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Los tumores de ovario borderline presentan riesgo disminuido para malignidad; representan del 10 al 15% de las neoplasias del ovario, común en pacientes jóvenes, diagnóstico en las primeras etapas clínicas, buen pronóstico. Paciente de sexo femenino de 25 años, inicia con dolor abdominal por tumoración de crecimiento progresivo; elevación de marcador tumoral CA-125. Por histopatología reporta tumor borderline extirpe seroso. Los tumores borderline se presentan a los 30-50 años de edad, con elevación del marcador tumor de CA-125, poco común en este rango de edad. Se debe descartar situación maligna.

This paper aims to interpret the role of the soul as ontological, intellectual or cognitive and as the moral principle within the frame of the holistic conception of human psychosomatic health that emerges from the context of Zalmoxian medicine in the proemium of Plato’s Charmides. It examines what the ontological status of the soul is in relation to the body and the body–soul complex of man considered as a psychosomatic whole. By comparing the presentation of the soul as principle in the Charmides and the Phaedrus, the paper defends the thesis that in the former dialogue, Plato develops his own anthropological ontology, which paves the way for the salvation of human existence and health. The soul is bestowed with an ontological primacy that determines the philosophical and medical presuppositions for treating human illness under a holistic view. The interpretation of the ontological relation of the soul to the body and the entire human being in the context of Zalmoxian holistic medicine is based on Hermias Alexandrinus’ exegesis of the conception of the soul as principle in the Phaedrus. This paper demonstrates that, from both the medical holistic viewpoint and the anthropological philosophical perspective, the soul is the principle and πρῶτον with regard to the body and the body–soul complex without being the whole that the corresponding medical epistemology must apprehend.

BackgroundCurrently available treatment options for Parkinson's disease are symptomatic and do not alter the course of the disease. Recent studies have raised the possibility that cardiovascular risk management may slow the progression of the disease.ObjectivesWe estimated the effect of baseline cardiovascular risk factors on the progression of Parkinson's disease, using measures for PD-specific motor signs and cognitive functions.MethodsWe used data from 424 de novo Parkinson's disease patients and 199 age-matched controls from the observational, multicenter Parkinson's Progression Markers Initiative (PPMI) study, which included follow-up of up to 9 years. The primary outcome was the severity of PD-specific motor signs, assessed with the MDS-UPDRS part III in the “OFF”-state. The secondary outcome was cognitive function, measured with the Montreal Cognitive Assessment, Symbol Digit Modalities Test, and Letter-Number Sequencing task. Exposures of interest were diabetes mellitus, hypertension, body mass index, cardiovascular event history and hypercholesterolemia, and a modified Framingham risk score, measured at baseline. The effect of each of these exposures on disease progression was modeled using linear mixed models, including adjustment for identified confounders. A secondary analysis on the Tracking Parkinson's cohort including 1,841 patients was performed to validate our findings in an independent patient cohort.ResultsMean age was 61.4 years, and the average follow-up was 5.5 years. We found no statistically significant effect of any individual cardiovascular risk factor on the MDS-UPDRS part III progression (all 95% confidence intervals (CIs) included zero), with one exception: in the PD group, the estimated effect of a one-point increase in body mass index was 0.059 points on the MDS-UPDRS part III per year (95% CI: 0.017 to 0.102). We found no evidence for an effect of any of the exposures on the rate of change in cognitive functioning in the PD group. Similar results were observed for the Tracking Parkinson's cohort (all 95% CIs overlapped with PPMI), but the 95% CI of the effect of body mass index on the MDS-UPDRS part III progression included zero.ConclusionsBased on this analysis of two large cohorts of de novo PD patients, we found no evidence to support clinically relevant effects of cardiovascular risk factors on the clinical progression of Parkinson's disease.

Brown rot of stone fruit, caused by Monilinia spp., is one of the most important diseases worldwide, causing significant production losses. Currently, the standard practices for controlling this infection consist of repetitive use of synthetic fungicides. The global tendency encourages the demand for high-quality food products harmless to health and the environment, leading to a reduction in the use of these types of substances. Zuccagnia punctata (Fabaceae) is a perennial shrub extensively used for the treatment of fungal and bacterial infections in Argentinean traditional medicine. In this study, we isolated and characterized (morphologically and molecularly) a pathogenic and virulent strain of Monilinia fructicola, which is the most hostile species of the genus. Consequently, we explored the in vitro antifungal activity of the ethanolic extract of Z. punctata against this phytopathogen. The chalcones 2′,4′-dihydroxy-3′-methoxychalcone and 2′,4′-dihydroxychalcone were isolated from the extract and evaluated against M. fructicola demonstrating that they were responsible for this activity. To promote full-spectrum extract rather than pure compounds, we performed ex-vivo assays using fresh peaches inoculated with the pathogen, and then treated by immersion in an extract solution of 250 µg/mL concentration. Treatment with Z. punctata extract did not show a statistically significant difference from commercial fungicides in the control of fruit rot. In addition, Huh7 cell cytotoxicity evaluation showed that Z. punctata extract was less cytotoxic than commercial fungicides at the assayed concentrations. Based on our research, this plant extract could potentially offer a safer alternative to commercial fungicides for treating peach brown rot.

