RESUMEN
BACKGROUND: Membranes based on triply periodic minimal surfaces (TPMS) have proven a superior gas transfer compared to the contemporary hollow fiber membrane (HFM) design in artificial lungs. The improved oxygen transfer is attributed to disrupting the laminar boundary layer adjacent to the membrane surface known as main limiting factor to mass transport. However, it requires experimental proof that this improvement is not at the expense of greater damage to the blood. Hence, the aim of this work is a valid statement regarding the structure-dependent hemolytic behavior of TPMS structures compared to the current HFM design. METHODS: Hemolysis tests were performed on structure samples of three different kind of TPMS-based designs (Schwarz-P, Schwarz-D and Schoen's Gyroid) in direct comparison to a hollow fiber structure as reference. RESULTS: The results of this study suggest that the difference in hemolysis between TPMS membranes compared to HFMs is small although slightly increased for the TPMS membranes. There is no significant difference between the TPMS structures and the hollow fiber design. Nevertheless, the ratio between the achieved additional oxygen transfer and the additional hemolysis favors the TPMS-based membrane shapes. CONCLUSION: TPMS-shaped membranes offer a safe way to improve gas transfer in artificial lungs.
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Órganos Artificiales , Hemólisis , Pulmón , Membranas Artificiales , Diseño de Equipo , Humanos , Impresión TridimensionalRESUMEN
BACKGROUND AIMS: Cell-based therapies of pulmonary diseases with mesenchymal stromal cells (MSCs) are increasingly under experimental investigation. In most of these, MSCs are administered intravenously or by direct intratracheal instillation. A parallel approach is to administer the cells into the lung by endoscopic atomization (spraying). In a previous study, the authors developed a flexible endoscopic atomization device that allows administration of respiratory epithelial cells in the lungs with high survival. METHODS: In this study, the authors evaluated the feasibility of spraying MSCs with two different endoscopic atomization devices (air and pressure atomization). Following atomization, cell viability was evaluated with live/dead staining. Subsequent effects on cytotoxicity, trilineage differentiation and expression of MSC-specific markers as well as on MSC metabolic activity and morphology were analyzed for up to 7 days. RESULTS: MSC viability immediately after spraying and subsequent metabolic activity for 7 days was not influenced by either of the devices. Slightly higher cytotoxicity rates could be observed for pressure-atomized compared with control and air-atomized MSCs over 7 days. Flow cytometry revealed no changes in characteristic MSC cell surface marker expression, and morphology remained unchanged. Standard differentiation into osteocytes, chondrocytes and adipocytes was inducible after atomization. CONCLUSIONS: In the literature, a minimal survival of 50% was previously defined as the cutoff value for successful cell atomization. This is easily met with both of the authors' devices, with more than 90% survival. Thus, there is a potential role for atomization in intrapulmonary MSC-based cell therapies, as it is a feasible and easily utilizable approach based on clinically available equipment.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Diferenciación Celular , Supervivencia Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Células Cultivadas , PulmónRESUMEN
As data about microbiological testing and the cellular composition of the broncho-alveolar lavage (BAL) fluid in patients ventilated due to coronavirus disease 2019 (COVID-19) are lacking, this was investigated in a retrospective analysis (n = 58). Co-infection with pathogens was detected in 31 patients, whereas the analysis of BAL cellularity showed an increased total cell count and an alveolitis dominated by neutrophils. None of the physicians performing bronchoscopies in COVID-19 patients had serological evidence of severe acute respiratory syndrome coronavirus 2 infection.
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COVID-19 , Síndrome de Dificultad Respiratoria , Líquido del Lavado Bronquioalveolar , Humanos , Síndrome de Dificultad Respiratoria/terapia , Estudios Retrospectivos , SARS-CoV-2 , Irrigación TerapéuticaRESUMEN
COVID-19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID-19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus-activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55-yo patient with proven COVID-19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in-label for co-existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID-19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS-CoV-2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID-19 pneumonia, preventing cytokine storm and ARDS.
