Prion-like strain effects in tauopathies.

Tau is a microtubule-associated protein that plays crucial roles in physiology and pathophysiology. In the realm of dementia, tau protein misfolding is associated with a wide spectrum of clinicopathologically diverse neurodegenerative diseases, collectively known as tauopathies. As proposed by the tau strain hypothesis, the intrinsic heterogeneity of tauopathies may be explained by the existence of structurally distinct tau conformers, "strains". Tau strains can differ in their associated clinical features, neuropathological profiles, and biochemical signatures. Although prior research into infectious prion proteins offers valuable lessons for studying how a protein-only pathogen can encompass strain diversity, the underlying mechanism by which tau subtypes are generated remains poorly understood. Here we summarize recent advances in understanding different tau conformers through in vivo and in vitro experimental paradigms, and the implications of heterogeneity of pathological tau species for drug development.

Safety of helicopter transport in patients with acute coronary syndrome.

BACKGROUND: ST-elevation myocardial infarction (STEMI) systems of care have reduced inter-hospital transfer times and facilitated timely reperfusion goals. Helicopters may be an option when land transportation is not feasible; however, the safety of air transport in patients with acute coronary syndrome (ACS) is a factor to consider. OBJETIVES: The aim of this study was to evaluate the safety of helicopter transport for patients with ACS. METHODS: Prospective, observational, and descriptive study including patients diagnosed with ACS within the STEMI network of a metropolitan city transferred by helicopter to a large cardiovascular center to undergo percutaneous coronary intervention. The primary outcome of the study was the incidence of air-travel-related complications defined as IV dislodgement, hypoxia, arrhythmia, angina, anxiety, bleeding, and hypothermia. Secondary outcomes included the individual components of the primary outcome. RESULTS: A total of 106 patients were included in the study; the mean age was 54 years and 84.9% were male. The most frequent diagnosis was STEMI after successful fibrinolysis (51.8%), followed by STEMI with failed fibrinolysis (23.7%) and non-reperfused STEMI (9.4%). Five patients (4.7%) developed at least one complication: IV dislodgement (1.8%) and hypoxemia (1.8%) in two patients and an episode of angina during flight (0.9%). A flight altitude of > 10,000 ft was not associated with complications. CONCLUSIONS: The results of this study suggest that helicopter transportation is safe in patients undergoing acute coronary syndrome, despite the altitude of a metropolitan area.

ANTECEDENTES: Los sistemas de atención de IAMCEST han reducido los tiempos de transferencia interhospitalaria y han facilitado las metas de reperfusión oportuna. Los helicópteros pueden ser una opción cuando el transporte terrestre no es factible; sin embargo, la seguridad del transporte aéreo en pacientes con síndrome coronario agudo (SICA) es un factor a considerar. OBJETIVOS: Evaluar la seguridad del transporte en helicóptero para pacientes con SICA. MÉTODOS: Estudio prospectivo, observacional, descriptivo. Se incluyeron pacientes con diagnóstico de SICA dentro de la red IAMCEST en metrópolis extensa, trasladados en helicóptero a un centro cardiovascular. El resultado primario del estudio fue la incidencia de complicaciones relacionadas con los viajes aéreos definidas cómo desalojo de catéter intravenoso, hipoxia, arritmia, angina, ansiedad, sangrado e hipotermia. RESULTADOS: Total de 106 pacientes; la edad media fue de 54 años y 84,9% eran hombres. La altitud media de vuelo fue de 10,100 pies y la distancia media de vuelo fue de 50,0 km. El diagnóstico más frecuente fue IAMCEST tras fibrinolisis exitosa (51,8%), seguido de IAMCEST con fibrinolisis fallida (23,7%). Cinco pacientes (4,7%) desarrollaron una complicación: desalojo IV (1,8%) e hipoxemia (1,8%) en dos pacientes y un episodio de angina durante el vuelo (0,9%). Una altitud de vuelo mayor de 10,000 pies no se asoció a complicaciones. CONCLUSIONES: Los resultados de este estudio sugieren que el transporte en helicóptero es seguro en pacientes con SICA, incluso en altitudes > 10,000 pies.

Distinctions between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia: A systematic review and meta-analysis.