Persicaria acuminata (Polygonaceae) is a perennial herb that grows in the central area of Argentina and it is commonly used by native populations to heal infected wounds and other conditions related to fungal infections. In this article, we explored the in vitro antifungal activity of its ethyl acetate extract against a panel of three fruit phytopathogenic fungi including: Penicillium digitatum, P. italicum, and Monilinia fructicola. The sesquiterpenes isolated from the extract were also evaluated against these strains, demonstrating that the dialdehyde polygodial was the responsible for this activity. In order to encourage the use of the extract rather than the pure compound, we displayed ex vivo assays using fresh oranges and peaches inoculated with P. digitatum and M. fructicola, respectively, and subsequently treated by immersion with an extract solution of 250 and 62.5 µg/mL, respectively. There were no statistically significant differences between the treatments with commercial fungicides and the extract over the control of both fruit rots. The concentration of the active compound present in the extract used on fruit experiments was determined by Gas Chromatography-Mass Spectroscopy. Finally, cytotoxicity evaluation against Huh7 cells showed that P. acuminata extract was less cytotoxic than the commercial fungicides at the assayed concentrations. After these findings we could conclude that a chemically characterized extract of P. acuminata should be further developed to treat fungal diseases in fruits from an agro-ecological model.

[Language of the article: Greek] Charmides is a dialogue highly indicative of the importance that the prologues to Plato’s works have for our understanding of the whole spirit and philosophical content of each dialogue as a whole. It is representative of the Platonic tendency to always combine philosophical content with dramatic form through narrative and drama, in order to enhance the reader’s and audience’s insight into the inquiries of his philosophical work. Following this line of presentation, the prologue of Charmides prefigures the understanding of the central themes of the dialogue; focusing on the depiction of Socrates as a therapist and of Dialectic as a therapy or a kind of remedy, which through the process of dialectical engagement and interaction reestablishes the relation of each interlocutor to his own self. The narrative about the Thracian doctors of the king and god Zalmoxis and their special medical knowledge, foreshadows the major philosophical issues which are examined in the sequence of the dialogue. Socrates’ reference to the good doctors and his criticism of the Greek doctors who ignore the whole that needs to be cured, reveals the central demand for the psychosomatic unity of man and the priority of the healing of the soul over the healing of the body. The holistic Zalmoxian medicine and theory of health corresponds to the first step of the Socratic Dialectic. Through the narrative about the Thracian doctors of Zalmoxis, Socratic-Platonic Dialectic has already begun to evolve, following a movement with clearly defined direction, namely from the part to the whole, where the part denotes and signifies the body and the whole denotes the psychosomatic unity of the human being. Sōphrosunē is already involved in this narrative since the incantations invoked by Socrates, which are identified with the “beautiful speeches,” induce sōphrosunē on which the well being of the soul depends. This raises the question as to whether these doctors apply medical knowledge which has a specified epistemological content, or knowledge equipped with a universal character—in the sense of being also prior to all other kinds of knowledge—which transcends the usual confines of the medical art. Charmides is invited by Socrates to look deep within himself in order to discover if he possesses sōphrosunē, and what sōphrosunē really is. That’s what Charmides is doing by formulating his first two definitions of sōphrosunē. Dialectic now follows a movement from without to within. Charmides’ first and second definitions reflect the social status to which he belongs, the corresponding behavior, and the inner psychic qualities (e.g., youthful shyness) of a person or persona who represents the system of values surrounding traditional virtue and the aristocratic conception of the ideal of “kalos kagathos.” It is probable that the dramatic time of the dialogue, which coincided with the outbreak of the Peloponnesian war, was associated with a criticism of the traditional view and model of virtue. When sōphrosunē is defined as “doing one’s own things,” Dialectic still has the tendency to move from without inwards, but this movement now is implemented in the field of praxis (action). Platonic Dialectic uses the device of change of interlocutor in order to signify the transition to a more demanding level of inquiry and thought. This definition of sōphrosunē, “doing one’s own things,” on the basis of a proleptic reading, stimulates us to trace the relation between sōphrosunē in Charmides and dikaiosunē (justice) in the Republic. What is important in the Socratic elenchus of this definition is that it highlights the connection between prattein (doing) and pratteintagatha (doing the good), between prattein and works (erga), and between the beneficial and the good. It is clarified that only the makings of good things are praxeis (doings) and that what is of harm must be avoided as “alien.” The definition of sōphrosunē as “doing good things” re-orientates Dialectic, which now starts moving from praxis to theōria, because “doing good things” presupposes knowing what is good. But if agathon (good) is what is kindred to oneself and one’s own, doing good things, or doing simpliciter, i.e., praxis, presupposes self-knowledge. Any practitioner of good must be a self-knowing agent. The Apollonian ideal of self-knowledge (know thyself) is construed as a “greeting” of the god to worshipers who enter the temple, not as a moral counsel or as a piece of advice. This distinction implies the difference between a knowledge conveyed from without and a knowledge discovered by insightful inner search of one’s self. Within the passages 165c to 175a, sōphrosunē is presented and examined as “the knowledge of what one knows and what one does not know.” It has been claimed that in this part of the dialogue, the Socratic model of self-knowledge is subjected by Plato to the Socratic elenchus, where he attempts to make a criticism of it. I believe that this section of the dialogue is an extended excursus, aimed towards introducing and examining a model of self-knowledge different from that of Socrates, Critias’ model of self-knowledge. This model of self-knowledge poses a whole series of philosophical problems; the relation between the subject and the object of knowledge, the possibility of their identification or the distinction between them, the possibility of the existence of an internal and external object of knowledge, the relation of this model of self-knowledge with other kinds or domains of knowledge, and the question whether external knowledge or knowledge of other knowledges is a constituent of knowledge of knowledge. The question of the possibility of knowledge of knowledge is not definitely rejected, especially if we consider that in all of this discussion there is a hint towards the way in which philosophy works and relates to other kinds of knowledge. I believe, however, that in the last part of the dialogue, where the knowledge of good and bad emerges, Plato again meets Socrates and becomes reconciled with him. The only knowledge that is useful and beneficial is knowledge of good and bad. In this way Plato chooses to put forward a self-conscious model of self-knowledge, which does not presuppose, as Critias’ model does, the critical examination of knowledge or the critical distance from knowledge. This self-conscious model of self-knowledge is connected with the knowledge of good and bad. On the one hand doing of good presupposes knowledge of good and bad and on the other, “doing one’s own things” presupposes self-knowledge. The possibility of knowing good and bad is ensured by each person, either through looking deep within himself or by orientating towards the Idea of the Good itself.

