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Primary objective: To study the predictive capacity of early S100 [beta] samples for long-term outcome prediction after severe TBI. Methods and procedures: Eighty-seven patients with severe TBI were studied. Clinical and CT scan were taken at admission. S100 [beta] concentration was quantified at admission and 24, 48 and 72 hours post-TBI (days 0, 1, 2 and 3). Outcome was assessed 12 months after discharge using Glasgow Outcome Score (GOS). Results: Significant negative correlations were found between 1-year GOS and S100 [beta] concentrations on days 1-3, but not on day 0. Deceased patients showed higher S100 [beta] concentration than survivors on days 1-3. Good (GOS = 4-5) vs poor outcome (GOS = 1-3) differed significantly on day 3. Death outcome was independently predicted by day 2 (>2.37 ug l-1), day 3 (>1.41 ug l-1) samples and absence of pupillary reaction. Poor outcome was predicted independently only by pupillary reaction and the 72-hour sample (>1.1 ug l-1), but this predictive model was less satisfactory than the predictive model for death. Conclusions: A temporal profile of S100 [beta] release from admission to 72 hours post-TBI is strongly recommended for use in identifying patients at risk of developing a worse outcome. The S100 [beta] protein might be an early biomarker for predicting long-term outcome in patients with acute severe TBI. [ABSTRACT FROM AUTHOR]

Engineered living systems (ELSs) represent purpose-driven assemblies of living components, encompassing cells, biomaterials, and active agents, intricately designed to fulfill diverse biomedical applications. Gelatin and its derivatives have been used extensively in ELSs owing to their mature translational pathways, favorable biological properties, and adjustable physicochemical characteristics. This review explores the intersection of gelatin and its derivatives with fabrication techniques, offering a comprehensive examination of their synergistic potential in creating ELSs for various applications in biomedicine. It offers a deep dive into gelatin, including its structures and production, sources, processing, and properties. Additionally, the review explores various fabrication techniques employing gelatin and its derivatives, including generic fabrication techniques, microfluidics, and various 3D printing methods. Furthermore, it discusses the applications of ELSs based on gelatin in regenerative engineering as well as in cell therapies, bioadhesives, biorobots, and biosensors. Future directions and challenges in gelatin fabrication are also examined, highlighting emerging trends and potential areas for improvements and innovations. In summary, this comprehensive review underscores the significance of gelatin-based ELSs in advancing biomedical engineering and lays the groundwork for guiding future research and developments within the field., (© 2025 Wiley‐VCH GmbH.)

Purpose: Imaging biomarkers bear great promise for improving the diagnosis and prognosis of cognitive impairment in Parkinson's disease (PD). We compared the ability of three commonly used neuroimaging modalities to detect cortical changes in PD patients with mild cognitive impairment (PD-MCI) and dementia (PDD)., Methods: 53 cognitively normal PD patients (PD-CN), 32 PD-MCI, and 35 PDD underwent concurrent structural MRI (sMRI), diffusion-weighted MRI (dMRI), and [ 18 F]FDG PET. We extracted grey matter volumes (sMRI), mean diffusivity (MD, dMRI), and standardized uptake value ratios ([ 18 F]FDG PET) for 52 cortical regions included in a neuroanatomical atlas. We assessed group differences using ANCOVA models and further applied a cross-validated machine learning approach to identify the modality-specific brain regions that are most indicative of dementia status and assessed their diagnostic accuracy for group separation using receiver operating characteristic analyses., Results: In sMRI, atrophy of temporal and posterior-parietal areas allowed separating PDD from PD-CN (AUC = 0.77 ± 0.07), but diagnostic accuracy was poor for separating PD-MCI from PD-CN (0.57 ± 0.10). dMRI showed most pronounced diffusivity changes in the medial temporal lobe, which provided excellent diagnostic performance for PDD (AUC = 0.87 ± 0.06), and a more modest but still significant performance for PD-MCI (AUC = 0.71 ± 0.09). Finally, [ 18 F]FDG PET revealed pronounced hypometabolism in posterior-occipital regions, which provided the highest diagnostic accuracies for both PDD (AUC = 0.89 ± 0.05) and PD-MCI (AUC = 0.78 ± 0.05). In statistical comparisons, both [ 18 F]FDG PET (p < 0.001) and dMRI (p < 0.031) outperformed sMRI for detecting PDD and PD-MCI., Conclusion: Among the tested modalities, [ 18 F]FDG PET was most accurate for detecting cortical changes associated with cognitive impairment in PD, especially at early stages. Diffusion measurements may represent a promising MRI-based alternative., Competing Interests: Declarations. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University hospital ‘Virgen del Rocío’ (Date: 08/01/2021, approval number: 2158-N-20). Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2025. The Author(s).)

Background: Combining antinociceptive drugs with different mechanisms of action can reduce the doses and the adverse effects, with a possible increase in the antinociceptive effect. This work evaluated the antinociceptive effect of the combination of an ethanol extract of Justicia spicigera (JSE) with naproxen (NPX) or tramadol (TML) using the formalin test in rats. Methods: Rats received JSE (30-200 mg/kg p.o.), NPX (50-300 mg/kg p.o.), or TML (5-50 mg/kg p.o.) 60 min before paw administration with formalin (5%). Different proportions of the combination between NPX and JSE, as well as TML and JSE, were used in the formalin test to obtain the dose-response curve of each drug and the experimental effective dose 50 (ED 50 ). The levels of IL-1β and COX2 were assessed using a Western blot analysis as a possible mechanism of action for the combination of JSE and analgesics. A pharmacokinetic study was conducted to evaluate the effect of JSE on the pharmacokinetic parameters of NPX. Results: The ED 50 values for the proportions NPX:JSE were 107.09 mg/kg (1:1), 102.44 mg/kg (3:1), and 73.82 mg/kg (1:3). The ED 50 values for the proportions TML:JSE were 66 mg/kg (1:1), 29.5 mg/kg (1:3), and 78 mg/kg (3:1). The combination NPX:JSE (1:3) showed the best synergistic interaction index (0.501). The pharmacokinetic study revealed that there were no significant changes in the pharmacokinetic parameters of NPX administered individually and the combination NPX:JSE. Conclusions: In this preclinical study, the combination NPX:JSE showed antinociceptive effects by decreasing the levels of COX2 and IL-1β without affecting NPX's pharmacokinetics.