Vaccine-inducing immune thrombocytopenia, thrombosis, and bleeding emerge as infrequent and potential complications with mortality risk in healthy subjects. However, differences between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia (VITT) are unclear. Methods: According to the PRISMA statement, we conducted a systematic review and meta-analysis, and the protocol was registered in PROSPERO. The main objective is to identify differences among survivors and non-survivors of SARS-CoV-2 VITT patients. We systematically searched through PubMed, Scopus, and Web of Science. We included cohorts, case series, and case reports. We classified bleeding complications according to the ISTH definition. Statistics: unpaired Student's t-test or one-way ANOVA, Wilcoxon, and Kruskal-Wallis. Results: We systematically searched from January 2021 to June 2021 and identified 51 studies that included 191 patients. Non-survivors had the most severe thrombocytopenia (p 0.02) and lower fibrinogen measurements (p 0.01). Subjects vaccinated with mRNA vaccines (BNT162b2 and mRNA-1273) had an earlier onset of adverse events following immunization (p 0.001). We identified a higher trend of overall thrombotic events (p 0.001) in recipients of viral mechanism-dependent vaccines (Table 2). Non-survivors with cerebral venous sinus thrombosis (CVST) had more severe thrombocytopenia (p 0.01) than survivors with CVST. Finally, 61 % of survivors and 50 % with thrombosis received heparin. Conclusion: We identified more severe thrombocytopenia, lower fibrinogen measurements, and a higher trend of overall thrombotic events, including CVST and thrombotic storm, particularly with viral mechanisms-dependent vaccines in non-survivors VITT patients.

Venous excess ultrasound score and acute kidney injury in patients with acute coronary syndrome.

AIMS: Systemic venous congestion is associated with an increased risk of acute kidney injury (AKI) in critically ill patients. Venous Excess Ultrasound Score (VExUS) has been proposed as a non-invasive score to assess systemic venous congestion. We aimed to evaluate the association between VExUS and AKI in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: This is a prospective study including patients with the diagnosis of ACS (both ST elevation and non-ST elevation ACS). VExUS was performed during the first 24 h of hospital stay. Patients were classified according to the presence of systemic congestion (VExUS 0/≥1). The primary objective of the study was to determine the occurrence of AKI, defined by KDIGO criteria. A total of 77 patients were included. After ultrasound assessment, 31 (40.2%) patients were categorized as VExUS ≥1. VExUS ≥1 was more frequently found in inferior vs. anterior myocardial infarction/non-ST-segment elevation acute myocardial infarction (48.3 vs. 25.8 and 22.5%, P = 0.031). At each increasing degree of VExUS, a higher proportion of patients developed AKI: VExUS = 0 (10.8%), VExUS = 1 (23.8%), VExUS = 2 (75.0%), and VExUS = 3 (100%; P < 0.001). A significant association between VExUS ≥1 and AKI was found [odds ratio (OR): 6.75, 95% confidence interval (CI): 2.21-23.7, P = 0.001]. After multivariable analysis, only VExUS ≥1 (OR: 6.15; 95% CI: 1.26-29.94, P = 0.02) remained significantly associated with AKI. CONCLUSION: In patients hospitalized with ACS, VExUS is associated with the occurrence of AKI. Further studies are needed to clarify the role of VExUS assessment in patients with ACS.

Regulatory assessment of in vitro skin corrosion and irritation data within the European framework: Workshop recommendations.

Validated in vitro methods for skin corrosion and irritation were adopted by the OECD and by the European Union during the last decade. In the EU, Switzerland and countries adopting the EU legislation, these assays may allow the full replacement of animal testing for identifying and classifying compounds as skin corrosives, skin irritants, and non irritants. In order to develop harmonised recommendations on the use of in vitro data for regulatory assessment purposes within the European framework, a workshop was organized by the Swiss Federal Office of Public Health together with ECVAM and the BfR. It comprised stakeholders from various European countries involved in the process from in vitro testing to the regulatory assessment of in vitro data. Discussions addressed the following questions: (1) the information requirements considered useful for regulatory assessment; (2) the applicability of in vitro skin corrosion data to assign the corrosive subcategories as implemented by the EU Classification, Labelling and Packaging Regulation; (3) the applicability of testing strategies for determining skin corrosion and irritation hazards; and (4) the applicability of the adopted in vitro assays to test mixtures, preparations and dilutions. Overall, a number of agreements and recommendations were achieved in order to clarify and facilitate the assessment and use of in vitro data from regulatory accepted methods, and ultimately help regulators and scientists facing with the new in vitro approaches to evaluate skin irritation and corrosion hazards and risks without animal data.

Investigating CRISPR/Cas9 gene drive for production of disease-preventing prion gene alleles.