The role of tumor necrosis factor-α (TNF-α) in shaping the tumor microenvironment is ambiguous. Consistent with its uncertain role in melanoma, TNF-α plays a dual role, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. TNF-α signals via two cognate receptors, namely TNFR1 (p55) and TNFR2 (p75), which mediate divergent biological activities. Here, we analyzed the impact of TNFR1 deficiency in tumor progression in the B16.F1 melanoma model. Tumors developed in mice lacking TNFR1 (TNFR1 knock-out; KO) were smaller and displayed lower proliferation compared to their wild type (WT) counterpart. Moreover, TNFR1 KO mice showed reduced tumor angiogenesis. Although no evidence of spontaneous metastases was observed, conditioned media obtained from TNFR1 KO tumors increased tumor cell migration. Whereas the analysis of tumor-associated immune cell infiltrates showed similar frequency of total and M2-polarized tumor-associated macrophages (TAMs), the percentage of CD8+ T cells was augmented in TNFR1 KO tumors. Indeed, functional ex vivo assays demonstrated that CD8+ T cells obtained from TNFR1KO mice displayed an increased cytotoxic function. Thus, lack of TNFR1 attenuates melanoma growth by modulating tumor cell proliferation, migration, angiogenesis and CD8+ T cell accumulation and activation, suggesting that interruption of TNF-TNFR1 signaling may contribute to control tumor burden.

In Nicomachean Ethics 1.6, Aristotle directs his criticism not only against the Platonic Idea of the Good but also against the notion of a universal Good. In this paper, I also examine some of the most interesting aspects of his criticism of the Platonic Good and the universal Good in Eudemian Ethics 1.8. In the EN, after using a series of disputable ontological arguments, Aristotle’s criticism culminates in a strong ethical or rather practical and, simultaneously, epistemological argument, from which a dialectical postulatum emerges. This argument aims to show that we have to discover the dialectical stages or grades which constitute the relation between the ultimate End, i.e., the Good simpliciter or the absolute Good, and the relational goods till the last prakton good in which each specific praxis ends. According to the present reading, Aristotle sets out to establish a kind of Dialectic of the ends (Dialektikē tōn telōn) or Dialectic of the goods (Dialektikē tōn agathōn), which puts emphasis on the descent to the specific good, which is appropriate to and cognate with each individual, be that a person, praxis, science or craft. It is also suggested that this might be relevant to Aristotle’s tendency to establish a separation of phronēsis, i.e., practical wisdom, from sophia, i.e., wisdom, in the Nicomachean Ethics.