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson's disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [ 18 F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [ 18 F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R 2  = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R 2  = 0.16, p = 0.01). Topographic correspondence analysis with the [ 18 F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman's ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Hospital ‘Virgen del Rocío’ (approval number: 2158-N-20). Consent for publication: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Middle meningeal artery embolization (MMAE) has emerged as a promising therapy for chronic subdural hematomas (cSDHs). The efficacy of standalone MMAE compared with MMAE with concurrent surgery is largely unknown., Methods: cSDH patients who underwent successful MMAE from 14 high volume centers with at least 30 days of follow-up were included. Clinical and radiographic variables were recorded and used to perform propensity score matching (PSM) of patients treated with standalone MMAE or MMAE with concurrent surgery. Multivariable logistic regression models were used for additional covariate adjustments. The primary outcome was recurrence requiring surgical rescue, and the secondary outcome was radiographic failure defined as <50% reduction of cSDH thickness., Results: 722 MMAE procedures in 588 cSDH patients were identified. After PSM, 230 MMAE procedures remained (115 in each group). Median age was 73 years, 22.6% of patients were receiving anticoagulation medication, and 47.9% had no preoperative functional disability. Median midline shift was 4 mm and cSDH thickness was 16 mm, representing modestly sized cSDHs. Standalone MMAE and MMAE with surgery resulted in similar rates of surgical rescue (7.8% vs 13.0%, respectively, P=0.28; adjusted OR (aOR 0.73 (95% CI 0.20 to 2.40), P=0.60) and radiographic failure (15.5% vs 13.7%, respectively, P=0.84; aOR 1.08 (95% CI 0.37 to 2.19), P=0.88) with a median follow-up duration of 105 days. These results were similar across subgroup analyses and follow-up durations., Conclusions: Standalone MMAE led to similar and durable clinical and radiographic outcomes as MMAE combined with surgery in select patients with moderately sized cSDHs and mild clinical disease., Competing Interests: Competing interests: AMS: grants or contracts from Penumbra, Microvention, Medtronic, and Stryker; consulting fees from Penumbra, Terumo, and Rapid AI; co-founder of the STAR collaboration; stock or stock options in Avail Medical. AHS: grants or contracts from NIH and Brain Aneurysm Foundation; consulting fees from Amnis Therapeutics, Apellis Pharmaceuticals, Boston Scientific, Canon Medical Systems USA, Cardinal Health 200, Cerebrotech Medical Systems, Cerenovus, Cordis, Corindus, Endostream Medical, Hyperfine Operations, Imperative Care, InspireMD, Integra, IRRAS AB, Medtronic, MicroVention, Minnetronix Neuro, Peijia Medical, Penumbra, Piraeus Medical, Q’Apel Medical, Rapid Medical, Serenity Medical, Silk Road Medical, StimMed, Stryker Neurovascular, VasSol, and Viz.ai; patents planned, issued, or pending for patent No US 11,464,528 B2; stock or stock options in Adona Medical, Bend IT Technologies, BlinkTBI, Borvo Medical, Cerebrotech Medical Systems, Code Zero Medical, Cognition Medical, Collavidence, CVAID, E8, Endostream Medical, Galaxy Therapeutics, Hyperion Surgical, Imperative Care, InspireMD, Instylla, Launch NY, Neurolutions, NeuroRadial Technologies (sold to Medtronic in 2021), Neurovascular Diagnostics, Peijia Medical, PerFlow Medical, Piraeus Medical, Q’Apel Medical, QAS.ai, Radical Catheter Technologies, Rebound Therapeutics (purchased in 2019 by Integra Lifesciences), Rist Neurovascular (purchased in 2020 by Medtronic), Sense Diagnostics, Serenity Medical, Silk Road Medical, Sim & Cure, Spinnaker Medical, StimMed, Synchron, Tulavi Therapeutics, Vastrax, Viseon, Whisper Medical, and Willow Medtech; national PI/steering committees for Cerenovus (EXCELLENT and ARISE II trial), Medtronic (SWIFT-PRIME, VANTAGE, EMBOLISE, and SWIFT DIRECT trials), MicroVention (FRED trial and CONFIDENCE study), MUSC (POSITIVE trial), Penumbra (3D Separator trial, COMPASS trial, INVEST trial, MIVI neuroscience EVAQ trial), Rapid Medical (SUCCESS trial), and InspireMD (C-GUARDIANS IDE Pivotal trial).TGJ: consulting fees from Stryker, Silk Road Medical, Blockade Medical, FreeOx Biomedical, Route 92, Neurotrauma Science, Viz.ai, Corindus, Anaconda, Medtronic, Contego, Methinks DAWN, AURORA, and Stryker Neurovascular. RG: consulting fees from Medtronic, Stryker, Cerenovus, Balt, and Rapid Medical. MRL: grants or contracts from NIH, The Aneurysm and AVM Foundation, Society of NeuroInterventional Surgery, and Congress of Neurosurgeons; consulting fees from Metis Innovative and Aeaean Advisers; support for attending meetings and/or travel from Penumbra; participated on the DSMB of Arsenal Medical; serves on the editorial boards of Journal of NeuroInterventional Surgery and Frontiers in Surgery; equity interest in Hyperion Surgical, Proprio, Apertur, Cerebrotech, Synchron, Fluid Biomed, and Stereotaxis; unrestricted educational grants from Medtronic and Stryker. CSO: DSMB for Medtronic (EMBOLISE) and Contour. BAG: consultant for Medtronic, Stryker, and Microvention. PK: grants or contracts from NIH, Siemens, Medtronic, and Joe Niekro Foundation; consulting fees from Stryker Neurovascular and Imperative Care; editorial board of Journal of NeuroInterventional Surgery; stock or stock options in Vena Medical., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The isocyanate-derived fraction resulting as the bottom phase from the split-phase glycolysis of conventional polyurethane flexible foams has been given a new life based on the formation of amine-based polymers (polyureas and polyamides). For that purpose, the bottom phase was first hydrolyzed, producing toluenediamine and diethylene glycol, and further subjected to controlled vacuum distillation in order to recover both products separately. The hydrolysis reaction and the separation process conditions were determined and optimized, obtaining products with a purity comparable to that of commercial ones. Then, the recovered diethylene glycol was used in a new glycolysis process, obtaining a split-phase product with properties similar to those obtained using commercial diethylene glycol. Finally, the recovered toluenediamine was used in the synthesis of polyureas and polyamides. Both syntheses were modified with respect to the state of the art, replacing benzene with limonene in the synthesis of polyamides, which implies environmental improvements., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background/objectives: Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adult patients with chronic immune thrombocytopenia (ITP). There is little information about dose tapering and sustained remission after discontinuation in ITP. In this retrospective multicenter study, we evaluated efficacy and safety of fostamatinib in adult patients with ITP before, during, and after tapering/discontinuation (T/D). Methods: T/D was performed on subjects who achieved complete platelet response (CR) with progressive, conditional dose reduction every four weeks. Results: Sixty-one patients were included from 14 reference centers between October 2021 and May 2023. In subjects that completed T/D (n = 9), the median time from treatment initiation to response was 21 days (IQR: 7.5-42), median time from treatment initiation to CR was 28 days (IQR: 28-42), median time from treatment initiation to the start of tapering was 116 days (IQR: 42-140), and duration of tapering was 112.5 days (IQR: 94.5-191). The median platelet count was 232 × 10 9 /L (IQR: 152-345 × 10 9 /L) at tapering and 190 × 10 9 /L (IQR: 142.5-316.5 × 10 9 /L) at discontinuation. With a median follow-up since discontinuation of 263 days (IQR: 247-313 days), only two patients have relapsed (at 63 and 73 days). Fostamatinib was restarted, achieving a new CR. Platelet counts higher than 100 × 10 9 /L in week 12 were the only positive predictive factors for successful tapering and discontinuation. Conclusions: Sustained response in patient with ITP treated with fostamatinib could be developed. The prognostic factors and recommended scheme of tapering still have to be evaluated.

