Autoimmune findings in patients with silicosis in Spain.

Background: Occupational exposure to silica is related to autoimmune diseases and features of autoimmunity, mainly autoantibodies. The study objectives were to estimate the prevalence of silicosis with associated autoimmune findings or diagnosed autoimmune diseases in Spain, and to assess the clinical and functional characteristics of affected patients. Methods: This is a multicentre prospective study in patients diagnosed with silicosis. Autoantibodies analysed were antinuclear antibodies, isotypes IgA, IgM and IgG, rheumatoid factor, anticyclic citrullinated peptide, anti-Scl70, anti-Ro, and anti-LA. Pulmonary function tests were performed. Results: Autoimmunity was assessed in 105 patients. Autoimmune findings were recorded in 29 (27%) patients, including antinuclear antibodies (n=21), anti-Ro (n=7), rheumatoid factor (n=5) and anti-Scl70 (n=3). Autoimmune disease was diagnosed in 16 (15%) patients, mainly rheumatoid arthritis (n=7) and systemic lupus erythematosus (n=4). Patients with silicosis and autoimmune findings had a lower mean time of exposure to silica and showed a trend toward lower values in pulmonary function tests. Conclusions: Autoimmune findings and diagnosis of autoimmune diseases were frequent in patients with silicosis in Spain.

Prognostic factors of progressive fibrotic hypersensitivity pneumonitis: a large, retrospective, multicentre, observational cohort study.

Background: Fibrotic hypersensitivity pneumonitis (fHP) is an immune-mediated interstitial lung disease caused by sensitisation to chronic allergen inhalation. This study aimed to determine prognostic indicators of progression and mortality in fHP. Methods: This was a retrospective, multicentre, observational, cross-sectional cohort study of consecutive patients diagnosed with fHP from 1 January 2012 to 31 December 2021. Multivariate Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals for predictors of progression and survival. Results: A total of 403 patients were diagnosed with fHP: median (interquartile range) age 66.5 (14.0) years, 51.9% females and 55.1% never-smokers. The cause of fHP was mainly fungal (39.7%) or avian (41.4%). Lung biopsy was performed in 269 cases (66.7%). In the whole cohort the variables that were related to mortality or lung transplant were older age (HR 1.08; p<0.001), percentage predicted forced vital capacity (HR 0.96; p=0.001), lymphocytosis in bronchoalveolar lavage (BAL) (HR 0.93; p=0.001), presence of acute exacerbation during follow-up (HR 3.04; p=0.001) and GAP (gender, age and lung physiology) index (HR 1.96; p<0.01). In the group of biopsied patients, the presence of fibroblastic foci at biopsy (HR 8.39; p<0.001) stands out in multivariate Cox regression analyses as a highly significant predictor for increased mortality or lung transplant. GAP index (HR 1.26; p=0.009), lymphocytosis in BAL (HR 0.97; p=0.018) and age (HR 1.03; p=0.018) are also predictors of progression. Conclusions: The study identified several prognostic factors for progression and/or survival in fHP. The presence of fibroblastic foci at biopsy was a consistent predictor for increased mortality and the presence of lymphocytosis in BAL was inversely related to mortality.

Engineering oncogene-targeted anisamide-functionalized pBAE nanoparticles as efficient lung cancer antisense therapies.

Non-small cell lung cancer (NSCLC) is one of the leading causes of worldwide death, mainly due to the lack of efficient and safe therapies. Currently, NSCLC standard of care for consist on the use of traditional chemotherapeutics, non-selectively distributed through the whole body, thus causing severe side effects while not achieving high efficacy outcomes. Consequently, the need of novel therapies, targeted to modify specific subcellular routes aberrantly expressed only in tumor cells is still urgent. In this context, the delivery of siRNAs that can know-down overexpressed oncogenes, such as mTOR, could become the promised targeted therapy. However, siRNA effective delivery remains a challenge due to its compromised stability in biological fluids and its inability to cross biological and plasmatic membranes. Therefore, polymeric nanoparticles that efficiently encapsulate siRNAs and are selectively targeted to tumor cells could play a pivotal role. Accordingly, we demonstrate in this work that oligopeptide end-modified poly(beta aminoester) (OM-pBAE) polymers can efficiently complex siRNA in small nanometric particles using very low polymer amounts, protecting siRNA from nucleases attack. These nanoparticles are stable in the presence of serum, advantageous fact in terms of in vivo use. We also demonstrated that they efficiently transfect cells in vitro, in the presence of serum and are able to knock down target gene expression. Moreover, we demonstrated their antitumor efficacy by encapsulating mTOR siRNA, as a model antisense therapy, which showed specific lung tumor cell growth inhibition in vitro and in vivo. Finally, through the addition of anisamide functionalization to the surface of the nanoparticles, we proved that they become selective to lung tumor cells, while not affecting healthy cells. Therefore, our results are a first step in the discovery of a tumor cell-targeted efficient silencing nanotherapy for NSCLC patients survival improvement.

