression were determined by quantitative PCR (qPCR) and flow cytometry. Clusters identification and characterization were performed using tSNE-CUDA dimensionality reduction algorithms. RESULTS: tSNE-CUDA analysis identified eight different clusters in PBMCs from HC and patients with SLE. Three of these clusters had EPC-like phenotype and the expression was elevated in patients with SLE. Moreover, four SLE-associated subclusters were found mainly expressed in patients with SLE, being only present in patients in remission with SLE and significantly associated with the 2021 Definition of Remission in SLE. Importantly, we also identified specific clusters in SLE patients with organ damage, according to the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI). These clusters showed an EPC-like phenotype, but the expression of angiogenic markers was lower compared to HC or patients without organ damage, suggesting an impaired angiogenic function. CONCLUSION: Our novel approach identified clusters of EPCs in patients with SLE that are associated with remission and damage. Therefore, these clusters might be useful biomarkers to predict disease progression and severity in SLE pathogenesis.

Bilateral humeral lengthening and deformity correction with hexapod external fixator in an achondroplastic patient: A case report.

INTRODUCTION AND IMPORTANCE: Achondroplasia, a prevalent skeletal dysplasia, often results in limb asymmetry and functional limitations, typically managed surgically with bone lengthening techniques. CASE PRESENTATION: We present the case of a 10-year-old girl with achondroplasia who underwent bilateral humeral lengthening using hexapod external fixators. The patient, previously treated for lower limb lengthening, exhibited significant upper limb shortening affecting daily activities. Surgical intervention involved two stages, employing two hexapod external fixators for precise correction and lengthening. Symmetrical lengthening of 6 cm in both humeri was achieved without major complications. Follow-up assessments revealed improved functionality and satisfactory outcomes, emphasizing the importance of addressing upper limb deformities in achondroplasia patients. CLINICAL DISCUSSION: While humeral lengthening is less common than lower extremity lengthening due to historical concerns about neurovascular complications and functional implications, recent advancements highlight its potential benefits, particularly in achieving functional and aesthetic balance. CONCLUSION: This case highlights the efficacy and safety of hexapod fixators in achieving multiplanar correction and functional improvement in upper limb lengthening. Further investigation should be carried out to study broader application in similar cases.

Safety of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: Pooled Analysis of Three Phase 3 Randomized Trials.

INTRODUCTION: Multi-modal analgesia is desirable for the management of acute pain since it can provide effective pain relief at lower doses, thereby aiding tolerability. Co-crystal of tramadol-celecoxib (CTC) provides effective analgesia in models of acute pain. Co-crystallization can alter the pharmacokinetics of individual components, potentially improving tolerability. We sought to better understand the safety and tolerability of CTC in patients with acute postoperative pain. METHODS: We conducted a pooled analysis of safety data from three phase 3 randomized controlled trials in adults with acute moderate-to-severe pain following oral surgery, bunionectomy, and elective abdominal hysterectomy. We present data for CTC 200 mg twice daily (BID) and its comparators: tramadol 50 mg four times daily (QID) (one trial), tramadol 100 mg QID (two trials), celecoxib 100 mg BID (two trials), and placebo (three trials). RESULTS: In total, n = 551 patients received CTC 200 mg BID, n = 183 received tramadol 50 mg QID, n = 368 received tramadol 100 mg QID, n = 388 received celecoxib 100 mg BID, and n = 274 received placebo. The prevalence of adverse events (AEs) related to study drug up to 48 h was numerically lower with CTC 200 mg BID (35.9%) than with tramadol 50 mg QID (47.5%) and 100 mg QID (44.8%) but greater than with celecoxib 100 mg BID (12.4%) and placebo (20.4%). The most frequent AEs related to study drug up to 48 h were somnolence, nausea, dizziness, and vomiting, which occurred more frequently in patients receiving tramadol 100 mg QID than in those receiving CTC 200 mg BID. CONCLUSION: CTC 200 mg BID appears to be better tolerated than tramadol 100 mg QID, possibly because of reduced total exposure to tramadol. This may contribute to a more favorable benefit-risk profile for CTC versus individual components, making it a promising treatment for acute pain. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03108482, NCT02982161 (EudraCT: 2016-000592-24), NCT03062644 (EudraCT: 2016-000593-38).

