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INTRODUCTION: EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC. METHODS: Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood. RESULTS: A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment. CONCLUSIONS: Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

Abstract Background Parkinson’s Disease (PD) is a chronic neurodegenerative disease associated with motor problems such as gait impairment. Different systems based on 3D cameras, accelerometers or gyroscopes have been used in related works in order to study gait disturbances in PD. Kinect Ⓡ has also been used to build these kinds of systems, but contradictory results have been reported: some works conclude that Kinect does not provide an accurate method of measuring gait kinematics variables, but others, on the contrary, report good accuracy results. Methods In this work, we have built a Kinect-based system that can distinguish between different PD stages, and have performed a clinical study with 30 patients suffering from PD belonging to three groups: early PD patients without axial impairment, more evolved PD patients with higher gait impairment but without Freezing of Gait (FoG), and patients with advanced PD and FoG. Those patients were recorded by two Kinect devices when they were walking in a hospital corridor. The datasets obtained from the Kinect were preprocessed, 115 features identified, some methods were applied to select the relevant features (correlation based feature selection, information gain, and consistency subset evaluation), and different classification methods (decision trees, Bayesian networks, neural networks and K-nearest neighbours classifiers) were evaluated with the goal of finding the most accurate method for PD stage classification. Results The classifier that provided the best results is a particular case of a Bayesian Network classifier (similar to a Naïve Bayesian classifier) built from a set of 7 relevant features selected by the correlation-based on feature selection method. The accuracy obtained for that classifier using 10-fold cross validation is 93.40%. The relevant features are related to left shin angles, left humerus angles, frontal and lateral bents, left forearm angles and the number of steps during spin. Conclusions In this paper, it is shown that using Kinect is adequate to build a inexpensive and comfortable system that classifies PD into three different stages related to FoG. Compared to the results of previous works, the obtained accuracy (93.40%) can be considered high. The relevant features for the classifier are: a) movement and position of the left arm, b) trunk position for slightly displaced walking sequences, and c) left shin angle, for straight walking sequences. However, we have obtained a better accuracy (96.23%) for a classifier that only uses features extracted from slightly displaced walking steps and spin walking steps. Finally, the obtained set of relevant features may lead to new rehabilitation therapies for PD patients with gait problems.

Abstract Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Abstract Background We used the Spanish national hospital discharge data from 2016 to 2022 to analyze procedures and hospital outcomes among patients aged ≥ 18 years admitted for ST-elevation myocardial infarction (STEMI) and non–ST-elevation myocardial infarction (NSTEMI) according to diabetes mellitus (DM) status (non-diabetic, type 1-DM or type 2-DM). Methods We built logistic regression models for STEMI/NSTEMI stratified by DM status to identify variables associated with in-hospital mortality (IHM). We analyzed the effect of DM on IHM. Results Spanish hospitals reported 201,950 STEMIs (72.7% non-diabetic, 0.5% type 1-DM, and 26.8% type 2-DM; 26.3% female) and 167,285 NSTEMIs (61.6% non-diabetic, 0.6% type 1-DM, and 37.8% type 2-DM; 30.9% female). In STEMI, the frequency of percutaneous coronary intervention (PCI) increased among non-diabetic people (60.4% vs. 68.6%; p

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Abstract Increasing evidence supports the hypothesis that cancer progression is under mitochondrial control. Mitochondrial fission plays a pivotal role in the maintenance of cancer cell homeostasis. The inhibition of DRP1, the main regulator of mitochondrial fission, with the mitochondrial division inhibitor (mdivi-1) had been associated with cancer cell sensitivity to chemotherapeutics and decrease proliferation. Here, using breast cancer cells we find that mdivi-1 induces the detachment of the cells, leading to a bulk of floating cells that conserved their viability. Despite a decrease in their proliferative and clonogenic capabilities, these floating cells maintain the capacity to re-adhere upon re-seeding and retain their migratory and invasive potential. Interestingly, the cell detachment induced by mdivi-1 is independent of DRP1 but relies on inhibition of mitochondrial complex I. Furthermore, mdivi-1 induces cell detachment rely on glucose and the pentose phosphate pathway. Our data evidence a novel DRP1-independent effect of mdivi-1 in the attachment of cancer cells. The generation of floating viable cells restricts the use of mdivi-1 as a therapeutic agent and demonstrates that mdivi-1 effect on cancer cells are more complex than anticipated.

