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Abstract The incorporation of digital pathology in clinical practice will require the training of pathologists in digital skills. Our study aimed to assess the reliability among pathologists in determining tumor percentage in whole slide images (WSI) of non-small cell lung cancer (NSCLC) using digital image analysis, and study how the results correlate with the molecular findings. Pathologists from nine centers were trained to quantify epithelial tumor cells, tumor-associated stromal cells, and non-neoplastic cells from NSCLC WSI using QuPath. Then, we conducted two consecutive ring trials. In the first trial, analyzing four WSI, reliability between pathologists in the assessment of tumor cell percentage was poor (intraclass correlation coefficient (ICC) 0.09). After performing the first ring trial pathologists received feedback. The second trial, comprising 10 WSI with paired next-generation sequencing results, also showed poor reliability (ICC 0.24). Cases near the recommended 20% visual threshold for molecular techniques exhibited higher values with digital analysis. In the second ring trial reliability slightly improved and human errors were reduced from 5.6% to 1.25%. Most discrepancies arose from subjective tasks, such as the annotation process, suggesting potential improvement with future artificial intelligence solutions.

Abstract Background Morbid obesity is a complex chronic condition characterized by a body mass index of 40 kg/m2 or higher. The incidence of the condition is on the rise in developed countries, and bariatric surgery has been proposed as a potential solution to address this trend. Nonetheless, bariatric surgery may also result in adverse effects, including a reduction in bone mineral density (BMD) and muscle mass, as well as an increased risk of fractures. The present study aims to elucidate the effects of bariatric surgery and whole-body vibration (WBV) training on body composition, microbiota, physical fitness, quality of life, and cardiometabolic markers. Methods Twenty-eight participants (14 females), aged 18 to 50 years, will undergo sleeve gastrectomy surgery. They will be randomly allocated into a control group or a WBV training group. The WBV group will train three times per week with increasing intensities and duration ranging from 30 to 45 min over the 4-month training period. Measurements of body composition (dual-energy X-ray absorptiometry and peripheral quantitative computed tomography), physical fitness (muscular strength, agility, cardiorespiratory fitness, and balance), gait biomechanics, cardiometabolic markers, gut microbiota, quality of life, and physical activity levels will be collected at four different time points: (1) prior to the surgery, (2) 45 days post-surgery, (3) 6 months post-surgery, and (4) 18 months post-surgery. Discussion Both groups are expected to experience improvements in most of the aforementioned variables. Nonetheless, we expect the WBV group to show larger improvements proving that the training is effective and safe. Trial registration Clinicaltrials.gov NCT05695599. Registered on January 25, 2023.

Single-cell RNA sequencing (scRNA-seq) technology has emerged as a powerful tool for dissecting cellular heterogeneity and understanding the intricate biology of diseases, including cancer. Endometrial cancer (EC) stands out as the most prevalent gynecological malignancy in Europe and the second most diagnosed worldwide, yet its cellular complexity remains poorly understood. In this review, we explore the contributions of scRNA-seq studies to shed light on the tumor cells and cellular landscape of EC. We discuss the diverse tumoral and microenvironmental populations identified through scRNA-seq, highlighting the implications for understanding disease progression. Furthermore, we address potential limitations inherent in scRNA-seq studies, such as technical biases and sample size constraints, emphasizing the need for larger-scale research encompassing a broader spectrum of EC histological subtypes. Notably, a significant proportion of scRNA-seq analyses have focused on primary endometrioid carcinoma tumors, underscoring the need to incorporate additional histological and aggressive types to comprehensively capture the heterogeneity of EC. By critically evaluating the current state of scRNA-seq research in EC, this review underscores the importance of advancing towards more comprehensive studies to accelerate our understanding of this complex disease.

Abstract Increased recruitment of transitional and non-classical monocytes in the lung during SARS-CoV-2 infection is associated with COVID-19 severity. However, whether specific innate sensors mediate the activation or differentiation of monocytes in response to different SARS-CoV-2 proteins remain poorly characterized. Here, we show that SARS-CoV-2 Spike 1 but not nucleoprotein induce differentiation of monocytes into transitional or non-classical subsets from both peripheral blood and COVID-19 bronchoalveolar lavage samples in a NFκB-dependent manner, but this process does not require inflammasome activation. However, NLRP3 and NLRC4 differentially regulated CD86 expression in monocytes in response to Spike 1 and Nucleoprotein, respectively. Moreover, monocytes exposed to Spike 1 induce significantly higher proportions of Th1 and Th17 CD4 + T cells. In contrast, monocytes exposed to Nucleoprotein reduce the degranulation of CD8 + T cells from severe COVID-19 patients. Our study provides insights in the differential impact of innate sensors in regulating monocytes in response to different SARS-CoV-2 proteins, which might be useful to better understand COVID-19 immunopathology and identify therapeutic targets.