Role of sarcopenia in complex abdominal wall surgery: does it increase postoperative complications and mortality?

BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and is associated with an increased risk or morbidity and mortality in complex surgical patient populations. Its role in complex abdominal wall surgery (AWS) is yet to be determined. The aim of this study is to establish if sarcopenia has an impact on postoperative complications, mortality and hernia recurrence. METHODS: Retrospective study of patients undergoing elective surgery for complex incisional hernias > 10 cm (W3 of European Hernia Society classification) between 2014-2023. Sarcopenia was stablished as the skeletal muscle index (SMI), measured at L3 transversal section of a preoperative CT-scan. Previously defined literature-based SMI cutoff values were used: men ≤ 52.4 cm2/m2, women ≤ 38.5 cm2/m2. RESULTS: 135 patients undergoing complex AWS were included. Of them, 38 were sarcopenic (28.1%). The median follow-up time was 13 months (IQR 12-25). In total, 11 patients died (8.1%). We found that sarcopenia was associated with a higher risk of mortality [HR 7.494 (95% CI 1.985-28.289); p 0.003]. There were no statistically significant differences in postoperative complications or hernia recurrence between both groups. CONCLUSION: Although sarcopenia does not seem to have an influence on hernia recurrence or the development of postoperative complications, whether local or systemic, in our study sarcopenia is associated with a higher risk of mortality after complex abdominal wall surgery. Nonetheless, with the results obtained in our study, we think that prehabilitation programs before complex AWS is advisable.

Innovative salt replacement for green Spanish-style olives using potassium, calcium, and magnesium chlorides during packaging.

This work aimed to enhance green Spanish-style Manzanilla table olives by replacing salt with K, Ca, and Mg chlorides in innovative packaging, utilising Response Surface Methodology (RSM). Both the added replacers and naturally occurring minerals were considered. RSM allowed the development of predictive models for K, Ca, Mg, and Mn (initially present) in olive flesh and their contributions to Reference Daily Intakes (RDI) based on the added salts. The sodium content in the new products decreased from 1.4 g/100 g flesh to 0.68 g/100 g flesh, while K, Ca, and Mg concentrations could increase up to 0.50, 0.45 and 0.15 g/100 g flesh, respectively. Added salt contributions to RDI could reach 25, 60, and 44 % for K, Ca, and Mg. Minimal differences between analytical data-derived minerals and predicted values were minimal, suggesting reliable model performance for nutrition labelling. Results assist the industry in creating nutritionally enhanced table olive products.

Impact on the nervous system of long COVID-19 infection in children.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a profound global impact, raising concerns about its long-term effects, particularly neurological complications. While studies have highlighted such complications in adults, there is a paucity of research focusing on children. OBJECTIVE: To examine the medium- to long-term neurological and cognitive symptoms in 18 year old children and below with positive versus negative COVID-19 antigens and to identify the probable risk factors to promote specific health actions. METHODS: An observational study was carried out to determine neurological symptoms in the medium and long terms after COVID 19. A random sample of 124 children, both symptomatic or asymptomatic, tested positive or negative for COVID-19 through swab tests. RESULTS: Neurological symptoms were assessed between 6 to 12 months and 2 years after the infection. Acute symptoms, including headache, anosmia, ageusia, and myalgia, were observed in more than 20% of the children, but they generally resolved within 6 to 12 months. Persistent functional difficulties, such as in studying, paying attention, and socializing, were reported in 3% of the cases. Behavioral symptoms at baseline were noted in 7.8% of children, but they were remitted in most cases, except for those with prior involvement. CONCLUSION: These findings underscore the need for continued monitoring of children following COVID-19 infection and the importance of tailored health interventions.

