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Abstract 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).

Abstract Background Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. Results DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. Conclusions DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

Abstract Druggable pockets are protein regions that have the ability to bind organic small molecules, and their characterization is essential in target-based drug discovery. However, deriving pocket descriptors is challenging and existing strategies are often limited in applicability. We introduce PocketVec, an approach to generate pocket descriptors via inverse virtual screening of lead-like molecules. PocketVec performs comparably to leading methodologies while addressing key limitations. Additionally, we systematically search for druggable pockets in the human proteome, using experimentally determined structures and AlphaFold2 models, identifying over 32,000 binding sites across 20,000 protein domains. We then generate PocketVec descriptors for each site and conduct an extensive similarity search, exploring over 1.2 billion pairwise comparisons. Our results reveal druggable pocket similarities not detected by structure- or sequence-based methods, uncovering clusters of similar pockets in proteins lacking crystallized inhibitors and opening the door to strategies for prioritizing chemical probe development to explore the druggable space.

Abstract Emotions and behavior can be affected by social chemosignals from conspecifics. For instance, olfactory signals from stressed individuals induce stress-like physiological and synaptic changes in naïve partners. Direct stress also alters cognition, but the impact of socially transmitted stress on memory processes is currently unknown. Here we show that exposure to chemosignals produced by stressed individuals is sufficient to impair memory retrieval in unstressed male mice. This requires astrocyte control of information in the olfactory bulb mediated by mitochondria-associated CB1 receptors (mtCB1). Targeted genetic manipulations, in vivo Ca2+ imaging and behavioral analyses reveal that mtCB1-dependent control of mitochondrial Ca2+ dynamics is necessary to process olfactory information from stressed partners and to define their cognitive consequences. Thus, olfactory bulb astrocytes provide a link between social odors and their behavioral meaning.

This article presents a methodology for compartmental model (CM) creation for long-term simulation of water resource recovery facilities (WRRFs). CMs are often focused on reproducing with a lower computational cost, previously simulated scenarios. In contrast, the methodology presented here can represent variable hydraulic conditions, based on the interpolation of data gathered from a set of computational fluid dynamics (CFD) simulations that reproduce representative hydraulic scenarios. This is achieved by modelling with bidirectional flows the exchange flows between fixed compartments, which are defined based on the geometry of the reactors. The resultant hydraulic surrogate model can be implemented in commercial water treatment software to solve biochemical kinetics. The methodology was applied to simulate in WEST®-DHI a WRRF in Vila-Real, Spain. In this contribution, the CM was validated with real plant data. The developed CM provided a quick response simulation with a high level of hydraulic and biochemical detail. This allowed observation of a spatial distribution of component concentration, which could help with sensor location or plant optimisation. The methodology presented here could also be a useful enabler of digital twins to be implemented in WRRF. HIGHLIGHTS A computational fluid dynamics (CFD)-based compartmental modelling methodology is presented to simulate the dynamic long-term operation of water resource recovery facilities (WRRFs).; A hydraulic surrogate model was developed for the compartmental model (CM) based on multiple CFD simulations to replicate variations in hydraulic conditions.; The CM was validated with real WRRF data.; The developed CM provided quick simulation with high detail and allowed observation of a spatial distribution of component concentration.;

Abstract 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.

Atopic dermatitis (AD) is a chronic inflammatory condition that significantly affects the quality of life of both patients and their families or caregivers. Recently, treatment for moderate-to-severe AD were limited to conventional immunosuppressive therapies. However, currently, with the approval of biologic treatments and oral small molecules in the past decade, the effective and safe management of patients with AD is possible. Despite these advancements, challenges and unmet needs in clinical practice remain. This includes patients who do not respond well to or cannot tolerate existing treatment options and inadequate therapies that can modify the disease course. This review aimed to provide an overview of the current treatment approach for AD, highlight the current challenges in treatment, and discuss the rationale for novel treatment options and emerging evidence on systemic treatment options for AD.