Serum exosome inflamma-miRs are surrogate biomarkers for asthma phenotype and severity.

BACKGROUND: Asthma is a heterogeneous disease with several phenotypes, endotypes and severity degrees, in which different T-cell subpopulations are involved. These cells express specific miRNAs (i.e. inflamma-miRs) that can be released to serum in exosomes after activation and be used as biomarkers of underlying inflammation. Thus, we aim to evaluate specific T-cell miRNA signatures in serum exosomes from different subgroups of asthmatic patients. METHODS: Samples from healthy donors (N = 30) and patients (N = 119) with different asthma endotypes (T2high -Atopic/T2high -Non-atopic/T2low ) and severity degrees (mild/MA and moderate-severe/MSA) were used. Demographic, clinical, haematological and biochemical characteristics were collected. Twelve miRNAs previously associated with different Th subsets were preselected and their levels in serum exosome samples were measured using RTqPCR. RESULTS: We detected five miRNAs with high confidence in serum exosomes: miR-16-5p, miR-21-5p, miR-126-3p, miR146a-5p and miR-215-5p. All of them, except miR-16-5p were upregulated in MSA patients compared to MA. A logistic regression model including each of these miRNAs was created to discriminate both conditions, rendering a ROC curve AUC of 0.896 (0.830-0.961). miR-21-5p and miR-126-3p, both involved in Th1/Th2 differentiation, were specifically augmented in T2high -Atopic patients. Of note, all these changes were found in samples collected in autumn. On the contrary, IL-6high patients with MSA, which were more obese, older, with higher neutrophil and basophil counts and TNF levels, displayed a decrease of miR-21-5p, miR-126-3p and miR-146a-5p. CONCLUSION: Immune-related miRNAs, including miR-21-5p, miR-126-3p, miR-146a-5p and miR-215-5p, can be used as clinically relevant non-invasive biomarkers of the phenotype/endotype and severity of asthma.

Caracterización de pacientes con enfermedad pulmonar obstructiva crónica en el Hospital General Provincial de Sancti Spíritus

Introducción: La Organización Mundial de la Salud, estima la prevalencia de la enfermedad pulmonar obstructiva crónica en la población general en torno al 1 % y crece del 8-10 % en los adultos mayores de 40 años. Es la tercera causa de muerte a escala mundial y quinta causa de discapacidad para 2020. Objetivo: Describir las características de los pacientes con enfermedad pulmonar obstructiva crónica ingresados en el Hospital General Provincial Camilo Cienfuegos de Sancti Spíritus durante el período 2019-2022. Métodos: Se realizó un estudio descriptivo, retrospectivo, de corte trasversal, que incluyó a todos los pacientes que fueron ingresados en el Servicio de Medicina Interna. La muestra no probabilística la integraron 746 pacientes adultos con enfermedad pulmonar obstructiva crónica, que fueron atendidos. Resultados: Existió predominio del grupo de 60 años y más en un 43,69 %, sobresalió el sexo masculino representado por el 56,7 %. El hábito tabáquico constituyó la principal causa de enfermedad pulmonar obstructiva crónica en el 67,29 % de los pacientes, el grado de obstrucción del flujo aéreo se comportó con mayor frecuencia la clasificación moderada representada por casi la mitad de los pacientes (47,31 %), la infección respiratoria fue la de mayor prevalencia con 52,68 %, seguido de un 42,22 % de complicaciones cardiovasculares y según la evolución de la enfermedad, en los pacientes adultos atendidos el 51,47 % presentó una evolución desfavorable. Conclusiones: Se evidenciaron formas moderadas y severas de presentación de la enfermedad en la mayoría de los casos, siendo las complicaciones respiratorias y cardiovasculares preponderantes.