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COVID-19/complicaciones , Inhibidores de las Cinasas Janus/uso terapéutico , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Síndrome de Liberación de Citoquinas/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Pandemias , Pirimidinas , Síndrome de Dificultad Respiratoria/prevención & control , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Endothelialized oxygenator devices (EndOxy) with a physiological, nonthrombogenic, and anti-inflammatory surface offer the potential to overcome current shortcomings of conventional extracorporeal membrane oxygenation such as complications like thromboembolism and bleeding that deteriorate adequate long-term hemocompatibility. The approach of endothelialization of gas exchange membranes, and thus the formation of a nonthrombogenic and anti-inflammatory surface, is promising. In this study, we investigated the mid-term shear stress resistance as well as gas transfer rates and cell densities of endothelial cells seeded on RGD-conjugated polydimethylsiloxane (RGD-PDMS) gas exchange membranes under dynamic conditions. Human umbilical vein endothelial cells were seeded on RGD-PDMS and exposed to defined shear stresses in a microfluidic bioreactor. Endothelial cell morphology was assessed by bright field microscopy and immunocytochemistry. Furthermore, gas transfer measurement of blank, RGD-conjugated, and endothelialized PDMS oxygenator membranes was performed. RGD-PDMS gas exchange membranes proved suitable for the dynamic culture of endothelial cells for up to 21 days at a wall shear stress of 2.9 dyn/cm2 . Furthermore, the cells resisted increased wall shear stresses up to 8.6 dyn/cm2 after a previous dynamic preculture of each one hour at 2.9 dyn/cm2 and 5.7 dyn/cm2 . Also, after a longer dynamic preculture of three days at 2.9 dyn/cm2 and one hour at 5.7 dyn/cm2 , increased wall shear stresses of 8.6 dyn/cm2 were tolerated by the cells and cell integrity could be remained. Gas transfer (GT) tests revealed that neither RGD conjugation nor endothelialization of RGD-PDMS significantly decrease the gas transfer rates of the membranes during short-term trials. Gas transfer rates are stable for at least 72 hours of dynamic cultivation of endothelial cells. Immunocytochemistry showed that the cell layer stained positive for typical endothelial cell markers CD31 and von Willebrand factor (VWF) after all trials. Cell density of EC on RGD-PDMS increased between 3 and 21 days of dynamic culture. In this study, we show the suitability of RGD-PDMS membranes for flow resistant endothelialization of gas-permeable membranes, demonstrating the feasibility of this approach for a biohybrid lung.
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Dimetilpolisiloxanos/química , Oxigenación por Membrana Extracorpórea/instrumentación , Oligopéptidos/química , Oxigenadores de Membrana , Reactores Biológicos , Adhesión Celular , Oxigenación por Membrana Extracorpórea/efectos adversos , Estudios de Factibilidad , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Dispositivos Laboratorio en un Chip , Oxígeno/metabolismo , Estrés MecánicoRESUMEN
BACKGROUND: Survey-based studies are frequently used to describe the economic impact of multiple sclerosis (MS). However, there is no validated health resource survey available, preventing comparison of study results and meaningful conclusions regarding the efficiency of long-term treatments. OBJECTIVE: The aim of this study was to develop and validate a tablet- and paper-based MS health resource utilization survey. METHODS: We developed and validated the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS), consisting of 24 cost items for paper and tablet users. Data for validation came from two large German observational studies. Survey practicability was assessed according to the response rate. Reliability was described using test-retest reliability as well as Guttman lambda. Construct validity was assessed as convergent and discriminant validity via correlations with associated patient-reported outcomes and known-group analyses. RESULTS: In total, 2207 out of 2388 (response rate: 92.4%) patients completed the survey and were included to determine psychometric properties. The test-retest reliability had an intraclass correlation coefficient of 0.828 over a course of 3 months. Convergent validity analyses showed that total costs correlated positively with increased disability (r=0.411, P<.001). For discriminant validity, correlations of total costs with the Treatment Satisfaction Questionnaire for Medication ranged from -0.006 (convenience) to -0.216 (effectiveness). The mean annual cost was 28,203 (SD 14,808) (US $39,203; SD US $20,583) with disease-modifying therapies. CONCLUSIONS: The MS-HRS is a multilingual, reliable, valid, electronically available, and easy-to-administer questionnaire providing a holistic cross-sectional and longitudinal assessment of resource utilization in patients with MS.