ANTECEDENTES: La pandemia por enfermedad por coronavirus 2019 (coronavirus disease 2019, COVID-19, en inglés) ha tenido un profundo impacto global y ha generado preocupación sobre sus efectos a largo plazo, especialmente sobre las complicaciones neurológicas. Si bien los estudios han destacado tales complicaciones en adultos, hay escasez de investigaciones centradas en niños. OBJETIVO: Examinar los síntomas neurológicos y cognitivos a mediano y largo plazo en niños de 18 años o menos, con antígenos positivos versus negativos para COVID-19, e identificar los posibles factores de riesgo para promover acciones de salud específicas. MéTODOS: Se llevó a cabo un estudio observacional para determinar los síntomas neurológicos en el medio y largo plazo tras COVID-19. Una muestra aleatoria de 124 niños se diagnosticó por tests de saliva. Los tests para COVID-19 podían ser negativos o positivos, en niños sintomáticos o asintomáticos. RESULTADOS: Los síntomas neurológicos se evaluaron entre 6 y 12 meses y 2 años posinfección. Se observaron síntomas agudos como cefalea, anosmia, ageusia y mialgias en más del 20% de los niños, que generalmente se resolvieron en un plazo de 6 a 12 meses. En el 3% de los casos, se informaron dificultades funcionales persistentes, como para estudiar, prestar atención y socializar. Los síntomas conductuales se produjeron en el 7.8% en el momento inicial, pero remitieron en la mayoría de los casos, excepto en aquellos con afectación previa. CONCLUSIóN: Estos hallazgos enfatizan la necesidad del monitoreo continuo de niños tras la infección por COVID-19 y la importancia de intervenciones de salud personalizadas.

Emergence of cooperation in the one-shot Prisoner's dilemma through Discriminatory and Samaritan AIs.

As artificial intelligence (AI) systems are increasingly embedded in our lives, their presence leads to interactions that shape our behaviour, decision-making and social interactions. Existing theoretical research on the emergence and stability of cooperation, particularly in the context of social dilemmas, has primarily focused on human-to-human interactions, overlooking the unique dynamics triggered by the presence of AI. Resorting to methods from evolutionary game theory, we study how different forms of AI can influence cooperation in a population of human-like agents playing the one-shot Prisoner's dilemma game. We found that Samaritan AI agents who help everyone unconditionally, including defectors, can promote higher levels of cooperation in humans than Discriminatory AI that only helps those considered worthy/cooperative, especially in slow-moving societies where change based on payoff difference is moderate (small intensities of selection). Only in fast-moving societies (high intensities of selection), Discriminatory AIs promote higher levels of cooperation than Samaritan AIs. Furthermore, when it is possible to identify whether a co-player is a human or an AI, we found that cooperation is enhanced when human-like agents disregard AI performance. Our findings provide novel insights into the design and implementation of context-dependent AI systems for addressing social dilemmas.

Comparative Hox genes expression within the dimorphic annelid Streblospio benedicti reveals patterning variation during development.

Hox genes are transcriptional regulators that elicit cell positional identity along the anterior-posterior region of the body plan across different lineages of Metazoan. Comparison of Hox gene expression across distinct species reveals their evolutionary conservation; however, their gains and losses in different lineages can correlate with body plan modifications and morphological novelty. We compare the expression of 11 Hox genes found within Streblospio benedicti, a marine annelid that produces two types of offspring with distinct developmental and morphological features. For these two distinct larval types, we compare Hox gene expression through ontogeny using hybridization chain reaction (HCR) probes for in situ hybridization and RNA-seq data. We find that Hox gene expression patterning for both types is typically similar at equivalent developmental stages. However, some Hox genes have spatial or temporal differences between the larval types that are associated with morphological and life-history differences. This is the first comparison of developmental divergence in Hox gene expression within a single species and these changes reveal how body plan differences may arise in larval evolution.

Decreased Systemic Monocyte Colony Protein-1 (MCP-1) Levels and Reduced sCD14 Levels in Curcumin-Treated Patients with Moderate Anxiety: A Pilot Study.