Introduction: The World Health Organization (WHO) estimates the prevalence of chronic obstructive pulmonary disease (COPD) in the general population at around 1%, and it grows to 8-10% in adults older than 40 years. COPD is the third cause of death worldwide and the fifth cause of disability by 2020. Objective: To describe the characteristics of patients with chronic obstructive pulmonary disease admitted to the Camilo Cienfuegos Provincial General Hospital of Sancti Spíritus during the period 2019-2022. Methods: A descriptive, retrospective, cross-sectional study was carried out, which included all the patients who were admitted to the Internal Medicine Service. The sample studied was the 746 adult patients with chronic obstructive pulmonary disease, who were attended. Results: There was a predominance of the group of 60 years and over in 43.69%, the male sex stood out, representing 56.70%, according to etiology, smoking was the main cause of chronic obstructive pulmonary disease in 67.29% of the patients, the degree of air flow obstruction behaved more frequently, the moderate classification represented by almost half of the patients (47.31%), respiratory infection was the most prevalent with 52.68%, followed by 42.22 % of cardiovascular complications and according to the evolution of this disease in the adult patients treated, 51.47% presented an unfavorable evolution. Conclusions: Moderate and severe forms of presentation of the disease were evidenced in most cases, with respiratory and cardiovascular complications being preponderant.

Efficacy of mepolizumab in usual clinical practice and characteristics of responders.

BACKGROUND: Severe eosinophilic asthma is a high-burden disease. Mepolizumab has been effective in several randomized clinical trials. However, such success might not be applicable to patients treated in usual clinical practice. The objectives of this article are to evaluate the efficacy of mepolizumab in severe uncontrolled eosinophilic asthma under usual clinical practice, and to determine characteristics associated with the response to this treatment. METHODS: We have conducted a retrospective, multicentre study, including all adult patients with severe uncontrolled eosinophilic asthma in Galicia, Spain, on whom mepolizumab treatment was started before June 2020, at least 6 months before the time of inclusion, and had received at least one dose of the drug. Patient characteristics, clinical data, respiratory function and comorbidities were collected at baseline and at the 6-month-follow-up. Responders and super-responders were defined according to clinical response and requirement of systemic corticosteroids. RESULTS: 122 patients (mean age 58 years old) were included. In the follow-up treatment 6 months later, 75.4% of the patients were well-controlled, displaying a significant reduction in blood eosinophil counts (p < 0.001), hospital admissions and disease exacerbations (p < 0.001), and had their systemic glucocorticosteroid dose significantly reduced (p < 0.001). The inhaled corticosteroid dose was also lowered (p < 0.01) after 6 months of treatment. Around two-thirds had a clinically significant increase in FEV1, 95% of the patients were considered responders and 43% super-responders. CONCLUSION: In routine clinical practice, mepolizumab is effective in patients with severe eosinophilic asthma and it has a good safety profile.

Synthesis and Characterization of mRNA-Loaded Poly(Beta Aminoesters) Nanoparticles for Vaccination Purposes.

Vaccination has been one of the major successes of modern society and is indispensable in controlling and preventing disease. Traditional vaccines were composed of entire or fractions of the infectious agent. However, challenges remain, and new vaccine technologies are mandatory. In this context, the use of mRNA for immunizing purposes has shown an enhanced performance, as demonstrated by the speedy approval of two mRNA vaccines preventing SARS-CoV-2 infection. Beyond success in preventing viral infections, mRNA vaccines can also be used for therapeutic cancer applications. Nevertheless, the instability of mRNA and its fast clearance from the body due to the presence of nucleases makes its naked delivery not possible. In this context, nanomedicines, and specifically polymeric nanoparticles, are critical mRNA delivery systems. Thus, the aim of this article is to describe the protocol for the formulation and test of an mRNA vaccine candidate based on the proprietary polymeric nanoparticles. The synthesis and chemical characterization of the poly(beta aminoesters) polymers used, their complexation with mRNA to form nanoparticles, and their lyophilization methodology will be discussed here. This is a crucial step for decreasing storage and distribution costs. Finally, the required tests to demonstrate their capacity to in vitro transfect and mature model dendritic cells will be indicated. This protocol will benefit the scientific community working on vaccination because of its high versatility that enables these vaccines to prevent or cure a wide variety of diseases.

Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines.

Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.

Nanomedicine in Non-Small Cell Lung Cancer: From Conventional Treatments to Immunotherapy.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related mortality. The heterogeneous nature of this disease hinders its diagnosis and treatment, requiring continuous advances in research aiming to understand its intricate nature. Consequently, the retrospective analysis of conventional therapies has allowed the introduction of novel tools provided by nanotechnology, leading to considerable improvements in clinical outcomes. Furthermore, the development of novel immunotherapies based on the recently understood interaction of the immune system with the tumor highlights the real possibility of definitively treating NSCLC from its early stages. Novel engineering approaches in nanomedicine will enable to overcome the intrinsic limits of conventional and emerging therapies regarding off-site cytotoxicity, specificity, resistance mechanisms, and administration issues. The convergence point of these therapies with nanotechnology lays the foundation for achieving currently unmet needs.