In the last 15 years, increasing evidences demonstrate a strong link between sphingosine-1-phosphate (S1P) in both normal physiology and progression of different diseases, including cancer and inflammation. Indeed, numerous studies show that tissue levels of this sphingolipid metabolite are augmented in many cancers, affecting survival, proliferation, angiogenesis and metastatic spread. Recent insights into the possible role of S1P as a therapeutic target has attracted enormous attention and opened new opportunities in this evolving field. In this review we will focus on the role of S1P in cancer with particular emphasis in new developments that highlight the many functions of this sphingolipid in the tumor microenvironment. We will discuss how S1P modulates phenotypic plasticity of macrophages and mast cells, tumor-induced immune evasion, differentiation and survival of immune cells in the tumor milieu, interaction between cancer and stromal cells and hypoxic response.

In the De Generatione et Corruptione II 9, Aristotle aims to achieve the confirmation of his theory of the necessity of the efficient cause. In this chapter he sets out his criticism on the one hand of those who wrongly attributed the efficient cause to other kinds of causality and on the other, of those who ignored the efficient cause. More specifically Aristotle divides all preceding theories which attempted to explain generation and corruption into two groups: i) those which offered an explanation by using the formal cause ii) those which provided an explanation by using the material or the instrumental causes. According to Philopo­nus, when Aristotle reproaches the other philosophers for adducing no proper notion of the efficient cause he alludes to both Anaxagoras and Plato. Regarding Anaxagoras, in our view this cannot be confirmed by internal textual evidence. In terms of Plato, in this chapter we trace an explicit and an implicit criticism of the Platonic Forms as causes. Aris­totle’s implicit criticism is that the Forms are not at all active causes. We can understand better the grounds for this criticism if we also consider his relevant arguments in Book Lambda of his Metaphysics. His explicit criticism, articulated in two arguments, is formulated in GC 335b18–24. We examine the different lines of its interpretation in the second­ary literature, but primarily we focus on Philoponus’ exegesis, which contributes significantly, not only to the clarification of Aristotle’s thinking, but also to the manifestation of the arguments articulated in defence of the Platonic theory of the Forms. In this paper, through the analysis of Philoponus’ exegesis we set out to prove that Aristotle’s criticism of the Platonic causes can be construed from the perspective of either Aristo­telian theory or the Platonic and Neoplatonic influence. Finally, based on Philoponus’ exegesis, we examine Aristotle’s criticism of those who posited matter or instrumental causes as efficient causes.

This paper analyzes and explains certain parts of Syrianus’s Commentary on book M of Aristotle’s Metaphysics, which details Syrianus’s response to Aristotle’s attack against the Platonic position of the separate existence of numbers. Syrianus defends the separate existence not only of eidetic but also of mathematical numbers, following a line of argumentation which involves a hylomorphic approach to the latter. He proceeds with an analysis of the mathematical number into matter and form, but his interpretation entails that form is the constituent of number, which has the status and role of a Platonic Form. This solution allows him not only to explain and justify the unity of number, but also to apply the Platonic thesis of the separate existence of numbers, to the mathematical or monadic numbers themselves. It also betrays its tendency to combine theses of the Platonic Ontology with fundamental Aristotelian doctrines.

This paper presents Olympiodorus’ and Damascius’ explanations of the philosopher’s practice of dying in Plato’s Phaedo. It also includes a presentation of Ammonius’ exegesis of the practice of death (meletē thanatou). The Neoplatonic commentators discern two kinds of death, the bodily or physical death and the voluntary death. Olympiodorus suggests that bodily death is only an image of voluntary death and cannot be recognized as an original death, because original death presupposes the preparation for death and the constant effort for the purification of the soul during the philosopher’s life-time. Only preparation for death and purification can ensure the complete separation of the soul from the body. Relative to this distinction is that between apothnēskein and tethnanai; these infinitives denote the dual meaning of death: death as an event or a process and death as a state. Our study examines thoroughly the subtle distinctions made by Olympiodorus and Damascius and offers a comparative analysis of the two definitions of death as well as that of purification. It reaches the conclusion that apothnēskein is a necessary condition of tethnanai, i.e. of a definitive release and parting of the soul from the body. On the other hand, the process of eventual purification, a notion which betrays the religious character of purification, can be identified with apothnēskein, which is the practice of dying by the true philosopher. Finally, our study also emphasizes and explains the difference between the voluntary philosophical death and the voluntary unphilosophical suicide; the latter guaranteeing only bodily or physical death.

This paper presents Aristotle’s method of understanding the first principles of natural things in the Physics I.1 and analyzes the three stages of which this method consists. In the Physics I.1, Aristotle suggests that the natural proper route which one has to follow in order to find out the first principles of natural things is to proceed from what is clearer and more knowable to us to what is more knowable and clear by nature. In the Physics I.1, the terms καθόλου (universal) and καθ΄ ἕκαστα (particular) are not used in their usual meaning (e.g., the meaning which the same terms have in the Posterior Analytics I. 2). This paper examines the Physics I.1 in comparison with the Posterior Analytics II. 19 in order to elucidate the meaning of καθόλου in the first chapter of Aristotle’s Physics. Furthermore, it reaches the conclusion that the structure of the natural world to which we belong determines the structure and the form of our knowledge. On the one hand, natural things are composite and, on the other hand, perception is involved in the initial grasping of natural things as composites. Thus, since perceptual knowledge is more accessible to us than any other kind of knowledge it is natural to reach knowledge of simple things, i.e., of the principles, starting our inquiry with the composites.