Abstract Background Prioritisation of chemical pollutants is a major challenge for environmental managers and decision-makers alike, which is essential to help focus the limited resources available for monitoring and mitigation actions on the most relevant chemicals. This study extends the original NORMAN prioritisation scheme beyond target chemicals, presenting the integration of semi-quantitative data from retrospective suspect screening and expansion of existing exposure and risk indicators. The scheme utilises data retrieved automatically from the NORMAN Database System (NDS), including candidate substances for prioritisation, target and suspect screening data, ecotoxicological effect data, physico-chemical data and other properties. Two complementary workflows using target and suspect screening monitoring data are applied to first group the substances into six action categories and then rank the substances using exposure, hazard and risk indicators. The results from the ‘target’ and ‘suspect screening’ workflows can then be combined as multiple lines of evidence to support decision-making on regulatory and research actions. Results As a proof-of-concept, the new scheme was applied to a combined dataset of target and suspect screening data. To this end, > 65,000 substances on the NDS, of which 2579 substances supported by target wastewater monitoring data, were retrospectively screened in 84 effluent wastewater samples, totalling > 11 million data points. The final prioritisation results identified 677 substances as high priority for further actions, 7455 as medium priority and 326 with potentially lower priority for actions. Among the remaining substances, ca. 37,000 substances should be considered of medium priority with uncertainty, while it was not possible to conclude for 19,000 substances due to insufficient information from target monitoring and uncertainty in the identification from suspect screening. A high degree of agreement was observed between the categories assigned via target analysis and suspect screening-based prioritisation. Suspect screening was a valuable complementary approach to target analysis, helping to prioritise thousands of substances that are insufficiently investigated in current monitoring programmes. Conclusions This updated prioritisation workflow responds to the increasing use of suspect screening techniques. It can be adapted to different environmental compartments and can support regulatory obligations, including the identification of specific pollutants in river basins and the marine environments, as well as the confirmation of environmental occurrence levels predicted by modelling tools. Graphical Abstract

Abstract Background The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. Methods A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. Results A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. Conclusions This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations.

Introduction: EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC. Methods: Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood. Results: A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment. Conclusions: Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

Il n'est plus besoin de démontrer que le Système International d'Unités (SI) est un fait. Il est normalement enseigné dans les lycées et universités. Les scientifiques l'utilisent systématiquement dans leurs publications; les nouveaux livres et banques de données s'en servent couramment. Cependant, certaines industries (la pétrolière entre autres) continuent à se servir de systèmes techniques. On trouve dans des archives de vieilles données ou des spécifications d'usines qui ont été faites dans d'autres systèmes. Il n'est pas rare, dans la vie professionnelle, de rencontrer un problème où une unité doit être transformée. Cet article souhaite aider les personnes qui doivent résoudre ce genre d'écueil en leur présentant une vision globale des différents systèmes d'unités qui ont historiquement existé. Une définition des unités, soit traditionnelles, soit étranges, accompagne également l'article. L'aide la plus importante sera sans doute trouvée dans le programme inclus dans une disquette. Un logiciel complet, sous Windows, permettra à quiconque de résoudre, sans erreur, son problème de conversion d'unité. La technique de conversion, basée sur l'utilisation du calcul dimensionnel, et utilisée dans le programme, est également expliquée. It is not longer necessary to prove that the International System of Units (SI) is a fact. It is normally used in schools and universities. Scientists systematically use SI in their publications. New books and databases are commonly built on it. Meanwhile, some industries (oil companies among others) keep on using technical systems. It is possible to find old data and plant designs that use other systems. It is not uncommon, in professional life, to find a problem in which units need to be transformed. This article aims to help people who have to solve this kind of difficulty, by giving an overview of the different unit systems. A description of traditional and unusual units is also included in this article. Undoubtedly, the best help will be found in the program included in a floppy disk. A software, in the Windows environment will enable whoever wants to solve, its units conversion problem accurately. The conversion technique, based on dimensional analysis, is used in the program and explained in this article.

