Antiviral treatment for SARS-CoV-2 infection in the current situation: a position paper of the Spanish Society of Emergency Medicine (SEMES). / Posicionamiento de la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) ante el tratamiento antiviral frente al SARS-CoV-2 en la situación epidemiológica actual.

SUMMARY: COVID-19 continues to pose a significant threat: mortality stands at nearly twice that of influenza, and the incidence rate is growing as the population's vaccination rate decreases, particularly in Spain and other areas of Europe. Given this situation, it is vitally important know whether medical protocols are consistent and appropriately implemented by health care staff in the interest of preventing possible inefficiency or inequity. Physicians from hospital emergency departments met to study their hospitals' usual clinical practices for managing SARS-CoV-2 infection and to determine their expert opinions on the use of antiviral agents. The participating physicians then reached consensus on evidencebased recommendations for strategies that would optimize emergency treatment.

RESUMEN: Actualmente, la COVID-19 sigue representando una amenaza significativa, con una mortalidad cercana al doble de la ocasionada por la gripe y con una incidencia variable debido a una disminución en la tasa de vacunación de la población, especialmente en el contexto europeo y español. Ante este panorama, es de vital importancia comprobar que los protocolos médicos están consolidados y son debidamente implementados por los profesionales sanitarios, con la finalidad de evitar posibles ineficiencias o inequidades. A través de reuniones con profesionales de urgencias se han observado las prácticas clínicas habituales en los servicios de urgencias hospitalarios para pacientes con infección por SARS-CoV-2, con la finalidad de comprender la perspectiva de estos profesionales acerca del uso de antivirales y, tras un consenso de expertos basados en la evidencia actual, se han generado estas de recomendaciones para poder enfocar estrategias que optimicen el tratamiento de los pacientes en estos servicios.

Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.

BACKGROUND: In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. RESULTS: In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. CONCLUSIONS: Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

Imaging mass cytometry analysis of Becker muscular dystrophy muscle samples reveals different stages of muscle degeneration.

Becker muscular dystrophy (BMD) is characterised by fiber loss and expansion of fibrotic and adipose tissue. Several cells interact locally in what is known as the degenerative niche. We analysed muscle biopsies of controls and BMD patients at early, moderate and advanced stages of progression using Hyperion imaging mass cytometry (IMC) by labelling single sections with 17 markers identifying different components of the muscle. We developed a software for analysing IMC images and studied changes in the muscle composition and spatial correlations between markers across disease progression. We found a strong correlation between collagen-I and the area of stroma, collagen-VI, adipose tissue, and M2-macrophages number. There was a negative correlation between the area of collagen-I and the number of satellite cells (SCs), fibres and blood vessels. The comparison between fibrotic and non-fibrotic areas allowed to study the disease process in detail. We found structural differences among non-fibrotic areas from control and patients, being these latter characterized by increase in CTGF and in M2-macrophages and decrease in fibers and blood vessels. IMC enables to study of changes in tissue structure along disease progression, spatio-temporal correlations and opening the door to better understand new potential pathogenic pathways in human samples.

Sex- and age-related patterns in the use of analgesics in older patients in the emergency department.

BACKGROUND: Treatment of acute pain in older patients is a common challenge faced in emergency departments (EDs). Despite many studies that have investigated chronic analgesic use in the elderly, data on patterns of acute use, especially in EDs, of analgesics according to patient characteristics is scarce. OBJECTIVE: To investigate sex- and age-related patterns of analgesic use in the Spanish EDs and determine differences in age-related patterns according to patient sex. DESIGN: A secondary analysis of the Emergency Department and Elderly Needs (EDEN) multipurpose cohort. SETTING: Fifty-two Spanish EDs (17% of Spanish EDs covering 25% of Spanish population). PARTICIPANTS: All patients' ≥65 years attending ED during 1 week (April 1-7, 2019). Patient characteristics recorded included age, sex, chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and opiates, comorbidity, dependence, dementia, depression, ability to walk and previous falls. Analgesics used in the ED were categorized in three groups: non-NSAID non-opioids (mainly paracetamol and metamizole, PM), NSAIDs, and opiates. OUTCOME MEASURES: Frequency of analgesic use was quantified, and the relationship between sex and age and analgesic use (in general and for each analgesic group) was assessed by unadjusted and adjusted logistic regression and restricted cubic spline models. Interaction between sex and age was explored. MAIN RESULTS: We included 24 573 patients, and 6678 (27.2%) received analgesics in the ED: 5551 (22.6%) PM, 1661 (6.8%) NSAIDs and 937 (3.8%) opiates (1312 received combinations). Analgesics were more frequently used in women (adjusted OR = 1.076, 95%CI = 1.014-1.142), as well as with NSAID (1.205, 1.083-1.341). Analgesic use increased with age, increasing PM and decreasing NSAIDs use. Opiate use remained quite constant across age and sex. Interaction of sex with age was present for the use of analgesics in general ( P  = 0.006), for PM ( P  < 0.001) and for opiates ( P  = 0.033), with higher use of all these analgesics in women. CONCLUSION: Use of analgesics in older individuals in EDs is mildly augmented in women and increases with age, with PM use increasing and NSAIDs decreasing with age. Conversely, opiate use is quite constant according to sex and age. Age-related patterns differ according to sex, with age-related curves of women showing higher probabilities than those of men to receive any analgesic, PM or opiates.

Influence of income on in-hospital mortality in older adults during the first wave of the COVID-19 pandemic: results from the EDEN-33 study. / Influencia de la renta económica en la mortalidad intrahospitalaria de las personas mayores durante la primera ola de la pandemia por COVID-19: resultados del estudio EDEN-33.

OBJECTIVES: To determine whether income was associated with unexpected in-hospital mortality in older patients treated in Spanish public health system hospital emergency departments. MATERIAL AND METHODS: Fifty-one public health system hospital emergency departments in Spain voluntarily participated in the study. Together the hospitals covered 25% of the population aged 65 years or older included in all patient registers during a week in the pre-pandemic period (April 1-7, 2019) and a week during the COVID-19 pandemic (March 30 to April 5, 2020). We estimated a patient's gross income as the amount published for the postal code of the patient's address. We then calculated the standardized gross income (SGI) by dividing the patient's estimated income by the mean for the corresponding territory (Spanish autonomous community). The existence and strength of an association between the SGI and in-hospital mortality was evaluated by means of restricted cubic spline (RCS) curves adjusted for 10 patient characteristics at baseline. Odds ratios (ORs) for each income level were expressed in relation to a reference SGI of 1 (the mean income for the corresponding autonomous community). We compared the COVID-19 and pre-pandemic periods by means of first-order interactions. RESULTS: Of the 35 280 patients attended in the 2 periods, gross income could be ascertained for 21 180 (60%), 15437 in the pre-pandemic period and 5746 during the COVID-19 period. SGIs were slightly higher for patients included before the pandemic (1.006 vs 0.994; P = .012). In-hospital mortality was 5.6% overall and higher during the pandemic (2.8% pre-pandemic vs 13.1% during COVID-19; P .001). The adjusted RCS curves showed that associations between income and mortality differed between the 2 periods (interaction P = .004). Whereas there were no significant income-influenced differences in mortality before the pandemic, mortality increased during the pandemic in the lowest-income population (SGI 0.5 OR, 1.82; 95% CI, 1.32-3.37) and in higher-income populations (SGI 1.5 OR, 1.32; 95% CI, 1.04-1.68, and SGI 2 OR, 1.92; 95% CI, 1.14-3.23). We found no significant differences between patients with COVID-19 and those with other diagnoses (interaction P = .667). CONCLUSION: The gross income of patients attended in Spanish public health system hospital emergency departments, estimated according to a patient's address and postal code, was associated with in-hospital mortality, which was higher for patients with the lowest and 2 higher income levels. The reasons for these associations might be different for each income level and should be investigated in the future.

OBJETIVO: Determinar si el nivel económico durante la primera ola pandémica tuvo una influencia diferente a la esperable en la mortalidad intrahospitalaria de los pacientes mayores atendidos en los servicios de urgencias (SU) de los hospitales públicos españoles. METODO: Cincuenta y un SU públicos españoles que participaron voluntariamente y que dan cobertura al 25% de la población incluyeron todos los registros de pacientes de edad 65 años atendidos durante una semana del periodo preCOVID (1-4-2019 a 7-4-2019) y una semana del periodo COVID (30-3-2020 a 5-4-2020). Se identificó la renta bruta (RB) asignada al código postal de residencia de cada paciente y se calculó la RB normalizada (RBN) dividiendo aquella por la RB media de su comunidad autónoma. La existencia y fuerza de la relación entre RBN y mortalidad intrahospitalaria se determinó mediante curvas spline cúbicas restringidas (SCR) ajustadas por 10 características basales del paciente. Las OR para cada situación económica se expresó en relación con una RBN de 1 (referencia, renta correspondiente a la media de la comunidad autónoma). La comparación entre periodo COVID y no COVID se realizó mediante el estudio de interacción de primer grado. RESULTADOS: De los 35.280 registros de pacientes atendidos en ambos periodos, se disponía de la RB en 21.180 (60%): 15.437 del periodo preCOVID y 5.746 del periodo COVID. La RBN de los pacientes incluidos fue discretamente superior en el periodo preCOVID (1,006 versus 0,994; p = 0,012). La mortalidad intrahospitalaria fue del 5,6%, y fue superior durante el periodo COVID (2,8% versus 13,1%; p 0,001). Las curvas SCR ajustadas mostraron una asociación entre nivel económico y mortalidad diferente entre ambos periodos (p interacción = 0,004): en el periodo preCOVID no hubo diferencias significativas de mortalidad en función de la RBN, mientras que en el periodo COVID la mortalidad se incrementó en rentas bajas (OR = 1,82, IC 95% = 1,32-3,37 para RBN de 0,5) y en rentas altas (OR = 1,32, IC 95% = 1,04-1,68 y OR = 1,92, IC 95% = 1,14-3,23 para RBN de 1,5 y 2, respectivamente), sin diferencias significativas entre pacientes con COVID y con otros diagnósticos (p interacción = 0,667). CONCLUSIONES: Durante la primera ola de la pandemia COVID, la RB asignada al código postal de residencia de los pacientes atendidos en los SU públicos españoles se asoció con la mortalidad intrahospitalaria, que aumentó en pacientes de rentas bajas y altas. Las razones de estas asociaciones pueden ser distintas para cada segmento económico y deben ser investigadas en el fututo.

Influencia de la renta económica en la mortalidad intrahospitalaria de las personas mayores durante la primera ola de la pandemia por COVID-19: resultados del estudio EDEN-33 / Influence of income on in-hospital mortality in older adults during the first wave of the COVID-19 pandemic: results from the EDEN-33 study

Objetivo: Determinar si el nivel económico durante la primera ola pandémica tuvo una influencia diferente a la esperable en la mortalidad intrahospitalaria de los pacientes mayores atendidos en los servicios de urgencias (SU) de los hospitales públicos españoles. Método: Cincuenta y un SU públicos españoles que participaron voluntariamente y que dan cobertura al 25% de la población incluyeron todos los registros de pacientes de edad $ 65 años atendidos durante una semana del periodo preCOVID (1-4-2019 a 7-4-2019) y una semana del periodo COVID (30-3-2020 a 5-4-2020). Se identificó la renta bruta (RB) asignada al código postal de residencia de cada paciente y se calculó la RB normalizada (RBN) dividiendo aquella por la RB media de su comunidad autónoma. La existencia y fuerza de la relación entre RBN y mortalidad intrahospitalaria se determinó mediante curvas spline cúbicas restringidas (SCR) ajustadas por 10 características basales del paciente. Las OR para cada situación económica se expresó en relación con una RBN de 1 (referencia, renta correspondiente a la media de la comunidad autónoma). La comparación entre periodo COVID y no COVID se realizó mediante el estudio de interacción de primer grado. (AU)

Objective: To determine whether income was associated with unexpected in-hospital mortality in older patients treated in Spanish public health system hospital emergency departments. Methods: Fifty-one public health system hospital emergency departments in Spain voluntarily participated in the study. Together the hospitals covered 25% of the population aged 65 years or older included in all patient registers during a week in the pre-pandemic period (April 1-7, 2019) and a week during the COVID-19 pandemic (March 30 to April 5, 2020). We estimated a patient’s gross income as the amount published for the postal code of the patient’s address. We then calculated the standardized gross income (SGI) by dividing the patient’s estimated income by the mean for the corresponding territory (Spanish autonomous community). The existence and strength of an association between the SGI and in-hospital mortality was evaluated by means of restricted cubic spline (RCS) curves adjusted for 10 patient characteristics at baseline. Odds ratios (ORs) for each income level were expressed in relation to a reference SGI of 1 (the mean income for the corresponding autonomous community). We compared the COVID-19 and pre-pandemic periods by means of first-order interactions. (AU)

Decoding the transcriptome of Duchenne muscular dystrophy to the single nuclei level reveals clinical-genetic correlations.

Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. The cellular and molecular consequences of the lack of dystrophin in humans are only partially known, which is crucial for the development of new therapies aiming to slow or stop the progression of the disease. Here we have analyzed quadriceps muscle biopsies of seven DMD patients aged 2 to 4 years old and five age and gender matched controls using single nuclei RNA sequencing (snRNAseq) and correlated the results obtained with clinical data. SnRNAseq identified significant differences in the proportion of cell population present in the muscle samples, including an increase in the number of regenerative fibers, satellite cells, and fibro-adipogenic progenitor cells (FAPs) and a decrease in the number of slow fibers and smooth muscle cells. Muscle samples from the younger patients with stable mild weakness were characterized by an increase in regenerative fibers, while older patients with moderate and progressive weakness were characterized by loss of muscle fibers and an increase in FAPs. An analysis of the gene expression profile in muscle fibers identified a strong regenerative signature in DMD samples characterized by the upregulation of genes involved in myogenesis and muscle hypertrophy. In the case of FAPs, we observed upregulation of genes involved in the extracellular matrix regeneration but also several signaling pathways. Indeed, further analysis of the potential intercellular communication profile showed a dysregulation of the communication profile in DMD samples identifying FAPs as a key regulator of cell signaling in DMD muscle samples. In conclusion, our study has identified significant differences at the cellular and molecular levels in the different cell populations present in skeletal muscle samples of patients with DMD compared to controls.

Endoscopic Vacuum Therapy for Upper Gastrointestinal Leaks and Perforations: Analysis From a Multicenter Spanish Registry.

INTRODUCTION: Endoscopic vacuum therapy (EVT) is a novel technique for closing upper gastrointestinal (UGI) defects. Available literature includes single-center retrospective cohort studies with small sample sizes. Furthermore, evidence about factors associated with EVT failure is scarce. We aimed to assess the efficacy and safety of EVT for the resolution of UGI defects in a multicenter study and to investigate the factors associated with EVT failure and in-hospital mortality. METHODS: This is a prospective cohort study in which consecutive EVT procedures for the treatment of UGI defects from 19 Spanish hospitals were recorded in the national registry between November 2018 and March 2022. RESULTS: We included 102 patients: 89 with anastomotic leaks and 13 with perforations. Closure of the defect was achieved in 84 cases (82%). A total of 6 patients (5.9%) had adverse events related to the EVT. The in-hospital mortality rate was 12.7%. A total of 6 patients (5.9%) died because of EVT failure and 1 case (0.9%) due to a fatal adverse event. Time from diagnosis of the defect to initiation of EVT was the only independent predictor for EVT failure (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05, P = 0.005). EVT failure (OR 24.5, 95% CI 4.5-133, P = 0.001) and development of pneumonia after EVT (OR 246.97, 95% CI 11.15-5,472.58, P = 0.0001) were independent predictors of in-hospital mortality. DISCUSSION: EVT is safe and effective in cases of anastomotic leak and perforations of the upper digestive tract. The early use of EVT improves the efficacy of this technique.

Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy.

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice.

Sarcoglycanopathies are a group of recessive limb-girdle muscular dystrophies, characterized by progressive muscle weakness. Sarcoglycan deficiency produces instability of the sarcolemma during muscle contraction, leading to continuous muscle fiber injury eventually producing fiber loss and replacement by fibro-adipose tissue. Therapeutic strategies aiming to reduce fibro-adipose expansion could be effective in muscular dystrophies. We report the positive effect of nintedanib in a murine model of alpha-sarcoglycanopathy. We treated 14 Sgca-/- mice, six weeks old, with nintedanib 50 mg/kg every 12 h for 10 weeks and compared muscle function and histology with 14 Sgca-/- mice treated with vehicle and six wild-type littermate mice. Muscle function was assessed using a treadmill and grip strength. A cardiac evaluation was performed by echocardiography and histological study. Structural analysis of the muscles, including a detailed study of the fibrotic and inflammatory processes, was performed using conventional staining and immunofluorescence. In addition, proteomics and transcriptomics studies were carried out. Nintedanib was well tolerated by the animals treated, although we observed weight loss. Sgca-/- mice treated with nintedanib covered a longer distance on the treadmill, compared with non-treated Sgca-/- mice, and showed higher strength in the grip test. Moreover, nintedanib improved the muscle architecture of treated mice, reducing the degenerative area and the fibrotic reaction that was associated with a reversion of the cytokine expression profile. Nintedanib improved muscle function and muscle architecture by reducing muscle fibrosis and degeneration and reverting the chronic inflammatory environment suggesting that it could be a useful therapy for patients with alpha-sarcoglycanopathy.

BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients.

Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT-mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes led to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT-mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease.

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. FINDINGS: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. INTERPRETATION: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. FUNDING: The Instituto de Salud Carlos III.

Corrigendum to 'A multicenter analysis of the role of prophylactic transfusion of blood products in patients with cirrhosis and esophageal varices undergoing endoscopic band ligation' [JHEP Reports 6 (2021)].

[This corrects the article DOI: 10.1016/j.jhepr.2021.100363.].

Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF / Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study

Objetivo. El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). Método. Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. Resultados. Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). Conclusiones. La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Background and objective. The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. Methods. Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. Results. A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. Conclusions. Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study / Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF

OBJECTIVES: The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. MATERIAL AND METHODS: Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. RESULTS: A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of ,the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. CONCLUSION: Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

OBJETIVO: El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). METODO: Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. RESULTADOS: Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). CONCLUSIONES: La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

COVID-19 Associated Pulmonary Aspergillosis (CAPA): Hospital or Home Environment as a Source of Life-Threatening Aspergillus fumigatus Infection?

Most cases of invasive aspergillosis are caused by Aspergillus fumigatus, whose conidia are ubiquitous in the environment. Additionally, in indoor environments, such as houses or hospitals, conidia are frequently detected too. Hospital-acquired aspergillosis is usually associated with airborne fungal contamination of the hospital air, especially after building construction events. A. fumigatus strain typing can fulfill many needs both in clinical settings and otherwise. The high incidence of aspergillosis in COVID patients from our hospital, made us wonder if they were hospital-acquired aspergillosis. The purpose of this study was to evaluate whether the hospital environment was the source of aspergillosis infection in CAPA patients, admitted to the Hospital Universitario Central de Asturias, during the first and second wave of the COVID-19 pandemic, or whether it was community-acquired aspergillosis before admission. During 2020, sixty-nine A. fumigatus strains were collected for this study: 59 were clinical isolates from 28 COVID-19 patients, and 10 strains were environmentally isolated from seven hospital rooms and intensive care units. A diagnosis of pulmonary aspergillosis was based on the ECCM/ISHAM criteria. Strains were genotyped by PCR amplification and sequencing of a panel of four hypervariable tandem repeats within exons of surface protein coding genes (TRESPERG). A total of seven genotypes among the 10 environmental strains and 28 genotypes among the 59 clinical strains were identified. Genotyping revealed that only one environmental A. fumigatus from UCI 5 (box 54) isolated in October (30 October 2020) and one A. fumigatus isolated from a COVID-19 patient admitted in Pneumology (Room 532-B) in November (24 November 2020) had the same genotype, but there was a significant difference in time and location. There was also no relationship in time and location between similar A. fumigatus genotypes of patients. The global A. fumigatus, environmental and clinical isolates, showed a wide diversity of genotypes. To our knowledge, this is the first study monitoring and genotyping A. fumigatus isolates obtained from hospital air and COVID-19 patients, admitted with aspergillosis, during one year. Our work shows that patients do not acquire A. fumigatus in the hospital. This proves that COVID-associated aspergillosis in our hospital is not a nosocomial infection, but supports the hypothesis of "community aspergillosis" acquisition outside the hospital, having the home environment (pandemic period at home) as the main suspected focus of infection.

RhoA/ROCK2 signalling is enhanced by PDGF-AA in fibro-adipogenic progenitor cells: implications for Duchenne muscular dystrophy.

BACKGROUND: The lack of dystrophin expression in Duchenne muscular dystrophy (DMD) induces muscle fibre and replacement by fibro-adipose tissue. Although the role of some growth factors in the process of fibrogenesis has been studied, pathways activated by PDGF-AA have not been described so far. Our aim was to study the molecular role of PDGF-AA in the fibrotic process of DMD. METHODS: Skeletal muscle fibro-adipogenic progenitor cells (FAPs) from three DMD treated with PDGF-AA at 50 ng/mL were analysed by quantitative mass spectrometry-based proteomics. Western-blot, immunofluorescence, and G-LISA were used to confirm the mass spectrometry results. We evaluated the effects of PDGF-AA on the activation of RhoA pathway using two inhibitors, C3-exoenzyme and fasudil. Cell proliferation and migration were determined by BrdU and migration assay. Actin reorganization and collagen synthesis were measured by phalloidin staining and Sircol assay, respectively. In an in vivo proof of concept study, we treated dba/2J-mdx mice with fasudil for 6 weeks. Muscle strength was assessed with the grip strength. Immunofluorescence and flow cytometry analyses were used to study fibrotic and inflammatory markers in muscle tissue. RESULTS: Mass spectrometry revealed that RhoA pathway proteins were up-regulated in treated compared with non-treated DMD FAPs (n = 3, mean age = 8 ± 1.15 years old). Validation of proteomic data showed that Arhgef2 expression was significantly increased in DMD muscles compared with healthy controls by a 7.7-fold increase (n = 2, mean age = 8 ± 1.14 years old). In vitro studies showed that RhoA/ROCK2 pathway was significantly activated by PDGF-AA (n = 3, 1.88-fold increase, P < 0.01) and both C3-exoenzyme and fasudil blocked that activation (n = 3, P < 0.05 and P < 0.001, respectively). The activation of RhoA pathway by PDGF-AA promoted a significant increase in proliferation and migration of FAPs (n = 3, P < 0.001), while C3-exoenzyme and fasudil inhibited FAPs proliferation at 72 h and migration at 48 and 72 h (n = 3, P < 0.001). In vivo studies showed that fasudil improved muscle function (n = 5 non-treated dba/2J-mdx and n = 6 treated dba/2J-mdx, 1.76-fold increase, P < 0.013), and histological studies demonstrated a 23% reduction of collagen-I expression area (n = 5 non-treated dba/2J-mdx and n = 6 treated dba/2J-mdx, P < 0.01). CONCLUSIONS: Our results suggest that PDGF-AA promotes the activation of RhoA pathway in FAPs from DMD patients. This pathway could be involved in FAPs activation promoting its proliferation, migration, and actin reorganization, which represents the beginning of the fibrotic process. The inhibition of RhoA pathway could be considered as a potential therapeutic target for muscle fibrosis in patients with muscular dystrophies.

A multicenter analysis of the role of prophylactic transfusion of blood products in patients with cirrhosis and esophageal varices undergoing endoscopic band ligation.

BACKGROUND & AIMS: Prophylactic administration of platelets and fresh frozen plasma (FFP) has been recommended in patients with cirrhosis with low platelets and/or prolonged international normalized ratio (INR) without scientific evidence to support this practice. In this analysis, we evaluated the use of prophylactic administration of blood products in outpatients with cirrhosis undergoing endoscopic band ligation (EBL). METHODS: This is a multicenter retrospective analysis of consecutive EBL procedures in patients with cirrhosis at 4 hospitals in Spain from 01/2010-01/2017. FFP and/or platelet transfusion were given at the discretion of the physician if INR was >1.5 and/or platelet count <50x109/L. Patient demographics, endoscopic findings, bleeding events after EBL, and the use of prophylactic FFP or platelets were recorded. RESULTS: A total of 536 patients underwent 1,472 EBL procedures: 72% male; main etiology HCV and alcohol (72%); median MELD score 11; Child-Pugh A/B/C (59/33/8%). EBL procedures were performed for primary (51%) or secondary (49%) prophylaxis. A median of 2 procedures per patient were performed.1-4 FFP and/or platelets were administered in 41 patients (7.6%). The prophylactic transfusion protocol was followed in 16% and 28% of procedures with high INR and/or low platelets, respectively. Post-EBL bleeding occurred in 26 out of 536 patients (4.8%) and in 33 out of 1,472 procedures (2.2%). Bleeding was due to post-EBL ulcers in 21 patients and due to band dislodgment in 5. In 6 patients, bleeding occurred within 24 hours and in the remaining patients it occurred within 2 weeks after EBL. In those that bled, 7 met criteria for transfusion (2 for FFP and 5 for platelets), of whom only 1 received FFP and 4 received platelets; the remaining 19 patients did not meet criteria for transfusion. There was no association between INR or platelet count and bleeding events. Univariate and multivariate analysis revealed that Child-Pugh and MELD scores were risk factors for post-EBL bleeding. CONCLUSIONS: The incidence of post-EBL bleeding is low and is associated with advanced liver disease. Post-EBL bleeding was not related to baseline INR/platelet count and most outpatients with post-EBL bleeding did not meet criteria for prophylactic transfusion. LAY SUMMARY: Patients with chronic liver disease or cirrhosis and enlarged veins (varices) of the esophagus that can potentially bleed commonly need an endoscopy to treat these varices with elastic rubber bands (endoscopic band ligation). Some patients have low platelet counts or prolonged coagulation tests. This analysis of 4 centers evaluated the use of prophylactic administration of blood products in outpatients with cirrhosis undergoing endoscopic band ligation. The results showed that bleeding after band ligation is uncommon and that if bleeding occurs it does not seem to be related with coagulation tests or the administration of blood products to prevent bleeding after band ligation of esophageal varices.