Ketamine, a dissociative anesthetic drug, has gained popularity as a recreational substance, particularly among young adults. However, chronic ketamine abuse can lead to various complications including ketamine-induced cystitis. We present the case of a 46-year-old Caucasian male with a history of HIV infection and daily recreational ketamine use for 7 months, who was admitted to the emergency room with hypogastric pain and hematuria. Laboratory examinations and contrast-enhanced abdominal CT tomography revealed significant irregular circumferential thickening of both ureters, substantial bilateral pyeloureteral ectasia, and a bladder with markedly thickened walls. Bilateral flexible ureteropyeloscopy, bladder transurethral resection, and bladder fulguration were performed, and pathology confirmed the diagnosis of ketamine-induced cystitis. Treatment consisted of ketamine withdrawal, pain relief, and support from psychiatrists and urologists. The patient's symptoms improved and he was discharged without complications. This case highlights the importance of recognizing the potential adverse effects of recreational ketamine use and the need for a multidisciplinary approach to managing ketamine-induced cystitis. Further research is necessary to elucidate the precise mechanisms underlying this condition and develop effective prevention and treatment strategies.

Abstract Streptococcus suis is a bacterial pathogen that causes important economic losses to the swine industry worldwide. Since there are no current commercial vaccines, the use of autogenous vaccines applied to gilts/sows to enhance transfer of passive immunity is an attractive alternative to protect weaned piglets. However, there is no universal standardization in the production of autogenous vaccines and the vaccine formulation may be highly different among licenced manufacturing laboratories. In the present study, an autogenous vaccine that included S. suis serotypes 2, 1/2, 5, 7 and 14 was prepared by a licensed laboratory and administrated to gilts using a three-dose program prior to farrowing. The antibody response in gilts as well as the passive transfer of antibodies to piglets was then evaluated. In divergence with previously published data with an autogenous vaccine produced by a different company, the increased response seen in gilts was sufficient to improve maternal antibody transfer to piglets up to 5 weeks of age. However, piglets would still remain susceptible to S. suis disease which often appears during the second part of the nursery period. Vaccination did not affect the shedding of S. suis (as well as that of the specific S. suis serotypes included in the vaccine) by either gilts or piglets. Although all antibiotic treatments were absent during the trial, the clinical protective effect of the vaccination program with the autogenous vaccine could not be evaluated, since limited S. suis cases were present during the trial, confirming the need for a complete evaluation of the clinical protection that must include laboratory confirmation of the aetiological agent involved in the presence of S. suis-associated clinical signs. Further studies to evaluate the usefulness of gilt/sow vaccination with autogenous vaccines to protect nursery piglets should be done.

Abstract Background Nowadays, there is no method to quantitatively characterize the material composition of acute ischemic stroke thrombi prior to intervention, but dual-energy CT (DE-CT) offers imaging-based multimaterial decomposition. We retrospectively investigated the material composition of thrombi ex vivo using DE-CT with histological analysis as a reference. Methods Clots of 70 patients with acute ischemic stroke were extracted by mechanical thrombectomy and scanned ex vivo in formalin-filled tubes with DE-CT. Multimaterial decomposition in the three components, i.e., red blood cells (RBC), white blood cells (WBC), and fibrin/platelets (F/P), was performed and compared to histology (hematoxylin/eosin staining) as reference. Attenuation and effective Z values were assessed, and histological composition was compared to stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. Results Histological and imaging analysis showed the following correlation coefficients for RBC (r = 0.527, p

Ticks are obligate hematophagous arthropods that transmit a wide range of pathogens to humans as well as wild and domestic animals. They also harbor a non-pathogenic microbiota, although our previous study has shown that the diverse bacterial microbiome in the midgut of Ixodes ricinus is quantitatively poor and lacks a core. In artificial infections by capillary feeding of ticks with two model bacteria (Gram-positive Micrococcus luteus and Gram-negative Pantoea sp.), rapid clearance of these microbes from the midgut was observed, indicating the presence of active immune mechanisms in this organ. In the current study, RNA-seq analysis was performed on the midgut of I. ricinus females inoculated with either M. luteus or Pantoea sp. or with sterile water as a control. While no immune-related transcripts were upregulated by microbial inoculation compared to that of the sterile control, capillary feeding itself triggered dramatic transcriptional changes in the tick midgut. Manual curation of the transcriptome from the midgut of unfed I. ricinus females, complemented by the proteomic analysis, revealed the presence of several constitutively expressed putative antimicrobial peptides (AMPs) that are independent of microbial stimulation and are referred to here as ‘guard’ AMPs. These included two types of midgut-specific defensins, two different domesticated amidase effector 2 (Dae2), microplusin/ricinusin-related molecules, two lysozymes, and two gamma interferon-inducible lysosomal thiol reductases (GILTs). The in vitro antimicrobial activity assays of two synthetic mature defensins, defensin 1 and defensin 8, confirmed their specificity against Gram-positive bacteria showing exceptional potency to inhibit the growth of M. luteus at nanomolar concentrations. The antimicrobial activity of midgut defensins is likely part of a multicomponent system responsible for the rapid clearance of bacteria in the tick midgut. Further studies are needed to evaluate the role of other identified ‘guard’ AMPs in controlling microorganisms entering the tick midgut.