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Recursos en Salud/normas , Esclerosis Múltiple/epidemiología , Medición de Resultados Informados por el Paciente , Psicometría/métodos , Adulto , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
AIM: Knowledge about cardiac stress related to seizures in electroconvulsive therapy (ECT) and spontaneously occurring generalized convulsive seizures (GCS) is limited. The aim of the present study was to analyze cardiac function and circulating markers of cardiac stress in the early postictal period after ECT and GCS. METHODS: Patients undergoing ECT in the Department of Psychiatry, Psychotherapy and Psychosomatics and patients undergoing diagnostic video-EEG monitoring (VEM) in the Department of Neurology were prospectively enrolled between November 2017 and November 2018. Cardiac function was examined twice using transthoracic echocardiography within 60â¯min and >4â¯h after ECT or GCS. Established blood markers (troponin T high-sensitive, N-terminal pro brain natriuretic peptide) of cardiac stress or injury were collected within 30â¯min, 4 to 6â¯h, and 24â¯h after ECT or GCS. In the ECT group, the troponin T values were also correlated with periprocedural heart rate and blood pressure values. Because of organizational or technical reasons, the measurement was not performed in all patients. RESULTS: Twenty patients undergoing ECT and 6 patients with epilepsy with a GCS during VEM were included. Postictal echocardiography showed no wall motion disorders and no change in left ventricular and right ventricular functions. Four of 17 patients displayed a transient increase in high-sensitive cardiac troponin T 4-6â¯h after the seizure (3 patients with ECT-induced seizure). None of these 4 patients had signs of an acute cardiac event, and periprocedural blood pressure or heart rate peaks during ECT did not significantly differ in patients with and without troponin T elevation. CONCLUSIONS: Signs of mild cardiac stress can occur in some patients following ECT or GCS without clinical complications, probably related to excessive catecholamine release during the seizure.
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Presión Sanguínea/fisiología , Ecocardiografía/métodos , Terapia Electroconvulsiva/efectos adversos , Epilepsia Generalizada/sangre , Frecuencia Cardíaca/fisiología , Convulsiones/sangre , Adulto , Anciano , Biomarcadores/sangre , Ecocardiografía/tendencias , Terapia Electroconvulsiva/tendencias , Electroencefalografía/métodos , Electroencefalografía/tendencias , Epilepsia Generalizada/diagnóstico por imagen , Epilepsia Generalizada/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Convulsiones/diagnóstico por imagen , Convulsiones/terapia , Troponina T/sangre , Adulto JovenRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD) often occur together. However, COPD is underdiagnosed among CHD patients. OBJECTIVES: This study investigated the prevalence of COPD and relevant pulmonary function test (PFT) impairments in patients with acute myocardial infarction (AMI). METHODS: Patients undergoing coronary angiography for AMI were prospectively included. Body plethysmography, lung diffusing capacity, blood gas analysis, and echocardiography were performed. The following patient subgroups were compared: with versus without COPD, ST elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). The prevalence of PFT impairments was also recorded. RESULTS: A total of 100 patients (51 with NSTEMI, 49 with STEMI) were included. Twenty patients had diagnosed COPD, of whom 15 were diagnosed for the first time; 80% of all COPD patients were not receiving COPD therapy. Patients with COPD had higher maximum creatine kinase (p = 0.008) and troponin T (p = 0.054) levels than those without COPD. Hypoxaemia was more common in COPD patients (lower oxygen saturation [p = 0.008] and partial pressure of oxygen [PaO2] [p = 0.005]). PaO2 was significantly lower in STEMI compared with NSTEMI (p = 0.017). Independent of a COPD diagnosis, 65 patients had relevant PFT impairments. CONCLUSIONS: The high prevalence of undiagnosed COPD and relevant pulmonary function impairments in this cohort of patients with AMI, and the fact that pulmonary disease was untreated in the majority of COPD patients, highlight the importance of a general pulmonary workup of patients with AMI. Furthermore, patients with CHD should undergo screening for COPD, given the fact that COPD patients had larger infarction size.