Abstract Baryon number is an accidental symmetry of the Standard Model at the Lagrangian level. Its violation is arguably one of the most compelling phenomena predicted by physics beyond the Standard Model. Furthermore, there is a large experimental effort to search for it including the Hyper-K, DUNE, JUNO, and THEIA experiments. Therefore, an agnostic, model-independent, analysis of baryon number violation using the power of Effective Field Theory is very timely. In particular, in this work we study the contribution of dimension six and seven effective operators to |∆(B − L)| = 0, 2 nucleon decays taking into account the effects of Renormalisation Group Evolution. We obtain lower limits on the energy scale of each operator and study the correlations between different decay modes. We find that for some operators the effect of running is very significant.

The aim of this pre-experimental study is to evaluate the acquisition level of counting skills of a 3-year-old classroom made up of 14 children through a specific instructional design. To this end, an instructional proposal to improve these mathematical skills was designed. Before and after the intervention, we measured the students' level regarding counting skills through an evaluation of their counting abilities. The results indicate that the designed intervention increased the acquisition level of skills related to counting principles, constituting an effective instrument to enhance counting skills for 3-year-old children. In particular, after the intervention children improved significantly in skills related to the one-to-one correspondence principle and the order-irrelevance principle, both showing a large effect size in their observed differences. The cardinality principle, stable-order principle and abstraction principle also showed gains, but the differences were found to be statistically nonsignificant. Finally, the role of the age of the participants was also analyzed in relation to their acquired counting skills, indicating that children in the older age range improved their counting skills more than children in the younger group.

BackgroundThe increasing use of non-specific immunoglobulins (NSIGs) and their current shortage show a need for NSIGs’ use prioritization. Data from a clinical perspective are necessary, mainly for pediatric patients.ObjectivesThe aim of the study was to assess the level of clinical evidence (LoE) of the indications that NSIGs are used for, the reasons for discontinuation, and the costs invested.MethodsA retrospective multicentric study was conducted on NSIG incident users between September 2019 and December 2021 retrieved from the Registry of Patients and Treatments (RPT) from Catalonia (Spain). LoE was categorized as A) authorized indications, B) unauthorized with scientific support, C) unauthorized without support, and D) unknown (UNK), following local and the United Kingdom’s guidelines as a sensitivity analysis. We also estimated overall spending and costs per patient visit.ResultsA total of 400 patients were included (17.3% pediatric), with a mean follow-up of 122.1/person-years for adults. The most frequent indications were nervous system and blood diseases. Almost all pediatric patients (56; 81.2%) were treated under A-level indications, as for 217 (65.6%) adults. In the sensitivity analysis, the A-level usage rate decreased to one-third and the B-level usage rate increased by 2–3 times. Furthermore, 37.8% (151) of individuals discontinued. This was predominantly due to remission or no response. The total costs were 868,462.6€/year, with median spending per visit amounting to 1,500€ for adults and 700€ for pediatric patients.ConclusionNSIGs are used in clinical practice mainly for approved indications; however, non-approved indications are still an important issue. This could represent a significant economic burden on the healthcare system, focusing on the pediatric population and those at risk for discontinuation with alternative therapeutic options.

El Museu Pedagògic de Castelló cuenta con un fondo material de la antigua Escuela Normal de Castellón. A partir del trabajo de conservación, restauración y difusión de este fondo, planteamos la creación de un Laboratorio Didáctico vinculado a los grados de Maestro/a de Educación Infantil y Primaria. Partimos de la concepción Foucaultiana de archivo, con la idea de ofrecer una segunda oportunidad formativa a este patrimonio histórico-educativo que permita contemporaneizar los usos de estos materiales en la escuela actual. Para llevarlo a cabo implementamos tres tipos de acciones asociadas a la investigación participativa, la innovación educativa y la formación superior.

Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that only male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) impairment. Notably, VTA dopamine neuronal activity is causally linked to the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent disruption of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.