While rights holders are not expressly mentioned as a group of stakeholders in CSDDD, the adoption of this important legislation creates a significant opportunity to involve rights holders to define how the content of the stand-alone article on stakeholder engagement can be filled with legal meaning by soliciting them directly.

Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.

Abstract The moss layer transfer technique has been developed to restore the carbon sequestration function and typical vegetation of Sphagnum-dominated peatlands after peat extraction in North America. However, the technique does not lead to successful bryophyte establishment when applied to peatlands with a richer residual fen peat. Therefore, we evaluated an alternative method of active rewetting and passive vegetation establishment using vegetation surveys and carbon dioxide and methane (CH4) flux measurements at a post-extracted fen in southern Manitoba, Canada. After one growing season post-rewetting, wetland vegetation established and the site was a net carbon sink over the growing season. However, high abundance of Carex lasiocarpa 10 years post-treatment led to higher CH4 emissions than the reference ecosystem. Successful establishment of wetland vegetation is attributed to the area being surrounded by undisturbed fens that can provide a local source of plant propagules. Bryophyte expansion was less successful than vascular plants, likely due to episodic flooding and shading from the sedge communities. Therefore, careful management of water levels to just below the peat surface is needed if reference vegetation community recovery is the goal of restoration. Water level management will also play a key role in controlling CH4 emissions to maximize carbon sequestration potential.

Wildfires present a major global environmental issue, exacerbated by climate change. The Iranian Northern Zagros Forests, characterized by a Mediterranean climate, are particularly vulnerable to fires during hot, dry summers. This study investigates the impact of climate change on forest fires in these forests from 2006 to 2023. The analysis revealed significant year-to-year fluctuations, with notable fire occurrence in years 2007, 2010, 2021, and 2023. The largest burned area occurred in 2021, covering 2655.66 ha, while 2006 had the smallest burned area of 175.27 ha. Climate variables such as temperature, humidity, precipitation, wind speed, heat waves, and solar radiation were assessed for their effects on fire behavior. Strong correlations were found between higher average temperatures and larger burned areas, as well as between heat waves and increased fire frequency. Additionally, higher wind speeds were linked to larger burned areas, suggesting that increased wind speeds may enhance fire spread. Multiple linear regression models demonstrated high predictive accuracy, explaining 84% of the variance in burned areas and 69.6% in the variance in fire frequency. These findings document the growing wildfire risk in the Northern Zagros region due to climate change, highlighting the urgent need to integrate scientific research with policies to develop effective wildfire management strategies for sustainable forest management.

Abstract Artificial membrane feeding (AMF) is a powerful and versatile technique with a wide range of applications in the study of disease vectors species. Since its first description, AMF has been under constant optimization and standardization for different tick species and life stages. In the USA, Ixodes scapularis is the main vector of tick-borne zoonoses including the pathogens causing Lyme disease in humans and animals. Seeking to improve the overall fitness of I. scapularis adult females fed artificially, here, we have optimized the AMF technique, considerably enhancing attachment rate, engorgement success, egg laying, and egg hatching compared to those described in previous studies. Parameters such as the membrane thickness and the light/dark cycle to which the ticks were exposed were refined to more closely reflect the tick’s natural behavior and life cycle. Additionally, ticks were fed on blood only, blood + ATP or blood + ATP + gentamicin. The artificial feeding of ticks on blood only was successful and generated a progeny capable of feeding naturally on a host, i.e., mice. Adding ATP as a feeding stimulant did not improve tick attachment or engorgement. Notably, the administration of gentamicin, an antibiotic commonly used in tick AMF to prevent microbial contamination, negatively impacted Rickettsia buchneri endosymbiont levels in the progeny of artificially fed ticks. In addition, gentamicin-fed ticks showed a reduction in oviposition success compared to ticks artificially fed on blood only, discouraging the use of antibiotics in AMF. Overall, our data suggest that the AMF of adult females on blood only, in association with the natural feeding of their progeny on mice, might be used as an integrated approach in tick rearing, eliminating the use of protected species under the Animal Welfare Act (AWA). Of note, although optimized for I. scapularis adult ticks, I. scapularis nymphs, other tick species, and sand flies could also be fed using the membrane described in this study, indicating that it might be a suitable alternative for the artificial feeding of a variety of hematophagous species.