Colonización nasofaríngea por serotipos de Streptococcus pneumoniae en niños uruguayos antes y después de la introducción de las vacunas antineumocóccicas conjugadas / Nasopharyngeal colonization from Streptococcus pneumoniae serotypes in Uruguayan children before and after pneumococcal conjugate vaccines / Colonização nasofaríngea por sorotipos de Streptococcus pneumoniae em crianças uruguaias antes e após da introdução de vacinas pneumocócicas conjugadas

Resumen: Las vacunas conjugadas neumocóccicas (VCN) son efectivas para el control de las infecciones severas en niños y también limitan la colonización nasofaríngea por los serotipos que integran sus fórmulas. En Uruguay, no se dispone de publicaciones recientes sobre los serotipos albergados en el reservorio nasofaríngeo de los niños, ni antes ni luego de la introducción de las VCN. Con el objetivo de caracterizar la colonización nasofaríngea de niños menores de 2 años y describir los serotipos de S. pneumoniae identificados antes y después de la introducción de las vacunas conjugadas antineumocóccicas en el certificado esquema de vacunación (CEV) de Uruguay, se llevó a cabo un estudio descriptivo, retrospectivo, incluyendo tres períodos de tiempo: años 2002- 2003 y 2014-2015 en Paysandú, y 2012-2013 en Montevideo. Los aislamientos de S. pneumoniae se realizaron en laboratorios locales y la serotipificación por "quellung" se efectuó en el Departamento de Laboratorios de Salud Pública. Se procesaron 831 muestras, con 54,8% de recuperación de neumococos (n=456), de los cuales 223 fueron tipificados. El estudio previo a la vacunación mostró portación de serotipos invasores, con predominio de los serotipos 6A, 6B, 14 y 19F, todos incluidos en la vacuna 13-valente. En los niños de la policlínica de HIV, la colonización por neumococos invasores fue mucho menor, y el otro estudio, también posvacunación, evidenció la casi desaparición de cepas invasoras (6/93), con predominio de serotipos poco habituales, lo que constituyó un llamado de atención para instrumentar una vigilancia que monitorice la dinámica de la colonización infantil.

Summary: Pneumococcal conjugate vaccines (PCV) are effective against children's severe infections and they also constrain nasopharyngeal colonization due to the serotypes in their formulas. There are no recent publications in Uruguay regarding serotypes hosted in the children's nasopharyngeal reservoir, either from before or after the introduction of the PCV. With the purpose of characterizing nasopharyngeal colonization of children under 2 years of age and describing the S. pneumoniae serotypes before and after the pneumococcal conjugate vaccines in the Uruguayan National Vaccination Report, we carried out a descriptive retrospective study including three periods: 2002- 2003 and 2014-2015 in Paysandú, and 2012-2013 in Montevideo. S. pneumoniae was isolated in local laboratories and the "quellung" serotypification was carried out in the Laboratories of the Public Health Department. We processed 831 samples and recovered 54.8% pneumococci (n=456), of which 223 were typified. Prior to the vaccination, the study showed invasive serotype carriage, mainly of the 6A, 6B, 14 and 19F serotypes, all included in the 13-valent vaccine. At the HIV clinic, colonization from invasive pneumococci was much lower and the post vaccination study showed the almost complete disappearance of the invasive strains (6/93), mainly of the less common serotypes, which called the attention towards the increase of vigilance towards the monitoring of children colonization dynamics.

Resumo: As Vacinas Pneumocócicas Conjugadas (VPC) são eficazes contra infecções graves em crianças e também restringem a colonização nasofaríngea, devido aos sorotipos utilizados em suas fórmulas. Não há publicações recentes no Uruguai relativas aos sorotipos que incluem reservatório nasofaringeos nas crianças, nem de antes ou depois das vacinas VPN. Com o objetivo de caracterizar a colonização nasofaríngea de crianças menores de 2 anos de idade e descrevendo os sorotipos S. pneumoniae antes e depois das vacinas antipneumocócicas conjugadas no Relatório Nacional de Vacinação do Uruguai, realizou-se um estudo retrospectivo descritivo, incluindo três períodos: 2002- 2003 e 2014-2015 em Paysandú e 2012-2013 em Montevideo. S. pneumoniae foi isolada em laboratórios locais e a soro tipificação "quellung" foi realizada nos Laboratórios do Departamento de Saúde Pública. Foram processadas 831 amostras e recuperado 54,8% de pneumococo (n = 456), dos quais 223 foram tipificados. Antes da vacinação, o estudo mostrou transporte de sorotipos invasores, principalmente dos sorotipos 6A, 6B, 14, 19F, todos incluídos na vacina 13-valente. Na clínica de HIV, a colonização invasiva de pneumococos foi muito menor, e o estudo pós-vacinação mostrou o desaparecimento quase total das cepas invasivas (6/93), principalmente dos sorotipos menos comuns, o que sugere a necessidade de aumentar a vigilância no monitoramento da dinâmica de colonização de crianças.