Psychosocial stress may alter cortisol and/or affect the normal functioning of the immune system. Curcuminoids can promote beneficial effects in neuropsychiatric diseases. We evaluated whether curcumin supplementation for 15 consecutive days (1800 mg/day) would decrease systemic MCP-1, sCD14, and TNF alpha levels in patients with moderate anxiety (n = 81). A total number of 81 subjects were enrolled in this study, divided into the following groups according to their Hamilton scores: a control group including patients without anxiety who were not taking curcumin (Cont, n = 22) and an anxiety group including patients with moderate anxiety (Anx, n = 22). The curcumin-treated patients experienced moderate anxiety, and they take curcumin for 15 consecutive days (Anx-Cur (after), n = 15, 1800 mg/day). An evaluation of 128 patients was conducted, which allowed for their assignment to the study groups according to their scores on Hamilton scale II. The cortisol levels were quantified in salivary samples through ELISA (ng/mL), and malonaldehyde (MDA) levels were measured in plasma via the TBARS assay as an index of lipoperoxidation. Several systemic proinflammatory cytokines (pg/mL: MCP-1, TNF alpha, IL-1 beta) and mediators were quantified through ELISA (pg/mL), including systemic sCD14 levels as a marker of monocyte activation. A two-way bifactorial ANOVA was conducted to evaluate the contributions of the anxiety factor (Anx) and/or curcumin factor (Cur) in all the tested markers, including interactions between both factors. High systemic MCP-1 and elevated sCD14 levels were observed in patients with moderate anxiety, which were reduced with curcumin supplementation. In addition, curcumin prevented cortisol overexpression and decreased MDA levels as an antioxidant response in these patients. Collectively, curcumin presented anti-chemotactic effects by reducing systemic MCP-1 levels in anxiety. Curcumin decreased systemic MCP-1 as well as sCD14 levels in patients with moderate anxiety.

Use of Milled Acanthocardia tuberculate Seashell as Fine Aggregate in Self-Compacting Mortars.

This study focuses on the feasibility of using ground Acanthocardia tuberculate seashells as fine aggregates for self-compacting mortar production. The obtained results show a promising future for coastal industries as their use eliminates waste products and improves the durability of these materials. The use of Acanthocardia tuberculate recycled aggregate, in terms of durability, improves the performance of all mixes made with seashells compared to those made with natural sand, although it decreases workability and slightly reduces mechanical strength. Proper mix design has beneficial effects, as it improves compressive strength, especially when the powder/sand ratio is 0.7. Three replacement ratios based on the volume (0%, 50%, and 100%) of natural limestone sand with recycled fine aggregate from Acanthocardia tuberculate seashells, and three different dosages modifying the powder/sand ratio (0.6, 0.7, and 0.8), were tested. The fresh-state properties of each self-compacting mixture were evaluated based on workability. The mineralogical phases of the hardened mixtures were characterised using X-ray diffraction, thermogravimetry, and differential analyses. Subsequently, the mechanical and durability properties were evaluated based on the compressive and flexural strengths, dry bulk density, accessible porosity for water and water absorption, drying shrinkage, mercury intrusion porosimetry, and water absorption by capillarity. Therefore, the use of Acanthocardia tuberculate seashells in cement-based systems contributes to circular economy.

Can Vitamin D Levels Influence Bone Metabolism and Osseointegration of Dental Implants? An Umbrella Review.

INTRODUCTION: Due to the large amount of scientific evidence on the subject and the limitations and incongruities in previous reviews, the primary aim of this umbrella review is to gather all the information regarding the importance of vitamin D levels in the osseointegration of dental implants. METHODS: The literature search was performed in PubMed, Web of Science, CINAHL Plus, Cochrane Library, and Academic Search Complete throughout the search expression ["vitamin D" AND ("dental implant" OR "dental implants")]. RESULTS: The initial search yielded 351 results, but at the end of the process, only five systematic reviews were selected. CONCLUSIONS: Vitamin D seems to have a positive effect on the osseointegration of dental implants and on the reduction of dental implant failures; however, it is recommended that future studies take into account the limitations mentioned in this study in order to increase the validity and quality of scientific evidence on the subject.

Influence of social determinants of health on quality of life in patients with multimorbidity and polypharmacy.