Los primeros auxilios están presentes en el sistema educativo español desde hace más de 30 años, adquiriendo importancia en las dos últimas leyes educativas. En este trabajo se analiza su presencia en la legislación educativa vigente. Se ha realizado un análisis de la presencia de los contenidos de primeros auxilios y soporte vital básico (SVB) presentes en los currículos autonómicos de educación secundaria obligatoria (ESO) en España. Todas las comunidades autónomas incorporan los primeros auxilios de manera similar a lo establecido en el Real Decreto que establece los contenidos mínimos. En el primer ciclo de la ESO los contenidos están enfocados a aprender el protocolo de SVB, el número de emergencias y el protocolo PAS (Proteger, Alertar y Socorrer). En el segundo ciclo, estos son más complejos, incluyendo las maniobras RCP, Heimlich y el uso del desfibrilador externo automático (DEA). Existen investigaciones que recomiendan comenzar el aprendizaje de los primeros auxilios con contenidos sencillos en educación primaria e ir aumentando la complejidad a lo largo de toda la etapa educativa, por lo que, aunque los contenidos planteados en la educación secundaria no son inadecuados, quizás algunos de ellos son propios de la etapa anterior, la Educación Primaria. Palabras Clave: Soporte vital básico, educación física, accidentes, emergencias, reanimación cardiopulmonar, currículo. Abstract. First aid has been part of the Spanish educational system for over 30 years, gaining prominence in the last two educational laws. This study examines its presence in the current educational legislation. An analysis has been conducted on the inclusion of first aid and basic life support (BLS) content in the autonomous curricula of compulsory secondary education (ESO) in Spain. All autonomous communities incorporate first aid in a manner similar to that stipulated in the Royal Decree that establishes the minimum contents. In the first cycle of ESO, the contents focus on learning the BLS protocol, the emergency number, and the PAS protocol (Protect, Alert, and Assist). In the second cycle, these become more complex, including CPR maneuvers, the Heimlich maneuver, and the use of an automated external defibrillator (AED). There are studies that recommend initiating the learning of first aid with simple content in primary education and gradually increasing the complexity throughout the entire educational stage. Therefore, while the contents proposed in secondary education are not inappropriate, some of them might be more suitable for the previous stage, namely, Primary Education. Keywords: Basic life support, physical education, accidents, emergencies, cardiopulmonary resuscitation, curriculum.

Introducción. La incidencia de cáncer colorrectal (CCR) de aparición temprana (CCR-ATem), definido como CCR en individuos menores de 50 años, está aumentando en todo el mundo. A pesar del incremento en la producción científica internacional sobre CCR-ATem, la investigación es limitada en Colombia. El objetivo de este estudio fue caracterizar clínicamente los adultos con CCR-ATem y CCR de aparición tardía (CCR-ATar, CCR en individuos ≥ 50 años). Métodos. Estudio observacional, retrospectivo, transversal, en el que se incluyeron los adultos con CCR atendidos en un centro médico de Medellín, Colombia. Los datos se obtuvieron del Registro Institucional de Cáncer. Se establecieron dos grupos de análisis: CCR-ATem y CCR-ATar. Se aplicó la prueba de Chi cuadrado para comparar las variables de interés entre ambos grupos. Resultados. La muestra incluyó 1,202 pacientes, 53.5 % fueron mujeres (N=643), y la mediana de edad fue de 65 años (rango intercuartil: 55-73). CCR-ATem representó el 15.9 % (N=192). CCR-ATar tuvo más casos de enfermedades cardiometabólicas y tabaquismo (p

