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Atopic dermatitis (AD) is a chronic inflammatory skin disorder with a complex pathogenesis involving epidermal barrier dysfunction and aberrant lipid composition, particularly ceramides and fatty acids (FA). Conventional management options, such as topical glucocorticoids (GC), often lead to adverse effects upon prolonged usage, prompting the exploration of alternative therapeutic strategies. The lipid extract from Black Soldier Fly larvae (BSFL) biomass, holding a rich blend of FA, holds substantial potential as a novel ingredient to tackle skin barrier impairment. This study aimed to achieve proof-of-concept validation of innovative nanotechnology-based formulations tailored to enhance the topical management of AD. Specifically, solid lipid nanoparticles (SLNs) with BSFL lipid extract were developed to perform both as a carrier for dexamethasone (DEX), a representative GC, and as skin barrier repair adjuvants. Through systematic optimization using Box-Behnken Design, BSFL lipid extract-based SLNs demonstrated favorable physicochemical properties for topical application and satisfactory stability over 2 months. Notably, these SLNs exhibited favorable drug release kinetics, delivering the total DEX payload within a therapeutically relevant timeframe. Furthermore, these nanocarriers showed the ability to permeate human keratinocytes without pronounced toxicity, suggesting their potential utility in enhancing drug delivery and cellular uptake. Overall, these findings suggest that BSFL lipid extract is a promising natural and sustainable ingredient for the development of nanotechnology-driven approaches to AD management, offering a potential avenue for addressing the unmet needs in this challenging dermatologic condition., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: The impact of viral infections on disease susceptibility and progression has predominantly been studied in patients with relapse-onset MS (RMS). Here, we determined immune responses to ubiquitous viruses in patients with primary progressive MS (PPMS)., Methods: Antibody responses to Epstein-Barr virus (EBV), specifically to the latent EBV nuclear antigen 1 and the lytic viral capsid antigen VCA, human herpesvirus 6 (HHV-6), human cytomegalovirus (HCMV), and measles virus were determined in a cohort of 68 PPMS patients with a mean follow-up of 8 years and compared with 66 healthy controls matched for sex and age., Results: Compared with controls, PPMS patients showed increased humoral immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to the lytic EBV capsid antigen (VCA) or to other viral antigens. Seroprevalence rates for HCMV were significantly higher in PPMS. Antiviral immune responses at baseline did not correlate with disability progression over time., Discussion: Elevated immune responses toward EBNA1 are selectively increased in people with primary progressive disease, indicating a link between EBNA1-targeting immune responses and the development of both RMS and PPMS. Our data also suggest that chronic HCMV infection is associated with progressive MS., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

This study aimed to examine sex differences in acute caffeine intake on repeated sprint performance. Fifty-two resistance-trained individuals (age: 24.6 ± 4.5 years and sex (female/male): 26/26) participated in a randomized, triple-blind, cross-over, and placebo-controlled study. Participants ingested 3 mg/kg caffeine or placebo and, after 60 min, performed 4 Wingate tests (Wt), consisting of a 30 s all-out lower-body sprint against an individualized resisted load, with 90 s rest periods between sprints. Mean (W mean ) and peak (W peak ) power showed an interaction between sprint and supplement (P = 0.038, η p 2  = 0.095 and P < 0.001, η p 2  = 0.157, respectively), but only W peak reported a supplement and sex interaction (P = 0.049 and η p 2  = 0.166). Caffeine increased W mean in Wt3 (3.5%, P = 0.004, and g = 1.059) and Wt4 (3.9%, P = 0.012, and g = 1.091) compared to placebo. Whereas, for W peak , caffeine increased W peak in the Wt1 (2.9%, P = 0.050 and g = 1.01) and Wt2 (3.2%, P = 0.050, and g = 1.01) in males and in Wt3 (5.2%, P = 0.008, and g = 1.79) and Wt4 (8.1%, P = 0.004, and g = 2.27) in female participants compared to placebo. No statistically significant sex differences were found in time to reach W peak , fatigue index. Acute caffeine intake stimulated a similar ergogenic effect on repeated sprint performance in men and women, except in peak power output, where caffeine increased performance during the first sprints in males and the last sprints in female participants., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Ruxolitinib has been approved for the treatment of adults and pediatric patients ≥12 years with steroid refractory graft-versus-host disease (GvHD). However, real-life studies are needed to confirm the results of clinical trials and further assess its efficacy in special populations. We performed a descriptive, retrospective, multi-center study of 352 adults and 42 pediatric patients treated with ruxolitinib for steroid-refractory acute or chronic GvHD. Among 119 and 233 adult patients with acute and chronic GvHD, overall response rate (ORR) was 58.8% (CR 33.6%) and 65.7% (CR 18.5%), respectively. Corticosteroids were withdrawn in 59.2% and 40.1%, and ruxolitinib in 47.2% and 34.8% in the acute and chronic groups of responders. Among 29 and 13 pediatric patients with acute and chronic GvHD, ORR was 82.7% (CR 51.7%) and 100% (CR 23%), respectively. Among responder patients, corticosteroids were withdrawn in 72.7% and 50%, and ruxolitinib in 75% and 30.7% in both groups respectively. Ruxolitinib in the real world setting, showed similar results as compared to clinical trials. Its efficacy is maintained in subsequent lines of treatment. In the pediatric population, the data are more favorable. In the long-term follow-up, corticosteroids, ruxolitinib and other inmunosuppressive drugs could be eliminated in a remarkably proportion of patients., Competing Interests: Competing interests: The study was funded by Novartis Company. VGG and GETH-TC received support from Novartis Company. The rest of the authors declare no competing financial interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In this mixed computational and experimental study, we report a catalytic system for alkane C 1 -C 6 functionalization in which the responsible step for C-H bond activation shows no barrier in the potential energy path. DFT modeling of three silver-based catalysts and four diazo compounds led to the conclusion that the Tp F Ag═C(H)CF 3 (Tp F = fluorinated trispyrazolylborate ligand) carbene intermediates interact with methane without a barrier in the potential energy surface, a prediction validated by experimentation using N 2 ═C(H)CF 3 as the carbene source. The array of alkanes from propane to n -hexane led to the preferential functionalization of the primary sites with unprecedented values of selectivity for an acceptor diazo compound. The lack of those barriers implies that selectivity can no longer be controlled by differences in the energy barriers. Molecular dynamics calculations (with propane as the model alkane) are consistent with the preferential functionalization of the primary sites due to a higher concentration of such C-H bonds in the vicinity of the carbenic carbon atom.