BACKGROUND: Multimorbidity is one of the biggest challenges faced by modern medicine, especially when managing older patients who are also often taking multiple medications. Multimorbidity is influenced by social determinants of health, giving rise to health inequalities in the population. Here, we sought to determine the influence of social determinants of health on quality of life in patients with multimorbidity and polypharmacy. METHODS AND MATERIALS: This cross-sectional observational study included 573 patients aged 65-74 with multimorbidity (≥3 diseases) and polypharmacy (≥5 drugs). Corresponding data was taken drawn from the Spanish MULTIPAP study, and included social and demographic variables, and data on health-related quality of life and overall self-perceived health status, assessed using the 5-level version of the EuroQol 5-dimensional questionnaire (EQ-5D-5L). Descriptive, bivariate and multivariate analyses with logistic regression models were performed. RESULTS: Mean patient age was 69.7 years, 55.8% of patients were female, 59.7% belonged to low social classes (V, VI), a monthly income of €1051-€1850 predominated, and the median number of diseases in the same patient was 6. Factors associated with higher quality of life were (odds ratio, OR) male gender (OR = 1.599, p = 0.013), a higher educational level (OR = 1.991, p = 0.036), an absence of urban vulnerability (OR = 1.605, p = 0.017), and the presence of medium social support (OR = 1.689, p = 0.017). Having a higher number of diseases was associated with poorer quality of life (OR = 0.912, p = 0.017). CONCLUSIONS: Our findings describe associations between social determinants of health and quality of life in patients aged 65-74 years with multimorbidity and polypharmacy. More illnesses, female gender, a lower education level, urban vulnerability, and less social support are associated with poorer quality of life, underscoring the need for a biopsychosocial approach in patient care.

Impact of Oil-in-Water Adjuvanted ß-Glucan on Innate Immune Memory in Piglets.

The non-specific protective effects offered by the concept of "innate immune memory" might represent a promising strategy to tackle early-life threatening infections. Here we tested the potential of an in vitro selected ß-glucan in inducing trained immunity using an in vivo porcine model. We assessed the leukocyte transcriptome using blood transcriptomic module (BTM), proinflammatory cytokines, and clinical scoring after a first "training" and a second "stimulation" phase. The possible induction of innate immune memory was tested during a "stimulation" by an LPS-adjuvanted Mycoplasma hyopneumoniae vaccine (Hyogen®) one day after weaning. Following the "training", no major group differences were found, with the exception of a plasma TNF that was only induced by Adj and Adj_BG treatment. After vaccination, all groups developed similar antibody responses. A significant induction of plasma TNF and IL-1ß was found in groups that received Adj and Adj_BG. However, following vaccination, the expected early innate BTMs were only induced by the PBS group. In conclusion, the adjuvant alone, adjuvant-formulated ß-glucan, or orally applied ß-glucan were unable to enhance innate immune reactivity but rather appeared to promote innate immune tolerance. Such an immune status could have both positive and negative implications during this phase of the piglet's life.

LYP regulates SLP76 and other adaptor proteins in T cells.

BACKGROUND: The LYP tyrosine phosphatase presents a SNP (1858C > T) that increases the risk of developing autoimmune diseases such as type I diabetes and arthritis. It remains unclear how this SNP affects LYP function and promotes the development of these diseases. The scarce information about LYP substrates is in part responsible for the poor understanding of LYP function. RESULTS: In this study, we identify in T lymphocytes several adaptor proteins as potential substrates targeted by LYP, including FYB, SLP-76, HS-1, Vav, SKAP1 and SKAP2. We also show that LYP co-localizes with SLP76 in microclusters, upon TCR engagement. CONCLUSIONS: These data indicate that LYP may modulate T cell activation by dephosphorylating several adaptor proteins, such as FYB, SLP-76, HS-1, Vav, SKAP1 and SKAP2 upon TCR engagement.

Predicting the Drivers of Bothrops Snakebite Incidence Across Brazil: A Spatial Analysis.

Snakebite envenoming poses a significant public health challenge on a global basis, affecting millions of people annually and leading to complications that may result in fatalities. Brazil stands as one of the countries most impacted by snakebite envenoming, with snakes of the Bothrops genus being responsible for most bites. The current study aimed to identify the determinants of Bothrops snakebite incidence across different regions of Brazil. An ecological study was conducted using municipality-aggregated data, with snakebite incidence as the dependent variable. The study period comprised the years 2015 to 2021. We constructed Species Distribution Models (SDMs) for Bothrops species, and information was collected on precipitation, runoff, maximum and minimum temperatures, native forest, historical forest loss, agriculture, and pasture in each Brazilian municipality. These data were employed to assess the association between snakebite incidence and biotic, climatic, and landscape factors. The data were analyzed using Generalized Least Squares (GLS) regression. The SDMs demonstrated good performance. The average annual snakebite incidence during the study period ranged from zero to 428.89 per 100,000 inhabitants, depending on the municipality. Higher incidence rates were concentrated primarily in municipalities in the northern region of the country. In this study, we found that nationwide, areas with extensive native forests and those that have historically experienced significant loss of forest cover exhibited higher snakebite incidence rates. Additionally, areas with higher temperatures and precipitation levels, as well as greater climatic suitability for the species B. jararaca, showed significantly higher snakebite incidence rates in the South and Southeast of Brazil, respectively. These associations may be linked to increased snake abundance and active behavior, as well as to engagement in activities favoring human-snake contact in these areas. The findings of this study can contribute to the improvement of prevention and control strategies for this public health issue in Brazil.