We developed a multi-source, integrated remote sensing approach to characterize the geomorphological features of the alluvial and coastal lowlands around the ancient Abdera (coastal Thrace, Gr.). By combining multi-temporal composites of satellite imagery, DEM-derived products, orthophotography, and different cartographic resources, more than 1000 linear km of ancient landforms have been identified and mapped. When crossed with archaeological and historical data, our results allowed to propose a reconstruction of the palaeogeographic evolution and geomorphological dynamics in the eastern lobe of the Nestos Delta, the Kosynthos plain, Lake Vistonida and the Porto Lagos coast since the Antiquity. Our results suggest that the delta developed mainly between Hellenistic times and the Late Antiquity, when it had reached a shape similar to the current. Most of the large palaeochannels visible in the delta seem to be Nestos’ short-lived avulsions occurring in late Byzantine and Ottoman periods. Eastwards progradation of the Kosynthos plain, especially during Byzantine and Ottoman periods and accelerating in the 20th c. due to river channelization, was the main cause of the silting and a significant size reduction of Lake Vistonida since the Antiquity. Lake Lafra was also partially silted in late Byzantine and Ottoman times, likely due to the sedimentary discharge of the Kosynthos after a change in its course. By contrast, other lagoons and wetlands in the coast of Porto Lagos seem relatively stable in the last millennia with only minor silting and coastline progradation. Further geomorphological and geoarchaeological research in the area will allow to draw more precisely long-term interaction of past societies with environmental dynamics and resulting landscape change.

Emerging evidence suggests the gut microbiome’s potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome’s impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.

Understanding the origin of eukaryotic cells is one of the most difficult problems in all of biology. A key challenge relevant to the question of eukaryogenesis is reconstructing the gene repertoire of the last eukaryotic common ancestor (LECA). As data sets grow, sketching an accurate genomics-informed picture of early eukaryotic cellular complexity requires provision of analytical resources and a commitment to data sharing. Here, we summarise progress towards understanding the biology of LECA and outline a community approach to inferring its wider gene repertoire. Once assembled, a robust LECA gene set will be a useful tool for evaluating alternative hypotheses about the origin of eukaryotes and understanding the evolution of traits in all descendant lineages, with relevance in diverse fields such as cell biology, microbial ecology, biotechnology, agriculture, and medicine. In this Consensus View, we put forth the status quo and an agreed path forward to reconstruct LECA's gene content.

Introduction Malaria molecular surveillance has the potential to generate information on biological threats that compromise the effectiveness of antimalarial interventions. This study aims to streamline surveillance activities to inform the new strategic plan of the Mozambican National Malaria Control Programme (2023–2030) for malaria control and elimination.Methods and analyses This prospective genomic surveillance study aims to generate Plasmodium falciparum genetic data to monitor diagnostic failures due to pfhrp2/3 deletions and molecular markers of antimalarial drug resistance, to characterise transmission sources and to inform the implementation of new antimalarial approaches to be introduced in Mozambique (chemoprevention and child malaria vaccination). The study, to be conducted between 2024 and 2026, will use three sampling schemes: a multicluster probabilistic health facility survey in the 10 provinces of the country to detect pfhrp2/3 deletions and markers of antimalarial drug resistance; dense sampling of all clinical cases in representative districts in the south targeted for elimination to characterise malaria importation and identify sources of transmission; and testing of pregnant women for malaria at their first antenatal care visit to assess malaria burden and molecular trends. Using a multiplex amplicon-based sequencing approach, the study will target microhaplotypes informative of genomic diversity and relatedness, as well as key drug resistance-associated genes, pfhrp2/3 deletion and malaria vaccine targets. Key genomic information will be visualised in a dashboard integrated into the District Health Information System V.2-based Malaria Information Storage System for programmatic use.Ethics and dissemination The protocol was reviewed and approved by the national ethics committee of Mozambique (Comité Nacional de Bioética para Saúde, Ref: 680/CNBS/23). Project results will be presented to all stakeholders using study-specific brochures and published in open-access journals.Trial registration number NCT06529237.