El sistema de salud mexicano ha experimentado cambios en su organización y gobernanza y se enfrenta a un perfil de salud que implica desafíos para alcanzar la cobertura universal en salud. Para dar cuenta de estos cambios se presenta un análisis comparativo de indicadores entre 2015-2017 y 2021-2022 según la disponibilidad de las fuentes de información. En el perfil de salud se presenta información de los fenómenos demográficos y sociales, las condiciones de salud de la población y el Covid-19. Como parte de organización y gobernanza se describe la estructura básica del sistema, el modelo de atención, la disponibilidad de recursos humanos, infraestructura, medicamentos y tecnología, y financiamiento del sistema. Finalmente se presentan los logros en términos de acceso a la atención de salud, cobertura, calidad y seguridad. A partir del análisis y discusión de la información se identifican algunos desafíos del sistema de salud mexicano para orientar la política en salud futura.

This paper addresses the influence of bubbling flow and service life of the Ti|Ti-Ru-Ir-oxides anode during the electrosynthesis of HClO in a laboratory-scale filter-press-type electrolyzer. The electrolyzer was assembled in a flow plant in recirculation mode. Polarization curves in rotating disk electrode (RDE) revealed the coexistence of the oxygen evolution reaction (OER) during HClO electrosynthesis in diluted chloride solutions (containing 35 mM NaCl at pH 3). CFD simulations of the two-phase (O 2 -H 2 O) flow were obtained by solving simultaneously the Navier-Stokes and charge conservation equations using a finite element method code. The O 2 -H 2 O simulations show the efficient gas release in the electrolyzer provoked by the continuous phase (H 2 O) inertia and the well-engineered cell design. The moderated O 2 dispersion caused a quasi-homogeneous current distribution along the anode. However, the current efficiency during HClO electrosynthesis gave values of ∼32% provoked by the OER on the anode. The HClO accumulations (from 3.02 to 6.64 mM) showed excellent agreement with CFD simulations. The accelerated life tests revealed that the Ti | Ti-Ru-Ir-oxides anode has a lifetime of at least 26 years during the HClO electrosynthesis in diluted chloride solutions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Keratoconus is a non-inflammatory bilateral disease, that usually occurs in the inferior-temporal region, where the cornea bulges out and becomes thinner, due to the gradual loss of structural organization in corneal tissue. Degenerated extracellular matrix and fibers breakage have been observed in keratoconic corneas, that may promote the progression of the pathology. While keratoconus histopathology has been widely described in literature, its etiology is still not clear. Being able to fully understand keratoconus growing process could be crucial to detect its development and improve prevention strategies. This work proposes a novel continuum-based keratoconus growth model. The proposed framework accounts for the structural changes occurring in the underlying tissue during the progression of the disease, as indicated in experiments. The developed formulation is able to replicate the typical bulging and thinning of keratoconic corneas, as well as different forms in terms of shape, as they are commonly classified in clinics (nipple, oval and globus cones). The cone that is obtained constitutes a permanent deformed state, not pressure dependent. The resulting model may help to better understand the etiology of the behavior of this disease with the aim of improving the diagnosis and the treatment of the pathology., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 78-year-old man with a previous diagnosis of rheumatoid arthritis on prolonged treatment with corticosteroids presented with intense and progressive pain at the cervical level that prevented him from resting his head and walking, in addition to an ulcerative lesion covering 80% of the lingual area that was previously treated as oral candidiasis without improvement. On arrival, with no clinical or serological data of rheumatoid arthritis, immunosuppressive treatment was suspended, and a biopsy of the oral cavity was requested, confirming the diagnosis of lingual tuberculosis, an extremely rare disease, occurring in less than 1% of extrapulmonary cases. MRI of the cervical spine showed a crush fracture of the C6 and C7 bodies associated with spondylitis of probably infectious etiology that required surgical treatment, and histopathological studies confirmed Pott's disease. The patient displayed no evidence of pulmonary tuberculosis from arrival until the end of the follow-up.