Impact of sarcopenic obesity on surgical complications and oncologic outcomes of upper gastrointestinal tumors: A systematic review and meta-analysis.

Sarcopenic obesity (SO) is a new entity whose definition encompasses the diagnosis of overweight in malnourished patients. The aim of the review was to assess the impact of body composition in patients with esophago-gastric tumors (EGT) on perioperative and oncological outcomes. This systematic review was conducted under the PRISMA guidelines. MEDLINE (PubMed), Embase, Web of Science and SCOPUS databases were searched until January 2024. Sixteen articles were identified for analysis analyzing 5,378 patients. The prevalence of SO was 10% (95%CI: 6-16; I2 = 94%). Preoperative diagnosis of SO was associated with a twofold increased risk of severe postoperative complications (OR 2.32 [95%CI 1.41-3.82] I2 = 70%). Meta-analysis of overall survival outcomes identified that SO was associated with worse overall survival (HR 2.30; 95%CI 1.46-3.61).

Effectiveness of Vortioxetine Treatment on Depression and Cognitive Functions in Patients with Alzheimer's Disease: A 12-Month, Retrospective, Observational Study.

This study aimed to assess the effectiveness of vortioxetine for improving depressive symptoms, cognitive performance, daily and global functioning in patients with Alzheimer's disease (AD) and major depressive disorder (MDD) in real-world clinical practice. We retrospectively identified 46 AD patients who had received treatment for 12 months with vortioxetine. Drug effects were evaluated at baseline, 4, 8, and 12 months. The primary endpoint was change from baseline in the Hamilton Depression Rating Scale (HDRS) and in the Cornell Scale for Depression in Dementia (CSDD) to month 12. Cognitive and daily and global functioning changes were also evaluated. Significant baseline-to-endpoint improvement in depressive symptom severity was observed (p < 0.0001). At month 12, the least-square mean (standard error) change score from baseline was -10.48 (±0.42) on the HDRS and -9.04 (±0.62) on the CSDD. Significant improvements in cognitive performance were observed for the Rey Auditory Verbal Learning Test, the Symbol Digit Modalities Test, the Letter Fluency Test, the Category Fluency Test, and the Trail Making Test-A. Patients also experienced significant improvements in daily and global functioning. Vortioxetine was safe and well tolerated. Patients with AD and MDD receiving vortioxetine showed meaningful improvements in depressive symptoms, cognitive performance, and daily and global functioning over the 12-month treatment period.

Is Obesity a Problem in New Cystic Fibrosis Treatments?

