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Abstract Background After almost 70 years of using indoor residual spraying (IRS) as the primary intervention for malaria vector control, the Republic of Panama wanted to evaluate the operational feasibility and acceptability of distributing long-lasting insecticidal hammock nets (LLIHNs) and long-lasting insecticidal nets (LLINs) in the country. Methods A pilot study conducted in 2019 distributed LLINs and LLIHNs to cover all sleeping spaces in 15 high burden localities of the indigenous Comarca of Guna Yala and measured retention, coverage, use and physical deterioration, washing and drying practices, as well as people’s satisfaction with product characteristics post-distribution. Results Overall, 89.9% of enumerated sleeping spaces were covered during the campaign. Monitoring post-distribution showed that 82.7% of the population received messages about the campaign before it happened and 92.4% claimed to know the purpose of the net and how to care for and repair it. Mild adverse reactions, specifically skin irritation associated with the insecticide in LLINs and LLIHNs, were reported by 38.4% of households. Two years after distribution, 86.3% of the LLIHN/LLINs were retained. Use was very high right after distribution (85%) but decreased to 57% six months after distribution and to 38% two years after distribution. The main reason for not using the LLIHN/LLINs was the reported absence of mosquitoes. Two years post-distribution, LLIHN/LLINs were preserved in good physical condition (4% torn), very few were washed with insecticide-damaging products (chlorine or detergent) (9%) or dried under the sun (15%), and LLIHN/LLINs were washed on average less than once every two months. The average number of people per sleeping space was 1.34. Conclusion Although the distribution of LLIHN/LLINs was operationally feasible and LLIHN/LLINs were initially well-accepted and cared for by these communities, use decreased drastically over the two years of follow up after distribution. Hence, should there be future LLIHN/LLIN distributions in this area, sufficient resources and efforts need to be allocated to promoting LLIHN/LLIN use. Further investigation into the reasons for low LLIHN/LLIN use are needed to guide such efforts.

Background Unknown cardioembolic sources are frequent causes of cryptogenic stroke. We analyzed the risk of atrial fibrillation (AF) or high burden of ectopic atrial activity (HBEA) in patients with cryptogenic stroke, assessing atrial function and 1‐year outcomes. Methods and Results The ARIES (Atrial Imaging and Cardiac Rhythm in Cryptogenic Embolic Stroke) study is an observational study including patients with cryptogenic stroke. We analyzed the frequency of AF and HBEA (>3000 atrial ectopic beats/day or >2 bursts or atrial tachycardia between 3 beats and ≤30 seconds) in two 30‐day Holter‐ECGs, comparing advanced echocardiography signs of left atrial (LA) dysfunction according to rhythm: AF, HBEA, and normal sinus rhythm. We also evaluated 1‐year stroke recurrence and mortality. The study included 109 patients; 35 (32.1%) patients had AF, 27 (24.8%) HBEA, and 47 (43.1%) normal sinus rhythm. Compared with those with normal sinus rhythm, patients with AF presented higher 2‐dimensional and 3‐dimensional LA indexed volumes (38.8±11.2 versus 27.3±11.8 mL/m2, and 50.6±17.2 versus 34.0±15.4 mL/m2, respectively, P

IntroductionBacteriophages have been shown to penetrate biofilms and replicate if they find suitable host cells. Therefore, these viruses appear to be a good option to tackle the biofilm problem and complement or even substitute more conventional antimicrobials. However, in order to successfully remove biofilms, in particular mature biofilms, phages may need to be administered along with other compounds. Phage-derived proteins, such as endolysins or depolymerases, offer a safer alternative to other compounds in the era of antibiotic resistance.MethodsThis study examined the interactions between phage Kayvirus rodi with a polysaccharide depolymerase (Dpo7) from another phage (Rockefellervirus IPLA7) against biofilms formed by different Staphylococcus aureus strains, as determined by crystal violet staining, viable cell counts and microscopy analysis.Results and discussionOur results demonstrated that there was synergy between the two antimicrobials, with a more significant decreased in biomass and viable cell number with the combination treatment compared to the phage and enzyme alone. This observation was confirmed by microscopy analysis, which also showed that polysaccharide depolymerase treatment reduced, but did not eliminate extracellular matrix polysaccharides. Activity assays on mutant strains did not identify teichoic acids or PNAG/PIA as the exclusive target of Dpo7, suggesting that may be both are degraded by this enzyme. Phage adsorption to S. aureus cells was not significantly altered by incubation with Dpo7, indicating that the mechanism of the observed synergistic interaction is likely through loosening of the biofilm structure. This would allow easier access of the phage particles to their host cells and facilitate infection progression within the bacterial population.

Antecedentes: El síndrome de QT largo es una canalopatía que afecta a la repolarización ventricular y aumenta el riesgo de sufrir arritmias ventriculares graves. Puede ser congénito o adquirido, y es una causa conocida de muerte súbita. Caso clínico: Gestante primigesta, de 28 años, sin antecedentes de interés. En ecografías prenatales se objetivó en el feto bradicardia sinusal mantenida desde la semana 28, sin repercusión hemodinámica, que persistió hasta la finalización de la gestación (semana 37+3). Al nacimiento se realizaron electrocardiogramas seriados que mostraron alteraciones en la repolarización con alargamiento del intervalo QT corregido. Se realizó estudio genético que confirmó síndrome de QT largo tipo 1 y se inició tratamiento oral con beta-bloqueantes, con buena respuesta. Conclusiones: El síndrome de QT largo suele diagnosticarse posnatalmente. Es importante conocer sus características clínicas prenatales para poder establecer un diagnóstico precoz y minimizar así el riesgo de muerte súbita de estos pacientes.

Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the “NEXT Generation CART MAD Consortium” (NEXT CART) in Madrid’s Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.

Summary: Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

Biological matrices are typically used in forensic toxicological or pharmacological analysis: mainly blood, vitreous humor or urine. However, there are many cases in which crimes are a consequence of drug intoxication or drug abuse and they are not closed because over the months or years the samples become altered or decomposed. A dried blood stains test (DBS-MS) has recently been proposed to be used in drug toxicology when blood is found at a crime scene. This test could help an investigator to reveal what a person had consumed before the perpetration of the crime. In order to check the possibilities of this test, we analyzed several dried blood stains located on a cotton fabric. Therefore, the aim of this study was to determine if the analysis of a dried blood spot located on a cotton fabric could be an alternate source of obtaining toxicological results, particularly regarding benzodiazepines. We splashed blood stains on cotton fabric with different concentrations of the following benzodiazepines: alprazolam, bromazepam, clonazepam, diazepam and lorazepam, which were dried for 96 h and subsequently quantified by high-performance liquid chromatography coupled mass spectrometry (HPLC-MS). Our results show that it is possible to identify several benzodiazepines contained in a cotton fabric blood stain; consequently, this method may add another sample option to the toxicological analysis of biological vestiges found at a crime scene.