There is strong scientific evidence on the academic, cognitive, social, and emotional benefits of Dialogic Literary Gatherings (DLG) for diverse people in a wide range of settings. However, the transference of DLG to a primary healthcare centre has not yet been studied. To address this gap a case study was conducted on the impact of a DLG in a primary healthcare centre on participants’ mental health and wellbeing from the perception of participants and professionals involved in it. To that end, four daily life stories and a focus group with women participating in the DLG, most of them over 75 years old with no higher education, were conducted, as well as two in-depth interviews, one with the DLG facilitator and one with the director of the health centre. Results show that participants perceived their mental health and wellbeing improved thanks to the functioning and type of dialogue in the DLG, promoting friendships, support and solidarity. Participants also reported that, by being aware of their capabilities in the DLG, they became agents of transformation within their families and environments, turning relationships between healthcare professionals and patients more egalitarian. These findings hold implications for public health and healthcare centres.

At the beginning of the COVID-19 pandemic, scientific literature published research about the presence of hoaxes and evidence in diverse social media, with a huge scientific and social impact. The main results showed that while in Western social media like X there was more false information and less scientific evidence than in the Chinese platform Weibo, but scientific evidence was more retweeted than hoaxes. This research allowed the identification of social activists for science in the social media, who multiplied their impact when scientists provided them with evidence. Mpox clade 1b outbreak, which has now been declared a global public health emergency by WHO, requires a fast reaction from science, already taking place. This article analyzes information disseminated in X and Weibo about mpox. 3089 messages published between 12 and 16 of August 2024 have been analyzed. The results show that while hoaxes around mpox are prevalent in social media, posts containing scientific evidence do receive more interaction. Such findings contribute to the understanding of the health crisis and underscore the need for health authorities to join efforts with citizens to co-create evidence-based communication strategies.

BackgroundFood-induced anaphylaxis (FIA) is a major public health problem resulting in serious clinical complications, emergency department visits, hospitalization, and death. ObjectiveThis study aims to assess the epidemiology and the trends in hospitalizations because of FIA in Spain between 2016 and 2021. MethodsAn observational descriptive study was conducted using data from the Spanish National Hospital discharge database. Information was coded based on the International Classification of Diseases, Tenth Revision. The study population was analyzed by gender and age group and according to food triggers, clinical characteristics, admission to the intensive care unit, severity, and in-hospital mortality. The annual incidence of hospitalizations because of FIA per 100,000 person-years was estimated and analyzed using Poisson regression models. Multivariable logistic regression models were constructed to identify which variables were associated with severe FIA. ResultsA total of 2161 hospital admissions for FIA were recorded in Spain from 2016 to 2021. The overall incidence rate was 0.77 cases per 100,000 person-years. The highest incidence was found in those aged

Este texto é a tradução da palestra da artista e professora uruguaia, Ana Laura López de la Torre, em 8 de julho de 2023, no I Encontro Internacional Artes, Comunidades e Educação, realizado na Unidade Litoral Norte da Universidade Estadual do Rio Grande do Sul (UERGS). Inicialmente, contempla sua trajetória artística, política e docente em Porto Alegre (RS) e em processos de cocriação realizados entre universidade e bairros em Montevidéu, sob sua coordenação. Narrando práticas implicadas com artes visuais, bairro, coletividade e autogestão, também trata de efeitos da pandemia de Covid-19 e dos marcos teóricos, conceituais e metodológicos que fundamentam suas práticas. A escrita mantém a vivacidade da expressão da conferência e algumas imagens contextualizam o que foi apresentado.