Objective: Transgenic mice with fluorescent protein (FP) reporters take full advantage of new in vivo imaging technologies. Therefore, we generated a TRPC5- and a TRPA1-reporter mouse based on FP C-terminal fusion, providing us with better alternatives for studying the physiology, interaction and coeffectors of these two TRP channels at the cellular and tissue level., Methods: We generated transgenic constructs of the murine TRPC5- and TRPA1-gene with a 3*GGGGS linker and C-terminal fusion to mCherry and mTagBFP, respectively. We microinjected zygotes to generate reporter mice. Reporter mice were examined for visible fluorescence in trigeminal ganglia with two-photon microscopy, immunohistochemistry and calcium imaging., Results: Both TRPC5-mCherry and TRPA1-mTagBFP knock-in mouse models were successful at the DNA and RNA level. However, at the protein level, TRPC5 resulted in no mCherry fluorescence. In contrast, sensory neurons derived from the TRPA1-reporter mice exhibited visible mTag-BFP fluorescence, although TRPA1 had apparently lost its ion channel function., Conclusions: Creating transgenic mice with a TRP channel tagged at the C-terminus with a FP requires detailed investigation of the structural and functional consequences in a given cellular context and fine-tuning the design of specific constructs for a given TRP channel subtype. Different degrees of functional impairment of TRPA1 and TRPC5 constructs suggest a specific importance of the distal C-terminus for the regulation of these two channels in trigeminal neurons., Competing Interests: Declaration of competing interest The authors declare no competing interests. The present work was performed in (partial) fulfillment of the requirements for obtaining the degree “Dr. med.” at Friedrich-Alexander-Universität Erlangen-Nürnberg., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To evaluate with an animal model of osteoarthritis (New Zealand rabbits) the effectiveness of treatment with active viscosupplements (hyaluronic acid loaded with nanoparticles (NPs) that encapsulate anti-inflammatory compounds or drugs., Material and Methods: Experimental study composed of 5 groups of rabbits in which section of the anterior cruciate ligament and resection of the internal meniscus were performed to trigger degenerative changes and use it as a model of osteoarthritis. The groups were divided into osteoarthrosis without treatment (I), treatment with commercial hyaluronic acid (HA) (II), treatment with HA with empty nanoparticles (III), treatment with HA with nanoparticles encapsulating dexamethasone (IV) and treatment with HA with nanoparticles that encapsulate curcumin (V). In groups II to V, the infiltration of the corresponding compound was carried out spaced one week apart.Macroscopic histological analysis was performed using a scale based on the Outerbridge classification for osteoarthritis., Results: We observed that this osteoarthritis model is reproducible and degenerative changes similar to those found in humans are observed.The groups that were infiltrated with hyaluronic acid with curcumin-loaded nanoparticles (V), followed by the dexamethasone group (IV) presented macroscopically less fibrillation, exposure of subchondral bone and sclerosis (better score on the scale) than the control groups (I) (osteoarthritis without treatment), group (II) treated with commercial hyaluronic acid and hyaluronic acid with nanoparticles without drug (III)., Conclusions: The use of active viscosupplements could have an additional effect to conventional hyaluronic acid treatment due to its antioxidant and anti-inflammatory effect. The most promising group was hyaluronic acid with nanoparticles that encapsulate curcumin and the second group was the one that encapsulates dexamethasone., (Copyright © 2024 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

A detailed analysis of the low collision energy (0.03-10 meV) integral reaction cross-section has been carried out for the F + HD ( v = 0, 1; j = 1)→ HF(DF) + D(H) reaction using accurate, fully converged time-independent hyperspherical quantum dynamics. Particular attention has been paid to the shape (orbiting) resonances and their assignment to the orbital ( L ) and total ( J ) angular momenta as well as to the product's state resolved cross-sections at the energies of the resonances. As in previous works, it has been found that the energy position of the resonances depends on the initial state, but is essentially the same for the two exit channels and the product's rovibrational states. The analysis in terms of the orbital and total angular momenta showed that each resonance is characterised by a given value of L but is contributed by several J . The main resonances are due to L = 3 and L = 5 for both F + HD ( v = 0, j = 1) and F + HD ( v = 1, j = 1) reactions, although they appear at different collision energies. The product's vibrationally resolved excitation functions are found to follow the same pattern as the integral cross-section summed over all final states. A more detailed analysis has been made for the rotationally resolved integral cross-sections associated with L = 3, which gives rise to the main resonance for the two reactions and both product channels, for different final j ' states, showing similar behaviour for all j ' states except for j ' = 0 due to parity conservation. The joint analysis of the final rotational and orbital angular momenta shows that L ' and j ' tend to have an antiparallel orientation.

The extraordinary preservation of Cueva de Los Murciélagos (Albuñol, Spain) provides a unique opportunity to identify the materials and the techniques involved in archery during the Early Neolithic period. Arrows with preserved feathers, tied fibres, adhesive substance, and two probable bowstrings have been studied trough an unprecedented multi-proxy investigation, including microscopy and biomolecular methods, to unravel archery techniques. The study has identified the oldest known sinew bowstrings, the first evidence for the use of olive tree (Olea europaea) and reed (Phragmites sp.) to produce arrow shafts in prehistoric European archery, and the identification of birch bark tar as a coating on the shafts. The results of this study provide insights into ancient craft, technological solutions, and adaptations to local resources in the production of these reed-shafted hardwood tipped arrows and bowstrings. Their deposition in a burial cave sheds new light on the role of these artefacts in a Neolithic farming community., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Glioblastoma (GB) is the most aggressive and prevalent glioma within the central nervous system. Despite considerable efforts, GB continues to exhibit a dismal 5-year survival rate (∼6%). This is largely attributed to unfavorable prognosis and lack of viable treatment options. Therefore, novel therapies centered around plant-derived compounds emerge as a compelling avenue to enhance patient survival and well-being. The South African species, Plectranthus hadiensis Schweinf. (P. hadiensis), a member of the Lamiaceae family, has a history of use in traditional medicine for treating a range of diseases, including respiratory, digestive, and liver disorders. This species exhibits diverse biological activities, such as anti-inflammatory and antitumoral properties, likely attributed to its rich composition of naturally occurring diterpenes, like the abietane diterpene, 7α-acetoxy-6β-hydroxyroyleanone (Roy). Roy has demonstrated promising antitumor effects in various cancer cell lines, making it a compelling candidate for further investigation into its mechanisms against GB., Aim of the Study: This study aims to investigate the antitumor activity and potential mechanism of Roy, a natural lead compound, in GB cells., Material and Methods: Roy was isolated from the acetonic extract of P. hadiensis and its antitumor mechanism was assessed in a panel of human GB cell lines (U87, A172, H4, U373, and U118) to mimic tumor heterogeneity. Briefly, the impact of Roy treatment on the metabolic activity of cells was evaluated by Alamar Blue® assay, while cell death, cell cycle regulation, mitochondrial membrane potential, and activated caspase-3 activity were evaluated by flow cytometry. Measurement of mRNA levels of target genes was performed by qPCR, while protein expression was assessed by Western blotting. Cell uptake and impact on mitochondrial morphology were evaluated by confocal microscopy., Results: Roy induced G 2 /M cell cycle arrest, mitochondrial fragmentation, and apoptosis by inhibiting the expression of anti-apoptotic proteins and increasing the levels of activated caspase-3. The concentrations of Roy needed to achieve significant inhibitory outcomes were notably lower (6-9 fold) than those of temozolomide (TMZ), the standard first-line treatment, for achieving comparable effects. In addition, at low concentrations (16 μM), Roy affected the metabolic activity of tumor cells while having no significant impact on non-tumoral cells (microglia and astrocytes)., Conclusion: Overall, Roy demonstrated a robust antitumor activity against GB cells offering a promising avenue for the development of novel chemotherapeutic approaches., 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 B.V. All rights reserved.)