Prion diseases are a group of fatal neurodegenerative disorders that includes chronic wasting disease, which affects cervids and is highly transmissible. Given that chronic wasting disease prevalence exceeds 30% in some endemic areas of North America, and that eventual transmission to other mammalian species, potentially including humans, cannot be ruled out, novel control strategies beyond population management via hunting and/or culling must be investigated. Prion diseases depend upon post-translational conversion of the cellular prion protein, encoded by the Prnp gene, into a disease-associated conformation; ablation of cellular prion protein expression, which is generally well-tolerated, eliminates prion disease susceptibility entirely. Inspired by demonstrations of gene drive in caged mosquito species, we aimed to test whether a CRISPR/Cas9-based gene drive mechanism could, in principle, promote the spread of a null Prnp allele among mammalian populations. First, we showed that transient co-expression of Cas9 and Prnp-directed guide RNAs in RK13 cells generates indels within the Prnp open-reading frame, indicating that repair of Cas9-induced double-strand breaks by non-homologous end-joining had taken place. Second, we integrated a ~1.2 kb donor DNA sequence into the Prnp open-reading frame in N2a cells by homology-directed repair following Cas9-induced cleavages and confirmed that integration occurred precisely in most cases. Third, we demonstrated that electroporation of Cas9/guide RNA ribonucleoprotein complexes into fertilised mouse oocytes resulted in pups with a variety of disruptions to the Prnp open reading frame, with a new coisogenic line of Prnp-null mice obtained as part of this work. However, a technical challenge in obtaining expression of Cas9 in the male germline prevented implementation of a complete gene drive mechanism in mice.

Further insights into to the role of statins against active tuberculosis: systematic review and meta-analysis.

Objectives: Tuberculosis is a major cause of global morbidity and mortality. Statins could be associated with a lower risk of some infectious diseases, including tuberculosis. Statins could reduce the risk of latent tuberculosis infection and active tuberculosis, acting as an adjuvant in treating tuberculosis. This study aimed to determine if statins reduce the risk of active tuberculosis. Methods: We systematically analyzed 8 databases from inception to December 2021. We included articles without language restriction if they met our inclusion and exclusion criteria and the PECO strategy (Population: adults without active pulmonary tuberculosis; Exposure: treatment with any statin; Comparator: no use of statins; Outcome: active tuberculosis). Odds Ratios (ORs) with 95% confidence intervals (CIs) were pooled using random- effects models regardless of heterogeneity quantified by Cochran's Q and I2 statistics. We performed subgroup analyses according to the participants' diabetic status and follow-up length (≤10 years or >10 years). Results: Twelve articles reporting observational studies involving 3.038.043 participants, including at least 32.668 cases of active tuberculosis. Eight reported retrospective cohort studies, three nested case-control study, and one was a case control study.According to our meta-analysis, statins may reduce the risk of active tuberculosis, in the general population (OR 0.66; 95% CI, 0.54-0.81), in non-diabetic (OR 0.66; 95% CI, 0.54-0.80) and in diabetic patients (OR 0.65; 95% CI, 0.49-0.87). This protective effect did not differ according to the participants' diabetic status nor follow-up length (test for subgroup differences I2=0). We found significant clinical and methodological heterogeneity. Similarly, the forest plot, and the I2 and Chi2 statistics suggested considerable statistical heterogeneity (I2=95%, p<0.05, respectively). Of the 12 included studies, 9 were at low risk of bias and 3 were at high risk of bias. Similarly, according to the funnel plot, it is very likely that there are important publication biases. Conclusion: Statin use may significantly reduce the risk of tuberculosis in the general population, diabetic and non-diabetic patients. Nevertheless, caution should be exercised when interpreting these conclusions, due to the quality of the evidence, the heterogeneity of the studies, the presence of bias, and the difficulty in extrapolating these results to populations of other races and ethnicities.

Periodontal disease as a non-traditional risk factor for acute coronary syndrome: a systematic review and meta-analysis.