Objective: COVID-19 has evidenced the importance of a Primary and Community Care (PCC), able to respond in the front line with capacity and adaptation to health and social crises. In order to reinforce its role, the Strategic Framework for Primary and Community Care was created in 2019, and one of its lines of action is to consolidate a budgetary and human resources policy. This translates into the Primary Care Action Plan 2022 and 2023, which includes the adequacy of HHRR based on the morbidity attended, health outcomes and sociodemographic characteristics. For this purpose, the development of the model for its calculation is urged. The objective of this paper was to offer a model as a guideline for the adequacy of the needs of Family Care Units (FAU)., Methods: The study was carried out in the Tenerife Health Area, which has 41 ZBS with 97 health care centers. The variables weighted in the model were: percentage of people over 65 years of age; utilization index; complexity by GMA (Adjusted Morbidity Groups) and frequentation. An Adequate Quota Index was calculated to establish the quota for each health care center between 1,200 and 1,600 per UAF and projection to 2025., Results: The total need for UAF increase was 62, compared to 57 with the capita criterion of 1,500, at the extremes of the model range there were 12 centers of 1,200 and 11 of 1,600., Conclusions: In a very heterogeneous Health Area, the model achieves a more equitable allocation without increasing in practice the need for FAUs compared to the capitated criterion.

Background:  Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes ( DNMT3A, TET2, and ASXL1 ). The objective of this study was to confirm this observation in a larger series of PV patients., Methods:  PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias., Results:  Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort ( p  = 0.007), as well as in low-risk patients ( p  = 0.039) and older patients ( p  = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation., Conclusion:  Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Secondary metabolites produced by the fermentation of Streptomyces avermitilis bacterium are powerful antiparasitic agents used in animal health, agriculture and human infection treatments. Avermectin is a macrocyclic lactone with four structural components (A1, A2, B1, B2), each of them containing a major and a minor subcomponent, out of which avermectin B1a is the most effective parasitic control compound. Avermectin B1a produces two homologue avermectins (B1 and B2) that have been used in agriculture as pesticides and antiparasitic agents, since 1985. It has a great affinity with the Cl-channels of the glutamate receptor, allowing the constant flow of Cl- ions into the nerve cells, causing a phenomenon of hyperpolarization causing death by flaccid paralysis. The purpose of this work was to gather information on the production of avermectins and their biocidal effects, with special emphasis on their role in the control of pests and phytopathogenic diseases. The literature showed that S. avermitilis is an important producer of macrocyclic lactones with biocidal properties. In addition, avermectin contributes to the control of ectoparasites and endoparasites in human health care, veterinary medicine and agriculture. Importantly, avermectin is a compound that is harmless to the host (no side effects), non-target organisms and the environment., Competing Interests: The authors declare no conflict of interest.

3D printing technology is a tremendously powerful technology to fabricate electrochemical sensing devices. However, current conductive filaments are not aimed at electrochemical applications and therefore require intense activation protocols to unleash a suitable electrochemical performance. Current activation methods based on (electro)chemical activation (using strong alkaline solutions and organic solvents and/or electrochemical treatments) or combined approaches are time-consuming and require hazardous chemicals and dedicated operator intervention. Here, pioneering spark-discharge-activated 3D-printed electrodes were developed and characterized, and it was demonstrated that their electrochemical performance was greatly improved by the effective removal of the thermoplastic support polylactic acid (PLA) as well as the formation of sponge-like and low-dimensional carbon nanostructures. This reagent-free approach consists of a direct, fast, and automatized spark discharge between the 3D-electrode and the respective graphite pencil electrode tip using a high-voltage power supply. Activated electrodes were challenged toward the simultaneous voltammetric determination of dopamine (DP) and serotonin (5-HT) in cell culture media. Spark discharge has been demonstrated as a promising approach for conductive filament activation as it is a fast, green (0.94 GREEnness Metric Approach), and automatized procedure that can be integrated into the 3D printing pipeline.

Immune thrombocytopenia (ITP) is characterized by low platelet counts (PLTs) and an increased risk of bleeding. Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved as a second-line treatment for ITP. Real-world data on fostamatinib are lacking. This observational, retrospective, multicentre study, conducted in the Andalusia region of Spain, evaluated 44 adult primary ITP patients (47.7% female; median age 58 years; newly diagnosed ITP 6.8%; persistent 13.6%; chronic 79.5%; median four prior treatments) after ≥ 4 weeks of fostamatinib therapy. The median PLT at the initiation of fostamatinib was 15 × 10 9 /L. Common reasons for starting fostamatinib were refractoriness or intolerance to prior therapy, oral medication preference, history of thrombosis and cardiovascular risk. Dosing was individualized based on efficacy and tolerance. After 2 weeks, global response rate was 56.8% (response and complete response). Response rates were 70.5%, 62.5% and 64% at 4 weeks, 12 weeks and at the end of the study respectively. Adverse events were mild, and no patients discontinued as a result. This real-world study demonstrated a response rate similar to fostamatinib as seen in the pivotal clinical trials while including newly diagnosed patients and allowing for individualized dosing., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy., Summary: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level., Key Messages: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The demand for natural products in the treatment of dermatological pathologies has boosted the use of bioactive substances such as lavender essential oil (LEO), which stands out for its anti-inflammatory and antioxidant properties and its antimicrobial potential. Biopolymers such as chitosan (CHT) and alginate (ALG) are biodegradable and biocompatible and have proven their viability in biomedical applications such as skin regeneration. The inhibitory effect of LEO on the growth of skin-related bacterial species Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa and the fungus Candida albicans was studied by incorporating 1% v/v LEO encapsulated in CHT, ALG, and CHT/ALG membranes. Despite the verification of the antimicrobial effect of all type of membranes, no synergistic effect was observed following the addition of LEO. S. aureus and P. aeruginosa showed the most growth on the different substrates and C. albicans demonstrated the highest inhibition. This is a first approach using microorganisms isolated from clinical samples or skin microbiota. Further investigation would be advisable using more clinical strains for each microorganism to validate their biomedical applicability.