Laser-Plasma ion acceleration is acquiring importance on a daily basis due to incipient applicability in certain research fields. However, the energy and divergence control of these brilliant sources can be considered a bottleneck in the development of some applications. In this work, we present the commissioning of a compact proton beamline based on a triplet of quadrupoles dedicated to focus and collect short and energetic pulses, open to the user community. The focused proton beam characterization has been carried out by imaging of scintillation detectors with different particle filters. Experimental results have been compared with numerical simulations performed with Monte Carlo code (MCNP6) and TSTEP that have been used to retrieve the deposited energy, the particle tracking, and the particle distribution in different focal configurations, respectively. Charges of nC (∼ [Formula: see text] protons with energies up to 17.25 MeV) have been measured at the focal planes reducing the beam to spot sizes of a few millimetres in RMS (root mean square). The percentage fluctuation of the transported charges values has been studied. Finally, the beam rigidity has been measured by transverse moving of the quadrupoles and subsequent beam centroid shift, allowing to cross correlate the deflected energy with the energy ranges resulting from the filtering process., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Diabetes is a chronic and multifactorial metabolic disease with increasing numbers of patients worldwide, characterized by loss of pancreatic β-cell mass and function with subsequent insulin deficiency. Thus, restoring functional β-cells could significantly impact disease management. The beneficial effects of natural compounds, namely (poly)phenols, in diabetes have gained increasing interest, due to their pleiotropic actions in several cellular processes, including in glucose homeostasis. These compounds are able to modulate nutri(epi)genomic mechanisms by interacting with cell signaling proteins and transcription factors (TFs). However, the underlying mechanisms of action, particularly of (poly)phenol metabolites resulting from digestion and colonic microbiota action, are yet to be elucidated. This study explored the multigenomic effects of (poly)phenols and their metabolites to uncover modulatory networks and mechanisms linked to diabetes. Published studies on gene expression alterations modulated by (poly)phenolic compounds or (poly)phenol-rich extracts were integrated, encompassing studies conducted on individuals with diabetes, animal models mimicking diabetes, and pancreatic β-cell lines. Bioinformatic analysis identified differentially expressed genes and potential regulatory factors, with roles in cell signaling pathways (FoxO, AMPK, p53), endocrine resistance, immune system pathways, apoptosis, and cellular senescence. Interestingly, in silico 3D docking analyses revealed potential interactions between key TFs (FOXO1, PPARG, SIRT1, and MAFA) and some metabolites. Apigenin, luteolin, and naringenin glucuronide forms showed the best binding capacity to SIRT1. The integrative analysis of (poly)phenol metabolites data highlights the potential of these molecules for nutraceutical/pharmaceutical development aimed at managing diabetes whose incidence increases with age., Competing Interests: Declaration of Competing Interest This research was funded by national funds through FCT—Foundation for Science and Technology, I.P. (Portugal), under the [DOI 10.54499/UIDB/04567/2020] and [DOI 10.54499/UIDP/04567/2020] projects. R.M. is funded by the FCT Scientific Employment Stimulus contract [DOI: 10.54499/CEECINST/00002/2021/CP2788/CT0004] and A.G. by the FCT Scientific Employment Stimulus contract. M.I.F. is funded by the FCT PhD grant 2023.01737.BDANA and received a Fulbright Research Award 23/24., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hydroxyurea (HU) constitutes the first-line treatment in most patients with essential thrombocythemia (ET), but criteria for changing therapy are not clearly established. The prognostic value of complete hematological response (CHR) and resistance/intolerance to HU was assessed in 1080 patients from the Spanish Registry of ET, classified according to revised IPSET-Thrombosis stratification (Very low- n = 61, Low- n = 83, Intermediate- n = 261, and High-risk n = 675). With a median therapy duration of 5 years, CHR was registered in 720 (67%) patients (1-year probability 51%) and resistance/intolerance in 219 (20%) patients (5-years probability 13%). After correction by other risk factors, High-risk patients achieving CHR showed a reduced risk of arterial thrombosis (HR: 0.35, 95%CI: 0.2-0.6, p = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2-1.02, p = 0.06) whereas no association was observed for intermediate- or low-risk patients. In comparison with non-responders, intermediate- and high-risk patients achieving CHR had longer survival and lower myelofibrosis incidence. Development of resistance/intolerance to HU, mainly cytopenia, was associated with higher probability of myelofibrosis but no effect on survival or thrombotic risk was demonstrated. In conclusion, CHR with HU is associated with better outcomes and might be an early indicator for selecting candidates to second-line clinical trials., Competing Interests: Competing interests: The Spanish registry of Essential thrombocythemia is financed with GEMFIN’s own funds without direct collaboration from any pharmaceutical company. This work has been funded by Instituto de Salud Carlos III (ISCIII) through the projects PI21/00231, PI21/00347, and PI21/00538 and co-funded by the European Union., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Sarcopenia is defined as the loss of skeletal muscle mass and is associated with an increased risk or morbidity and mortality in complex surgical patient populations. Its role in complex abdominal wall surgery (AWS) is yet to be determined. The aim of this study is to establish if sarcopenia has an impact on postoperative complications, mortality and hernia recurrence., Methods: Retrospective study of patients undergoing elective surgery for complex incisional hernias > 10 cm (W3 of European Hernia Society classification) between 2014-2023. Sarcopenia was stablished as the skeletal muscle index (SMI), measured at L3 transversal section of a preoperative CT-scan. Previously defined literature-based SMI cutoff values were used: men ≤ 52.4 cm 2 /m 2 , women ≤ 38.5 cm 2 /m 2 ., Results: 135 patients undergoing complex AWS were included. Of them, 38 were sarcopenic (28.1%). The median follow-up time was 13 months (IQR 12-25). In total, 11 patients died (8.1%). We found that sarcopenia was associated with a higher risk of mortality [HR 7.494 (95% CI 1.985-28.289); p 0.003]. There were no statistically significant differences in postoperative complications or hernia recurrence between both groups., Conclusion: Although sarcopenia does not seem to have an influence on hernia recurrence or the development of postoperative complications, whether local or systemic, in our study sarcopenia is associated with a higher risk of mortality after complex abdominal wall surgery. Nonetheless, with the results obtained in our study, we think that prehabilitation programs before complex AWS is advisable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Functional recovery remains a core clinical objective for patients with bipolar disorder (BD). Sociodemographic, clinical, and neurocognitive variables are associated with long-term functional impairment, yet the impact of sex differences is unclear. Functional remediation (FR) is a validated intervention aimed at achieving functional recovery in BD. The present study assessed the effect of sex differences of FR on psychosocial functioning at post-treatment (6-months) and 12-month follow-up (FUP). To the best of our knowledge, this is the first study to explore the role of sex as a factor in the efficacy of FR., Methods: 157 participants with BD were randomly assigned to either FR (N = 77) or treatment as usual group (80). Clinical, sociodemographic, neuropsychological, and functional data were obtained using a comprehensive assessment battery. Sex differences were explored via a general linear model (GLM) for repeated measures to compare the effect of sex on the intervention over time (6 months and FUP)., Results: Results demonstrated that FR benefits both sexes, males (p = 0.001; d' = 0.88) and females (p = 0.04; d' = 0.57), at 6 months suggesting a generalized functional improvement. Conversely, at 12-month FUP sex differences were observed only in males (p = 0.005; d' = 0.68)., Conclusions: FR is a beneficial intervention for males and females after treatment, suggesting that there are no relevant distinct needs. Females may benefit from ongoing psychosocial functioning booster sessions after the intervention to maintain original improvements. Future research exploring sex differences could help to identify strategies to offer personalized FR intervention approaches in individuals with BD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study generated evidence to guide anticoagulation in patients with VTE after vaccination for COVID-19. We provided data on the low recurrence rate after cessation of anticoagulant therapy and the findings for this study offer timely insights into the management of a potentially vaccine-related adverse event., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Chronic heart failure (CHF) represents a challenge for the healthy system due to its high prevalence, high burden of morbidity and mortality, and high consumption of health resources. To address this problem, it is necessary to develop efficient management strategies that include both hospital care and outpatient care. The primary objective is to stabilize the patient and prevent decompensation, with the consequent improvement in quality of life, reduction in hospital admissions and emergency department care, and, consequently, reduction in healthcare costs. In this context, the heart failure and atrial fibrilation working group of the Spanish Society of Internal Medicine has developed a protocol for the management of outpatient CHF, that addresses, from the perspective of Internal medicine, all the problems suffered by the patient with CHF. This protocol aims to optimize pharmacological treatment, control cardiovascular risk factors and various comorbidities, educate the patient and their environment about the disease, promote adherence to treatment and stablish follow-up adapted to their condition., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Background: With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes., Methods: We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR., Results: Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet., Conclusion: These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background and Objective: Intravesical mitomycin C (MMC) instillations are recommended to prevent recurrence of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC); however, the optimal regimen and dose are uncertain. Our aim was to assess the effectiveness of adjuvant MMC and compare different MMC regimens in preventing recurrence., Methods: We performed a comprehensive search in PubMed, Scopus, and Web of Science in November 2023 for studies investigating recurrence-free survival (RFS) among patients with IR-NMIBC who received adjuvant MMC. Prospective trials with different MMC regimens or other intravesical drugs as comparators were considered eligible., Key Findings and Limitations: Overall, 14 studies were eligible for systematic review and 11 for meta-analysis of RFS. Estimates of 1-yr, 2-yr, and 5-yr RFS rates were 84% (95% confidence interval [CI] 79-89%), 75% (95% CI 68-82%), and 51% (95% CI 40-63%) for patients treated with MMC induction plus maintenance, and 88% (95% CI 83-94%), 78% (95% CI 67-89%), and 66% (95% CI 57-75%) for patients treated with bacillus Calmette-Guérin (BCG) maintenance, respectively. Estimates of 2-yr RFS rates for MMC maintenance regimens were 76% (95% CI 69-84%) for 40 mg MMC (2 studies) and 66% (95% CI 60-72%) for 30 mg MMC (4 studies). Among the studies included, BCG maintenance provided comparable 2-yr RFS to 40 mg MMC with maintenance (78% vs 76%). RFS did not differ by MMC maintenance duration (>1 yr vs 1 yr vs <1 yr)., Conclusions and Clinical Implications: MMC induction and maintenance regimens seem to provide short-term RFS rates equivalent to those for BCG maintenance in IR-NMIBC. For adjuvant induction and maintenance, 40 mg of MMC appears to be more effective in preventing recurrence than 30 mg. We did not observe an RFS benefit for longer maintenance regimens., Patient Summary: For patients with intermediate-risk non-muscle-invasive bladder cancer, bladder treatments with a solution of a drug called mitomycin C (MMC) seem to be as effective as BCG (bacillus Calmette-Guérin) in preventing recurrence after tumor removal. Further trials are needed for stronger evidence on the best MMC dose and treatment time., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