Abstract Permanently polarized biphasic calcium phosphate composed of hydroxyapatite and brushite (pp‐HAp/Bru), which is prepared by applying the thermally stimulated polarization treatment to calcined HAp, is used as a sustainable catalyst to transform CO2 into value‐added products. In this work, the stability of pp‐HAp/Bru is studied from structural, electrical, and catalytic perspectives, applying a thermal depolarization process with temperatures (Td) ranging from 200 to 1000 °C. Results show that the Bru phase is not stable when Td ≤ 400 °C, while the structure of the HAp refines and transforms into Bru when Td ≥ 600 °C. Besides, the electrical resistance and capacitance of the pp‐HAp/Bru increase with Td, evidencing the progressive electrical depolarization of the material. Thermal depolarization also influences the specific orientation of the OH– ions, which is partially lost (≈50%). All such changes affect the catalytic efficiency of pp‐HAp/Bru, which is proven using a reaction that transforms CO2 gas into acetic acid and formic acid. Results show that the total reaction yield linearly decreases with increasing Td. Based on such observations, a simple process is designed that allows the reconstitution of the structure and restores the activity of such green catalysts.

IntroductionBacteremia is a life-threatening condition that can progress to sepsis and septic shock, leading to significant mortality in the emergency department (ED). The standard diagnostic method, blood culture, is time-consuming and prone to false positives and false negatives. Although not widely accepted, several clinical and artificial intelligence-based algorithms have been recently developed to predict bacteremia. However, these strategies require further identification of new variables to improve their diagnostic accuracy. This study proposes a novel strategy to predict positive blood cultures by assessing sepsis-induced immunosuppression status through endotoxin tolerance assessment.MethodsOptimal assay conditions have been explored and tested in sepsis-suspected patients meeting the Sepsis-3 criteria. Blood samples were collected at ED admission, and endotoxin (lipopolysaccharide, LPS) challenge was performed to evaluate the innate immune response through cytokine profiling.ResultsClinical variables, immune cell population biomarkers, and cytokine levels (tumor necrosis factor [TNFα], IL-1β, IL-6, IL-8, and IL-10) were measured. Patients with positive blood cultures exhibited significantly lower TNFα production after LPS challenge than did those with negative blood cultures. The study also included a validation cohort to confirm that the response was consistent.DiscussionThe results of this study highlight the innate immune system immunosuppression state as a critical parameter for sepsis diagnosis. Notably, the present study identified a reduction in monocyte populations and specific cytokine profiles as potential predictive markers. This study showed that the LPS challenge can be used to effectively distinguish between patients with bloodstream infection leading to sepsis and those whose blood cultures are negative, providinga rapid and reliable diagnostic tool to predict positive blood cultures. The potential applicability of these findings could enhance clinical practice in terms of the accuracy and promptness of sepsis diagnosis in the ED, improving patient outcomes through timely and appropriate treatment.

The experimental approach developed in this research demonstrated how the cloud, the Internet of Things (IoT), edge computing, and Artificial Intelligence (AI), considered key technologies in Industry 4.0, provide the expected horizon for adaptive vision in Continued Process Verification (CPV), the final stage of Process Validation (PV). Pichia pastoris producing Candida rugosa lipase 1 under the regulation of the constitutive GAP promoter was selected as an experimental bioprocess. The bioprocess worked under hypoxic conditions in carbon-limited fed-batch cultures through a physiological control based on the respiratory quotient (RQ). In this novel bioprocess, a digital twin (DT) was built and successfully tested. The implementation of online sensors worked as a bridge between the microorganism and AI models, to provide predictions from the edge and the cloud. AI models emulated the metabolism of Pichia based on critical process parameters and actionable factors to achieve the expected quality attributes. This innovative AI-aided Adaptive-Proportional Control strategy (AI-APC) improved the reproducibility comparing to a Manual-Heuristic Control strategy (MHC), showing better performance than the Boolean-Logic-Controller (BLC) tested. The accuracy, indicated by the Mean Relative Error (MRE), was for the AI-APC lower than 4%, better than the obtained for MHC (10%) and BLC (5%). Moreover, in terms of precision, the same trend was observed when comparing the Root Mean Square Deviation (RMSD) values, becoming lower as the complexity of the controller increases. The successful automatic real time control of the bioprocess orchestrated by AI models proved the 4.0 capabilities brought by the adaptive concept and its validity in biopharmaceutical upstream operations.