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. https://bit.ly/3i43wb6

Introducción. El cáncer colorrectal es uno de los tipos de cáncer más comunes y mortales a nivel mundial. Aunque los avances médicos han mejorado el manejo, la cirugía sigue siendo fundamental. La resección anterior baja (RAB) de recto ha ganado relevancia, a pesar de que puede llevar al síndrome de resección anterior baja de recto (LARS, por sus siglas en inglés), afectando la calidad de vida. Métodos. Estudio de corte transversal con intención analítica en un centro de referencia en Medellín, Colombia. Los pacientes con cáncer de recto sometidos a RAB entre enero de 2016 y diciembre de 2022 completaron el cuestionario LARS para evaluar disfunción intestinal. Se evaluaron factores relacionados con la presencia de LARS por medio de un análisis bivariado. Resultados. De 234 pacientes elegibles, 110 (47 %) respondieron la encuesta, predominantemente mujeres (58,2 %). La edad promedio fue 62 años. Dos tercios de los pacientes recibieron neoadyuvancia y el 69 % requirieron ileostomía. La prevalencia de LARS fue 47,3 %. El 80,9 % llevaban más de 12 meses desde la cirugía o el cierre del estoma. Factores estadísticamente significativos asociados a LARS fueron edad mayor de 65 años (p=0,03), estadío patológico avanzado (p=0,02) y requerimiento de estoma (p=0,03). Conclusiones. El LARS afecta a casi la mitad de los pacientes en diferentes etapas posquirúrgicas. El LARS score es una herramienta práctica para evaluar la función intestinal en el seguimiento del paciente. La prevalencia y los factores de riesgo identificados contribuyen a la comprensión del impacto de la cirugía conservadora del esfínter en la calidad de vida de los pacientes.

Introducción. La Comisión Nacional de Residencias Médicas (CONAREM) es el principal sistema de admisión para la tutoría clínica de residencias médicas en Paraguay, avalado por Ministerio de Salud Pública y Bienestar Social. Objetivos. Determinar la relación entre el puntaje final obtenido y el promedio de grado en postulantes a convocatorias CONAREM 2019-2023. Metodología. Estudio transversal con variables sociodemográficas, académicas, puntajes del examen y puntaje final. Se aplicaron métodos descriptivos y pruebas de Kolmogórov-Smirnov, t de Student, U de Mann-Whitney, Kruskal-Wallis y correlación de Spearman; utilizando software Stata© 17.0 de StataCorp LLC. Se consideraron significativos cuando p

En este artículo de revisión se muestran los principales aportes de la literatura científica relacionados con el problema SBPR (Sorting Permutations By Prefix Reversals, en español, Ordenamiento de permutaciones con reversión de prefijos) realizados en los últimos 47 años que han servido como base en la secuenciación completa del genoma humano. De hecho, este estudio tiene como propósito describir los principales antecedentes del problema desde sus orígenes hasta su aplicación final en la secuenciación del genoma humano. La metodología utilizada está basada en la revisión documental, la cual permitió construir una matriz y un grafo, en donde se resumen todas las interconexiones bibliográficas posibles. Sin embargo, los principales hallazgos demuestran que los años 90 fueron claves para desarrollar una teoría sólida en cuanto a construcción y verificación en lo que refiere a algoritmos. Finalmente, se brindan las conclusiones y perspectivas a futuro de los principales resultados obtenidos.

Objective. Develop a map of publications showing spatialized scientific research through geographic coordinate points in the Loreto region, preliminary with publications from the journal Amazon Folia. Method. Cartographic and bibliometric techniques were applied to analyze 255 scientific articles published between 1988 and 2016 in the journal Amazon Folia. Results. The publications were centralized in the area of influence of the Iquitos – Nauta, Jenaro Herrera, low and middle basin of the Nanay river and left sector of the Marañón river basin. The scientific network generated through the journal Amazonian Folia showed a "non-related" figure. Institutional affiliations corresponded to 71 entities, 12 countries and 386 authors, where Peru and France had the highest scientific output, inso day as the United States had more institutions affiliated with the journal Amazonian Folia after Peru. Conclusion. The publication map represents a great research tool with projection of development and scientific management. Integration with other journals will allow to guide projects that contribute to the development of the Loreto region and in the future in the Amazonian field.

Abstract The ability of MALDI-TOF for the identification of nontuberculous mycobacteria (NTM) has improved recently thanks to updated databases and optimized protein extraction procedures. Few multicentre studies on the reproducibility of MALDI-TOF have been performed so far, none on mycobacteria. The aim of this study was to evaluate the reproducibility of MALDI-TOF for the identification of NTM in 15 laboratories in 9 European countries. A total of 98 NTM clinical isolates were grown on Löwenstein-Jensen. Biomass was collected in tubes with water and ethanol, anonymized and sent out to the 15 participating laboratories. Isolates were identified using MALDI Biotyper (Bruker Daltonics). Up to 1330 MALDI-TOF identifications were collected in the study. A score ≥ 1.6 was obtained for 100% of isolates in 5 laboratories (68.2–98.6% in the other). Species-level identification provided by MALDI-TOF was 100% correct in 8 centres and 100% correct to complex-level in 12 laboratories. In most cases, the misidentifications obtained were associated with closely related species. The variability observed for a few isolates could be due to variations in the protein extraction procedure or to MALDI-TOF system status in each centre. In conclusion, MALDI-TOF showed to be a highly reproducible method and suitable for its implementation for NTM identification.