This is the summary report of the 5th Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH) and held in Seville, Spain, in October 2023. The meeting aimed to provide an update on the latest advances in the field of basic and translational hepatology, covering different molecular, cellular, and pathophysiological aspects of the most relevant clinical challenges in liver pathologies. This includes the identification of novel biomarkers and diagnostic tools, the understanding of the relevance of immune response and inflammation in liver diseases, the characterization of current medical approaches to reverse liver diseases, the incorporation of novel molecular insights through omics techniques, or the characterization of the impact of toxic and metabolic insults, as well as other organ crosstalk, in liver pathophysiology., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Species of Leishmania and Trypanosoma genera are the causative agents of relevant parasitic diseases. Survival inside their hosts requires the existence of a potent antioxidant enzymatic machinery. Four iron superoxide dismutases have been described in trypanosomatids (FeSODA, FeSODB1, FeSODB2, and FeSODC) that hold a potential as therapeutic targets. Nonetheless, very few studies have been developed that make use of the purified enzymes. Moreover, FeSODC remains uncharacterised in Leishmania . In this work, for the first time, we describe the purification and enzymatic activity of recombinant versions of the four Leishmania FeSOD isoforms and establish an improved strategy for developing inhibitors. We propose a novel parameter [( V * cyt. c  -  V cyt. c )/ V cyt. c ] which, in contrast to that used in the classical cytochrome c reduction assay, correlates linearly with enzyme concentration. As a proof of concept, we determine the IC 50 values of two ruthenium carbosilane metallodendrimers against these isoforms.

Forest disturbance regimes across biomes are being altered by interactive effects of global change. Establishing baselines for assessing change requires detailed quantitative data on past disturbance events, but such data are scarce and difficult to obtain over large spatial and temporal scales. The integration of remote sensing with dense time series analysis and cloud computing platforms is enhancing the ability to monitor historical disturbances, and especially non-stand replacing events along climatic gradients. Since the integration of such tools is still scarce in Mediterranean regions, here, we combine dense Landsat time series and the Continuous Change Detection and Classification - Spectral Mixture Analysis (CCDC-SMA) method to monitor forest disturbance in continental Spain from 1985 to 2023. We adapted the CCDC-SMA method for improved disturbance detection creating new spectral libraries representative of the study region, and quantified the year, month, severity, return interval, and type of disturbance (stand replacing, non-stand replacing) at a 30 m resolution. In addition, we characterised forest disturbance regimes and trends (patch size and severity, and frequency of events) of events larger than 0.5 ha at the national scale by biome (Mediterranean and temperate) and forest type (broadleaf, needleleaf and mixed). We quantified more than 2.9 million patches of disturbed forest, covering 4.6 Mha over the region and period studied. Forest disturbances were on average larger but less severe in the Mediterranean than in the temperate biome, and significantly larger and more severe in needleleaf than in mixed and broadleaf forests. Since the late 1980s, forest disturbances have decreased in size and severity while increasing in frequency across all biomes and forest types. These results have important implications as they confirm that disturbance regimes in continental Spain are changing and should therefore be considered in forest strategic planning for policy development and implementation., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

This study examined the impact of positive psychology variables, namely trait emotional intelligence (EI), positive affect and self-care, on academic engagement (AE) in an online learning environment during COVID-19. The study involved 717 undergraduates in Lebanon and utilised structural equation modelling for data analysis. The results demonstrated that positive affect and self-care mediated the relationship between trait EI and AE. In women, both self-care and positive affect were mediators, whereas in men, positive affect was the only mediator. For students who received a mix of synchronous and asynchronous lessons, both self-care and positive affect mediated the relationship between trait EI and AE. However, for those who received only synchronous lessons, positive affect was the sole mediator. Furthermore, AE significantly predicted academic performance (AP) in both models. These findings suggest the importance of interventions that enhance trait EI, positive emotions and self-care to improve AE and ultimately AP in online learning., (© 2024 The Author(s). International Journal of Psychology published by John Wiley & Sons Ltd on behalf of International Union of Psychological Science.)

Anthropogenic environments such as wastewater treatment plants (WWTPs) and landfills are sources of antimicrobial resistance (AMR). Black-headed gulls (Chroicocephalus ridibundus) frequently use WWTPs and may be vectors for AMR. We used GPS tracking data for 39 gulls for up to 8 months, combined with a shedding curve, to study sources and dispersal distances of AMR in Iberia. The gulls used 21 different WWTPs (684 visits) and three landfills (21 visits). Areas of high risk of AMR dissemination were an average of 25 km from the infection source, with a maximum of 500 km. Solar saltworks and natural waterbodies were particularly exposed to AMR dissemination, followed by agriculture, sports facilities, and tourist beaches. There was important variability between individual gulls in their habitat specialization, and which WWTPs they visited. Studying the spatial movements of gulls after visiting WWTPs and landfills helps pinpoint sensitive locations where pathogen transmission is most likely., Competing Interests: Declarations. Ethics approval: All fieldwork procedures were approved by the CSIC ethical committee (REF: 1183/2021), and the Consejería de Agricultura, Pesca y Desarrollo Rural de la Junta de Andalucía. Permission to conduct the work in Doñana Natural Space was given by the Dirección General de Espacios Naturales Protegidos (permit 2021/14). In Costa Ballena, permission was granted by the local councils in Rota (2022-E-RE-14542) and Chipiona (13043). Consent to participate: This declaration is not applicable. Consent for pubication: This declaration is not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Peritonitis is a frequent complication of PD that can lead to technique discontinuation and increase morbidity and mortality. It is caused mainly by gram-positive bacteria (up to 70%); however, gram-negative organisms usually have relatively poor outcomes. Among gram-negative bacteria, Acinetobacter is rare, especially Acinetobacter ursingii., Case Report: We report the third case of PD peritonitis caused by Acinetobacter ursingii, treated with directed intraperitoneal antibiotics with good clinical response and favorable outcome., Conclusion: Although Acinetobacter ursingii is rare, it is potentially harmful because of its challenging identification and antibiotic resistance with therapeutic consequences, requiring at least two antibiotics and careful follow up. Keeping in mind that it is ubiquitous, careful technique, training/retraining seems highly recommended., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent to publish: Informed consent was obtained from the patient for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The evaluation of measurement uncertainty involves combining available experimental data with additional knowledge on the impact of sources of uncertainty on the measured value to quantify combined uncertainty. This uncertainty should express the impact of relevant random and systematic effects on the measured value to allow an objective interpretation of the performed quantification. This research discusses how to assess and account for the impact on measurement uncertainty evaluation of uncontrolled high temperature of sample preparation and of supporting experimental validation data on a single calibration of the instrumental method of analysis used. After the detailed inspection of the measurand and measurement process, the various uncertainty components were quantified from experimental data and/or additional information. This research illustrates that experimental limitations can be overcome by a detailed and quantitative understanding of the measurement process. Melatonin content in tea was quantified between 3.7 g kg -1 and 196 g kg -1 with a relative expanded uncertainty between 28% and 40%, lower than the target or maximum admissible relative expanded uncertainty of 40%. The use of HPLC-FD calibration several days before sample analysis is the major uncertainty component responsible for up to 82.7% of the measurement uncertainty.