Three-dimensional (3D) printing technology has emerged as a powerful technology for the fabrication of low-cost microfluidics. Nevertheless, the fabrication of microfluidic devices integrating high-performance electrochemical sensors in practical applications is still an open challenge. Although automatic fabrication of the microfluidic device and the electrodes can be successfully carried out using a one-step multimaterial fused filament fabrication (FFF) approach, the as-printed electrochemical performance of these electrodes is not good enough for chemical (bio)sensing and their surface modification is challenging because after closing the channel there is no physical access to the electrode. Thus, here a pause-print-pause (PPP) microfabrication approach was implemented. The fabrication was paused before printing the microfluidics, and the filament-based electrodes were directly modified on the printing bed via stencil printing, drop casting, and electrodeposition. To exemplify this versatile workflow, the design of a microfluidic glucose sensor was proposed. To this end, first, the working and counter electrodes were stencil printed with graphite ink while the reference electrode was stencil printed with Ag|AgCl ink. Then, Prussian blue was formed on the working electrode either by drop casting or by electrodeposition, and glucose oxidase was drop cast on top. At this point, the microfabrication process was resumed, and the microfluidics were printed on top of the modified electrodes to complete the construction of hybrid electrochemical fluidic fused filament fabricated devices (h-eF 4 Ds). This print-pause-print approach is not limited to ink-based electrodes or glucose oxidase, and we envisage these results will pave the way for the effective integration of electrodes in microfluidic devices in a simple and clean-room-free approach, allowing the development of highly customized eF 4 Ds for a plethora of analytes with high significance.

Aims: Depression and anxiety are the leading contributors to the global burden of disease among young people, accounting for over a third (34.8%) of years lived with disability. Yet there is limited evidence for interventions that prevent adolescent depression and anxiety in low- and middle-income countries (LMICs), where 90% of adolescents live. This article introduces the 'Improving Adolescent mentaL health by reducing the Impact of poVErty (ALIVE)' study, its conceptual framework, objectives, methods and expected outcomes. The aim of the ALIVE study is to develop and pilot-test an intervention that combines poverty reduction with strengthening self-regulation to prevent depression and anxiety among adolescents living in urban poverty in Colombia, Nepal and South Africa., Methods: This aim will be achieved by addressing four objectives: (1) develop a conceptual framework that identifies the causal mechanisms linking poverty, self-regulation and depression and anxiety; (2) develop a multi-component selective prevention intervention targeting self-regulation and poverty among adolescents at high risk of developing depression or anxiety; (3) adapt and validate instruments to measure incidence of depression and anxiety, mediators and implementation parameters of the prevention intervention; and (4) undertake a four-arm pilot cluster randomised controlled trial to assess the feasibility, acceptability and cost of the selective prevention intervention in the three study sites., Results: The contributions of this study include the active engagement and participation of adolescents in the research process; a focus on the causal mechanisms of the intervention; building an evidence base for prevention interventions in LMICs; and the use of an interdisciplinary approach., Conclusions: By developing and evaluating an intervention that addresses multidimensional poverty and self-regulation, ALIVE can make contributions to evidence on the integration of mental health into broader development policy and practice.

Despite multiple studies of the impact of climate change on temperate tree species, experiments on tropical and economically important tree crops, such as cacao (Theobroma cacao L.), are still limited. Here, we investigated the combined effects of increased temperature and atmospheric carbon dioxide concentration ([CO2]) on the growth, photosynthesis and development of juvenile plants of two contrasting cacao genotypes: SCA 6 and PA 107. The factorial growth chamber experiment combined two [CO2] treatments (410 and 700 p.p.m.) and three day/night temperature regimes (control: 31/22 °C, control + 2.5 °C: 33.5/24.5 °C and control + 5.0 °C: 36/27 °C) at a constant vapour pressure deficit (VPD) of 0.9 kPa. At elevated [CO2], the final dry weight and the total and individual leaf areas increased in both genotypes, while the duration for individual leaf expansion declined in PA 107. For both genotypes, elevated [CO2] also improved light-saturated net photosynthesis (Pn) and intrinsic water-use efficiency (iWUE), whereas leaf transpiration (E) and stomatal conductance (gs) decreased. Under a constant low VPD, increasing temperatures above 31/22 °C enhanced the rates of Pn, E and gs in both genotypes, suggesting that photosynthesis responds positively to higher temperatures than previously reported for cacao. However, dry weight and the total and individual leaf areas declined with increases in temperature, which was more evident in SCA 6 than PA 107, suggesting the latter genotype was more tolerant to elevated temperature. Our results suggest that the combined effect of elevated [CO2] and temperature is likely to improve the early growth of high temperature-tolerant genotypes, while elevated [CO2] appeared to ameliorate the negative effects of increased temperatures on growth parameters of more sensitive material. The evident genotypic variation observed in this study demonstrates the scope to select and breed cacao varieties capable of adapting to future climate change scenarios., (© The Author(s) 2023. Published by Oxford University Press.)

Although several scores stratify venous thromboembolism (VTE) risk in solid tumors, hematologic malignancies (HM) are underrepresented. To develop an internal and external validation of a logistic regression model to predict VTE risk in hospitalized HM patients. Validation of the existing VTE predictive model was performed through a prospective case-control study in 496 hospitalized HM patients between December 2010 and 2020 at the Arnaldo Milián University Hospital, Cuba. The predictive model designed with data from 285 patients includes 5 predictive factors: hypercholesterolemia, tumoral activity, use of thrombogenic drugs, diabetes mellitus, and immobilization. The model was internally validated using bootstrap analysis. External validation was realized in a prospective cohort of 211 HM patients. The predictive model had a 76.4% negative predictive value (NPV) and an 81.7% positive predictive value (PPV) in the bootstrapping validation. The area under curve (AUC) in the bootstrapping set was 0.838. Accuracy was 80.1% and 82.9% in the internal and external validation, respectively. In the external validation, the model produced 89.7% of NPV, 67.7% of PPV, 74.6% of sensitivity, and 86.2% of specificity. The AUC in the external validation was 0.900. VTE predictive model is a reproducible and simple tool with good accuracy and discrimination., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset., Competing Interests: The authors declare no conflict of interest.

Over the past few years, the COVID-19 pandemic has exerted various impacts on the world, notably concerning mental health. Nevertheless, the precise influence of psychosocial stressors on this mental health crisis remains largely unexplored. In this study, we employ natural language processing to examine chat text from a mental health helpline. The data was obtained from a chat helpline called Safe Hour from the "It Gets Better" project in Chile. This dataset encompass 10,986 conversations between trained professional volunteers from the foundation and platform users from 2018 to 2020. Our analysis shows a significant increase in conversations covering issues of self-image and interpersonal relations, as well as a decrease in performance themes. Also, we observe that conversations involving themes like self-image and emotional crisis played a role in explaining both suicidal behavior and depressive symptoms. However, anxious symptoms can only be explained by emotional crisis themes. These findings shed light on the intricate connections between psychosocial stressors and various mental health aspects in the context of the COVID-19 pandemic., (© 2023. The Author(s).)

Neural adaptations to resistance training (RT) and their correlation with muscle strength remain partially understood. We conducted a systematic review and multivariate meta-analysis to examine the effects of metronome-paced (MP), self-paced (SP), and isometric (IM) training on M1 and corticospinal pathway activity. Following MP RT, a significant increase in corticospinal excitability was observed, correlating with increased strength. Conversely, no significant relationship was found after SP or IM training. RT also reduced the duration of the cortical silent period, but this change did not predict strength changes and was not specific to any training modality. No significant effects were found for short-interval intracortical inhibition. Our findings suggest that changes in corticospinal excitability may contribute to strength gains after RT. Furthermore, the relationship between these adaptations and strength appears dependent on the type of training performed., Competing Interests: Competing interest The authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Whether cirrhotic patients with Streptococcus bovis bacteremia have an increased risk of colorectal neoplasm is uncertain. A multicentric retrospective cohort study was conducted investigating associations between S. bovis biotype and species, cirrhosis, and colorectal neoplasm. Out of 779 patients with S. bovis bacteremia, 69 (8.7%) had cirrhosis. No differences were found in the prevalence of colorectal neoplasm between cirrhotic and non-cirrhotic patients undergoing colonoscopy. Among cirrhotic patients, prevalence of colorectal neoplasms was higher in S. bovis biotype I (S. gallolyticus) bacteremia (80%) than in S. bovis biotype II (33.3%; p < 0.007). In conclusion, risk of colorectal neoplasm is high among cirrhotic patients with S. gallolyticus bacteremia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

For chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14, p = 0.019) and were older (65.1 vs. 55.7 years, p = 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79, p = 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months, p = 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice.

Introduction and Objective: Headache is a frequent reason for consultation between primary care physicians, emergency services physicians, and neurology specialists; however, it is not always well managed. The Andalusian Society of Neurology's Headache Study Group (SANCE) aimed to analyse headache management at different levels of care., Material and Methods: We conducted a descriptive cross-sectional study with data gathered through a retrospective survey in July 2019. Participants completed a series of structured questionnaires on different social and work-related variables from 4 different groups of healthcare professionals (primary care [PC], emergency departments, neurology departments, headache units)., Results: A total of 204 healthcare professionals completed the survey: 35 emergency department physicians, 113 PC physicians, 37 general neurologists, and 19 neurologists specialising in headache. Eighty-five percent of PC physicians reported prescribing preventive drugs, which were maintained for at least 6 months (59%), with flunarizine and amitriptyline being the most commonly used. Most patients attended at neurology consultations (65%) are referred by PC physicians, with changes in the headache pattern being the main reason for referral (74%). Healthcare professionals across all levels of care showed great interest in headache and in receiving training in headache management (97% of PC physicians, 100% of emergency services physicians, 100% of general neurologists)., Conclusions: Migraine sparks great interest among healthcare professionals from different levels of care. Our results also reveal a lack of resources for headache management, which is reflected in the long waiting times. Other means of bilateral communication between different levels of care should be explored (eg, e-mail)., (Copyright © 2023 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Garlic ( Allium sativum ) has historically been associated with antioxidant, immunomodulatory, and microbiocidal properties, mainly due to its richness in thiosulfates and sulfur-containing phytoconstituents. Sepsis patients could benefit from these properties because it involves both inflammatory and refractory processes. We evaluated the effects of thiosulfinate-enriched Allium sativum extract (TASE) on the immune response to bacterial lipopolysaccharide (LPS) by monocytes from healthy volunteers (HVs) and patients with sepsis. We also explored the TASE effects in HIF-1α, described as the key transcription factor leading to endotoxin tolerance in sepsis monocytes through IRAK-M expression. Our results showed TASE reduced the LPS-triggered reactive oxygen species (ROS) production in monocytes from both patients with sepsis and HVs. Moreover, this extract significantly reduced tumor necrosis factor (TNF)-α, interleukin-1β, and interleukin-6 production in LPS-stimulated monocytes from HVs. However, TASE enhanced the inflammatory response in monocytes from patients with sepsis along with increased expression of human leukocyte antigen-DR. Curiously, these dual effects of TASE on immune response were also found when the HV cohort was divided into low- and high-LPS responders. Although TASE enhanced TNFα production in the LPS-low responders, it decreased the inflammatory response in the LPS-high responders. Furthermore, TASE decreased the HIF-1α pathway-associated genes IRAK-M , VEGFA and PD-L1 in sepsis cells, suggesting HIF-1α inhibition by TASE leads to higher cytokine production in these cells as a consequence of IRAK-M downregulation. The suppression of this pathway by TASE was confirmed in vitro with the prolyl hydroxylase inhibitor dimethyloxalylglycine. Our data revealed TASE's dual effect on monocyte response according to status/phenotype and suggested the HIF-1α suppression as the possible underlying mechanism.

Non-isocyanate polyurethanes (NIPUs) based on biobased polyamines and polycarbonates are a sustainable alternative to conventional polyurethanes (PU). This article discloses a novel method to control the crosslinking density of fully biobased isocyanate-free polyurethanes, synthesized from triglycerides carbonated previously in scCO 2 and different diamines, such as ethylenediamine (EDA), hexamethylenediamine (HMDA) and Priamine TM -1075 (derived from a dimerized fatty acid). As capping substances, water or bioalcohols are used in such a way that the crosslinking density can be adjusted to suit the requirements of the intended application. An optimization of the NIPU synthesis procedure is firstly carried out, establishing the polymerization kinetics and proposing optimal conditions set for the synthesis of the NIPUs. Then, the influence of the partial blocking of the active polymerization sites of the carbonated soybean oil (CSBO), using monofunctional amines, on the physical properties of the NIPUS is explored. Finally, the synthesis of fully biobased NIPUs with a targeted crosslinking density is achieved using hybrid NIPUs, employing partially carbonated oil and H 2 O or ethanol as blockers to achieve the desired physical properties in a very precise manner.