Este artículo presenta los resultados obtenidos a partir de la experiencia del caso de estudio desarrollado con y por jóvenes de AEI Raval en el marco de un proyecto europeo en el que participa el Departamento de Comunicación de la Universitat Pompeu Fabra. Se analiza el proceso de creación de dos piezas audiovisuales producidas por los y las jóvenes que emergen a partir de la aplicación de metodologías audiovisuales participativas en el marco de la Investigación Acción Participativa. De este modo se pone el énfasis en el aporte de la metodología participativa audiovisual como un potente recurso para que las personas se piensen desde la colectividad, se problematicen como grupo social y construyan discursos desde la crítica y resistencia al sistema. Para ello se hace recorrido por los fundamentos teóricos y metodológicos que han guiado la aplicación del caso de estudio, se describe minuciosamente las etapas de trabajo y se plantean en los resultados y conclusiones cuestiones a reflexionar para futuros abordajes en la aplicación de la metodología, especialmente con colectivos en contextos vulnerables.

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.

Abstract Objectives The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non‐small cell lung cancer (NSCLC) patients treated with first‐ or second‐generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods Stage IV NSCLC patients with locally confirmed EGFR‐TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first‐ or second‐generation EGFR‐TKI as first‐line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression‐free survival (PFS) event or until study completion (72‐week follow‐up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. Results A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty‐six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow‐up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48–2.54; p

Reliable neurotrophin kinase (NTRK) fusion assessment is of special relevance since durable responses to targeted therapies have been observed regardless tumor type, NTRK gene or fusion partner. The most prevalent NTRK fusion in solid tumors is the ETV6-NTRK3, although alternative NTRK3 translocations with new partners are increasingly described across a wide variety of tumor types.NTRK fusions occur at low frequencies in non-small-cell lung cancer and are less common than other gene rearrangements. Here we describe a novel TRIM24-NTRK3 fusion in a lung adenocarcinoma patient that was missed by immunohistochemistry and DNA-based NGS but detected using a commercial targeted RNA-based NGS panel. To the best of our knowledge, this fusion has never been previously reported in any cancer type and allowed eligibility of patient for treatment with a small molecule inhibitor. This case also remarks the role of NGS in reliable detection of challenging novel NTRK fusions.

El hemitruncus arterioso es una cardiopatía congénita rara caracterizada por el origen anómalo de alguna de las ramas de la arteria pulmonar a partir de la aorta ascendente. En la mayoría de los casos su diagnóstico se realiza durante la infancia; además, por su elevada morbimortalidad es extremadamente inusual su evolución asintomática y supervivencia hasta la etapa adulta. Presentamos el caso de un varón de 30 años con antecedente de cierre quirúrgico de persistencia del conducto arterioso en la infancia, que cursó asintomático hasta hace un año, y se le diagnosticó hemitruncus arterioso a partir de episodios recurrentes de hemoptisis.

El uso social de las nuevas tecnologías de la información y comunicación es un elemento central en las dinámicas culturales contemporáneas. Estas tecnologías están configurando estructuras políticas, económicas y causando cambios al nivel de la identidad y de la intimidad. Dentro de las ciencias sociales pueden encontrarse perspectivas tanto pesimistas como optimistas. Aquellas teorías que analizan la modernidad en términos de procesos de individualización, centradas en las cuestiones de los estilos de vida y de la subjetividad, están especialmente relacionadas con el tema. Mientras se generalizan dichas tecnologías, es mayor el interés por su uso y el desarrollo de una nueva cultura en torno al mismo, especialmente entre la población joven. Este interés es paralelo a la percepción social según la cual las tecnologías pueden afectar negativamente a las personas, generando incluso adicción. Este artículo aborda el uso problemático de las nuevas tecnologías desde la perspectiva de la antropología social. La primera parte reúne datos sobre el uso de nuevas tecnologías y aborda la discusión sobre cómo se está aplicando el término de «adicción». La segunda parte explica por qué es necesaria la perspectiva socioantropológica en el contexto del debate científico actual. Finalmente, se presentan los resultados de una investigación antropológica en curso.

Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53. The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.

Abstract Background Immunohistochemistry (IHQ) is commonly used for the detection of mismatch repair proteins deficiency (MMRD). One very infrequent abnormal pattern of MMR protein expression is the loss of PMS2 and MSH6, with intact expression of MLH1 and MSH2. Case presentation We review the frequency of this MMRD IHC pattern among 108 colorectal (CRCs) and 35 endometrial cancers in our files with loss of expression of at least one protein, and present two CRCs showing loss of PMS2 and MSH6 protein expression (1.9% of CRCs). NGS analysis of these tumours identified PMS2 mutations (R134* germline mutation in one tumour and M1R and c.1239delA somatic mutation in the other) as the primary event and somatic MSH6 mutation (c.3261dupC) as the secondary event in both tumours. Conclusions This study suggests that Next Generation Sequencing (NGS) tumour analysis should be considered in the algorithm of Lynch syndrome screening to detect MMR gen somatic mutation in inconclusive cases.

Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3–6, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 3–6, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 3–6 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.

Gasdermins (GSDM) genes play complex roles in inflammatory diseases and cancer. Gasdermin-B (GSDMB) is frequently upregulated in human cancers, especially in HER2-amplified breast carcinomas, and can promote diverse pro-tumor functions (invasion, metastasis, therapy-resistance). In particular, the GSDMB shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB can also have tumor suppressor (cell death induction) effects in specific biological contexts. However, whether GSDMB has inherent oncogenic, or tumor suppressor function in vivo has not been demonstrated yet in preclinical mouse models, since mice lack GSDMB orthologue. Therefore, to decipher GSDMB cancer functions in vivo we first generated a novel knock-in mouse model (R26-GB2) ubiquitously expressing human GSDMB2. The comprehensive histopathological analysis of multiple tissues from 75 animals showed that nucleus-cytoplasmic GSDMB2 expression did not clearly affect the overall frequency nor the histology of spontaneous neoplasias (mostly lung carcinomas), but associated with reduced incidence of gastric tumors, compared to wildtype animals. Next, to assess specifically the GSDMB2 roles in breast cancer, we generated two additional double transgenic mouse models, that co-express GSDMB2 with either the HER2/NEU oncogene (R26-GB2/MMTV-NEU mice) or the Polyoma middle-T antigen (R26-GB2/MMTV-PyMT) in breast tumors. Consistent with the pro-tumor effect of GSDMB in HER2+ human breast carcinomas, R26-GB2/MMTV-NEU GSDMB2-positive mice have double breast cancer incidence than wildtype animals. By contrast, in the R26-GB2/MMTV-PyMT model of fast growing and highly metastatic mammary tumors, GSDMB2 expression did not significantly influence cancer development nor metastatic potential. In conclusion, our data prove that GSDMB2 in vivo pro-tumor effect is evidenced only in specific biological contexts (in concert with the HER2 oncogene), while GSDMB2 alone does not have overall intrinsic oncogenic potential in genetically modified mice. Our novel models are useful to identify the precise stimuli and molecular mechanisms governing GSDMB functions in neoplasias and can be the basis for the future development of additional tissue-specific and context-dependent cancer models.

As the rate of discovery of new antibacterial compounds for multidrug-resistant bacteria is declining, there is an urge for the search for molecules that could revert this tendency. Acinetobacter baumannii has emerged as a highly virulent Gram-negative bacterium that has acquired multiple resistance mechanisms against antibiotics and is considered of critical priority. In this work, we developed a quantitative structure-property relationship (QSPR) model with 592 compounds for the identification of structural parameters related to their property as antibacterial agents against A. baumannii. QSPR mathematical validation (R2 = 70.27, RN = −0.008, a(R2) = 0.014, and δK = 0.021) and its prediction ability (Q2LMO= 67.89, Q2EXT = 67.75, a(Q2) = −0.068, δQ = 0.0, rm2¯ = 0.229, and Δrm2 = 0.522) were obtained with different statistical parameters; additional validation was done using three sets of external molecules (R2 = 72.89, 71.64 and 71.56). We used the QSPR model to perform a virtual screening on the BIOFACQUIM natural product database. From this screening, our model showed that molecules 32 to 35 and 54 to 68, isolated from different extracts of plants of the Ipomoea sp., are potential antibacterials against A. baumannii. Furthermore, biological assays showed that molecules 56 and 60 to 64 have a wide antibacterial activity against clinically isolated strains of A. baumannii, as well as other multidrug-resistant bacteria, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Finally, we propose 60 as a potential lead compound due to its broad-spectrum activity and its structural simplicity. Therefore, our QSPR model can be used as a tool for the investigation and search for new antibacterial compounds against A. baumannii.