The conventional dichotomy between human health and disease has historically been approached through reductionist models that emphasize the exclusive causal relevance of physiological and pathological processes. Consequently, self-awareness and affective dimensions, integral to a phenomenological perspective, are often relegated to secondary traits, affording little consideration for the causal role of embodied living organization. Our interest lies in exploring the potential relevance of the phenomenology of embodied self-awareness in relation to interoceptive processes within therapeutic settings. As we illustrate, when the unfolding processes of interoceptive awareness and its affective capacity take precedence, the agent assumes an active, rather than passive, role in their own experience of health or illness. Departing from an enactive, phenomenological, and ecological standpoint, we propose a distinctive perspective on interoceptive processes, relying on an affective conceptualization of a spectrum of experiences of bodily being-in-the-world. Our primary argument posits that considering interoceptive processes from an embodied and ecological viewpoint of the self, interacting with the material and social environment, enables an approach to the gradient of affective experiences of embodied self-awareness—where pleasure or suffering is perceived and felt—in a naturalized, non-reductive, and relational manner. We discern two ways in which interoceptive processes interrelate with the experience of embodied self-awareness: sensitivity (self-affective) and affective-laden perception. Drawing on this distinction, we provide a nuanced description of these experiences within communities of cis-women, exemplified through the contexts of menstruation and endometriosis. This exploration seeks to enhance our understanding of the phenomenology of embodied, ecological, and affective self-experience from within diverse and situated bodies. The goal is to contribute to their autonomy and ability to adapt and self-regulate within therapeutic contexts.

Amblyomma ticks are vectors of both Rickettsia rickettsii and R. parkeri in the Americas, where capybaras (Hydrochoerus hydrochaeris) are the main hosts in urban areas, thus contributing to the transmission of spotted fever. Herein, we studied: (i) the seasonal dynamics and abundance of ticks in areas where capybaras live, (ii) the effect of environmental variables on tick abundance, and (iii) the presence of Rickettsia-infected ticks. Between September 2021 and September 2022, we sampled ticks using cloth-dragging at 194 sites on the shore of Lake Paranoá in Brasília, Brazil. We measured environmental data (season, vegetation type, canopy density, temperature, humidity, and presence or vestige of capybara) at each site. Nymphs and adults were morphologically identified to the species level, and a selected tick sample including larvae was subjected to genotypic identification. We investigated Rickettsia-infected ticks by PCR (gltA, htrA, ompB, and ompA genes) and associations between tick abundance and environmental variables using Generalized Linear Models. A total of 30,334 ticks (96% larvae) were captured. Ticks were identified as Amblyomma, with A. sculptum comprising 97% of the adult/nymphs. Genotype identification of a larval sample confirmed that 95% belonged to A. dubitatum. Seasonal variables showed significant effects on tick abundance. Most larvae and nymphs were captured during the early dry season, while the adults were more abundant during the wet season. Vegetation variables and the presence of capybaras showed no association with tick abundance. Rickettsia parkeri group and R. bellii were identified in A. dubitatum, while A. sculptum presented R. bellii. We conclude that: (i) Amblyomma ticks are widely distributed in Lake Paranoá throughout the year, especially larvae at the dry season, (ii) the abundance of Amblyomma ticks is explained more by climatic factors than by vegetation or presence of capybaras, and (iii) A. dubitatum ticks are potential vectors of R. parkeri in Brasília.

Introduction Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide, which is partly contributed to the increasing prevalence of COPD owning to a demographic shift towards an older population. Conversely, recent studies on COPD mortality that take this demographic shift in age into account find decreasing overall age-standardised COPD mortality rates over time. This decrease in the age-standardised COPD mortality rate is contributed advances in COPD diagnostics and treatment, decreasing smoking prevalence and general advances in medical care particularly in western countries. However, it is unknown if patients with COPD have experienced a comparable relative increase in survival in line with the general population.Hence, there is a need for longitudinal studies comparing trends in mortality in patients with COPD compared with matched non-COPD individuals from the background population.Methods and analyses This is a cohort study with a matched non-COPD comparator cohort. Data are retrieved from the Danish national registers. Data from multiple registries from 1983 to 2018 will be merged on an individual level using the 10-digit Civil Registration numbers that are unique to each citizen in Denmark. Time trends in mortality in patients with COPD compared with the matched comparator cohort will be examined in three study periods: 1983–1993, 1994–2007 and 2008–2018.Ethics and dissemination The study is entirely based on registry data and ethical approval is not required according to Danish Law and National Ethics Committee Guidelines. The results will be published in peer-reviewed journals and reported at appropriate national and international conferences.

