IL-1R and inflammasomes mediate early pulmonary protective mechanisms in respiratory brucella abortus infection

Brucella spp. infection is frequently acquired through contaminated aerosols. The role of interleukin-1 beta (IL-1β) in the early pulmonary response to respiratory Brucella infection is unknown. As shown here, IL-1β levels in lung homogenates and bronchoalveolar lavage fluid (BALF) of mice intratracheally inoculated with B. abortus were increased at 3 and 7 days p.i. At 7 days p.i., pulmonary CFU numbers were higher in IL-1 receptor (IL-1R) knockout (KO) mice than in wild type (WT) mice. At different times p.i. CFU in lungs and BALF were higher in mice lacking some inflammasome components (caspase-1, AIM2, NLRP3) than in WT mice. At 2 days p.i. pulmonary levels of IL-1b and CXCL1 (neutrophils chemoattractant) were lower in caspase-1/11 KO mice. At day 3 p.i., neutrophils counts in BALF were lower in caspase-1/11 KO mice than in WT mice. During in vitro infections, IL-1β secretion was lower in alveolar macrophages from caspase-1/11, NLRP3 or AIM2 KO mice than in WT controls. Similarly, IL-1β production by B. abortus-infected alveolar epithelial cells was reduced by pretreatment with a specific caspase-1 inhibitor. This study shows that IL-1R, probably through IL-1β action, and the NLRP3 and AIM2 inflammasomes are involved in pulmonary innate immune protective mechanisms against respiratory B. abortus infection.Fil: Hielpos, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Fernandez, Andrea Giselle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Falivene, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Alonso Paiva, Iván Mathias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Muñoz González, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Ferrero, Mariana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Campos, Priscila C.. Universidade Federal de Minas Gerais; BrasilFil: Vieira, Angelica T.. Universidade Federal de Minas Gerais; BrasilFil: Oliveira, Sergio Costa. Universidade Federal de Minas Gerais; BrasilFil: Baldi, Pablo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentin

<i>orsai</i>, the Drosophila homolog of human ETFRF1, links lipid catabolism to growth control

BACKGROUND: Lipid homeostasis is an evolutionarily conserved process that is crucial for energy production, storage and consumption. Drosophila larvae feed continuously to achieve the roughly 200-fold increase in size and accumulate sufficient reserves to provide all energy and nutrients necessary for the development of the adult fly. The mechanisms controlling this metabolic program are poorly understood. RESULTS: Herein we identified a highly conserved gene, orsai (osi), as a key player in lipid metabolism in Drosophila. Lack of osi function in the larval fat body, the regulatory hub of lipid homeostasis, reduces lipid reserves and energy output, evidenced by decreased ATP production and increased ROS levels. Metabolic defects due to reduced Orsai (Osi) in time trigger defective food-seeking behavior and lethality. Further, we demonstrate that downregulation of Lipase 3, a fat body-specific lipase involved in lipid catabolism in response to starvation, rescues the reduced lipid droplet size associated with defective orsai. Finally, we show that osi-related phenotypes are rescued through the expression of its human ortholog ETFRF1/LYRm5, known to modulate the entry of β-oxidation products into the electron transport chain; moreover, knocking down electron transport flavoproteins EtfQ0 and walrus/ETFA rescues osi-related phenotypes, further supporting this mode of action. CONCLUSIONS: These findings suggest that Osi may act in concert with the ETF complex to coordinate lipid homeostasis in the fat body in response to stage-specific demands, supporting cellular functions that in turn result in an adaptive behavioral response. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01417-w

The Effects of a “Health at Every Size®”-Based Approach in Obese Women: A Pilot-Trial of the “Health and Wellness in Obesity” Study

This study explored the effects of Health at Every Size®-based intervention on obese women by qualitatively evaluating participants’ perception towards the program and quantitatively evaluating changes related to psychological, behavioral and body composition assessments. A prospective one-year quasi-experimental mixed-method trial was conducted. The mixed method design was characterized by a spiral method, and quantitative and qualitative findings were combined during the interpretation phase. The qualitative data involved three focus groups; and quantitative data comprised physiological, psychological and behavioral assessments. Initially, 30 participants were recruited; 14 concluded the intervention. From the focus groups, the following interpretative axes were constructed: the intervention as a period of discoveries; shifting parameters: psychological, physical and behavioral changes; eating changes, and; redefining success. Body weight, body mass index, total body fat mass and body fat percentage were significantly decreased after the intervention (-3.6, -3.2, -13.0, and -11.1%, respectively; p≤0.05, within-time effect). Participants reported being more physically active, and perceiving better their bodies. Eating-wise, participants reported that the hunger and satiety cues and the consumption of more frequent meals facilitated their eating changes. Finally, participants reported that they could identify feelings with eating choices and refrain from the restrained behavior. These qualitative improvements were accompanied by modest but significant improvements in quantitative assessments. Clinicaltrials.gov registration: NCT02102061