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Infarto del Miocardio/complicaciones , Intervención Coronaria Percutánea , Pletismografía Total/métodos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Análisis de los Gases de la Sangre/métodos , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Mortalidad Hospitalaria/tendencias , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/cirugía , Prevalencia , Pronóstico , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Sistema de Registros , Factores de Riesgo , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND AND OBJECTIVES: Dyspnea is one of the most disturbing symptoms for patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF). This study investigated dyspnea triggers and factors associated with worsening dyspnea in patients with COPD or HF. METHODS: COPD support group members and HF patients with reduced ejection fraction (HFrEF) and no airway obstruction answered a questionnaire describing different weather conditions (rising/falling air pressure, sunny, foggy, rainy, windy, snowy, hazy, high ozone levels, and airborne pollen) and environmental circumstances (cooking, grilling, perfumes, cigarette smoke, gasoline odor, and flower scents) and were asked to estimate the occurrence and severity of dyspnea under these conditions using predefined scales. RESULTS: 230 patients with COPD and 90 with HFrEF (left ventricular ejection fraction 34 ± 10%, Tiffeneau index > 70%) were analyzed. COPD patients reported dyspnea more often than HF patients in almost all weather and environmental conditions (p = 0.004 to p < 0.001), with the exception of outdoor floral scents and cigarette smoke. Severe to very severe dyspnea was reported more in COPD versus HF in all weather and environmental conditions except sunny weather (p = 0.01 to p < 0.001). COPD was associated with more severe dyspnea than HF in all conditions (all p < 0.001). CONCLUSIONS: Dyspnea was triggered by a variety of weather and other environmental triggers in patients with COPD and occurred more often than in HF patients under the same conditions. Foggy weather and exposure to perfumes were associated with severe dyspnea in the majority of COPD patients, but only a minority of HF patients.
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Disnea/etiología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Insuficiencia Cardíaca/complicaciones , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Tiempo (Meteorología) , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Disnea/diagnóstico , Disnea/fisiopatología , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Perfumes/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Humo/efectos adversosRESUMEN
The COPD Patient Management European Trial (COMET) investigated the efficacy and safety of a home-based COPD disease management intervention for severe COPD patients.The study was an international open-design clinical trial in COPD patients (forced expiratory volume in 1 s <50% of predicted value) randomised 1:1 to the disease management intervention or to the usual management practices at the study centre. The disease management intervention included a self-management programme, home telemonitoring, care coordination and medical management. The primary end-point was the number of unplanned all-cause hospitalisation days in the intention-to-treat (ITT) population. Secondary end-points included acute care hospitalisation days, BODE (body mass index, airflow obstruction, dyspnoea and exercise) index and exacerbations. Safety end-points included adverse events and deaths.For the 157 (disease management) and 162 (usual management) patients eligible for ITT analyses, all-cause hospitalisation days per year (mean±sd) were 17.4±35.4 and 22.6±41.8, respectively (mean difference -5.3, 95% CI -13.7 to -3.1; p=0.16). The disease management group had fewer per-protocol acute care hospitalisation days per year (p=0.047), a lower BODE index (p=0.01) and a lower mortality rate (1.9% versus 14.2%; p<0.001), with no difference in exacerbation frequency. Patient profiles and hospitalisation practices varied substantially across countries.The COMET disease management intervention did not significantly reduce unplanned all-cause hospitalisation days, but reduced acute care hospitalisation days and mortality in severe COPD patients.