Background: Studies have reported increased incidence of BSI over the past decades and indicate that it is necessary to investigate the causes. The aim of this study was to determine the factors affecting trends in the incidence of bacteraemias and associated mortality., Methods: We conducted a retrospective cohort study assessing prospectively collected data of all clinically significant bacteraemias between 1991 and 2020 in a 450-bed hospital. We determined the evolution of bacteraemia-associated incidence, adjusted 30-day mortality and performed multivariable logistic regression to compare the evolution of variables associated with mortality between 5-year periods., Results: 6777 episodes were included, 59.7% males, age 66.5 ± 18.2, 39.4% ≥ 75 years. The incidence total increased: 43.8/100,000/year in 1991-1995 to 205 in 2016-2020; community-acquired bacteraemia (24.9 to 139) and hospital-acquired (0.36/1000 inpatients-days to 1.09). Bacteraemia with source in vascular catheter, urinary and biliary tract increased. The 30-day mortality rate of patients was 1179/6777 (17.4%) in the whole series and population-adjusted mortality incidence increased from 11.4/100,000 in 1991-1996 to 28.4 in 2016-2020 (RR 2.49, 95% CI 2.01-3.08). Mortality was higher in men (18.2% vs 16.3%) and those over 74 years (22.2% vs 14.3%). Appropriate empirical antimicrobial treatment improved (66.5% to 73.1%), 30-day mortality of patients decreased from 26.1 to 13.9%. When comparing the evolution of the factors associated with mortality between 1991 and 1996 vs 2016-2020, the frequency of some variables associated with higher mortality increased: male sex (OR 1.38, 95% CI 1.10-1,74), age (OR 1.02, 1.01-10.3), immunosuppressive treatment (OR 3.1, 2.09-4.6), polymicrobial bacteraemia (OR 1.76, 1.12-2.79), and others decreased: severe sepsis/septic shock (OR 0.70, 0.52-0.93), spontaneous bacterial peritonitis in cirrhosis (OR 0.06, 0.02-0.23), endocarditis (OR 0.54, 0.35-0.83); on the other hand, the frequency of factors associated with lower mortality increased: urinary (OR 1.67, 95% CI 1.23-2.27) and bile tract source (OR 1.59, 1.04-2.43), and adequate empirical treatment (OR 1.42, 95% CI 1.10-1.83)., Conclusions: The incidence of bacteraemia increased due to more elderly, co-morbid patients undergoing procedures and more device related bacteraemia. The percentage of mortality decreased because adequate empirical treatment improved, decreased spontaneous bacterial peritonitis in cirrhosis and endocarditis, and increased bacteraemia of urinary and biliary tract source., (© 2023. The Author(s).)

Background: Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment., Objective: To study the correlation between homocysteine levels and cognitive impairment in patients with PD., Methods: We conducted a case-control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped., Results: Our case-control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD., Conclusions: Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD., (© 2022. The Author(s).)

Organ on-a-chip (OoC) is a promising technology that aims to recapitulate human body pathophysiology in a more precise way to advance in drug development and complex disease understanding. However, the presence of OoC in biological laboratories is still limited and mainly restricted to laboratories with access to cleanroom facilities. Besides, the current analytical methods employed to extract information from the organ models are endpoint and post facto assays which makes it difficult to ensure that during the biological experiment the cell microenvironment, cellular functionality and behaviour are controlled. Hence, the integration of real-time biosensors is highly needed and requested by the OoC end-user community to provide insight into organ function and responses to stimuli. In this context, electrochemical sensors stand out due to their advantageous features like miniaturization capabilities, ease of use, automatization and high sensitivity and selectivity. Electrochemical sensors have been already successfully miniaturized and employed in other fields such as wearables and point-of-care devices. We have identified that the explanation for this issue may be, to a large extent, the accessibility to microfabrication technologies. These fields employ preferably digital manufacturing (DM), which is a more accessible microfabrication approach regardless of funding and facilities. Therefore, we envision that a paradigm shift in microfabrication that adopts DM instead of the dominating soft lithography for the in-lab microfabrication of OoC devices will contribute to the dissemination of the field and integration of the promising real-time sensing.

To date, there have been no new drugs or adjuvants able to decrease both morbidity and mortality in the context of sepsis and septic shock. Our objective was to evaluate the use of thiosulfinate-enriched Allium sativum and black garlic extracts as adjuvants in the management of sepsis. An experimental in vivo study was carried out with male Sprague-Dawley ® rats. Animals were randomized in four treatment groups: antibiotic (ceftriaxone) treatment (group I), ceftriaxone plus thiosulfinate-enriched extract (TASE, group II), ceftriaxone plus thiosulfinate-enriched extract and black garlic extracts (TASE + BGE, group III), and ceftriaxone plus black garlic extract (BGE, group IV). All animals were housed and inoculated with 1 × 10 10 CFU/15 mL of intraperitoneal Escherichia coli ATCC 25922. Subsequently, they received a daily treatment according to each group for 7 days. Clinical, analytical, microbiological, and histopathological parameters were evaluated. Statistically significant clinical improvement was observed in rats receiving garlic extracts in weight (groups II and III), ocular secretions, and piloerection (group IV). Moreover, less liver edema, vacuolization, and inflammation were observed in groups receiving adjuvant support (groups II, III, and IV). When comparing interleukins 24 h after bacteria inoculum, we found statistically significant differences in TNF-alpha levels in groups receiving BGE (groups III and IV, p ≤ 0.05). Blood and peritoneal liquid cultures were also analyzed, and we detected a certain level of Enterococcus faecalis in peritoneal cultures from all treatment groups and less bacteria presence in blood cultures in rats receiving garlic extracts (groups II, III, and IV). In conclusion, TASE and BGE could be promising nutraceutical or medicinal agents as coadjuvants in the treatment of sepsis because of its effects in modulating the inflammatory response.