Efetividade das intervenções contra violência no trabalho sofrida por profissionais de saúde e apoio: metanálise

Objetivo:&nbsp;avaliar a efetividade das intervenções direcionadas à prevenção e redução da violência no trabalho sofrida por profissionais de saúde e apoio.&nbsp;Método:&nbsp;revisão sistemática com metanálise realizada em oito bases de dados e na literatura cinzenta. O risco de viés foi realizado por meio das ferramentas da Cochrane e a certeza da evidência pelo&nbsp;Grading of Recommendations Assessment, Development and Evaluation. A análise foi realizada de forma descritiva e pela metanálise, incluindo avaliação da heterogeneidade.&nbsp;Resultados:&nbsp;11 estudos aleatorizados e quasi-aleatorizados foram elegíveis, dos quais seis estudos (54,5%) implementaram habilidades individuais, quatro multiabordagem (36,4%) e um (9,1%) ações governamentais. Quatro estudos (36,4%) tiveram efeito positivo e significativo na redução da violência. O risco de viés foi classificado como alto ou incerto. A metanálise foi realizada com dois estudos que testaram habilidade individual (grupo intervenção)&nbsp;versus habilidade individual (grupo comparador), porém não houve evidência científica (IC 95%: -0,41 a 0,25, p=0,64) para o desfecho prevenção/redução da violência.&nbsp;Conclusão:&nbsp;esta revisão não obteve alta evidência na prevenção ou redução da violência no trabalho. O número reduzido de ensaios aleatorizados, a falta de estudos com baixo risco de viés e a alta consistência podem ter sido fatores dificultadores para recomendar intervenções efetivas.Objective:&nbsp;to assess the effectiveness of the interventions targeted at preventing and reducing the workplace violence suffered by health and support professionals.&nbsp;Method:&nbsp;a systematic review with meta-analysis conducted in eight databases and in the gray literature. Risk of bias was assessed by means of the Cochrane tools and certainty of the evidence, through&nbsp;Grading of Recommendations Assessment, Development and Evaluation. The analysis was performed in a descriptive manner and through the meta-analysis, including a heterogeneity assessment. Results:&nbsp;a total of 11 randomized and quasi-randomized studies were eligible, of which six (54.5%) implemented individual skills, four used a multiple approach (36.4%) and one (9.1%) resorted to governmental actions. Four studies (36.4%) exerted a positive and significant effect on reducing violence. Risk of bias was classified as high or uncertain. The meta-analysis was performed with two studies that tested individual skill (intervention group)&nbsp;versus individual skill (comparator group), although there was no scientific evidence (95% CI: -0.41 - 0.25, p=0.64) for the violence prevention/reduction outcome.&nbsp;Conclusion:&nbsp;this review did not obtain a high level of evidence in the prevention or reduction of workplace violence. The reduced number of randomized trials, the lack of studies with low risk of bias and the high consistency may have been factors that hindered recommending effective interventions.Objetivo:&nbsp;evaluar la efectividad de las intervenciones dirigidas a prevenir y reducir la violencia laboral que sufren los profesionales de la salud y de apoyo.&nbsp;Método:&nbsp;revisión sistemática con metanálisis realizada en ocho bases de datos y en la literatura gris. El riesgo de sesgo se evaluó mediante herramientas Cochrane y la certeza de la evidencia mediante el&nbsp;Grading of Recommendations Assessment, Development and Evaluation. El análisis se realizó de forma descriptiva y por metanálisis, e incluyó la evaluación de la heterogeneidad.&nbsp;Resultados:&nbsp;fueron elegibles 11 estudios aleatorios y cuasialeatorios, de los cuales seis estudios (54,5%) implementaron habilidades individuales, cuatro multienfoque (36,4%) y uno (9,1%) acciones gubernamentales. Cuatro estudios (36,4%) tuvieron un efecto positivo y significativo en la reducción de la violencia. El riesgo de sesgo se clasificó como alto o incierto. El metanálisis se realizó con dos estudios que evaluaron la capacidad individual (grupo de intervención)&nbsp;versus la capacidad individual (grupo de comparación), pero no se encontró evidencia científica (IC del 95 %: -0,41 a 0,25, p = 0,64) para el resultado prevención/reducción de la violencia.&nbsp;Conclusión:&nbsp;esta revisión no obtuvo alta evidencia sobre la prevención o reducción de la violencia laboral. El número reducido de ensayos aleatorios, la falta de estudios con bajo riesgo de sesgo y la alta consistencia pueden haber sido factores que dificultaron la recomendación de intervenciones efectivas