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Servicios de Atención a Domicilio Provisto por Hospital/organización & administración , Hospitalización/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/terapia , Autocuidado/métodos , Anciano , Causas de Muerte , Manejo de la Enfermedad , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Análisis de Regresión , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Endobronchial administration of lidocaine is commonly used for cough suppression during diagnostic bronchoscopy. Recently, nebulization of lidocaine during bronchoscopies under deep sedation with fiberoptic intubation using a distinct spray catheter has been shown to have several advantages over conventional lidocaine administration via syringe. However, there are no data about this approach in bronchoscopies performed under moderate sedation. Therefore, this study compared the tolerability and safety of nebulized lidocaine with conventional lidocaine administration via syringe in patients undergoing bronchoscopy with moderate sedation. METHODS: Patients requiring diagnostic bronchoscopy were randomly assigned to receive topical lidocaine either via syringe or via nebulizer. Endpoints were consumption of lidocaine and sedative drugs, as well as patient tolerance and safety. RESULTS: Sixty patients were included in the study (n = 30 in each group). Patients required lower doses of endobronchial lidocaine when given via nebulizer versus syringe (164.7 ± 20.8 mg vs. 250.4 ± 42.38 mg; p < 0.0001) whereas no differences in the dosage of sedative drugs were observed between the two groups (all p > 0.05). Patients in the nebulizer group had higher mean oxygen saturation (96.19 ± 2.45% vs. 94.21 ± 3.02%; p = 0.0072) and a lower complication rate (0.3 ± 0.79 vs. 1.17 ± 1.62 per procedure; p = 0.0121) compared with those in the syringe group. CONCLUSIONS: Endobronchial lidocaine administration via nebulizer was well-tolerated during bronchoscopies under moderate sedation and was associated with reduced lidocaine consumption, a lower complication rate and better oxygenation compared with lidocaine administration via syringe. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov ( NCT02262442 ; 13th October 2014).
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Anestésicos Locales/administración & dosificación , Broncoscopía/normas , Sedación Consciente/normas , Lidocaína/administración & dosificación , Nebulizadores y Vaporizadores/normas , Docilidad , Administración Tópica , Anciano , Broncoscopía/instrumentación , Sedación Consciente/instrumentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiologíaRESUMEN
BACKGROUND: Fibroblast growth factor 23 (FGF23) regulates phosphate metabolism by increasing renal phosphate excretion and decreasing 1.25-dihydroxyvitamin D synthesis. Reports about hypophosphatemia in patients with chronic obstructive pulmonary disease (COPD) suggest altered phosphate metabolism. Therefore, we hypothesized that disturbances in phosphate-regulatory hormones such as FGF23 and parathyroid hormone (PTH) are present in COPD patients. METHODS: We investigated 40 COPD patients (63.5 ± 9.9 years, 27 male), each matched with two age- and sex-matched controls without any primary lung disease. COPD patients underwent lung function testing in advance. All patients had a glomerular filtration rate (GFR) > 60 mL/min/1.73m2. We measured concentrations of intact FGF23 (iFGF23) and c-terminal FGF23 (c-term FGF23), phosphate, parathyroid hormone (PTH) and C-reactive protein (CRP) levels in COPD patients and controls. RESULTS: Phosphate (1.0 ± 02 vs. 1.1 ± 0.2 mmol/L; p = 0.027), PTH (54.2 ± 29.4 vs. 68.7 ± 31.8 pg/mL; p = 0.002) and iFGF23 (46.3 ± 29.0 vs. 57.5 ± 33.5 pg/mL; p = 0.026 ) levels were significantly lower in COPD patients compared with controls. There was a significant negative correlation between c-term FGF23 and total lung capacity (r = - 0.4; p = 0.01), and between c-term FGF23 and CRP in COPD patients (r = 0.48; p = 0.002). iFGF23 and c-term FGF23 were positively correlated with phosphate and PTH in the control group. CONCLUSION: We confirmed lower average serum phosphate levels in COPD patients compared with controls. However, our data do not suggest a causative role for FGF23 or PTH in COPD because levels of both phosphate-lowering hormones appear to be adaptively decreased as well. Therefore, further investigations are needed to identify the pathogenesis of low phosphate levels in patients with COPD and the relationship between phosphate-regulatory hormones and disease progression.
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Factores de Crecimiento de Fibroblastos/sangre , Hormona Paratiroidea/sangre , Fosfatos/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Estudios Transversales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31-dependent gene expression was determined in three-dimensional organotypic skin models. IL-31-regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.