RESOLUCIÓN DEL CASO Ante la imposibilidad de retirar el Impella 5.0 (figura 1), y debido al riesgo quirúrgico (EuroSCORE II 48,9%, Society of Thoracic Surgeons score 16%), se decidió realizar una reparación mitral percutánea con un dispositivo MitraClip (Abbott Laboratories, Estados Unidos). Con el soporte de Impella 5.0 a 2 l/min y bajo control con ecocardiograma transesofágico, se implantó un MitraClip NTW a nivel de A3-P3 (mayor orificio de regurgitación), con lo que se logró una reducción del chorro de insuficiencia (vídeos 1 y 2 del material adicional), una mejoría del flujo en las venas pulmonares y un gradiente transmitral de 4 mmHg. Se reevaluó el resultado disminuyendo transitoriamente el soporte hemodinámico a 1 l/min y se observó un chorro central de grado III-IV. Se implantó un segundo clip NT a nivel de A2-P2 (vídeos 3 y 4 del material adicional). Durante su posicionamiento hubo dificultades por interferencia con el Impella 5.0, por lo que fueron necesarias maniobras de inversión del dispositivo hacia la aurícula. Finalmente se realizó captura o prensión, que fue eficaz y se confirmó la ausencia de insuficiencia mitral residual, aunque hubo un aumento del gradiente transmitral hasta 7 mmHg. Tras reducir el soporte hemodinámico a 0,5 l/min, el...

CASE RESOLUTION Given the impossibility to remove the Impella 5.0 device (figure 1) and due to the high surgical risk involved (EuroSCORE II, 48,9%; Society of Thoracic Surgeons score (STS), 16%), percutaneous mitral valve repair was attempted with a MitraClip device (Abbott Laboratories, United States). Figure 1. Normal position of the Impella device as seen on the transesophageal echocardiography. With support from an Impella 5.0 device at a rate of 2 L/min and under transesophageal echocardiography guidance the MitraClip NTW device was implanted at A3-P3 level (greater effective regurgitant orifice area), which resulted in a reduced regurgitant jet (videos 1 and 2 of the supplementary data), improved blood flow into the pulmonary veins, and a transmitral gradient of 4 mmHg. Result was reassessed by reducing hemodynamic support temporarily at 1 L/min. A grade III-IV central regurgitant jet was seen. A second MitraClip NT was implanted at A2-P2 level (videos 3 and 4 of the supplementary data). Difficulties during its positioning due to interference with the Impella 5.0 device were reported, which is why reversal maneuvers towards the atrium were performed. Finally, capture or grasping turned out effective, and the lack of residual mitral regurgitation was confirmed. However, although transmitral gradient increased up to...

BackgroundInfections by the pathogen Staphylococcus aureus currently represent one of the most serious threats to human health worldwide, especially due to the production of enterotoxins and the ability to form biofilms. These structures and the acquisition of antibiotic resistance limit the action of antibiotics and disinfectants used to combat this microorganism in the industry and the clinic.MethodsThis work reports a comparative phenotypic and genotypic study of 18 S. aureus strains from different origins: clinical samples, milk from mastitic cows and food industry surfaces, most of which were isolated in Northern Spain.ResultsGenetically, the strains were very diverse but, in most cases, a closer proximity was observed for those from the same source. Notably, the average number of virulence genes was not significantly different in strains from the food sector. Of the 18 strains, 10 coded for at least one enterotoxin, and four of them carried 6 or 7 enterotoxin genes. The latter were all veterinary or clinical isolates. Most strains carried prophages, plasmids and/or pathogenicity islands. Regarding antibiotic resistance, although phenotypically all strains showed resistance to at least one antibiotic, resistance genes were only identified in 44.5% of strains, being mastitis isolates those with the lowest prevalence. Virulence-related phenotypic properties such as haemolytic activity, staphyloxanthin production, biofilm-forming capacity and spreading ability were widely distributed amongst the isolates.ConclusionsOur results indicate that production of virulence factors, antibiotic resistance and biofilm formation can be found in S. aureus isolates from diverse environments, including the food industry, although some of these traits are more prevalent in strains isolated from infections in cows or humans. This emphasizes on the importance of monitoring the spread of these determinants not only in samples from the clinical environment, but also along the food chain, a strategy that falls under the prism of a one-health approach.

Environmental cues sometimes have a direct impact on phage particle stability, as well as bacterial physiology and metabolism, having a profound effect on phage infection outcome. Here, we explore the impact of temperature on the interplay between phage Kayvirus rodi (phiIPLA-RODI) and its host, Staphylococcus aureus. Our results show that phiIPLA-RODI is a more effective predator at room (25 °C) compared to body temperature (37 °C) against planktonic cultures of several strains with varying degrees of phage susceptibility. This result differs from most known examples of temperature-dependent phage infection, in which optimum infection is correlated with the host growth rate. Further characterization of this phenomenon was carried out with strains IPLA15 and IPLA16, whose respective MICs were 7 log units and a 1-log unit higher at 37 °C than at 25 °C. Our results demonstrated that the phage also had a greater impact at room temperature during biofilm development and for the treatment of preformed biofilms. There was no difference in phage adsorption between the two temperatures for strain IPLA16. Conversely, adsorption of phiIPLA-RODI to IPLA15 was reduced at 37 °C compared to 25 °C. Moreover, confocal microscopy analysis indicated that the biofilm matrix of both strains has a greater content of PIA/PNAG at 37 °C than at 25 °C. Regarding infection parameters, we observed longer duration of the lytic cycle at 25 °C for both strains, and infection of IPLA15 by phiIPLA-RODI resulted in a smaller burst size at 37 °C than at 25 °C. Finally, we also found that the rate of phage resistant mutant selection was higher at 37 °C for both strains. Altogether, this information highlights the impact that bacterial responses to environmental factors have on phage-host interactions. Moreover, phage phiIPLA-RODI appears to be a highly effective candidate for biofilm disinfection at room temperature, while its efficacy in biofilm-related infections will require combination with other antimicrobials.