Sustained low disease activity measured by ASDAS slow radiographic spinal progression in axial spondyloarthritis patients treated with TNF-inhibitors: data from REGISPONSERBIO

Background To evaluate the influence of the disease activity on radiographic progression in axial spondyloarthritis (axSpA) patients treated with TNF inhibitors (TNFi). Methods The study included 101 axSpA patients from the Spanish Register of Biological Therapy in Spondyloarthritides (REGISPONSERBIO), which had clinical data and radiographic assessment available. Patients were classified into 2 groups based on the duration of TNFi treatment at baseline: (i) long-term treatment (>= 4 years) and (ii) no long-term treatment (= 2 mSASSS units. At inclusion, approximately half of the patients (45.5%) were receiving long-term treatment with TNFi (>= 4 years). In this group of subjects, a significant difference in averaged Ankylosing Spondylitis disease Activity Score (ASDAS) across follow-up was found between progressors and non-progressors (2.33 vs 1.76, p=0.027, respectively). In patients not under long-term TNFi treatment (54.5%) though, no significant ASDAS differences were observed between progressors and non-progressors until the third year of follow-up. Furthermore, no significant differences were found in progression status, when disease activity was measured by Bath Ankylosing spondylitis Disease Activity Index (BASDAI) and C reactive protein (CRP). Conclusions Patients on long-term TNFi treatment with a mean sustained low disease activity measures by ASDAS presented lower radiographic progression than those with active disease

Incidence and risk factors for acute gastroenteritis among pilgrims following the French way to Santiago de Compostela (Spain) in summer 2008.

[ES] Conocer la incidencia de gastroenteritis aguda en los peregrinos del Camino de Santiago, los factores de riesgo asociados y su caracterización microbiológica. Se diseñaron dos estudios simultáneos, uno transversal mediante encuestas autocumplimentadas de peregrinos llegados a Santiago y otro de casos y controles a los peregrinos en el camino. Se hizo un análisis multivariado mediante regresión logística. En el estudio transversal la densidad de incidencia fue de 23,5 episodios de gastroenteritis aguda por 1.000 peregrinos-día (intervalo de confianza del 95% [IC95%]: 18,9–29,4/103). En el estudio de casos y controles los factores de mayor riesgo fueron la edad <20 años (odds ratio [OR]=4,72; IC95%: 2,16–10,28), viajar en grupo (tres personas o más) (OR=1,49; IC95%: 0,98–2,28) y consumir agua no embotellada (OR=2,09; IC95%: 0,91–4,82). Norovirus fue el microorganismo aislado con más frecuencia (56%). Ser peregrino menor de 20 años, realizar el camino en grupo y consumir agua no embotellada se asocian con un mayor riesgo de presentar gastroenteritis aguda. [EN] To determine the incidence of acute gastroenteritis in pilgrims on St. James' Way, as well as associated risk factors and microbiological characteristics. Two studies were designed simultaneously: a cross-sectional study through self-completed questionnaires among pilgrims reaching Santiago, and a case-control study of pilgrims traveling along the Way. Multivariate analysis was performed using logistic regression. In the cross-sectional study, the incidence rate was 23.5 episodes of acute gastroenteritis/10³ pilgrims-day (95% CI: 18.9-2.4/10³. In the case-control study, the major risk factors were age <20 years (OR=4.72; 95% CI: 2.16-10.28), traveling in groups (three or more) (OR=1.49; 95% CI: 0.98-2.28), and drinking unbottled water (OR=2.09; 95% CI: 0.91-4.82). The most frequent etiologic agent was norovirus (56%). Age less than 20 years, traveling in groups and drinking unbottled water were important risk factors for acute gastroenteritis.Para desarrollar el trabajo de campo, el Centro Nacional de Epidemiología (Instituto de Salud Carlos III) financió el desplazamiento y las dietas de los miembros del PEAC, la Consellería de Sanidade de Galicia aportó el material técnico necesario y cedió un vehículo para los desplazamientos a lo largo del Camino, y S.A. de Xestion do Xacobeo facilitó el alojamiento de los investigadores de campo.S

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe

Predictive Power of the "Trigger Tool" for the detection of adverse events in general surgery: a multicenter observational validation study

Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality