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AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Purpose: This study explores the impact of new technologies, such as simulation and virtual reality, on the pedagogy and learning of engineering students. It aims to compare the effectiveness of these digital tools against traditional teaching methods in enhancing student learning experiences. Design/methodology/approach: Utilizing a quantitative research approach, the study involved third-year engineering students from the "Production Management" course at the School of Engineering of Vitoria-Gasteiz. Data were collected through an ad hoc questionnaire and analyzed using SPSS software, focusing on student satisfaction, challenges in adopting new technologies and the evolving roles of students and teachers. Findings: The research highlighted several key aspects. Firstly, it identified the need for adapting teaching methods to incorporate new technologies effectively. Secondly, the integration of simulation and virtual reality was found to facilitate a deeper understanding of real-world problems, as students could engage with these issues in a simulated, virtual environment. Finally, the study emphasized the importance of pedagogical approaches that leverage these technologies to increase student involvement and motivation. The results suggest a positive impact of digital tools on the learning process in engineering education. Research limitations/implications: The study's scope was limited to one course within a single institution, suggesting the need for broader research across various disciplines and educational settings. Originality/value: This research offers valuable insights into the integration of simulation and virtual reality in engineering education, underscoring their potential to enhance the learning experience and knowledge acquisition among students.

Letter knowledge and word identification are key skills for reading and spelling. Letter knowledge facilitates the application of sublexical letter-sound mappings to decode words. With reading experience, word identification becomes a key lexical skill to support decoding. In transparent orthographies, however, letter knowledge might be an enduring predictor of decoding and spelling, even in children with some reading experience. This study investigated the association of children's sublexical (letter knowledge) and lexical skills (word identification and vocabulary) with word decoding and spelling accuracy in Spanish, which is a transparent orthography. The sample consisted of 117 Spanish-speaking children, aged 8 to 10. Results revealed that (1) letter knowledge and word identification were independently associated with children's word spelling; (2) word identification was uniquely associated with word decoding; and (3) children's vocabulary level was associated with word identification. The implications of these findings were examined within the framework of reading models and the characteristics of a transparent orthography.

Background: Letter knowledge is crucial in the first stages of reading development. It supports learning letter-sound mappings and the identification of the letters that make up words. Previous studies have investigated the longitudinal impact of early letter knowledge on children's further word reading abilities. This study employed an artificial orthography learning paradigm to explore whether the rate of letter learning modulates children's reading and word identification skills. Methods: In an initial training phase, 8-year-old Spanish children (N = 30) learned nine artificial letters and their corresponding sounds (two vowels and six consonants). The letter learning rate was set according to the number of attempts needed to name at least seven letters (i.e., 80% correct). These ranged from 1 to 4. In a second training phase, children visualized words made up of the trained letters while listening to their pronunciations. Some words included a context-dependent syllable (i.e., leading to grapheme-to-phoneme inconsistency), and others had an inconsistent syllable (i.e., phoneme-to-grapheme inconsistency). The post-test consisted of a reading aloud task and an orthographic-choice task in which the target word was presented with a distractor equal to the target except for the substitution of a letter. Results: Children showed a high accuracy rate in the post-test tasks, regardless of whether words contained context-dependent or inconsistent syllables. Critically, the letter learning rate predicted both reading aloud and identification accuracy of words in the artificial orthography. Conclusions: We provide evidence for the vital role of letter knowledge acquisition ability in children's decoding and word identification skills. Training children on this ability facilitates serial letter-sound mapping and word identification skills. Artificial orthography paradigms are optimal for exploring children's potential to achieve specific literacy skills.

Abstract While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.

Abstract Objective In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1β. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU. Methods BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer. Results We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1β. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1β in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1β by peripheral blood mononuclear cells from healthy donors. Conclusion Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.

El objetivo del estudio fue analizar los factores clave en la valorización de la carrera docente en Perú. Mediante una revisión documental de datos estadísticos presentados por el Ministerio de Educación del Perú (Minedu) a través de la Encuesta Nacional de Docentes (Endo) se reveló que la percepción de la carrera docente está fuertemente influenciada por factores como la remuneración económica, el acceso a la formación continua, el apoyo institucional y la valoración social de la profesión. Además, se identifican barreras estructurales que limitan el desarrollo profesional, como la falta de recursos y la inadecuada infraestructura educativa. Se requiere un enfoque multidimensional, donde se integran aspectos económicos, sociales y culturales para lograr un cambio significativo en la percepción y el reconocimiento de la labor educativa en el país. Concluye que a pesar de las políticas educativas implantadas en los últimos años persiste una percepción negativa sobre la profesión, provocando desmotivación entre los educadores.

IntroductionInnovative medicines and vaccines can provide direct health benefits to patients and populations by preventing, treating and curing diseases, and also drive wider socioeconomic and productivity gains. However, researching and developing them is complex and risky. Funding for life sciences R&D has different sources: public, charitable/NGO, and private sector. We believe there is consensus that all are required, although there is less understanding about their respective roles, synergies, and funding priorities. The purpose of this paper is to provide an overview of the current life sciences innovation ecosystem in Europe, highlighting challenges for funding and innovation of new therapies and our proposed options to address these.MethodsThe basis of this paper stems from the reflections made by the co-authors during a webinar with title “Collaboration for new therapies: maximising funding and innovation,” in March 2023, with further targeted literature reviews.ResultsWe identify eight challenges in the European life sciences ecosystem, some closely related, and nine options that we think might be helpful to address them. Each option on its own can have different levels of ‘impact’, but collectively will provide synergies among them, and thus maximize their impact.DiscussionIt is critical to ascertain how the strengths of each actor can be leveraged to bring new medicines/treatments to market, quicker and more efficiently. We need a trusted environment, with strategic collaborations between the public and private sectors, and policy initiatives and incentives should be targeted to strengthen the infrastructure with the aim of fostering such optimal alliances.

