Efficacy of rituximab in slowing down progression of rheumatoid arthritis-related interstitial lung disease: data from the NEREA Registry.

OBJECTIVES: To asses the clinical course in RA-related interstitial lung disease (RA-ILD) patients with and without rituximab (RTX). The influence of other variables was also evaluated. METHODS: A longitudinal multicentre study was conducted in RA diagnosed with ILD from 2007 until 2018 in Madrid. Patients were included in a registry [pNEumology RhEumatology Autoinmune diseases (NEREA)] from the time of ILD diagnosis. The main endpoint was functional respiratory impairment (FI), when there was a decline ≥5% in the predicted forced vital capacity compared with the previous one. Pulmonary function was measured at baseline and in follow-up visits every 6-12 months. The independent variable was therapy with RTX. Covariables included sociodemographic, clinical, radiological and other therapies. Survival techniques were used to estimate the incidence rate (IR) and 95% CI of functional impairment, expressed per 100 patient-semesters. Cox multivariate regression models were run to examine the influence of RTX and other covariates on FI. Results were expressed as the hazard ratio (HR) and CI. RESULTS: A total of 68 patients were included. FI occurred in 42 patients [IR 23.5 (95% CI 19, 29.1)] and 50% of them had FI within 1.75 years of an ILD diagnosis. A multivariate analysis showed that RTX exposure resulted in a lower risk of FI compared with non-exposure [HR 0.51 (95% CI 0.31, 0.85)]. Interstitial pneumonia, glucocorticoids, disease activity and duration also influenced FI. CONCLUSION: RA-ILD patients deteriorate over time, with the median time free of impairment being <2 years. Patients exposed to RTX had a higher probability of remaining free of FI compared with other therapies. Other factors have also been identified.

Effects of Quercetin in a Rat Model of Hemorrhagic Traumatic Shock and Reperfusion.

BACKGROUND: We hypothesized that treatment with quercetin could result in improved hemodynamics, lung inflammatory parameters and mortality in a rat model of hemorrhagic shock. METHODS: Rats were anesthetized (80 mg/kg ketamine plus 8 mg/kg xylazine i.p.). The protocol included laparotomy for 15 min (trauma), hemorrhagic shock (blood withdrawal to reduce the mean arterial pressure to 35 mmHg) for 75 min and resuscitation by re-infusion of all the shed blood plus lactate Ringer for 90 min. Intravenous quercetin (50 mg/kg) or vehicle were administered during resuscitation. RESULTS: There was a trend for increased survival 84.6% (11/13) in the treated group vs. the shock group 68.4% (13/19, p > 0.05 Kaplan-Meier). Quercetin fully prevented the development of lung edema. The activity of aSMase was increased in the shock group compared to the sham group and the quercetin prevented this effect. However, other inflammatory markers such as myeloperoxidase activity, interleukin-6 in plasma or bronchoalveolar fluid were similar in the sham and shock groups. We found no bacterial DNA in plasma in these animals. CONCLUSIONS: Quercetin partially prevented the changes in blood pressure and lung injury in shock associated to hemorrhage and reperfusion.

Testing for Vitamin D in High-Risk COPD in Outpatient Clinics in Spain: A Cross-Sectional Analysis of the VITADEPOC Study.

Background: Vitamin D deficiency has been associated with an accelerated deterioration in lung function and increased exacerbations in chronic obstructive pulmonary disease (COPD). 25(OH) vitamin D levels have been indicated as a potentially useful marker for adverse results related to COPD. Methods: VITADEPOC is a cross-sectional clinical study recruiting consecutive patients with high-risk COPD. The objective of our study was to investigate vitamin D determination frequency in patients with high-risk COPD in clinical practice at outpatient clinics in Spain and to describe the factors associated with vitamin D testing. We also aimed to determine the frequency of vitamin D deficiency in these patients. Results: Only 51 (44%) patients underwent vitamin D determination and 33 (28.4%) had received vitamin D supplements in clinical practice. The patients who underwent testing for vitamin D in clinical practice were more often women (58.8% vs. 26.2%, p < 0.001) with comorbidities such as osteoporosis (19.6% vs. 6.2%, p < 0.001) or chronic renal failure (7.8% vs. 0%, p < 0.001) and with exacerbator phenotype (55% vs. 32.3%, p = 0.015). A total of 63 (54.3%) patients had serum vitamin D levels <20 ng/mL at the inclusion visit. Of these, 29 (46%) had serum vitamin D levels <12 ng/mL (severe deficiency). Having a history of inhaled corticosteroids (OR 3.210, p < 0.016), being treated with a cycle of systemic corticosteroids (OR 2.149, p < 0.002), and having a lower physical activity level (OR 3.840, p < 0.004) showed a statistically significant positive association with vitamin D deficiency. Conclusion: The testing of vitamin D levels in patients with high-risk COPD treated at outpatient respiratory clinics in Spain is infrequent. However, when tested, a severe deficiency is detected in one in four patients. Efforts to optimize case detection in COPD are needed.