El Síndrome de Alienación Parental es definido por la doctrina jurídica y por la jurisprudencia como el accionar de un progenitor sobre sus descendientes menores de edad con el fin de generar una concepción negativa hacia el otro progenitor. A pesar de que la ciencia jurídica valida este concepto no hay un consenso en las ciencias médicas acerca de su rigor científico. A nivel mundial el mismo no es concebido como un trastorno psiquiátrico según los Manuales de Psiquiatría DSM. En nuestro país: la Facultad de Psicología de la Universidad de la República; el Instituto del Niño y el Adolescente del Uruguay; y la Fiscalía General de la Nación, han declarado que el Síndrome de Alienación Parental no está validado científicamente. El presente trabajo realiza un relevamiento de la jurisprudencia nacional describiendo en como ésta en un primer momento convalida el Síndrome de Alienación Parental, para luego reconocer su carácter acientífico en unos casos, y su inadmisibilidad como argumento probatorio en otros.

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.

Más allá de las tipologías sepulcrales, es en el campo de la ritualidad donde es posible apreciar con mayor nitidez la lucha interna que tuvieron los habitantes de la ciudad ante la tesitura de tener que elegir entre mantener su rosario de creencias previas, o bien adaptarse a la normalización del rito que fue imponiéndose como resultado de la conquista romana. Aun cuando la mayor parte de la extensión de las necrópolis de esta ciudad nos es aún desconocida, las evidencias que ya han visto la luz, así como los estudios que se comienzan a realizar a este respecto, muestran una realidad funeraria mucho más compleja de lo esperado, llena de matices que sólo pueden ser entendidos si no olvidamos que su historia no se inicia con la llegada de Roma. Es esta realidad fruto de la construcción de una identidad cultural propia y única, nacida tras los primeros contactos con el Imperio Romano gracias a la configuración de una realidad híbrida en la que se tomaron aspectos de la cultura fenicia y púnica/turdetana previa, y la romana posterior. Tal es así, que esa nueva construcción funeraria no tuvo ningún reparo en demostrar su romanidad a nivel visual mediante la adopción de las tipologías sepulcrales más representativas del Imperio Romano, o en la organización topográfica de las necrópolis dentro de ese escenario de representación y juego de poder en el que se convirtieron, pero que se guardó para sus rituales y creencias, muchas más íntimas y con las que se era más permisivas, ciertas pervivencias que entroncaban con ese pasado. En definitiva, en este artículo se presenta la manera en la que la sociedad del momento configuró su identidad cultural, así como su progresiva normalización durante el transcurrir de los años.

Abstract Background This report is based on the 2021 annual meeting of the Asia–Pacific Malaria Elimination Network Surveillance and Response Working Group held online on November 1–3, 2021. In light of the 2030 regional malaria elimination goal, there is an urgency for Asia–Pacific countries to accelerate progress towards national elimination and prevent re-establishment. The Asia Pacific Malaria Elimination Network (APMEN) Surveillance Response Working Group (SRWG) supports elimination goals of national malaria control programmes (NMCPs) by expanding the knowledge base, guiding the region-specific operational research agenda and addressing evidence gaps to improve surveillance and response activities. Methods An online annual meeting was hosted from 1 to 3 November 2021, to reflect on research needed to support malaria elimination in the region, challenges with malaria data quality and integration, current surveillance-related technical tools, and training needs of NMCPs to support surveillance and response activities. Facilitator-led breakout groups were held during meeting sessions to encourage discussion and share experience. A list of identified research priorities was voted on by attendees and non-attending NMCP APMEN contacts. Findings 127 participants from 13 country partners and 44 partner institutions attended the meeting, identifying strategies to address malaria transmission amongst mobile and migrant populations as the top research priority, followed by cost effective surveillance strategies in low resource settings, and integration of malaria surveillance into broader health systems. Key challenges, solutions and best practices for improving data quality and integrating epidemiology and entomology data were identified, including technical solutions to improve surveillance activities, guiding priority themes for hosting informative webinars, training workshops and technical support initiatives. Inter-regional partnerships and SRWG-led training plans were developed in consultation with members to be launched from 2022 onwards. Conclusion The 2021 SRWG annual meeting provided an opportunity for regional stakeholders, both NMCPs and APMEN partner institutions, to highlight remaining challenges and barriers and identify research priorities pertaining to surveillance and response in the region, and advocate for strengthening capacity through training and supportive partnerships.

Objective: To characterize the agroproductive systems of the Colonche parish in Santa Elena, Ecuador. Materials and Methods: Data were collected through participatory techniques with interviews and the application of surveys carried out in a total of 313 farms, corresponding to eight agroproductive communes. For the characterization, description and grouping of the farms and productive units, descriptive statistics and the hierarchical cluster method were used. The data were processed by the program IBM SPSS® Statistics 22. Results: The agricultural systems are characterized by monoculture (58,8 %), little diversification and animal husbandry (23,0 %), as well as by the scarce management of agroecological practices. Lack of knowledge and little interest in the adoption of soil use practices and integrated pest management (91,7 %) with chemical control only, low educational level (92,7 %) of primary level, prevailed. From the cluster analysis two groups were formed: 99,4 % of the farms appear in the first group, which has predominance of traditional monoculture; group 2 includes two farms, which have a productive system under agroecological transition. Conclusions: The agricultural systems in the Colonche parish are in correspondence with the traditional agriculture model and are characterized by monoculture, little diversification and animal production, as well as by scarce management of agroecological practices and little level in their application.

IntroductionThe Addenbrooke’s Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD.MethodsWe enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated.ResultsThe ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD.ConclusionOur study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD.

IntroductionRefractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation.MethodsIn this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells’ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality.ResultsIn vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells.DiscussionThe data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.

El angiomixoma agresivo pélvico es un tumor de partes blandas extremadamente raro, del cual se han reportado alrededor de 350 casos hasta la fecha. A continuación se reporta el caso clínico de una paciente que presentó dicho tumor y se describe el proceso diagnóstico y su tratamiento quirúrgico. Por otro lado, se realiza una breve revisión de la literatura disponible hasta el momento sobre el tema.