INTRODUCTION: Malnutrition has always been a problem in CF (cystic fibrosis) patients; however, new treatments with CFTR (cystic fibrosis transmembrane conductance regulator protein) modulators have led to weight gain, with some patients at risk of overweight and obesity. OBJECTIVE: Our study aimed to analyze the evolution of BMI (body mass index) after one year of treatment with triple therapy and the factors associated with weight gain in CF patients undergoing treatment with triple therapy with CFTR protein modulators (ETI) (elexacaftor/tezacaftor/ivacaftor). METHODS: We conducted a prospective, observational, longitudinal, multicenter study in patients diagnosed with cystic fibrosis, aged 18 years or older, with at least one F508del allele and who underwent ETI therapy for at least one year, from 2020 to 2023. One hundred and eight patients from two cystic fibrosis units in Spain, Princess University Hospital of Madrid (74 patients) and Central University Hospital of Asturias (HUCA) (34 patients), were included. Demographic data, anthropometric data, lung function, and exacerbations were collected, comparing the data in the previous year to the start of therapy with the results after one year of treatment. Multivariant models were developed to account for repeated weight and BMI measurements, using a mixed effects model approach and accounting for possible modifying factors Results: One hundred and eight patients were included in the study, 58 men (53.7%) and 50 women (46.3%) with a mean age of 29.5 ± 9.4 years (18-59). Patient weight and BMI were recorded at baseline and at 3-month intervals during the study period. The weight increased from 59.6 kg to 62.6 kg and BMI increased from 21.9 kg/m2 to 23.0 kg/m2 after one year of treatment (p < 0.0001 for both). The proportion of underweight individuals decreased after one year of ETI therapy, from 9.3% to 1.9%, while the proportion of overweight or obese individuals increased from 8.3% to 22.9 % at the same time (p < 0.001). In relation to exacerbations, there is a significant increase in the number of patients who did not have any exacerbations after one year of treatment, which increased from 10.2% to 46.2% (p < 0.001), while the number of patients who had >4 exacerbations decreased significantly, from 40.7% to 1.9% (p < 0.001). FEV1% (forced expiratory volume) increased from 63.9 ± 20.9 to 76.8 ± 21.4 (p < 0.001) and the VR/TLC (residual volume/total lung capacity) value decreased from 45.1 ± 10.9 to 34.9 ± 6.2 (p < 0.001). The proportion with FEV1% > 80% increased from 23.1% before ETI therapy to 49.1% one year after ETI therapy. We performed multivariate mixed models to evaluate the evolution of BMI changes with time, accounting for repeated measures and for possible modifying factors. After the introduction of the triple therapy, patients included in the study had significant weight gain during the 12 months, and when including different covariates in the multivariate mixed model, we found that lower baseline BMI, lower baseline FEV1 and FVC (forced vital capacity), and higher VR/TLC value and higher number of exacerbations were associated with higher BMI changes over the study period. CONCLUSIONS: CF patients treated with triple therapy experience significant weight gain, increasing the proportion of overweight patients. CF patients who experienced greater weight gain were those with worse BMI at the start of treatment, as well as patients with worse lung function and a greater number of exacerbations in the year before starting ETI therapy.

Connecting genomic and proteomic signatures of amyloid burden in the brain.

Background: Alzheimer's disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease. Methods: We performed a meta-analysis of GWAS of CSF Aß42 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of Aß phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of loci modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses. Results: After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and nine suggestive hits were annotated. We replicated the APOE loci using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel GADL1 locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any Aß PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF Aß42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Conclusions: The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD.

Water availability and biological interactions shape amphibian abundance and diversity in Mediterranean temporary rivers.

Amphibians, the most threatened vertebrates globally, face risks due to climate change, habitat loss, and fragmentation. Their sensitivity to environmental changes highlights their importance as ecological indicators. Temporary rivers, influenced by geological, climatic, and anthropogenic factors, play a critical role in shaping biodiversity and community structure. Some species of amphibians may be adapted to these temporary waters, a fact reflected in their life cycles and various biological traits. However, to develop effective conservation strategies for amphibians, it is essential to address the knowledge gaps surrounding the complex interactions between biological dynamics and fluvial habitat conditions. In this study, we investigated how trophic interactions between amphibians and other aquatic organisms (diatoms, macroinvertebrates, and fish), coupled with environmental factors (water availability and riparian structure), can affect amphibian abundance and diversity in temporary rivers. The study was conducted in a Mediterranean river network located in Sant Llorenç del Munt i l'Obac Natural Park (Catalonia, Spain). Our expectations were that habitats suitable for egg deposition, lacking predators (e.g. tadpole-predators and fish), and abundant in food sources would likely support higher amphibian abundance and diversity. However, water availability was identified as a crucial factor shaping abundance and diversity in the studied amphibian communities, even if it correlated with fish presence, and especially impacting amphibian species usually linked to permanent water bodies. Concerning biotic interactions, while our results suggested that amphibian populations in temporary rivers are more dependent on top-down than bottom-up interactions, the presence of aquatic predators was not as conclusive as expected, suggesting that in temporary rivers the fish-avoiding amphibian species can survive using microhabitats or breeding opportunities linked to natural river dynamics. Overall, our findings highlight the importance of considering multi-trophic interactions, hydroperiod and habitat heterogeneity in temporary river ecosystems for effective amphibian conservation.