Objectives: Previous observational studies have suggested an association between periodontal disease (PD) and cardiovascular and cerebrovascular diseases. Nonetheless, evidence linking PD with coronary heart disease (CHD) and acute coronary syndrome (ACS) is still contradictory. We aim to systematically review the role of PD as a risk factor for ACS (myocardial infarction and unstable angina). Methods: The protocol was registered in PROSPERO (CRD42021286278) and we followed the recommendations of the PRISMA and AMSTAR 2 guidelines. We systematically searched for 7 databases and electronic thesis repositories from inception to February 2022. We included articles without language restriction following the PECO strategy (population: "adult participants"; exposure: "periodontal disease"; comparator: "no periodontal disease"; outcome: "acute coronary syndrome" OR "acute myocardial infarction" OR "unstable angina"). Odds ratios (OR) with 95% confidence intervals (95% CI) were pooled using random effects and heterogeneity was quantified by Cochran's Q and Higgins' I2 statistics. Subgroup analyses were carried out according to the participants' sex, type of diagnosis of PD, type of study, and continent of origin of studies. Results: We included 46 papers (17 cohort, 25 case-control, and 4 cross-sectional studies) that met the inclusion criteria. This meta-analysis includes a total of 6,806,286 participants and at least 68,932 ACS events, mainly myocardial infarction (MI). In accordance with our results, PD is associated with a higher risk of ACS (OR 1.35; 95% CI 1.25-1.45). However, clinical and methodological heterogeneity was significant (I2=86%, p<0.05). In the sensitivity analysis, the exclusion of some studies with "extreme" results (outliers) did not significantly affect the overall estimate or heterogeneity. In subgroup analysis, we found no statistically significant differences between men and women according to subgroup difference tests (I2=0%, p=0.67). Conversely, there were differences according to the type of diagnosis of PD (clinical or self-reported diagnosis), type of study (cohort, case-control, or cross-sectional study), and the continent of origin (North America, South America, Asia, or Europe) of the studies (I2=79%-96%, p<0.10). Of the 46 studies, only 4 had a high risk of bias. Additionally, the funnel plot suggested publication bias. Conclusion: PD may be an important non-traditional risk factor for ACS. Although, this meta-analysis brings together more studies, and therefore more evidence, than any other previous similar study, its results should be interpreted with caution due to the great heterogeneity and the potential presence of bias.

Safety of helicopter transport in patients with acute coronary syndrome / Seguridad del transporte en helicóptero en pacientes con síndrome coronario agudo

Abstract Background: ST-elevation myocardial infarction (STEMI) systems of care have reduced inter-hospital transfer times and facilitated timely reperfusion goals. Helicopters may be an option when land transportation is not feasible; however, the safety of air transport in patients with acute coronary syndrome (ACS) is a factor to consider. Objetives: The aim of this study was to evaluate the safety of helicopter transport for patients with ACS. Methods: Prospective, observational, and descriptive study including patients diagnosed with ACS within the STEMI network of a metropolitan city transferred by helicopter to a large cardiovascular center to undergo percutaneous coronary intervention. The primary outcome of the study was the incidence of air-travel-related complications defined as IV dislodgement, hypoxia, arrhythmia, angina, anxiety, bleeding, and hypothermia. Secondary outcomes included the individual components of the primary outcome. Results: A total of 106 patients were included in the study; the mean age was 54 years and 84.9% were male. The most frequent diagnosis was STEMI after successful fibrinolysis (51.8%), followed by STEMI with failed fibrinolysis (23.7%) and non-reperfused STEMI (9.4%). Five patients (4.7%) developed at least one complication: IV dislodgement (1.8%) and hypoxemia (1.8%) in two patients and an episode of angina during flight (0.9%). A flight altitude of > 10,000 ft was not associated with complications. Conclusions: The results of this study suggest that helicopter transportation is safe in patients undergoing acute coronary syndrome, despite the altitude of a metropolitan area.

Resumen Antecedentes: Los sistemas de atención de IAMCEST han reducido los tiempos de transferencia interhospitalaria y han facilitado las metas de reperfusión oportuna. Los helicópteros pueden ser una opción cuando el transporte terrestre no es factible; sin embargo, la seguridad del transporte aéreo en pacientes con síndrome coronario agudo (SICA) es un factor a considerar. Objetivos: Evaluar la seguridad del transporte en helicóptero para pacientes con SICA. Métodos: Estudio prospectivo, observacional, descriptivo. Se incluyeron pacientes con diagnóstico de SICA dentro de la red IAMCEST en metrópolis extensa, trasladados en helicóptero a un centro cardiovascular. El resultado primario del estudio fue la incidencia de complicaciones relacionadas con los viajes aéreos definidas cómo desalojo de catéter intravenoso, hipoxia, arritmia, angina, ansiedad, sangrado e hipotermia. Resultados: Total de 106 pacientes; la edad media fue de 54 años y 84,9% eran hombres. La altitud media de vuelo fue de 10,100 pies y la distancia media de vuelo fue de 50,0 km. El diagnóstico más frecuente fue IAMCEST tras fibrinolisis exitosa (51,8%), seguido de IAMCEST con fibrinolisis fallida (23,7%). Cinco pacientes (4,7%) desarrollaron una complicación: desalojo IV (1,8%) e hipoxemia (1,8%) en dos pacientes y un episodio de angina durante el vuelo (0,9%). Una altitud de vuelo mayor de 10,000 pies no se asoció a complicaciones. Conclusiones: Los resultados de este estudio sugieren que el transporte en helicóptero es seguro en pacientes con SICA, incluso en altitudes > 10,000 pies.