The Aconcagua region constitutes a classical site to study the growth of the Andes, being host of the highest mountain of South America and focus of numerous investigations since its first description by Charles Darwin almost 200 years ago. The last detailed works in this area characterized it as a typical thin-skinned fold-thrust belt with a basal detachment located in the lower evaporitic units of the Mesozoic sequences. Previous authors in this area correlated the different thrust sheets on the basis of their marine fossils, sedimentological characteristics and structural relations. Although these criteria were useful for the identification of the marine and evaporitic units, the resemblance between the nonmarine red beds and among the different volcanic units has difficulted their unequivocal assignment. Moreover, the inaccessibility of the outcrops and the lack of an adequate geochronological control has led to underestimate the importance of the Aconcagua fold-thrust belt in the last couple of years, being characterized as a secondary feature in Andean orogenesis. A series of new field observations, sedimentological studies and geochronological analyses were performed to update the geological map of this area and build a schematic cross section along the Río Cuevas at 32°50’S in west-central Argentina. These studies allowed the identification of important variations on the thickness of the Upper Jurassic nonmarine sequences associated with the activity of normal faults and the development of structural highs. Many of these normal faults are presently inverted, which suggests that tectonic inversion played an important role in the structuration of this region, leading to a deformational style that varies from a thick-skinned inner domain towards a thin-skinned frontal sector. A series of sedimentological profiles aided by four new U-Pb detrital zircon analyses and its integration with new geochronological databases allowed the documentation of previously unrecognized Paleogene deposits, the age reassignation of several volcanic and sedimentary units and the modification of the stratigraphy. Finally, at least three contractional events with different structural mechanisms were identified along this transect, revealing a dynamic tectonic evolution that underscores the role of structural inheritance and the relevance of the Aconcagua fold-thrust belt in the Andean orogeny.

Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall‐cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene‐edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild‐type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell‐type‐specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.

Antimicrobial resistance (AMR) has emerged as a global health challenge, sparking worldwide interest in exploring the antimicrobial potential of natural compounds as an alternative to conventional antibiotics. In recent years, one area of focus has been the utilization of bacteriophages and their derivative proteins. Specifically, phage lytic proteins, or endolysins, are specialized enzymes that induce bacterial cell lysis and can be efficiently produced and purified following overexpression in bacteria. Nonetheless, a significant limitation of these proteins is their vulnerability to certain environmental conditions, which may impair their effectiveness. Encapsulating endolysins in vesicles could mitigate this issue by providing added protection to the proteins, enabling controlled release, and enhancing their stability, particularly at temperatures around 4 °C. In this work, the chimeric lytic protein CHAPSH3b was encapsulated within non-ionic surfactant-based vesicles (niosomes) created using the thin film hydrating method (TFH). These protein-loaded niosomes were then characterized, revealing sizes in the range of 30–80 nm, zeta potentials between 30 and 50 mV, and an encapsulation efficiency (EE) of 50–60%. Additionally, with the objective of exploring their potential application in the food industry, these endolysin-loaded niosomes were incorporated into gelatine films. This was carried out to evaluate their stability and antimicrobial efficacy against Staphylococcus aureus.

Abstract The application of bacteriophages as antibacterial agents has many benefits in the “post-antibiotic age”. To increase the number of successfully targeted bacterial strains, phage cocktails, instead of a single phage, are commonly formulated. Nevertheless, there is currently no consensus pipeline for phage cocktail development. Thus, although large cocktails increase the spectrum of activity, they could produce side effects such as the mobilization of virulence or antibiotic resistance genes. On the other hand, coinfection (simultaneous infection of one host cell by several phages) might reduce the potential for bacteria to evolve phage resistance, but some antagonistic interactions amongst phages might be detrimental for the outcome of phage cocktail application. With this in mind, we introduce here a new method, which considers the host range and each individual phage-host interaction, to design the phage mixtures that best suppress the target bacteria while minimizing the number of phages to restrict manufacturing costs. Additionally, putative phage-phage interactions in cocktails and phage-bacteria networks are compared as the understanding of the complex interactions amongst bacteriophages could be critical in the development of realistic phage therapy models in the future.

Summary: Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.

Estuaries are excellent environments for identifying pollution episodes that have affected river basins, as their sediments are the final destination of some of the pollutants. This paper studies the geochemical evolution of five elements (As, Co, Cu, Pb, Zn) in a core extracted from the middle estuary of the Tinto River (SW Spain). The results are based on facies interpretation, ICP atomic emission spectrometry analysis, the application of a regional background to obtain the geoaccumulation index and dating. The main objective of this communication is the detection of natural or anthropogenic pollution episodes in the middle estuary of the Tinto River (SW Spain). Four pollution episodes have been detected: (1) ~5.8 cal. kyr BP, probably caused by natural acid rock drainage processes derived from the oxidation of the Iberian Pyritic Belt deposits found in its drainage basin; (2) 4.7–4.5 kyr BP, coming from the first mining activities and characterized by a significant increase in the concentrations of the five elements analyzed; (3) 1850–1960 interval, coinciding with intensive mining and characterized by increasing values of As and, to a lesser extent, Pb (intensive mining); and (4) the second half of the 20th century, with high element concentrations from mining and industrial effluents. All episodes show an increase in their geochemical classes deduced from the geoaccumulation index. This communication can serve as an example for assessing the impact of different types of pollution in estuarine environments.

Aunque las interrupciones pueden afectar negativamente a la comunicación, en el caso de la enseñanza y aprendizaje de segundas lenguas también pueden entenderse como una ayuda del interlocutor para cubrir alguna carencia lingüística del hablante. Con el objetivo de comprobar cuál es la opinión que los estudiantes de segundas lenguas tienen de la interrupción, realizamos una encuesta entre 161 alumnos del Grado de Traducción e Interpretación de la Universidad Pablo de Olavide (Sevilla). En este artículo presentamos los resultados obtenidos que indican que los alumnos encuestados se sienten más molestos al ser interrumpidos por compañeros en su segunda lengua que en su lengua nativa, ya que consideran que expresarse en una lengua que no es la suya les supone un esfuerzo extra. También se observa que un alto porcentaje de los encuestados no se molesta al ser interrumpido por el profesorado, puesto que lo interpretan como parte de su aprendizaje.

Abstract CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA− T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.