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF-κB activation, confirming that the derivative bearing the 4-pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK-dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Introduction: Sex differences exist in risk factors and comorbidities of older adults (aged ⩾ 65 years) with pulmonary embolism (PE). Clinically relevant sex-based treatment disparities for PE have not been adequately addressed. The few existing show conflicting results due to small sample size (type II error) and suboptimal methods (overreliance on p -value, which may detect differences of small clinical relevance)., Methods: We assessed sex differences in anticoagulation and advanced therapies for PE in older adults, utilizing data from Registro Informatizado Enfermedad TromboEmbolica (RIETE), a large PE registry with predominant participation from Europe, and data from US Medicare beneficiaries. We prespecified a standardized difference (SRD) > 10% as clinically relevant. RIETE included 33,462 (57.7% female) and Medicare included 102,391 (55.0% female) older adults with PE., Results: In RIETE, there were no overall sex differences in the use of anticoagulation (median: 181 vs 180 days, SRD < 1%), fibrinolysis (SRD < 3%), thrombectomy (SRD < 2%), or inferior vena cava (IVC) filters (SRD: 4.4%). However, fibrinolytic therapy (systemic or catheter-based) was less often used in female than male patients with intermediate-risk PE (8.0% vs 12.1%, SRD: 13.6%). No sex differences were noted with advanced PE therapies in Medicare beneficiaries. In unadjusted analyses, fibrinolysis and IVC filter placement were more frequent in Medicare than RIETE participants regardless of sex ( p < 0.001)., Conclusion: In a predominantly European PE registry and a US study of older adults, there were no overall sex differences in anticoagulation patterns or advanced therapy utilization. Future studies should determine if sex disparities in fibrinolytic therapy for intermediate-risk PE and greater use of advanced therapies in US older adults correlate with clinical outcomes., Competing Interests: Declaration of conflicting interestsOutside the submitted work, the authors disclosed the following. Dr Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814) and the Heart and Vascular Center Junior Faculty Award from Brigham and Women’s Hospital. Dr Bikdeli is a member of the Medical Advisory Board for the North American Thrombosis Forum and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Science. Dr Goldhaber reports research support from Bayer, BMS, Boston Scientific, Janssen, and the National Heart, Blood, and Lung Institute (NHBLI). Dr O’Donoghue reports grants from Amgen, Novartis, AstraZeneca, Merck, and Janssen, and consulting for Amgen, NovoNordisk, Janssen, Novartis, and AstraZeneca. Dr Rosovsky reports research support ( to the institution) from BMS and Janssen. She is an advisor/consultant to Abbott, BMS, Dova, Inari, Janssen, and Penumbra; national lead investigator for the Storm-PE trial funded by Penumbra; and President of the Pulmonary Embolism Response Team Consortium. Dr Piazza reports grants from BMS/Pfizer, Janssen, Bayer, Amgen, BSC, Esperion, and 1R01HL164717-01. He has an advisory role with BSC, Amgen, BCRI, PERC, NAMSA, BMS, Janssen, and Regeneron. Dr Bertoletti reports personal fees and nonfinancial support from Aspen, Bayer, BMS-Pfizer, Léo-Pharma, MSD, and Johnson & Johnson. Dr Bates receives unencumbered salary support from the Eli Lilly Canada/May Cohen Chair in Women’s Health at McMaster University. She reports honoraria from Léo Pharma Canada, Inc., ROVI, and Sanofi, as well as payment for work from Elsevier. Dr Krumholz is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services, Janssen, Johnson & Johnson Consumer, and Pfizer; is a recipient of grants from AHA, Agency for Healthcare Research and Quality, NIH, Centers for Disease Control and Prevention; is a consulting expert for Massachusetts Medical Society, EyeDentifeye, F-prime, UpToDate, and Ensight; serves on the Data Safety Monitoring Board for Element Science; holds stocks for Element Science and EyeDentifyeye; and is a cofounder of Refactor Health, Ensight AI, and Hugo Health. Dr Monreal received an unrestricted grant for research from Sanofi and Rovi laboratories to sponsor the RIETE registry. All other authors have no disclosures to report.

Introduction: Ophthalmological conditions in international travelers may be associated with low mortality but high morbidity. Eye involvement in travelers is less frequently reported than febrile, gastrointestinal and respiratory infections, but data probably represent a degree of under-notification., Methods: an extensive narrative review of the main viral, bacterial, fungal and parasitic infections affecting the eye in travelers was performed., Main Findings: Common respiratory tract viral infections may cause ocular complications in travelers, human influenza viruses have been associated with conjunctivitis and emerging avian influenza subtypes may also affect the eye. Vector-borne viral infections may affect travelers, usually with systemic symptoms, but eye disease may be the first presenting feature. A spectrum of manifestations have been described with dengue, chikungunya and Zika infections, including conjunctivitis, anterior uveitis, posterior uveitis with chorioretinitis and macular involvement. Staphylococcus spp, Streptococcus spp, and Pseudomonas spp (especially associated with use of contact lenses) are common causes of keratitis, however, resistance patterns to antimicrobials might vary depending on area of travel. Less frequent infections, such as Burkholderia pseudomallei, associated with environmental exposure, and Bartonella spp. may rarely present with ophthalmological involvement in travelers. Fungal ocular infections, especially after ocular trauma caused by plants and contact lens use, should be considered in patients with stromal keratitis not improving with antibiotic eye drops. Parasitic eye infections tend to occur in tropical areas, but some, such as acanthamoebic keratitis or Toxoplasma spp retinitis, are found worldwide. Increasing exposure to animals, undercooked food consumption or poor hygiene during international travels might be leading to the emergence of certain parasitic eye diseases., Conclusions: Clinical features, with identification of risk factors and geographical region of exposure, can assist in the definitive diagnosis of imported ophthalmological infections. Management of imported eye infections requires a multi-disciplinary approach involving ophthalmologists, travel medicine/infectious diseases physicians and other specialists., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julio J Gonzalez-Lopez reports financial support and article publishing charges were provided by Roche. If there are other authors, they 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: One in 10 patients with hyperuricemia may develop gout over time, with urate deposition sometimes asymptomatic. Recent reviews and guidelines support ultrasound (US) to assess asymptomatic hyperuricemic (AH) patients to detect gout lesions, showing double contour (DC) and tophus the highest specificities and positive predictive values. Hyperuricemia and gout are common in chronic kidney disease (CKD), especially with glomerular filtration rate (GFR) <60, and both are associated with worse prognosis, although treatment of AH in CKD is not yet recommended in all guidelines. US gout lesions have been found more frequently in AH (up to 35%) than in normouricemic (NU) patients, but evidence is scarce in CKD., Objectives: To assess the prevalence of urate deposit in stages 3-5 CKD detected by US, and to investigate if there are differences between AH and NU patients., Methods: Multicenter cross-sectional study, recruiting patients aged ≥18 years with AH and stages 3-5 CKD in 4 hospitals. A comparator group of NU patients with stage 3-5 CKD was included., Exclusion Criteria: previous diagnosis of gout, tophi. Hyperuricemia was defined as serum uric acid (sUA) >7 mg/dl, documented at least twice during the last 12 months. A standardized US exam of the knees and bilateral first metatarsophalangeal joints was performed to assess patients for DC/tophus as defined by OMERACT. Demographic, clinical and laboratory data were recorded. A descriptive analysis was performed using SPSS. Pre-clinical gout (PCG: DC and/or tophus) was considered as outcome variable. Chi-square and Fisher's exact test were used for qualitative variables, and Mann-Whitney U test for quantitative variables; significant threshold p < 0.05., Results: Fifty-three patients with stages 3-5 CKD (59.6% stage 3, 19.1% stage 4, 21.3% stage 5) were recruited, 38 AH (71.7%) and 15 NU. A higher prevalence of US findings was observed in HU patients compared to NU patients (DC 23.7% vs 13.3%, tophus 31.6% vs 26.7%, PCG 39.5% vs 33.3%), although the differences were not statistically significant. NU patients had CKD of longer duration than HU patients [11 (7.2-13.5) vs 6 (2-9.2) years; p = 0.02], with no differences in sex, age, comorbidities, or urate-lowering therapy (ULT) (66.7% vs 44.7%; p = 0.05) and other treatments. Seventy percent of NU patients with TRU had AH before starting treatment. In patients with tophi, we observed a trend towards shorter duration of CKD and shorter duration of treatment with ULT compared to those without tophi [3.5 (2-6.7) vs 7 (3-12) years; p = 0.05] and [22 (12-44) vs 39 (29-73) months; p = 0.08], respectively. This trend was also observed in PCG, but not in DC, first US sign to disappear after initiation of ULT. Ninety percent of patients (100% in non-dialyzed patients) with PCG had a median uricemia ≥5 mg/dl in the past 12 months., Conclusion: We found a significant prevalence of asymptomatic urate deposition in patients with stage 3-5 CKD, mostly in subjects with median uricemia ≥5 mg/dl in the last 12 months. Early diagnosis of PCG by musculoskeletal US in CKD may allow earlier introduction and optimization of ULT. This will probably contribute to slowing down the progression of this pathology, which makes it essential to promote collaboration between Nephrology and Rheumatology., Competing Interests: Conflicts of interest Enrique Calvo-Aranda has received fees for lectures and consultations, or travel or course organisation grants from Menarini, Grünenthal, Asac Pharma, MSD, Lilly, Pfizer, Janssen, Roche, Astra-Zeneca and Galapagos. Marta Novella-Navarro has received fees for lectures or grants to attend scientific conferences from Novartis, Amgen, UCB, Lilly, Galapagos and Janssen. Laura Barrio Nogal has received fees for lectures or grants to attend scientific conferences from Novartis, UCB, Lilly, Galapagos and Janssen. Boris Anthony Blanco Caceres has received fees for lectures and grants to attend scientific conferences from Novartis, Gebro, Grünenthal, Pfizer, UCB, Janssen, Lilly, MSD and Nordic. Jaime Arroyo Palomo has received fees for lectures and grants to attend scientific conferences from Grünenthal, Amgen, Janssen, Pfizer, Rubió, UCB and Novartis. Roberto Alcázar Arroyo has received fees for lectures, travel or course organisation grants from AstraZeneca, Rubió, Boehringer, CLS-Vifor, Bayer, Fresenius Medical Care and Novo Nordisk. Milagros Fernandez Lucas has received fees for lectures from Nipro and AstraZeneca. Diana Peiteado, Eugenio De Miguel, Juan Antonio Martín Navarro, Martha Elizabeth, Diaz Dominguez, Marco Antonio Vaca Gallardo, Elda Besada Estevez and Leticia Lojo Oliveira: none., (Copyright © 2023 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Chronic low back pain is associated with dysfunctions in endogenous analgesia mechanisms, as evaluated through conditioned pain modulation paradigms. Although mobilization with movement has demonstrated enhancements in conditioned pain modulation among patients with conditions such as knee osteoarthritis, its efficacy in chronic low back pain patients has yet to be established., Objectives: To investigate the effects of mobilization with movement compared to sham mobilization in conditioned pain modulation, mechanical hyperalgesia, and pain intensity in chronic low back pain patients., Design: Randomized controlled trial following CONSORT and TIDieR guidelines., Method: Fifty-eight patients with chronic low back pain (mean age 48.77 ± 13.92 years) were randomized into the experimental group, which received real mobilization with movement (n = 29), or the sham mobilization with movement group (n = 29). Only one intervention was performed. Patients were assessed before and after intervention. Conditioned pain modulation, mechanical hyperalgesia and pain intensity were assessed., Results: Mobilization with movement resulted in no statistically significant differences compared to sham mobilization for conditioned pain modulation (post-treatment difference: 0.023 [-0.299, 0.345], p = 0.158), mechanical hyperalgesia (post-treatment difference: -0.198 [-0.505, 0.109], p = 0.207), or movement-related pain intensity (post-treatment difference: 0.548 [-0.068, 1.236], p = 0.079) improvements post-intervention. Effect sizes were small for conditioned pain modulation (r = 0.126), mechanical hyperalgesia (r = 0.101), and pain intensity (r = 0.208)., Conclusions: Mobilization with movement resulted in no significant differences compared to sham mobilization with movement after one intervention for conditioned pain modulation, mechanical hyperalgesia or pain intensity, with small effect sizes. However, the findings should be interpreted with caution due to absence of screening for appropriately eligible patients., Competing Interests: Declaration of interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/objectives: This narrative review examines resilience and social reconstruction strategies implemented during the 1742-1743 plague along the Royal Road between Buenos Aires and Lima. The study explores how colonial authorities managed the epidemic and its long-term effects, providing insights into historical crisis management and public health governance., Methods: A systematic analysis of primary and secondary historical records was conducted to identify public health measures, such as quarantines, hospital construction, and administrative reforms. Sources were retrieved from archives and databases, focusing on resilience strategies and institutional responses to the epidemic., Results: The findings highlight key public health interventions designed to contain the epidemic and mitigate its impacts. These included the establishment of quarantines, the construction of temporary hospitals, and administrative adaptations. Religious practices, such as novenas and community prayers, complemented institutional responses. The study underscores the role of colonial governance in adapting under epidemic pressures, illustrating an emergent institutional resilience., Conclusions: The 1742-1743 plague along the Royal Road serves as a case study for understanding the intersection of health crises and institutional adaptability. The review emphasizes the importance of coordinated public health measures and governance in addressing pandemics, offering lessons on resilience and social reconstruction applicable to contemporary health crises. This historical perspective enriches current discussions on crisis management and public health policy.