Abstract Background Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes. Methods Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays. Results We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF. Conclusion These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract

Abstract In cost–benefit decision-making, women and men often show different trade-offs. However, surprisingly little is known about sex differences in instrumental tasks, where physical effort is exerted to gain rewards. To this end, we tested 81 individuals (47 women) with an effort allocation task, where participants had to repeatedly press a button to collect food and money tokens. We analyzed the motivational phases of invigoration and effort maintenance with varying reward magnitude, difficulty, and reward type. Whereas women and men did not differ in invigoration, we found that women showed higher effort maintenance as well as higher subjective wanting and exertion ratings for small rewards compared with men. Notably, men increased their effort more than women for higher rewards to match women’s levels of performance. Crucially, we found no sex differences depending on reward type or difficulty, indicating that sex differences were specific to the encoding of the magnitude of benefits, not costs. To summarize, women exerted higher physical effort for small rewards, which corresponded with an elevated subjective value in women compared with men. Therefore, sex differences in perceived reward magnitude may contribute to differential behavioral preferences highlighting the potential of cost–benefit decision-making to provide insights about potential mechanisms.

Contexto: A Diante do avanço das grandes empresas de tecnologia no mercado internacional, percebe-se que tais multinacionais apresentam aspectos específicos de funcionamento que chamam atenção das autoridades reguladoras da concorrência, ensejando discussões e produções de regulações, tais como o Digital Markets Act (DMA), a propor uma cooperação antitruste que não se limita às fronteiras nacionais. Objetivo: Face ao contexto observado, a presente pesquisa tem por objetivo investigar, a partir de uma abordagem descritiva e explicativa, de que modo a União Europeia, por meio da adoção do DMA, tem regulado a defesa da livre-concorrência no setor digital, em especial sobre as condutas adotadas pelas grandes empresas do setor, partindo do pressuposto de que a defesa da concorrência, em âmbito meramente nacional, não se demonstra plenamente suficiente para garantir o bem-estar dos consumidores. Método: Os autores utilizam-se de metodologia documental, bibliográfica e qualitativa nas fontes, selecionando, sobretudo, artigos de origem estrangeira. Quanto aos objetivos, a pesquisa é explicativa e descritiva. O DMA é utilizado como case de estudo. Conclusões: Após a análise realizada sobre o DMA como regulação voltada à concorrência nos mercados digitais, conclui-se que, em razão das peculiaridades e efeitos transnacionais produzidos pela ação das big techs, uma abordagem cooperativa e transnacional poderá trazer, como já tem sido observado, resultados mais efetivos na defesa da livre-concorrência no setor, sempre se levando em consideração os aspectos econômicos, jurídicos e regulatórios peculiares de cada Estado.

Early strategies of researching readers turned scholars to hermeneutic shortcuts like Iser’s ‘implied’ or Fish’s ‘informed’ reader. However, these shortcuts cannot be seen as studying ‘actual’ readers. One approach to studying actual readers has been turning to empirical methods. However, even though the institutions that do these types of research are located in culturally complex cities, the process of participant selection in empirical studies often does not take the city’s make-up into account. Therefore, this article aims to present a participant sampling strategy for empirical reader response research with Antwerp as the location for a study of urban readers in a European context. Opting for a qualitative approach and thus a purposeful sampling strategy and taking the hyper-diverse nature of major cities into account, we suggest using social milieu rather than traditional descriptive markers by recruiting from different neighbourhoods. This as neighbourhoods have their own culture and play an important role in a person’s identity. Turning to local libraries for participant recruitment means a step towards studying actual readers and will lead to a deeper insight into the effects of texts on readers. Moreover, apart from obtaining a richer variety of idiosyncratic responses, this can also result in a deeper understanding of (sub)cultural responses to narratives.

Tick saliva helps blood feeding by its antihemostatic and immunomodulatory activities. Tick salivary gland transcriptomes (sialotranscriptomes) revealed thousands of transcripts coding for putative secreted polypeptides. Hundreds of these transcripts code for groups of similar proteins, constituting protein families, such as the lipocalins and metalloproteases. However, while many of these transcriptome-derived protein sequences matches sequences predicted by tick genome assemblies, the majority are not represented in these proteomes. The diversity of these transcriptome-derived transcripts could derive from artifacts generated during assembly of short Illumina reads or derive from polymorphisms of the genes coding for these proteins. To investigate this discrepancy, we collected salivary glands from blood-feeding ticks and, from the same homogenate, made and sequenced libraries following Illumina and PacBio protocols, with the assumption that the longer PacBio reads would reveal the sequences generated by the assembly of Illumina reads. Using both Rhipicephalus zambeziensis and Ixodes scapularis ticks, we have obtained more lipocalin transcripts from the Illumina library than the PacBio library. To verify whether these unique Illumina transcripts were real, we selected 9 uniquely Illumina-derived lipocalin transcripts from I. scapularis and attempted to obtain PCR products. These were obtained and their sequences confirmed the presence of these transcripts in the I. scapularis salivary homogenate. We further compared the predicted salivary lipocalins and metalloproteases from I. scapularis sialotranscriptomes with those found in the predicted proteomes of 3 publicly available genomes of I. scapularis. Results indicate that the discrepancy between the genome and transcriptome sequences for these salivary protein families is due to a high degree of polymorphism within these genes.