Abstract Staphylococcus aureus is considered a priority pathogen due to its increasing acquisition of antibiotic resistance determinants. Additionally, this microbe has the ability to form recalcitrant biofilms on different biotic and inert surfaces. In this context, bacteriophages and their derived lytic proteins may be a forward-looking strategy to help combat staphylococcal biofilms. However, these antimicrobials exhibit individual limitations that may be overcome by combining them with other compounds. This work investigates the combination of a phage-derived lytic protein, CHAPSH3b, and the virulent bacteriophage phiIPLA-RODI. The obtained results show the synergy between both antimicrobials for the treatment of 24-h-old S. aureus biofilms, with greater reductions in viable cell counts observed when phage and lysin are applied together compared to the individual treatments. Time-kill curves and confocal microscopy revealed that the fast antibacterial action of CHAPSH3b reduces the population up to 7 hours after initial exposure, which is subsequently followed by phage predation, limiting regrowth of the bacterial population. Moreover, at least 90% of bacteriophage insensitive mutants are susceptible to the lytic protein. Therefore, CHAPSH3b might help curtail the development of phage resistance during treatment. The combination of the lysin and phiIPLA-RODI also showed promising results in an ex vivo pig skin model of wound infection. Overall, the results of this study demonstrate that the combination of phage-derived lytic proteins and bacteriophages can be a viable strategy to develop improved antibiofilm products.

Introducción y objetivos: La enfermedad diverticular complicada constituye un problema de salud que afecta a pacientes añosos y muchas veces requiere tratamiento quirúrgico. Las opciones son múltiples, siendo la operación de Hartmann una alternativa antigua y aún vigente. El objetivo del presente estudio fue evaluar la vigencia de dicha intervención en nuestro medio a través del estudio analítico de una población en un Hospital universitario de Montevideo. Materiales y métodos: Se analizaron las historias clínicas de los pacientes mayores de 20 años operados en el período 2009-2018. Se consideraron las siguientes variables: procedimientos quirúrgicos, complicaciones peri operatorias, re intervenciones, tasa y tiempo de reconstrucción del tránsito digestivo y mortalidad.Resultados: El número total de pacientes operados en el período analizado fue de 27, con una media de edad de 59,4 años. En 15 de ellos se realizó un procedimiento de Hartmann, En los restantes pacientes los procedimientos realizados fueron abocamiento de ambos cabos, anastomosis primaria con y sin estoma proximal y lavado y drenaje video-asistido sin resección. Presentaron complicaciones peri operatorias 11 pacientes (40 %). La mortalidad peri operatoria fue de cuatro pacientes (14.8 %), correspondiendo todos a la operación de Hartmann. La tasa de reconstrucción fue seis de 11 pacientes sobrevivientes. Discusión: La operación de Hartmann mantiene vigencia y es el procedimiento más utilizado, siendo su morbimortalidad considerable y la tasa de reconstrucción de aproximadamente la mitad de los pacientes. La anastomosis primaria debe ser reservada para casos seleccionados. El desarrollo de la cirugía laparoscopia también ha permitido procedimientos conservadores, como el lavado y drenaje, evitando la resección en agudo, siendo esta opción una tendencia creciente. Conclusiones: Se concluyó que la serie, si bien corta, reproduce lo revisado en la bibliografía.

Abstract Background The main aim of the present study was to examine the relationships among work environment, job satisfaction and burnout in dentists and to analyse the way in which certain sociodemographic variables, such as gender, professional experience and weekly working hours, predict the perception of the work environment. Methods A battery of online questionnaires was sent to 3876 dentists officially registered in the triple-province region of Valencia; the battery included the Survey of Organizational Attributes for Dental Care, the Warr–Cook–Wall Overall Job Satisfaction Scale, the Maslach Burnout Inventory and a series of sociodemographic questions formulated for the specific purpose of this study. To assess the relations with the independent variables, we calculated the Pearson correlation coefficient, the Z-scores were calculated to make effect sizes comparable, and the associations between the scales and the sociodemographic variables were investigated by adjusted multiple regression analysis. Results A total of 336 participants (9.4%) correctly completed the survey in this study. The mean (M) age was 37.6 years old (standard deviation (SD) = 9.6, median (Me) = 34). Participants reported high scores on the work environment and job satisfaction scales, with only limited experiences of burnout (3.8%). Work environment and burnout were significantly and positively predicted by years of professional experience (β = .078; p = .000 and β = .107; p = .004, respectively), and job satisfaction was significantly and positively predicted by weekly hours of work (β = .022; p = .001), without significant differences according to gender. Conclusions Dentists who work over 20 hours a week and have more years of professional experience report having better perceptions of well-being at work, with no significant difference according to gender. It is important to highlight the aspects that improve well-being in dentistry to reduce burnout, which would lead to greater work engagement and better attention to patients.

Introducción: el estudio citológico por punción ecoguiada se caracteriza por ser rápido, confiable, mínimamente invasivo y rentable. Permite reducir procedimientos quirúrgicos innecesarios y clasifica apropiadamente a los pacientes con nódulos sospechosos o malignos para una intervención quirúrgica oportuna. Objetivo: el objetivo del presente estudio es evaluar la correlación citológica–anatomopatológica del sistema Bethesda en un centro universitario (Hospital de Clínicas) de Uruguay. Metodología: se realizó un estudio de tipo observacional, retrospectivo, descriptivo, basado el análisis de historias clínicas de pacientes sometidos a cirugía tiroidea en el Hospital de Clínicas, en el período comprendido entre enero de 2008 y diciembre de 2018. Resultados: del total inicial de 119 pacientes, 93 cumplieron los criterios de inclusión. El rango de edad de la muestra fue entre 15 y 79 años. Del total de puncionados 49,5% (46) fueron informados como benignos y 50,5% (47) como malignos. Se calculó en forma global una sensibilidad de 96% (0,96) con IC 1,0-0,90, especificidad de 98% (0,97) con IC 1,0-0,93, un VPP de 98% y VPN de 96%. La sensibilidad diagnóstica para la categoría IV, V y VI fue de 96%, con una especificidad de 100, 94 y 100% respectivamente. Conclusiones: el sistema Bethesda aplicado a las PAAF de nódulos tiroideos potencia la certeza diagnóstica y asiste en la decisión terapéutica. En nuestra institución contamos con una buena correlación citopatológica, similar a otros trabajos reportados en la literatura, lo que permite predecir adecuadamente el riesgo de malignidad y facilitar la toma de decisiones.

Tetracycline resistance in streptococci is mainly due to ribosomal protection mediated by the tet(M) gene that is usually located in the integrative and conjugative elements (ICEs) of the Tn916-family. In this study, we analyzed the genes involved in tetracycline resistance and the associated mobile genetic elements (MGEs) in Streptococcus dysgalactiae subsp. equisimilis (SDSE) causing invasive disease. SDSE resistant to tetracycline collected from 2012 to 2019 in a single hospital and from 2018 in three other hospitals were analyzed by whole genome sequencing. Out of a total of 84 SDSE isolates, 24 (28.5%) were resistant to tetracycline due to the presence of tet(M) (n = 22), tet(W) (n = 1), or tet(L) plus tet(W) (n = 1). The tet(M) genes were found in the ICEs of the Tn916-family (n = 10) and in a new integrative and mobilizable element (IME; n = 12). Phylogenetic analysis showed a higher genetic diversity among the strains carrying Tn916 than those having the new IME, which were closely related, and all belonged to CC15. In conclusion, tetracycline resistance in SDSE is mostly due to the tet(M) gene associated with ICEs belonging to the Tn916-family and a new IME. This new IME is a major cause of tetracycline resistance in invasive Streptococcus dysgalactiae subsp. equisimilis in our settings.

The “Magude project” aimed but failed to interrupt local malaria transmission in Magude district, southern Mozambique, by using a comprehensive package of interventions, including indoor residual spraying (IRS), pyrethroid-only long-lasting insecticide treated nets (LLINs) and mass-drug administration (MDA). Here we present detailed information on the vector species that sustained malaria transmission, their association with malaria incidence and behaviors, and their amenability to the implemented control interventions. Mosquitoes were collected monthly between May 2015 and October 2017 in six sentinel sites in Magude district, using CDC light traps both indoors and outdoors. Anopheles arabiensis was the main vector during the project, while An. funestus s.s., An. merus, An. parensis and An. squamosus likely played a secondary role. The latter two species have never previously been found positive for Plasmodium falciparum in southern Mozambique. The intervention package successfully reduced vector sporozoite rates in all species throughout the project. IRS was effective in controlling An. funestus s.s. and An. parensis, which virtually disappeared after its first implementation, but less effective at controlling An. arabiensis. Despite suboptimal use, LLINs likely provided significant protection against An. arabiensis and An. merus that sought their host largely indoors when people where in bed. Adding IRS on top of LLINs and MDA likely added value to the control of malaria vectors during the Magude project. Future malaria elimination attempts in the area could benefit from i) increasing the use of LLINs, ii) using longer-lasting IRS products to counteract the increase in vector densities observed towards the end of the high transmission season, and iii) a higher coverage with MDA to reduce the likelihood of human infection. However, additional interventions targeting vectors that survive IRS and LLINs by biting outdoors or indoors before people go to bed, will be likely needed to achieve local malaria elimination.

During the last years, the formalism of the pseudophase kinetic model (PKM) has been successfully applied to determine the distributions of antioxidants and their effective interfacial concentrations, and to assess the relative importance of emulsion and antioxidant properties (oil and surfactant nature, temperature, acidity, chemical structure, hydrophilic-liphophilic balance (HLB), etc.) on their efficiency in intact lipid-based emulsions. The PKM permits separating the contributions of the medium and of the concentration to the overall rate of the reaction. In this paper, we report the results of a specifically designed experiment to further test the suitability of the PKM to evaluate the distributions of antioxidants among the various regions of intact lipid-based emulsions and provide insights into their chemical reactivity in multiphasic systems. For this purpose, we employed the antioxidants α- and δ-TOCopherol (α- and δ-TOC, respectively) and determined, at different acidities well below their pKa, the interfacial rate constants kI for the reaction between 16-ArN2+ and α- and δ-TOC, and the antioxidant distributions in intact emulsions prepared with olive and soybean oils. Results show that the effective interfacial concentration of δ-TOC is higher than that of α-TOC in 1:9 (v/v) soybean and 1:9 olive oil emulsions. The effective interfacial concentrations of tocopherols are much higher (15-96-fold) than the stoichiometric concentrations, as the effective interfacial concentrations of both δ-TOC and α-TOC in soybean oil emulsions are higher (2-fold) than those in olive oil emulsions. Overall, the results demonstrate that the PKM grants an effective separation of the medium and concentration effects, demonstrating that the PKM constitutes a powerful non-destructive tool to determine antioxidant concentrations in intact emulsions and to assess the effects of various factors affecting them.

Dietary fats are important for human health, yet it is not fully understood how different fats affect various health problems. Although polyunsaturated fatty acids (PUFAs) are generally considered as highly oxidizable, those of the n-3 series can ameliorate the risk of many age-related disorders. Coenzyme Q (CoQ) is both an essential component of the mitochondrial electron transport chain and the only lipid-soluble antioxidant that animal cells can synthesize. Previous work has documented the protective antioxidant properties of CoQ against the autoxidation products of PUFAs. Here, we have explored in vitro and in vivo models to better understand the regulation of CoQ biosynthesis by dietary fats. In mouse liver, PUFAs increased CoQ content, and PUFAs of the n-3 series increased preferentially CoQ10. This response was recapitulated in hepatic cells cultured in the presence of lipid emulsions, where we additionally demonstrated a role for n-3 PUFAs as regulators of CoQ biosynthesis via the upregulation of several COQ proteins and farnesyl pyrophosphate levels. In both models, n-3 PUFAs altered the mitochondrial network without changing the overall mitochondrial mass. Furthermore, in cellular systems, n-3 PUFAs favored the synthesis of CoQ10 over CoQ9, thus altering the ratio between CoQ isoforms through a mechanism that involved downregulation of farnesyl diphosphate synthase activity. This effect was recapitulated by both siRNA silencing and by pharmacological inhibition of farnesyl diphosphate synthase with zoledronic acid. We highlight here the ability of n-3 PUFAs to regulate CoQ biosynthesis, CoQ content, and the ratio between its isoforms, which might be relevant to better understand the health benefits associated with this type of fat. Additionally, we identify for the first time zoledronic acid as a drug that inhibits CoQ biosynthesis, which must be also considered with respect to its biological effects on patients.

Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.

Staphylococcus aureus causes various infections in humans and animals, the skin being the principal reservoir of this pathogen. The widespread occurrence of methicillin-resistant S. aureus (MRSA) limits the elimination and treatment of this pathogen. Phage lytic proteins have been proven as efficient antimicrobials against S. aureus. Here, a set of 12 engineered proteins based on endolysins were conceptualized to select the most optimal following a stepwise funnel approach assessing parameters including turbidity reduction, minimum inhibitory concentration (MIC), time-kill curves, and antibiofilm assays, as well as testing their stability in a broad range of storage conditions (pH, temperature, and ionic strength). The engineered phage lysins LysRODIΔAmi and ClyRODI-H5 showed the highest specific lytic activity (5 to 50 times higher than the rest), exhibited a shelf-life up to 6 months and remained stable at temperatures up to 50°C and in a pH range from 3 to 9. LysRODIΔAmi showed the lower MIC values against all staphylococcal strains tested. Both proteins were able to kill 6 log units of the strain S. aureus Sa9 within 5 min and could remove preformed biofilms (76 and 65%, respectively). Moreover, LysRODIΔAmi could prevent biofilm formation at low protein concentrations (0.15–0.6 μM). Due to its enhanced antibiofilm properties, LysRODIΔAmi was selected to effectively remove S. aureus contamination in both intact and disrupted keratinocyte monolayers. Notably, this protein did not demonstrate any toxicity toward human keratinocytes, even at high concentrations (22.1 μM). Finally, a pig skin ex vivo model was used to evaluate treatment of artificially contaminated pig skin using LysRODIΔAmi (16.5 μg/cm2). Following an early reduction of S. aureus, a second dose of protein completely eradicated S. aureus. Overall, our results suggest that LysRODIΔAmi is a suitable candidate as antimicrobial agent to prevent and treat staphylococcal skin infections.

Background: Although considerable research has been conducted on post-COVID-19 syndrome (PCS), cognitive symptoms, particularly those related to language, are still not well understood. Aims: To provide a detailed quantitative and qualitative analysis of language performance in PCS patients using a comprehensive set of semantic and verbal production tasks. Methods & Procedures: The study involved 195 PCS patients aged 26-64 years and 50 healthy controls aged 25-61 years. Participants were assessed using two semantic tasks, three naming tasks and four types of verbal fluency tasks, designed to evaluate different aspects of language processing. Outcomes & Results: PCS patients demonstrated significantly poorer performance compared with controls across all verbal fluency tasks. This was evident in both the total number of words generated and their types, with patients tending to choose more easily accessible words. In naming tasks, the pattern of errors was similar in both groups, although patients showed a higher number of non-responses and made more errors, reflecting difficulties in word retrieval. The analysis highlighted the impact of factors such as stimulus availability, educational level and cognitive reserve on performance. Notably, younger patients performed worse than older, a paradoxical trend also observed in previous research. Conclusions & Implications: These findings reveal significant word retrieval difficulties in PCS patients, suggesting that cognitive impairment related to language may be more pronounced than previously understood. The results underscore the need for a thorough evaluation of language functions in PCS patients and the development of more targeted and individualized language rehabilitation strategies to address these specific challenges.

The present paper explores disagreement and impoliteness in a WhatsApp interaction within a Spanish family that took place during the 2018 International Women’s Day. The conversation is linguistically examined using categories of disagreement strategies proposed by previous authors (Pomerantz 1984, Brown and Levinson 1987, Rees-Miller 2000, Locher 2004, Kreutel 2007, Malamed 2010, Shum and Lee 2013). Furthermore, multimodal analysis (Dresner and Herring 2010, 2013, Jewitt 2013, Bourlai and Herring 2014; Herring 2015) is used to consider not only participants’ linguistic strategies for expressing disagreement, but also the function of multimedia elements and emojis (Dresner and Herring 2010, 2013, Yus 2014, 2017, Sampietro 2016a, 2016b, Aull 2019). The analysis is followed by an interview to better understand the participants’ communicative intentions towards disagreements in relation to (im)politeness. A total of 427 instances of disagreement are identified, with the most common strategies being giving opposite opinions and emotional or personal reasons. This is to be expected since the group is divided from the very beginning into detractors and supporters of feminism, and they are also defending their opposite viewpoints by giving examples from their own life experience. Based on the participants’ opinions, the most significant result is the fact that, although disagreement may lead to face-threat, and thus impoliteness in other contexts (Langlotz and Locher 2012, Sifianou 2012, Shum and Lee 2013), in this WhatsApp interaction, the Spanish family members did not consider it to be impolite, and it is even evaluated in positive terms by some of the participants (Angouri and Locher 2012).

Los profesionales de la salud presentan un alto nivel de burnout siendo la odontología una especialidad poco estudiada. El objetivo del presente estudio es analizar las experiencias de burnout de los odontólogos de la Comunidad Valenciana, analizando su relación con la percepción de satisfacción laboral, autoestima general y el estrés percibido. Se recogieron los datos de 366 odontólogos, que cumplimentaron una batería de cuestionarios online y de manera anónima entre enero y mayo de 2018. Los resultados mostraron que los participantes presentaban niveles de burnout por debajo de la media, un nivel de estrés ligeramente superior a la media y una buena percepción con su satisfacción laboral y nivel de autoestima. La autoestima se relacionaba positiva y significativamente con la satisfacción y negativamente con el estrés y el burnout. Finalmente, los análisis de regresiones lineares mostraron que la percepción de estrés predecía positiva y significativamente la sensación de burnout global, mientras que la percepción de satisfacción laboral y autoestima predecían negativa y significativamente el burnout global de los participantes. Concluimos que para evitar el desarrollo de burnout es necesario promover una adecuada satisfacción laboral y unos bajos niveles de estrés junto con una alta autoestima en la vida del profesional.

Abstract Mozambique has historically been one of the countries with the highest malaria burden in the world. Starting in the 1960s, malaria control efforts were intensified in the southern region of the country, especially in Maputo city and Maputo province, to aid regional initiatives aimed to eliminate malaria in South Africa and eSwatini. Despite significant reductions in malaria prevalence, elimination was never achieved. Following the World Health Organization’s renewed vision of a malaria-free-world, and considering the achievements from the past, the Mozambican National Malaria Control Programme (NMCP) embarked on the development and implementation of a strategic plan to accelerate from malaria control to malaria elimination in southern Mozambique. An initial partnership, supported by the Bill and Melinda Gates Foundation and the La Caixa Foundation, led to the creation of the Mozambican Alliance Towards the Elimination of Malaria (MALTEM) and the Malaria Technical and Advisory Committee (MTAC) to promote national ownership and partner coordination to work towards the goal of malaria elimination in local and cross-border initiatives. Surveillance systems to generate epidemiological and entomological intelligence to inform the malaria control strategies were strengthened, and an impact and feasibility assessment of various interventions aimed to interrupt malaria transmission were conducted in Magude district (Maputo Province) through the “Magude Project”. The primary aim of this project was to generate evidence to inform malaria elimination strategies for southern Mozambique. The goal of malaria elimination in areas of low transmission intensity is now included in the national malaria strategic plan for 2017–22 and the NMCP and its partners have started to work towards this goal while evidence continues to be generated to move the national elimination agenda forward.