We explored the association between aerobic capacity (AC) and the skeletal muscle proteome of McArdle (n = 10) and wild-type (n = 8) mice, as models of intrinsically 'low' and 'normal' AC, respectively. AC was determined as total distance achieved in treadmill running until exhaustion. The quadriceps muscle proteome was studied using liquid chromatography with tandem mass spectrometry, with the Search Tool for the Retrieval of Interacting Genes/Proteins database used to generate protein-protein interaction (PPI) networks and enrichment analyses. AC was significantly associated (P-values ranging from 0.0002 to 0.049) with 73 (McArdle) and 61 (wild-type) proteins (r-values from -0.90 to 0.94). These proteins were connected in PPI networks that enriched biological processes involved in skeletal muscle structure/function in both groups (false discovery rate <0.05). In McArdle mice, the proteins associated with AC were involved in skeletal muscle fibre differentiation/development, lipid oxidation, mitochondrial function and calcium homeostasis, whereas in wild-type animals AC-associated proteins were related to cytoskeleton structure (intermediate filaments), cell cycle regulation and endocytic trafficking. Two proteins (WEE2, THYG) were associated with AC (negatively and positively, respectively) in both groups. Only 14 of the 132 proteins (∼11%) associated with AC in McArdle or wild-type mice were also associated with those previously reported to be modified by aerobic training in these mice, providing preliminary evidence for a large divergence in the muscle proteome signature linked to aerobic training or AC, irrespective of AC (intrinsically low or normal) levels. Our findings might help to gain insight into the molecular mechanisms underlying AC at the muscle tissue level., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

A facile and efficient method for synthesizing mono- and bi-metallic pincer complexes (3-Ni/Ni and 3-Ni/Pd) has been developed. The procedure involves a 1 : 1 stoichiometric reaction of a para -hydroxy POCOP pincer complex with cyanuric chloride in the presence of [NaB(OMe) 4 ], which selectively affords the mono-substituted pincer complexes (2-Ni and 2-Pd). These complexes are then further reacted with another equivalent of the para -hydroxy POCOP pincer complex to produce the desired multimetallic species (3-Ni/Ni and 3-Ni/Pd). The complexes can be easily isolated in moderate to good yields using chromatographic column purification. This straightforward synthesis procedure offers an attractive option for the preparation of multimetallic complexes. Furthermore, the molecular structures of complexes 2-Ni, 2-Pd, 3-Ni/Pd and 3-Ni/S were determined. The crystal packing of the structures was stabilized by various interactions including C-H⋯X (X = N, Cl, and F), π⋯π, and C-F⋯F interactions, contributing to their unique topologies. While 2-Ni and 2-Pd complexes exhibit similar molecular structures, they display distinct arrangements in their crystalline packing, such as monomeric chains in 1D arrangement along the c -axis for 2-Ni, and a symmetric dimeric species creating a 2D arrangement in the direction of the bc -axes for 2-Pd. The latter was corroborated by Hirshfeld surface analysis and 2D dimensional fingerprint plots of each crystal structure.

Background: Ponatinib and asciminib are approved for third-line therapy in chronic-phase chronic myeloid leukemia (CP-CML) and are the only drugs approved for patients with the T315I mutation in the United States. In Europe, only ponatinib is approved for patients with the T315I mutation., Methods: Clinical trials evaluating ponatinib or asciminib in patients with relapsed and refractory (R/R) CP-CML who failed one or more second-generation TKIs or had the T315I mutation were identified in a systematic review of medical literature databases. A matching-adjusted indirect comparison (MAIC) analysis with individual patient-level data with ponatinib was used to balance baseline characteristics between ponatinib and asciminib groups. After matching, the response rate was calculated using the MAIC weight for each patient and the difference in response rate was calculated using a two-independent proportion Z-test. Cumulative rates of BCR::ABL1 IS ≤1% and major molecular response (MMR) in patients without baseline response were compared. Patients were further stratified by T315I mutation status., Results: The MAIC included four trials (ponatinib: NCT02467270, NCT01207440; asciminib: NCT02081378, NCT03106779). In patients without baseline response of BCR::ABL1 IS ≤1%, the adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 9.33% (95% confidence interval [CI]: 0.79%-17.86%; adjusted MMR rate difference: 6.84% [95% CI: -0.95%-14.62%]) by 12 months in favor of ponatinib. In patients with the T315I mutation, adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 43.54% (95% CI: 22.20%-64.87%; adjusted MMR rate difference: 47.37% [95% CI: 28.72%-66.02%]) by 12 months., Conclusion: After key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup., Competing Interests: VG-G reports research funding, consulting role, and scientific advisory board with Incyte. FH, AA, and MD are employees of Takeda Development Center Americas, Inc. VL-K, MR, and HM are employees of Cytel Inc and provided consulting services to Takeda. PP is an employee of Incyte Biosciences International Sàrl. MB receives honoraria from Novartis, Incyte, Pfizer, Bristol Myers Squibb, AOP Health, and GlaxoSmithKline. EJ reports consulting or advisory role with AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte, Pfizer, and Takeda; and research funding from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma, Pfizer, and Takeda. The authors declare that this study received funding from Takeda Development Center Americas, Inc. Takeda Development Center Americas, Inc. had the following involvement in the study: design, data collection, analysis, interpretation of data, reviewing the manuscript for intellectual content, and the decision to submit for publication., (Copyright © 2024 Garcia-Gutierrez, Huang, Ashaye, Dalal, Laliman-Khara, Breccia, Rutherford, Moradian, Patos and Jabbour.)

Background: The increasing availability of neuroimaging tests has led to a rise in the identification of incidental unruptured intracranial aneurysms (UIAs). Their management is under debate, with no consensus on their follow-up strategy, which can cause anxiety in patients. Our aim is to evaluate the impact of diagnosis and imaging follow-up on daily activities and quality of life., Methods: A multicenter cross-sectional study was carried out in patients with UIAs undergoing watchful waiting. Exclusion criteria were history of stroke, renal polycystic disease, symptomatic aneurysms, intervention or scheduled for intervention. The patients completed an anonymous 36-question survey about their habits and perceived quality of life after diagnosis through a validated questionnaire (PROMIS)., Results: We obtained 73 responses from 183 patients identified in eight hospitals (40%), 68 of which were included in the study (50 women (74%), median (IQR) age 62 (55-70) years). Forty-nine patients (72%) underwent at least one imaging follow-up per year. Forty-two patients (63%) found follow-up tests reassuring and 12 (18%) experienced concern about the results. Nineteen patients (28%) reported adopting a healthier lifestyle since diagnosis, while 13 (19%) acknowledged a negative impact on their daily activities. Forty-six (68%) admitted avoiding or conditioning at least one activity or situation from a list. PROMIS scores were similar to those of the general reference population. Overall, 77% rated their quality of life as 'good' or better., Conclusions: The diagnosis of UIAs seems to influence the activities of the majority of patients. However, follow-up yielded more benefit in the form of healthier lifestyles than harm to daily activities, without detriment to their perceived quality of life., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Women researchers have been shown to be underrepresented in science, especially among the most productive scholars. This is especially relevant in the social sciences and humanities fields, where gender parity is closer, but disparities among top scholars are still pronounced. The gender gap in the field of communication has been explored from several approaches, but studies focusing on gender differences in representation, citations, and h-index are rather scarce. Drawing upon data retrieved from SciVal, we conducted a comparative study of the top 500 and top 100 most productive scholars (N = 5000) for each of the ten most productive countries in communication research in the 2019-2022 period: the United States, the United Kingdom, China, Spain, Germany, India, Australia, Canada, Italy, and the Netherlands. The results indicate a consistent underrepresentation of women, particularly among the top 500, across countries. Despite women being cited more frequently than men in some countries over shorter time frames, a gender bias persists favoring men, particularly when considering the h-index. All in all, our study shows that, despite hints of gender equality in citation patterns, the gender gap still constitutes a structural part of the field of communication when addressing gender representation in research productivity and long-term dynamics of research impact., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Goyanes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Behaviour is a fundamental parameter for understanding the animal fitness, serving as an indicator of exposure to stressors. In ecosystems, animals often face multiple stressors simultaneously. Their behavioural responses may vary when exposed to individual stressors, whilst synergistic, additive, or antagonistic effects can result from the interaction of multiple stressors. Therefore, it is imperative to conduct studies that take into account the common occurrence of multi-stress scenarios in aquatic ecosystems. We tested the effects of three sources of stress (acidity (A), toxicity with acetone (T) and conspecific chemical cues (S)) on the behaviour of the aquatic snail Potamopyrgus antipodarum (Tateidae, Mollusca). We evaluated the impact of each stressor, as well as in combinations of two or three stressors simultaneously. The highest time to initiate movement was shown by the animals of the low water pH (A) followed by those exposed to the combination of low water pH and acetone exposure (AT). The differences between the time to initiate movement of each treatment with control revealed a marked decrease in the differences for the snails from the conspecific chemical cues (S) and ST treatments, which mean a higher time to initiate movements. It is concluded that behaviour varied depending on the source and combination of stress. While an acid environment and conspecific signals had contrasting effects when applied separately, their simultaneous exposure resulted in no significant impact. This highlights the importance of considering the combined effects of multiple stressors when extrapolating laboratory results to real-world scenarios, where organisms are often exposed to more than one stressor at a time., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Consent for publication: Author provides consent for publication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs are heterogeneous; however, how MOL subpopulations are specified and balanced in physiological settings is poorly understood. Previous works have demonstrated an essential role of the small GTPases R-Ras1 and R-Ras2 in the survival and myelination of oligodendrocytes. In this study, we aimed to determine how R-Ras1 and R-Ras2 contribute to the heterogeneity of MOL subpopulations. Our results evidence that R-Ras1 and R-Ras2 affect specification into the distinct subpopulations MOL1, MOL2, and MOL5/6, which in turn vary in their dependence of these GTPases. In R-Ras1 and/or R-Ras2 mutant mice, we observed an increase in the MOL1 subpopulation and a decrease in the MOL2 and MOL5/6 subpopulations. We identified R-Ras1 and R-Ras2 as key elements in balancing the heterogeneity of MOLs. Our results contribute to the understanding of the molecular mechanisms underlying the heterogeneity of MOLs and the myelination processes, which is crucial for innovating regenerative therapies for nervous system disorders., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Importance: Blood transfusions are commonly administered to patients with acute brain injury. The optimal hemoglobin transfusion threshold is uncertain in this patient population., Objective: To assess the impact on neurological outcome of 2 different hemoglobin thresholds to guide red blood cell transfusions in patients with acute brain injury., Design, Setting, and Participants: Multicenter, phase 3, parallel-group, investigator-initiated, pragmatic, open-label randomized clinical trial conducted in 72 intensive care units across 22 countries. Eligible patients had traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage; hemoglobin values below 9 g/dL within the first 10 days after injury; and an expected intensive care unit stay of at least 72 hours. Enrollment occurred between September 1, 2017, and December 31, 2022. The last day of follow-up was June 30, 2023., Interventions: Eight hundred fifty patients were randomly assigned to undergo a liberal (transfusion triggered by hemoglobin <9 g/dL; n = 408) or a restrictive (transfusion triggered by hemoglobin <7 g/dL; n = 442) transfusion strategy over a 28-day period., Main Outcomes and Measures: The primary outcome was occurrence of an unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score between 1 and 5, at 180 days following randomization. There were 14 prespecified serious adverse events, including occurrence of cerebral ischemia after randomization., Results: Among 820 patients who completed the trial (mean age, 51 years; 376 [45.9%] women), 806 had available data on the primary outcome, 393 in the liberal strategy group and 413 in the restrictive strategy group. The liberal strategy group received a median of 2 (IQR, 1-3) units of blood, and the restrictive strategy group received a median of 0 (IQR, 0-1) units of blood, with an absolute mean difference of 1.0 unit (95% CI, 0.87-1.12 units). At 180 days after randomization, 246 patients (62.6%) in the liberal strategy group had an unfavorable neurological outcome compared with 300 patients (72.6%) in the restrictive strategy group (absolute difference, -10.0% [95% CI, -16.5% to -3.6%]; adjusted relative risk, 0.86 [95% CI, 0.79-0.94]; P = .002). The effect of the transfusion thresholds on neurological outcome at 180 days was consistent across prespecified subgroups. In the liberal strategy group, 35 (8.8%) of 397 patients had at least 1 cerebral ischemic event compared with 57 (13.5%) of 423 in the restrictive strategy group (relative risk, 0.65 [95% CI, 0.44-0.97])., Conclusions and Relevance: Patients with acute brain injury and anemia randomized to a liberal transfusion strategy were less likely to have an unfavorable neurological outcome than those randomized to a restrictive strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT02968654.

Since prehistory, humans have altered the composition of ecosystems by causing extinctions and introducing species. However, our understanding of how waves of species extinctions and introductions influence the structure and function of ecological networks through time remains piecemeal. Here, focusing on Australia, which has experienced many extinctions and introductions since the Late Pleistocene, we compared the functional trait composition of Late Pleistocene (130,00-115,000 years before present [ybp]), Holocene (11,700-3,000 ybp), and current Australian mammalian predator assemblages (≥70% vertebrate meat consumption; ≥1 kg adult body mass). We then constructed food webs for each period based on estimated prey body mass preferences. We found that introduced predators are functionally distinct from extinct Australian predators, but they rewire food webs toward a state that closely resembles the Late Pleistocene, prior to the megafauna extinctions. Both Late Pleistocene and current-day food webs consist of an apex predator and three smaller predators. This leads to food web networks with a similar total number of links, link densities, and compartmentalizations. However, this similarity depends on the presence of dingoes: in their absence, food webs become simplified and reminiscent of those following the Late Pleistocene extinctions. Our results suggest that recently established predators, even those implicated in species extinctions and declines, can restore complexity to food webs simplified by extinction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Anemia, primarily due to iron deficiency, is a key risk factor in both elective and emergency surgeries. Immediate preoperative treatment with ferric carboxymaltose (FCM) in anemic patients can reduce the need for transfusions and the length of hospital stay, thereby optimizing surgical outcomes. The objective of this study was to assess the effectiveness and describe the use of administering intravenous FCM prior to elective scheduled surgery for patients diagnosed with anemia., Methods: Multicenter, retrospective cohort study that encompassed patients aged 18 years and older who underwent surgery between January 2017 and December 2018. Demographic variables, dose scheme, baseline and perioperative haemoglobin (Hb), transfusion requirements, and admission days were collected. The primary endpoints were the response rate and effectiveness of FCM, defined as the proportion of patients with Hb preoperative levels of ≥13 g/dL. A patient response was deemed to occur when Hb level increased by 1 g/dL or more. The secondary endpoints were the appropriateness of FCM dose, transfusion requirement rate, and length of hospital stay., Results: 446 patients (55.2% women, median age 69 IQR:52-78 years) were included. The median total dose of FCM administered was 1000 mg over a span of 5 day (IQR: 0-16) days before surgery. 62.8% of patients received lower doses, 24.9% had an INCREASE of Hb ≥ 1 g/dL, 11.6% had Hb ≥ 13 g/dL and 21.3% required blood transfusions, with a mean of 0.73 units transfused. The length of the hospital stay was 12 days (IQR:6-23)., Conclusion: Low percentage of patients achieved a hemoglobin level of 13 g/dL or experienced an increase in hemoglobin of 1 g/dL or more following the administration of FCM, indicating the low effectiveness of FCM in treating perioperative anaemia in our surgical patients. There is underdosing of FCM and insufficient time between FCM administration and surgery in most patients. Both transfused and non-transfused patients show similar Hb increases, while those receiving a standard 1000 mg dose of FCM experience shorter hospital stays compared to those receiving 500 mg, and patients with more transfusions have longer hospital stays., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yuste Gutierrez et al.)

Trichotillomania (TTM) is an obsessive-compulsive disorder in which affected individuals recurrently pull-out hair from any region of the body, causing hair loss or alopecia. The management of TTM is a therapeutic challenge for dermatologists and consists of a combination of pharmacological and non-pharmacological alternatives. Cognitive-behavioral therapy has successfully been used to treat TTM. However, not all patients are willing to follow this treatment strategy. Unconventional support tools are proposed, such as electronic devices, Internet therapies and microneedling. N-acetylcysteine and memantine are considered suitable first-line therapies thanks to their favorable safety and efficacy profile, low risk of adverse effects, and significant benefits. The use of other drugs, including fluoxetine, clomipramine, olanzapine, and naltrexone has limited evidence of variable efficacy. The present review illustrates the current treatment modalities for the management of TTM., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)