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Dermatitis Atópica/patología , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Uniones Estrechas/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/biosíntesis , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Proteínas Filagrina , Humanos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucinas/farmacología , Proteínas de Filamentos Intermediarios/metabolismo , Queratinocitos/citología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores de Interleucina-1/antagonistas & inhibidores , Transducción de Señal/fisiología , Piel/citología , Piel/crecimiento & desarrollo , Uniones Estrechas/efectos de los fármacosRESUMEN
BACKGROUND: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. METHOD/DESIGN: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI), and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. DISCUSSION: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. TRIAL REGISTRATION: BfArM6532; Trial Registration Date: 20/05/2015.
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Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Progresión de la Enfermedad , Documentación/métodos , Monitoreo de Drogas/métodos , Registros Electrónicos de Salud , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Seguridad , Resultado del TratamientoRESUMEN
BACKGROUND: Endobronchial administration of local anesthetics such as lidocaine is often used for cough suppression during bronchoscopy. To achieve a better distribution of lidocaine in the tracheobronchial tree, spray catheters have been developed, allowing nebulization of the local anesthetic solution. However, there are little data on the efficacy and safety of this approach, or on the consumption of sedative drugs and lidocaine during nebulized administration. OBJECTIVES: To investigate the tolerability of nebulized lidocaine compared to conventional lidocaine administration via syringe through the working channel of the bronchoscope in patients undergoing bronchoscopy. Consumption of sedative drugs and lidocaine was also compared between the two lidocaine administration approaches. METHODS: Patients requiring bronchoscopy with endobronchial or transbronchial biopsy were randomly assigned to receive topical lidocaine either via syringe or via nebulizer. Endpoints were consumption of lidocaine and sedative drugs, as well as patient tolerance and safety. RESULTS: Thirty patients were included, 15 in each group. Patients in the nebulizer group required lower doses of endobronchial lidocaine (184.7 ± 67.98 vs. 250.7 ± 21.65 mg, p = 0.0045) and intravenous fentanyl (0.033 ± 0.041 vs. 0.067 ± 0.045 mg, p = 0.0236) than those in the syringe group; midazolam or propofol dosages did not differ between the two groups. In addition, there were no between-group differences in patient tolerance or safety (all p > 0.05). CONCLUSION: Endobronchial administration of lidocaine during bronchoscopy via nebulizer was found to be well tolerated and safe and was associated with reduced lidocaine and fentanyl dosages compared to administration via syringe.
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Anestésicos Locales/administración & dosificación , Broncoscopía/métodos , Lidocaína/administración & dosificación , Nebulizadores y Vaporizadores , Jeringas , Administración Intravenosa , Administración Tópica , Anciano , Anestésicos Intravenosos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Fentanilo/administración & dosificación , Humanos , Masculino , Midazolam/administración & dosificación , Persona de Mediana Edad , Propofol/administración & dosificaciónRESUMEN
BACKGROUND: Fingolimod (Gilenya) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. METHODS: PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. DISCUSSION: PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.
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Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Proyectos de Investigación , Industria Farmacéutica , Femenino , Clorhidrato de Fingolimod/economía , Alemania , Humanos , Inmunosupresores/economía , Masculino , Seguridad del Paciente , Vigilancia de Productos Comercializados , Glicoles de Propileno/uso terapéutico , Estudios Prospectivos , Calidad de VidaAsunto(s)
Aneurisma Falso/etiología , Aneurisma de la Aorta/etiología , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/instrumentación , Enfisema/terapia , Hemorragia/etiología , Anciano , Aneurisma Falso/diagnóstico por imagen , Aneurisma de la Aorta/diagnóstico por imagen , Angiografía por Tomografía Computarizada , Resultado Fatal , Femenino , HumanosRESUMEN
Introduction: Airflow obstruction (AO) is evidenced by reduced forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) with the threshold for diagnosis often being set at <0.7. However, currently the ATS/ERS standards for interpretation of lung function tests recommend the lower limit of normal (LLN), calculated by reference equations of the Global Lung Initiative from 2012 (GLI-12), as a threshold for AO diagnosis. The present study aims to investigate phenotypes, with focus on hyperinflation, which influence AO prevalence defined by FEV1/FVC < LLN when compared to the fixed 0.7 threshold. Methods: Data from 3,875 lung function tests (56.4% men, aged 18-95) including 3,824 body plethysmography recordings performed from July 2021 to June 2022 were analysed. The difference between both classifiers was quantified, before and after stratification by sex, age, and hyperinflation. Results: AO diagnosis was significantly less frequent with the LLN threshold (18.2%) compared to the fixed threshold (28.0%) (p < 0.001) with discordance rate of 10.5%. In the presence of mild or moderate hyperinflation, there was substantial agreement (Cohen's kappa: 0.616, 0.718) between the classifiers compared to near perfect agreement in the presence of severe hyperinflation (Cohen's kappa: 0.896). In addition, subgroup analysis after stratification for sex, age, and hyperinflation showed significant differences between both classifiers. Conclusion: The importance of using the LLN threshold instead of the fixed 0.7 threshold for the diagnosis of AO is highlighted. When using the fixed threshold AO, misdiagnosis was more common in the presence of mild to moderate hyperinflation.