Introduction The objectives of this study were to examine temporal trends in the incidence of bariatric surgery (Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG)) in patients with and without type 2 diabetes mellitus (T2DM). Outcomes of hospitalization and the impact of T2DM on these outcomes were also analyzed.Research design and methods We performed an observational study with the Spanish national hospital discharge database. Obese patients with and without T2DM who underwent RYGB and SG between 2016 and 2022 were identified. Propensity score matching (PSM) and logistic regression were used to compare patients with and without T2DM and to evaluate the effect of T2DM and other variables on outcomes of surgery. A variable “severity” was created to cover patients who died in hospital or were admitted to the intensive care unit (ICU).Results A total of 32,176 bariatric surgery interventions were performed (28.86% with T2DM). 31.57% of RYGBs and 25.53% of SG patients had T2DM. The incidence of RYGB and SG increased significantly between 2016 and 2022 (p

BackgroundPrior to the onset of dementia, individuals commonly undergo a phase marked by subtle cognitive changes, known as subtle cognitive decline. Recognizing these early cognitive alterations is crucial, as they can serve as indicators of an impending decline in cognitive function, warranting timely intervention and support.ObjectivesTo determine the incidence of subtle cognitive decline in a population of Spanish women and establish the relationship with possible protective and/or risk factors such as cognitive reserve, cardiovascular risk factors, medication consumption and psychosocial factors.Design and participantsThis is a cross-sectional observational study with women from the general population and a more homogeneous population composed of nuns from the Valencian region (Spain).MeasurementsA validated questionnaire was used including lifestyle variables, chronic illnesses, level of education and pharmacological treatments. Three validated subtle cognitive decline screening tests with varying levels of sensitivity and specificity were used: Memory Impairment Screening, Pfeiffer’s Short Portable Mental State Questionnaire, and Semantic Verbal Fluency.ResultsOur results suggest that nuns may have a significantly reduced risk of cognitive decline compared to the general population (20.67% in nuns vs. 36.63% in the general population). This lower risk for subtle cognitive decline in nuns may be partly attributed to their higher cognitive reserve and long-time engagement in intellectually stimulating activities. Additionally, nuns tend to adopt healthy lifestyles, they are not isolated because they live in community and obtained lower scores for risk factors such as depression, anticholinergic burden, and benzodiazepine consumption.ConclusionA healthy lifestyle combined with intellectually stimulating activities is related with preserved cognitive function.

IntroductionUpon the onset of the COVID-19 pandemic, the Public Health Laboratory Support Unit (ZIG4) at the Robert Koch Institute (RKI), the German National Public Health Institute, developed and delivered an online training on SARS-CoV-2 qPCR diagnostics to 17 partner countries in low- and middle-income countries (LMIC). This article analyses the usefulness and cost savings of this training.MethodsThe authors performed a concurrent mixed-methodology study based on key informant interviews, interviewer-administered questionnaires, and document reviews. Economic costs were estimated from the perspective of RKI.ResultsResponding participants indicated that the course provided good and comprehensive information on up-to-date scientific knowledge and laboratory practice in PCR diagnostics. Respondents appreciated how the technical content of the training enhanced their ability to apply diagnostic methods in their daily work. Interviewees highlighted that the fast implementation and the low threshold of attending an online training had allowed them to quickly build skills that were crucial during, and beyond, the COVID-19 crisis. The total estimated cost of the online SARS-CoV-2 qPCR training was 61,644 euros. The total estimated cost of the equivalent face-to-face training was estimated at 267,592 euros. Programme weaknesses identified included the top-down approaches taken, lack of interactive components and opportunities to directly engage with other course participants and with teachers.ConclusionsAn online training was developed and implemented to support RKI partner countries in SARS-CoV-2 qPCR diagnostics during the COVID-19 pandemic, thereby strengthening pandemic response and health system resilience. The training incurred in important cost savings compared to the equivalent face-to-face training. Post-pandemic studies could usefully build on these research findings and explore ways to enhance end user involvement and improve interactive features to build stronger communities of learners and facilitate exchange of information and mutual learning.