CHARACTERIZATION AND EXPERIMENTAL MEASUREMENTS OF SCATTER DOSE AT CARDIOLOGIST'S EYES DURING PAEDIATRIC INTERVENTIONAL CARDIOLOGY PROCEDURES IN COSTA RICA.

This paper presents the results of the first characterization and experimental measurements of scatter dose at cardiologist's eyes for the only X-ray system that performs all paediatric Interventional cardiology procedures in Costa Rica. Entrance surface air kerma (ESAK) and the scatter dose values were measured on phantoms of 4-20 cm thicknesses of polymethyl methacrylate slabs. Image quality was evaluated using DICOM images of a test object Leeds TOR 18-FG, through the numerical parameters signal-to-noise ratio (SNR), high-contrast spatial resolution (HCSR) and figure of merit (FOM). When PMMA thickness is increased and during a move from low fluoroscopy to cine modes, ESAK, SNR, HCSR and FOM values range from 0.44 to 391.0 µGy fr-1; 2.8 to 14.89; 3.17 to 15.54 and 0.51 to 79.94, respectively. The highest scattered dose rates recorded during the simulations were 1.79 and 8.04 mSv h-1 for the high fluoroscopy and cine modes, respectively.

Las necesidades de formación docente y el empleo de un modelo para su determinación / Training needs of teachers and implementation of a model for their determination

Fundamento: en el estudio de un proceso formativo conocido, en el cual se van a considerar factores relacionados con nuevos conocimientos, es preciso identificar cuáles son las necesidades que lo justifican.Objetivo: discutir la metodología utilizada para la determinación de necesidades de formación de los profesores universitarios a partir del empleo de un modelo deductivo, ejemplificándose en un programa de formación docente. Métodos: se empleó el análisis de documentos en el análisis de contenidos del informe de tesis, además se enfatizó en el uso de los métodos inductivo-deductivo y analítico-sintético. Resultados: se describe el desarrollo de los pasos del modelo deductivo de David Leyva en las diferentes etapas del proceso investigativo realizado, siguiendo la coherencia y lógica en su aplicación.Conclusiones: la metodología utilizada es viable en la determinación de necesidades de formación de los tutores científicos y posibilitó dar solución al problema de investigación(AU)

Background: in the study of training process, which will consider factors related to new knowledge, it is necessary to identify the needs that justify it. Objective: to discuss the methodology used to determine training needs of university teachers based on the implementation of a deductive model, which was illustrated in a teacher-training program. Methods: document analysis was conducted to examine the contents of the thesis paper; the use of inductive-deductive and analytic-synthetic methods was also emphasized. Results: the coherent and consistent application of the steps of the David Leyvas deductive model in the different stages of the research process is described. Conclusions: the methodology used is suitable for determining training needs of research tutors and allowed solving the research problem(AU)

El Real Hospital Ntra. Sra. del Pilar en el siglo XVIII: um hospital para los esclavos del Rey - 1764-1793 / The Real Hospital Ntra. Sra. del Pilar in the eighteenth century: a hospital for the slaves of the king - 1764-1793

Narra a história do "Real Hospital de Nuestra Señora del Pilar", criado em 1764 para atender a classe pobre e as escravas. Coloca a condiçöes, culturais sociais, políticas e econômicas da época. Descreve os detalhes da construçäo e criaçäo do Hospital. (JGC)

Estructuras plegadas

El tema que ocupa esta proyecto de grado, es de una estructura plegada piramidal, cuya solucion se considera como una estructura formada unicamente por placas triangulares rigidas; basandose el calculo en simples condiciones de equilibrio. A consideracion se abarca los temas: Consideraciones generales. Evaluacion de la presion meridional. Evaluacion de la presion horizontal. Momentos flectores y la observacion. Viga de bordes: esfuerzos longitudinales. Momentos flectores por carga vertical : torsion luego se tiene dimensionamiento y por ultimo dos laminas el primero tensiones h-t y el ultimo estructura plegada: armadura.

Reformulacion del proyecto I.N.E.R. de electrificacion del valle de Luribay

Contenido:1. Antecedentes 2.La electrificacion rural 3.Condiciones del sector economico y agropecuario a nivel Nacional, departamental y regional provincias del sud de La Paz: Ingavi, Loayza, Inquisivi, Aroma, Sud de Murillo 4.Caracteristicas del sector electrico a nivel nacional, central y rural regional 5.Otros estudios complementarios a nivel regional 6.El proyecto elaborado por INER para electrificacion rural del valle del Luribay y su reformulacion 7.Conclusiones generales y recomendaciones.