Toxicidad pulmonar por riluzole / Pulmonary toxicity by riluzole

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Ampollas, úlceras y costras en paciente con infección VIH / Blisters, scars and healing crusts in a HIV infected patient

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Infiltración pulmonar linfoproliferativa: una opción diagnóstica a tener presente ante infiltrados pulmonares en un paciente con leucemia linfoide crónica / Lymphoproliferative pulmonary infiltration: A diagnosis to keep in mind in pulmonary infiltrates in patient with chronic lymphocytic leukemia

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Estudio NonaSantfeliu. Valoración inicial y 10 años de seguimiento / The NonaSantfeliu study. Baseline assessment and ten years of follow-up

Se presenta una revisión de los diversos estudios que forman parte de la valoración global inicial y de los estudios realizados durante 10 años de seguimiento de una cohorte de personas nonagenarias: el estudio NonaSantfeliu. Se trata de un estudio poblacional de 186 personas, 76,5% mujeres, con una edad media al inicio del estudio de 93,06 años, una cuarta parte de ellas (26%) institucionalizadas. La media del índice de Barthel basal fue de 60,8 y del miniexamen cognitivo de Lobo de 21. Los nonagenarios varones y con baja comorbilidad tenían un envejecimiento más satisfactorio que las mujeres con alta comorbilidad cuantificada con el índice de Charlson. Como era previsible la tasa de supervivencia a los 10 años de seguimiento era muy baja, así el 95,6% de los habitantes habían fallecido. Esto representaba una tasa anual de mortalidad del 9,5%. Un denominador común en la evaluación en todos los diferentes cortes anuales es el de la mayor importancia de factores asociados a mortalidad relacionados con la valoración geriátrica, como función, cognición-demencia, y de la comorbilidad acumulada y la polifarmacia frente a factores de riesgo más clásicos descritos en grupos poblacionales más jóvenes (AU)

NonaSantfeliu study: A review is presented of the studies that are part of the initial overall assessment and the studies performed during the 10 years of follow-up of a cohort of nonagenarians. It is a population-based study of 186 subjects, 76.5% women, mean age at baseline of 93.06 years, a quarter (26%) being institutionalized. The mean of baseline Barthel index was 60.8, and the mean for the Lobo's cognitive minimental was 21. Nonagenarian males with low comorbidity had more successful aging criteria than women with high comorbidity quantified with the Charlson Index. The survival rate at 10 years follow-up was very low, and 95.6% of the population had died. This represented an annual mortality rate of 9.5%. A common denominator on assessing all different annual cuts, is that the most important factors associated with mortality are those related to geriatric assessment, such as a function, cognition, dementia, and cumulative comorbidity and multiple medications, compared to more traditional risk factors described in younger populations (AU)

[The NonaSantfeliu study. Baseline assessment and ten years of follow-up]. / Estudio NonaSantfeliu. Valoración inicial y 10 años de seguimiento.

NonaSantfeliu study: A review is presented of the studies that are part of the initial overall assessment and the studies performed during the 10 years of follow-up of a cohort of nonagenarians. It is a population-based study of 186 subjects, 76.5% women, mean age at baseline of 93.06 years, a quarter (26%) being institutionalized. The mean of baseline Barthel index was 60.8, and the mean for the Lobo's cognitive minimental was 21. Nonagenarian males with low comorbidity had more successful aging criteria than women with high comorbidity quantified with the Charlson Index. The survival rate at 10 years follow-up was very low, and 95.6% of the population had died. This represented an annual mortality rate of 9.5%. A common denominator on assessing all different annual cuts, is that the most important factors associated with mortality are those related to geriatric assessment, such as a function, cognition, dementia, and cumulative comorbidity and multiple medications, compared to more traditional risk factors described in younger populations.