Abstract Real‐world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review characterized 85 regulatory applications with RWE. A total of 31 were in oncology and 54 were in non‐oncology therapeutic areas. Most were for indications in adults only (N = 42, 49.4%), while 13 were in pediatrics only (15.3%), and 30 were in both (35.3%). In terms of regulatory context, 59 cases (69.4%) were for an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) were for label modification. Most also received special regulatory designations (e.g., orphan indication, breakthrough therapy, fast track, conditional, and accelerated approvals). There were 42 cases that utilized RWE to support single‐arm trials. External data to support single‐arm trials were utilized in various ways across use cases, including direct matching, benchmarking, natural history studies as well as literature or previous trials. A variety of data sources were utilized, including electronic health records, claims, registries, site‐based charts. Endpoints in oncology use cases commonly included overall survival, progression‐free survival. In 13 use cases, RWE was not considered supportive/definitive in regulatory decision‐making due to design issues (e.g., small sample size, selection bias, missing data). Overall, RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide range of approaches. Multifaceted cross‐sector efforts are needed to further improve the quality and utility of RWE in regulatory decision‐making.

The prevalence of diabetes mellitus type 2 (DMT2) is increasing exponentially worldwide. DMT2 patients have been found to be at a higher risk for bone fractures than the healthy population. Hence, improving our understanding of the impact of antidiabetic drugs on bone metabolism is crucial.

La prevalencia de la diabetes mellitus tipo 2 (DMT2) está aumentando de forma exponencial en todo el mundo, habiéndose comprobado que estos pacientes tienen mayor riesgo de presentar fracturas óseas, con respecto a la población sana, por lo que resulta de gran relevancia el conocimiento del efecto de los fármacos antidiabéticos sobre el metabolismo óseo.

Abstract To assess full-field electroretinogram findings in long-term type 1 diabetes patients without diabetic retinopathy. Prospective study including 46 eyes of 23 patients with type 1 diabetes and 46 age-matched healthy eyes evaluated by the RETI-port/scan21 and the portable system RETeval following ISCEV guidelines. The average duration of diabetes was 28.88 ± 8.04 years. In scotopic conditions, using the RETI-port/scan21, diabetic patients showed an increase in b-wave implicit time (IT) (p = 0.017) with the lowest stimuli; a diminished b-wave amplitude (p = 0.005) in the mixed response, an increased IT (p = 0.004) with the high-intensity stimuli and an OP2 increased IT (p = 0.008) and decreased amplitude (p = 0.002). Under photopic conditions, b-wave amplitude was lower (p

Understanding visitor motivations provides an opportunity for destination managers to be better prepared to meet visitor expectations. In the increasingly competitive tourism environment, the uptake of ICT, particularly in developing countries avails an additional avenue to enhance visitors’ experiences and simultaneously promote the destination. This study aims to explore tourists’ motivations for visiting the coastal town of Limbe and the use of Information Communication Technology to enhance the experience. A questionnaire was used to collect data from 250 randomly selected visitors to the beachfront. Using both exploratory statistics and analysis of variance, the study finds that the motivation to rest and rejuvenate is rated quite highly (mean score = 3.49) by the respondents and ICT is used mainly to capture and share experiences (3.47). Further examination of the analysis of variance reveals no statistically significant difference between females and males (p = 0.2), but statistically significant differences among age groups (p = 0.05). This study recommends, inter alia, that destinations such as Limbe make ICT a functional and complementary aspect of their product experience. The study contributes important insights to the literature on visitor motivations and the use of ICT in the global South and Cameroon in particular.

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production.SignificanceMDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476.

La universidad española incorpora cada vez a un mayor número de personas con discapacidad y con necesidades específicas de apoyo (NEA). Esta incorporación se realiza en el marco de la ley conocida como LOSU, que insta a las universidades a favorecer la inclusividad y accesibilidad en las enseñanzas universitarias. Pese a esta ley, las universidades españolas no suelen contar con los recursos humanos y económicos necesarios para afrontar convincentemente dicha inclusión. Un grupo de estudiantes con NEA especialmente numeroso es el de aquellos con dislexia. Para este estudiantado existen en muchas universidades guías y orientaciones, si bien no parecen provenir de un estudio suficientemente amplio y riguroso de la bibliografía especializada. En este trabajo realizamos una revisión profunda de la bibliografía específica sobre la atención universitaria al estudiantado con dislexia y analizamos los resultados obtenidos. Fruto de la amplia revisión bibliográfica se generan una serie de propuestas de carácter institucional y de práctica docente que tienen por objeto mejorar la inclusión y accesibilidad de los estudios universitarios al estudiantado con dislexia. Para cumplir con la legislación española en relación con la inclusión y accesibilidad del estudiantado con NEA, es necesario realizar inversiones y tomar nuevas decisiones basadas en la información que aporta la bibliografía disponible.