Head and neck squamous cell carcinoma (HNSCC) is a remarkably heterogeneous disease with around 50% mortality, a fact that has prompted researchers to try new approaches to improve patient survival. Hemoxygenase-1 (HO-1) is the rate-limiting step for heme degradation into carbon monoxide, free iron and biliverdin. We have previously reported that HO-1 protein is upregulated in human HNSCC samples and that it is localized in the cytoplasmic and nuclear compartments; additionally, we have demonstrated that HO-1 nuclear localization is associated with malignant progression. In this work, by using pharmacological and genetic experimental approaches, we begin to elucidate the mechanisms through which HO-1 plays a role in HNSCC. We found that high HO-1 mRNA was associated with decreased patient survival in early stages of HNSCC. In vitro experiments have shown that full-length HO-1 localizes in the cytoplasm, and that, depending on its enzymatic activity, it increases cell viability and promotes cell cycle progression. Instead, HO-1 does not alter migration capacity. Furthermore, we show that C-terminal truncated HO-1 localizes into the nucleus, increases cell viability and promotes cell cycle progression. In conclusion, we herein demonstrate that HO-1 displays protumor activities in HNSCC that depend, at least in part, on the nuclear localization of HO-1.

This paper investigates the paleoenvironmental evolution of a core extracted in the middle sector of the Tinto River estuary, SW Spain, one of the most polluted areas in the world due to mining over thousands of years (>4 kyr BP) and recent industrial discharges. This evolution includes alluvial sands (>6.4 cal kyr BP), bioclastic sands and silts deposited in subtidal and intertidal channels during and after the Holocene transgression maximum (6.4-4.3 cal kyr BP), the sedimentation of clayey-sandy silts in low and high marshes during the last 2.4 kyr BP and a final anthropic filling. Three sharp peaks of pollution have been detected, representing a) a natural origin during the Holocene transgression; b) the impact of the first mining activities (~4.5 cal kyr BP); and c) the effect of industrial discharge and a new period of mining activity throughout the 19th and 20th centuries. Foraminifera, ostracods and molluscs disappeared during these last two peaks.

1. Background: Peri-implantitis affects a high percentage of patients treated with dental implants. Among the risk factors that can cause this pathology, limited evidence exists regarding the absence of keratinized mucosa. The main objective of this study was to compare the amount of keratinized mucosa around healthy implants versus implants in patients with peri-implantitis, in order to analyze its influence on esthetics and the development of this pathology, and to study the possible influence of keratinized mucosa on various clinical parameters. 2. Methods: A retrospective case-control study was carried out in which 203 implants were evaluated, 103 of which presented a healthy peri-implant state, versus 100 which had peri-implantitis. The following elements were recorded: keratinized mucosa, recession, plaque index, bleeding, suppuration, probing depth, and bone level. 3. Results: Keratinized mucosa was present in 51% of the peri-implantitis group versus 97.1% of the healthy implants. In implants without keratinized mucosa, both recession and plaque index, bleeding on probing (96.2%), suppuration (57.7%), mean probing depth and bone level were higher. Implants without keratinized mucosa presented worse esthetics. 4. Conclusions: Absence of Keratinized mucosa around dental implants seems to be associated with the appearance of peri-implantitis modifying certain clinical parameters: there is a greater probability of recession, bleeding, suppuration, deficient hygiene, greater probing depth and greater bone loss in implants without keratinized mucosa.

Since the initial proposal of the past existence of a southward-directed mid-ocean ridge–subduction interaction in the Andes during Late Cretaceous–Paleogene times, several studies have been devoted to uncover the tectonomagmatic evidence of this process. The collision of a spreading ridge against a subduction margin provokes important tectonomagmatic changes, including, between them, variations in arc-related magmatic activity and in the plate-margin stress regime. However, the cryptic nature of the geological record often hampers assessing the influence and along-strike evolution of this process. In this study, we integrate new isotopic data with previous field and geochemical data on Andean arc-related magmatism, together with seismic tomography to track the main tectonic changes that affected the Andes between 35° and 42°S from Latest Cretaceous to early Miocene times. In particular, we carry out a new tomotectonic analysis combining the regional bedrock record of the Late Cretaceous–early Miocene arc with upper–lower mantle seismic tomography. This analysis allowed us to unravel the main geodynamic changes that affected the Andean active-margin when the Farallon–Aluk spreading ridge was subducting. Besides, new isotopic analyses reveal the variable nature of the mantle source that fed the Late Cretaceous–early Miocene arc. Hence, the integration of geological, geochemical, and geophysical data, together with new isotopic data studying the geochemical composition of the main Andean arc-related magmatic units in three main periods – (1) Latest Cretaceous–early Paleocene, (2) Early Paleocene–late Eocene, and (3) Late Eocene–early Miocene – allow us to understand with an unprecedented detail the geochemical and spatiotemporal evolution of the passage of this spreading ridge along the Andean margin.

La obtención de alimentos sanos y seguros requiere de técnicas de conservación inocuas para el consumidor y para el me­dio ambiente, entre las que se destaca la bioconservación. A su ca­tálogo de compuestos naturales o microorganismos, utilizados de forma habitual, la bioconservación ha incorporado recientemente los bacteriófagos (fagos) y las proteínas fágicas con actividad lítica (endolisinas). La utilización de fagos y endolisinas en el biocontrol ofrece importantes ventajas frente a otros sistemas de conserva­ción tradicionales. Entre dichas ventajas destacan su inocuidad, especificidad y versatilidad. Por otra parte, la acuciante necesidad de reducir el uso de antibióticos en la cadena alimentaria ha impul­sado la investigación basada en estos antimicrobianos con el fin de aplicarlos en producción primaria (terapia fágica). Sin embargo, y a pesar de la gran eficacia ya demostrada en múltiples sectores, la falta de legislación de la Unión Europea sobre el uso de bacteriófa­gos junto con la necesidad de ser aceptados por los consumidores, son factores que están afectando negativamente a su implantación como bioconservantes. En este contexto, este artículo recoge los últimos resultados relacionados con este tipo de antimicrobianos en la industria agro-alimentaria, y resume los puntos clave para entender las posibilidades reales de su aplicación ante los nuevos requisitos asociados con una producción sostenible tanto desde una perspectiva económica como ambiental