Infectious Bursal Disease Virus (IBDV) is the causative agent of an immunosuppressive disease that affects domestic chickens ( Gallus gallus ) severely affecting poultry industry worldwide. IBDV infection is characterized by a rapid depletion of the bursal B cell population by apoptosis and the atrophy of this chief lymphoid organ. Previous results from our laboratory have shown that exposure of infected cells to type I IFN leads to an exacerbated apoptosis, indicating an important role of IFN in IBDV pathogenesis. It has been described that recognition of the dsRNA IBDV genome by MDA5, the only known cytoplasmic pattern recognition receptor for viral RNA in chickens, leads to type I IFN production. Here, we confirm that TRIM25, an E3 ubiquitin ligase that leads to RIG-I activation in mammalian cells, significantly contributes to positively regulate MDA5-mediated activation of the IFN-inducing pathway in chicken DF-1 cells. Ectopic expression of chTRIM25 together with chMDA5 or a deletion mutant version exclusively harboring the CARD domains (chMDA5 2CARD) enhances IFN-β and NF-ĸB promoter activation. Using co-immunoprecipitation assays, we show that chMDA5 interacts with chTRIM25 through the CARD domains. Moreover, chTRIM25 co-localizes with both chMDA5 and chMDA5 2CARD, but not with chMDA5 mutant proteins partially or totally lacking these domains. On the other hand, ablation of endogenous chTRIM25 expression reduces chMDA5-induced IFN-β and NF-ĸB promoter activation. Interestingly, ectopic expression of either wild-type chTRIM25, or a mutant version (chTRIM25 C59S/C62S) lacking the E3 ubiquitin ligase activity, restores the co-stimulatory effect of chMDA5 in chTRIM25 knockout cells, suggesting that the E3-ubiquitin ligase activity of chTRIM25 is not required for its downstream IFN-β and NF-ĸB activating function. Also, IBDV-induced expression of IFN-β , Mx and OAS genes was reduced in chTRIM25 knockout as compared to wild-type cells, hence contributing to the enhancement of IBDV replication. Enhanced permissiveness to replication of other viruses, such as avian reovirus, Newcastle disease virus and vesicular stomatitis virus was also observed in chTRIM25 knockout cells. Additionally, chTRIM25 knockout also results in reduced MAVS-induced IFN-β promoter stimulation. Nonetheless, similarly to its mammalian counterpart, chTRIM25 overexpression in wild-type DF-1 cells causes the degradation of ectopically expressed chMAVS., Competing Interests: The AG-S laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapuetics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. AG-S has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen and Pfizer, outside of the reported work. AG-S has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. AG-S is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Diaz-Beneitez, Cubas-Gaona, Candelas-Rivera, Benito-Zafra, Sánchez-Aparicio, Miorin, Rodríguez, García-Sastre and Rodríguez.)

Introduction: Vitamin D - concretely its active form 1,25-dihydroxyvitamin D (1,25(OH) 2 D) - maintains several physiological processes. Oxylipins are oxidized lipids derived from ω-6 and ω-3 polyunsaturated fatty acids involved in inflammation. Little is known about the association of 1,25(OH) 2 D with inflammatory parameters in middle-aged populations - who could be at risk of vitamin D deficiency -. The aim of this study was to investigate the relationship between 1,25(OH) 2 D plasma levels with circulating white blood cells, platelets counts and oxylipins levels., Materials and Methods: A total of 74 (53 % women) middle-aged (40-65 years old) adults were recruited for this cross-sectional study. 1,25(OH) 2 D plasma levels were measured using an immunochemiluminometric assay. White blood cells and platelets were analyzed by hemocytometry. ω-6 and ω-3 oxylipins plasma levels were measured using liquid chromatography - tandem mass spectrometry. Simple and multiple linear regression models, and Pearson correlation analyses, were performed to study the association of 1,25(OH) 2 D levels with WBC and platelets counts, and oxylipins, respectively., Results: 1,25(OH) 2 D plasma levels were positively related with linoleic acid-derived oxylipins and isoprostanes plasma levels, whereas an inverse relationship with dihomo-γ-linolenic acid/linoleic acid and arachidonic acid/linoleic acid ratios was unveiled. No significant associations were observed for circulating ω-3 oxylipins, white blood cells levels or platelets count., Conclusions: Linoleic acid-derived oxylipins and isoprostanes plasma levels may be influenced by 1,25(OH) 2 D plasma levels. Further investigations are needed to elucidate the impact of other vitamin D forms upon circulating oxylipins levels., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular hybridization consists of the combination of two or more non-identical pharmacophores in a single molecule. It has emerged as a promising strategy that allows the design of molecular frameworks with enhanced activity and affinity compared to their parent drugs. In this work, two novel hybrids that combine the well-known anticancer chemotherapeutic agent 5-fluorouracil with antioxidant coumarin derivatives have been synthesized and characterized by means of a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The conjugates showed good antioxidant properties and a high tendency to aggregate and form stable nanoparticles in aqueous media, with regular shape and uniform size. These materials have proven to be preferential cytotoxic agents in vitro against human pancreatic cancer cells PANC-1, with an activity superior to free 5-fluorouracil. These results open up the possibility of exploiting the synergistic combination between 5-fluorouracil and coumarin derivatives and warrant further investigation of these hybrids as promising pancreatic anticancer agents.

Secondary acrocyanosis after spinal cord injury is extremely rare. We describe a case with secondary acrocyanosis in a complete T12 paraplegic patient. A 41-year-old man with complete T12 paraplegia after a gunshot wound to the thoracic spine 20 years prior presented with a four-month history of bilateral foot bluish discoloration precipitated when he sat with his legs down, improving rapidly after a few minutes of leg elevation. Changes in the skin color of the lower extremities were evaluated in the seated position for two hours. The skin color became darker, progressing to a bluish discoloration through the entire length of the legs. After two hours, the feet and most of the legs appeared deep purple. The color of the legs returned to their baseline three minutes later after the patient was placed supine in the bed. The diagnosis of secondary acrocyanosis due to the T12 spinal cord injury was established based on the physical examination and ancillary tests showing no peripheral ischemia. Other causes of secondary acrocyanosis were excluded during the work-up. This report presents the first case of a paraplegic patient with spinal cord injury presenting secondary acrocyanosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ruiz-Rodríguez et al.)

Right atrial masses raised pose 3 major possibilities including tumors, thrombi, or vegetations. We present 2 cases: first, a 34-year-old male with no medical history, who presented with dyspnea, pleuritic pain, and fever; and the second, 65-year-old male with similar symptoms and a history of a left renal carcinoma. Both patients had right atrial masses found on a transthoracic echocardiogram. Cardiac magnetic resonance imaging and an 18 FDG-PET were necessary finding thrombi in the first patient; and tumoral thrombi in the second one. A multimodality imaging approach to right atrial masses is essential for proper diagnosis and therapeutic decision-making., (© 2022 The Authors.)