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Background: Dyspnea is a common persistent symptom after acute coronavirus disease 2019 illness (COVID-19). One potential explanation for post-COVID-19 dyspnea is a reduction in diffusion capacity. This longitudinal study investigated diffusion capacity and its relationship with dyspnea on exertion in individuals previously hospitalized with COVID-19. Methods: Eligible participants had been hospitalized for the treatment of acute COVID-19 and were assessed at 6 weeks, 6 months, and 12 months after discharge. Pulmonary function testing, diffusion capacity of carbon monoxide (DLCO), blood gas analysis and the level of dyspnea (Borg scale; before and after a 6 min walk test [6 MWT]) were performed. Participants were divided into subgroups based on the presence or absence of dyspnea during the 6 MWT at 12 months after hospitalization. Results: Seventy-two participants (twenty-two female, mean age 59.8 ± 13.5 years) were included. At 12 months after discharge, 41/72 participants (57%) had DLCO below the lower limit of normal and 56/72 (78%) had DLCO < 80% of the predicted value. Individuals with exertional dyspnea had significantly lower DLCO than those without exertional dyspnea (p = 0.001). In participants with DLCO data being available at three timepoints over 12 months (baseline, 6 months, and 12 months) after discharge (n = 25), DLCO improved between 6 weeks and 6 months after hospital discharge, but not thereafter (p = 0.017). Conclusions: About 2/3 of the post-COVID individuals in this study had impaired diffusion capacity at 12 months after hospital discharge. There was an association between persisting dyspnea on exertion and significantly reduced DLCO. Impaired diffusion capacity improved over the first 6 months after hospitalization but not thereafter.
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BACKGROUND: Procalcitonin (PCT) is widely used in critically ill patients to diagnose clinically significant infection and sepsis. Aim of this study was to evaluate the prognostic value of PCT in comparison to white blood cell count (WBC) and C-reactive protein (CRP) for clinical outcome and its correlation with microbiological etiology in patients with infective endocarditis (IE). METHODS: A retrospective single-center analysis was performed from 2007 till 2009. All patients were diagnosed having IE according to Duke standard criteria. Before starting antibiotic therapy, WBC, CRP and PCT were measured and blood cultures were taken for microbiological diagnosis of the etiological pathogen. Patients were followed up during in-hospital stay for poor outcome, defined as death or serious complications due to IE. RESULTS: During the study period 50 patients (57 ± 17 years, 72% male) fulfilling Duke criteria for IE were identified. In all patients PCT measurements before start of antibiotic therapy were available. In ROC analysis, a cut-off for PCT > 0.5 ng/mL was most accurate for the prediction of poor outcome with a sensitivity of 73% and specificity of 79%, a positive predictive value of 79% and a negative predictive value of 73%. Patients with a PCT > 0.5 ng/mL had an odds ratio of 12.8 (95% CI 2.5-66.2) for finding Staphylococcus aureus in blood cultures. CONCLUSIONS: For the first time, this study shows that in IE, an initial value of PCT > 0.5 ng/mL is a useful predictor of poor outcome, i.e. death or serious infectious complications. PCT > 0.5 ng/mL should raise the suspicion of Staphylococcus aureus as the etiological pathogen, whereas PCT levels < 0.5 ng/mL make staphylococcal infection unlikely.