The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9–108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of 2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease.

We present a comprehensive study of the velocity operator, $\hat{\boldsymbol{v}}=\frac{i}{\hbar} [\hat{H},\hat{\boldsymbol{r}}]\,$, when used in crystalline solids calculations. The velocity operator is key to the evaluation of a number of physical properties and its computation, both from a practical and fundamental perspective, has been a long-standing debate for decades. Our work summarizes the different approaches found in the literature, but never connected before in a comprehensive manner. In particular we show how one can compute the velocity matrix elements following two different routes. One where the commutator is explicitly used and another one where the commutator is avoided by relying on the Berry connection. We work out an expression in the latter scheme to compute velocity matrix elements, generalizing previous results. In addition, we show how this procedure avoids ambiguous mathematical steps and how to properly deal with the two popular gauge choices that coexist in the literature. As an illustration of all this, we present several examples using tight-binding models and local density functional theory calculations, in particular using Gaussian-type localized orbitals as basis sets. We show how the the velocity operator cannot be approximated, in general, by the $k$-gradient of the Bloch Hamiltonian matrix when a non-orthonormal basis set is used. Finally, we also compare with its real-space evaluation through the identification with the canonical momentum operator when possible. This comparison offers us, in addition, a glimpse of the importance of non-local corrections, which may invalidate the naive momentum-velocity correspondence.

The recent European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) 2020 consensus classification proposes criteria to define coronavirus 2019 (COVID-19)-associated invasive pulmonary aspergillosis (CAPA), including mycological evidence obtained via non-bronchoscopic lavage. Given the low specificity of radiological findings in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, this criterion makes it difficult to differentiate between invasive pulmonary aspergillosis (IPA) and colonization. This unicenter and retrospective study includes 240 patients with isolates of any Aspergillus species in any respiratory samples during a 20-month study (140 IPA and 100 colonization). Mortality was high in the IPA and colonization groups (37.1% and 34.0%, respectively; p = 0.61), especially in patients with SARS-CoV-2 infection, where mortality was higher in colonized patients (40.7% vs. 66.6.%; p: 0.021). Multivariate analysis confirmed the following variables to be independently associated with increased mortality: age > 65 years, acute or chronic renal failure at diagnosis, thrombocytopenia (Aspergillus spp. in respiratory samples, whether associated with disease criteria or not, is associated with high mortality, especially in patients with SARS-CoV-2 infection, and suggests an early initiation of treatment given its high mortality rate.

The role of SARS-CoV-2 as a direct cause in the cardiac lesions in patients with severe COVID-19 remains to be established. Our objective is to report the pathological findings in cardiac samples of 30 patients who died after a prolonged hospital stay due to Sars-Cov-2 infection. We performed macroscopic, histological and immunohistochemical analysis of the hearts of 30 patients; and detected Sars-Cov-2 RNA by RT-PCR in the cardiac tissue samples. The median age of our cohort was 69.5 years and 76.6% were male. The median time between symptoms onset and death was 36.5 days. The main comorbidities were arterial hypertension (13 patients, 43.3%), dyslipidemia (11 patients, 36.7%), cardiovascular conditions (8 patients, 26.7%), and obesity (8 patients, 26.7%). Cardiovascular conditions included ischemic cardiopathy in 4 patients (13.3%), hypertrophic cardiomyopathy in 2 patients (6.7%) and valve replacement and chronic heart failure in one patient each (3.3%). At autopsy, the most frequent histopathological findings were coronary artery atherosclerosis (8 patients, 26.7%), left ventricular hypertrophy (4 patients, 13.3%), chronic epicardial inflammation (3 patients, 10%) and adipose metaplasia (2 patients, 6.7%). Two patients showed focal myocarditis, one due to invasive aspergillosis. One additional patient showed senile amyloidosis. Sars-Cov-2 RNA was detected in the heart of only one out of 30 patients, who had the shortest disease evolution of the series (9 days). However, no relevant cardiac histological alterations were identified. In present series, cardiac pathology was only modest in most patients with severe COVID-19. At present, the contribution of a direct effect of SARS-CoV-2 on cardiac lesions remains to be established.

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