The presence and outcome of biliary sphincter disorders in liver-transplant recipients according to the Rome IV classification.

BACKGROUND: Biliary sphincter disorders after liver transplantation (LT) are poorly described. We aim to describe the presence and outcome of patients with papillary stenosis (PS) and functional biliary sphincter disorders (FBSDs) after LT according to the updated Rome IV criteria. METHODS: We reviewed all endoscopic retrograde cholangiopancreatographies (ERCPs) performed in LT recipients between January 2003 and December 2019. Information on clinical and endoscopic findings was obtained from electronic health records and endoscopy databases. Laboratory and clinical findings were collected at the time of ERCP and 1 month after ERCP. RESULTS: Among the 1,307 LT recipients, 336 underwent 849 ERCPs. Thirteen (1.0%) patients met the updated Rome IV criteria for PS [former sphincter of Oddi dysfunction (SOD) type I] and 14 patients (1.0%) met the Rome IV criteria for FBSD (former SOD type II). Biliary sphincterotomy was performed in 13 PS and 10 FBSD cases. One month after sphincterotomy, bilirubin, gamma-glutamyl transferase and alkaline phosphatase levels decreased in 85%, 61%, and 92% of those in the PS group (P = 0.019, 0.087, and 0.003, respectively) and in 50%, 70%, and 80% of those in the FBSD group (P = 0.721, 0.013, and 0.093, respectively). All the 14 patients initially suspected of having a FBSD turned out to have a different diagnosis during the follow-up. CONCLUSIONS: PS after LT is uncommon and occurs in only 1% of LT recipients. Our data do not support the presence of an FBSD after LT. Sphincterotomy is a safe and effective procedure in LT recipients with PS.

Factors associated with poor prognosis in patients with atrial fibrillation: An emergency department perspective the EMERG-AF study.

OBJECTIVE: We sought to identify the factors associated with a worse prognosis in Emergency Department (ED) patients with atrial fibrillation (AF), crucial information to guide management decisions. METHODS: This is a secondary analysis of a prospective, multicenter, observational cohort of consecutive AF patients attended in 62 EDs in Spain. Clinical variables were collected on enrollment. Follow-up was performed at 30 days and one year. The primary composite outcome was all-cause mortality, major bleeding and/or stroke at one year. Secondary outcomes were each of these components considered separately, plus one-year cardiovascular mortality and the composite outcome at 30 days. RESULTS: We analyzed 1107 patients. The primary outcome occurred in 209 patients (18.9%), one-year all-cause mortality in 151 (13.6%), major bleeding in 47 (4.2%), and stroke in 31 (2.8%). Disability (HR 2.064, 95% CI 1.478-2.882), previous known AF (HR 1.829, 95% CI 1.096-3.051), long duration of the AF episode (HR 1.849, 95% CI 1.052-3.252) and renal failure (HR 2.073, 95% CI 1.433-2.999) were independently associated with the primary outcome, whereas anticoagulation at discharge was inversely associated (HR 0.576, 95% CI 0.415-0.801). Disability was associated with mortality, cardiovascular mortality, and the composite at 30 days, and renal failure with mortality and major bleeding. CONCLUSIONS: Comorbidities like renal failure, long AF duration and disability were related to adverse outcomes and should be decisive to guide management decisions in ED patients with AF. Anticoagulation had a positive impact on prognosis and should be the mainstay of therapy in AF patients attended in ED.