Neutral sphingomyelinase, NADPH oxidase and reactive oxygen species. Role in acute hypoxic pulmonary vasoconstriction.

The molecular mechanisms underlying hypoxic pulmonary vasoconstriction (HPV) are not yet properly understood. Mitochondrial electron transport chain (ETC) and NADPH oxidase have been proposed as possible oxygen sensors, with derived reactive oxygen species (ROS) playing key roles in coupling the sensor(s) to the contractile machinery. We have recently reported that activation of neutral sphingomyelinase (nSMase) and protein kinase C ζ (PKCζ) participate in the signalling cascade of HPV. Herein, we studied the significance of nSMase in controlling ROS production rate in rat pulmonary artery (PA) smooth muscle cells and thereby HPV in rat PA. ROS production (analyzed by dichlorofluorescein and dihydroethidium fluorescence) was increased by hypoxia in endothelium-denuded PA segments and their inhibition prevented hypoxia-induced voltage-gated potassium channel (K(V) ) inhibition and pulmonary vasoconstriction. Consistently, H(2) O(2) , or its analogue t-BHP, decreased K(V) currents and induced a contractile response, mimicking the effects of hypoxia. Inhibitors of mitochondrial ETC (rotenone) and NADPH oxidase (apocynin) prevented hypoxia-induced ROS production, K(V) channel inhibition and vasoconstriction. Hypoxia induced p47(phox) phosphorylation and its interaction with caveolin-1. Inhibition of nSMase (GW4869) or PKCζ prevented p47(phox) phosphorylation and ROS production. The increase in ceramide induced by hypoxia (analyzed by immunocytochemistry) was inhibited by rotenone. Exogenous ceramide increased ROS production in a PKCζ sensitive manner. We propose an integrated signalling pathway for HPV which includes nSMase-PKCζ-NADPH oxidase as a necessary step required for ROS production and vasoconstriction.

Accelerated immunosenescence, oxidation and inflammation lead to a higher biological age in COPD patients.

Chronic obstructive pulmonary disease (COPD) is characterised by inflammatory and oxidative alterations in the lung and extrapulmonary compartments, through involvement of the immune system. Several leukocyte functions are health markers and good predictors of longevity, and high pro-inflammatory and oxidative states are related to more aged profiles. Here, we aimed to investigate the aging rate in terms of immunosenescence in COPD men with respect to healthy age-matched controls. Several neutrophil (adherence, chemotaxis, phagocytosis, superoxide anion stimulated production) and lymphocyte (adherence, chemotaxis, lymphoproliferation, natural killer activity) functions, cytokine concentrations released in response to lipopolysaccharide (tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, IL-10) and redox parameters (intracellular glutathione content, basal superoxide anion level) were assessed in circulating leukocytes of men with moderate and severe stages of COPD, and compared to healthy age-matched volunteers. The biological age or aging rate in each participant was determined using the values of leukocyte functions. The results indicated impairment of immune functions in COPD patients, both in innate and adaptive immunity, and higher pro-inflammatory and oxidative states in peripheral leukocytes than controls. In general, these changes were more remarkable at the severe stage of airway obstruction. Importantly, COPD patients were found to be aging at a faster rate than age-matched healthy counterparts.

Noninvasive electrical stimulation of oropharyngeal muscles in obstructive sleep apnea.

Introduction: Continuous positive airway pressure (CPAP) therapy remains the standard treatment for obstructive sleep apnea. However, its proven effect is useless if the patient does not tolerate the treatment. The electrical stimulation approach has been investigated for several decades now and it seems that the implantable devices for invasive electrical stimulation of hypoglossal nerve are viewed as effective with some of them already approved for human use.Areas covered: in this review, we intent to summarize the existing records of noninvasive stimulation in sleep apnea to make the scientific community aware of the details before deciding on its future. We believe that this is a battle still to fight and more could be done bearing in mind the safety of this method.Expertopinion: noninvasive electrical stimulation has been left behind based on few, small and inconsistent studies using different stimulation parameters. These studies are difficult to compare and to draw conclusions.Electrical stimulation is a field for research in the treatment of obstructive sleep apnea, with many aspects still to be discovered, and which may become a therapeutic alternative to the use of CPAP in certain patients.

Assessing the Usefulness of the Prevexair Smartphone Application in the Follow-Up High-Risk Patients with COPD.

INTRODUCTION: This manuscript analyzes the exacerbations recorded by the Prevexair application through the daily analysis of symptoms in high-risk patients with COPD and explores its usefulness in assessing clinical stability with respect to that reported in visits. PATIENTS AND METHODS: This study is a multi-centre cohort of COPD patients with the exacerbator phenotype who were monitored over 6 months. The Prevexair application was installed on the patients' smartphones. Patients used the app to record symptom changes, use of medication and use of healthcare resources. It is not established a recommended action plan when worsening of symptoms. At their clinical visit during the follow-up period, patients were asked about exacerbations suffered during these 6 months of monitoring. The investigators who conducted the visit were blinded about the Prevexair app records. RESULTS: The patients experienced a total of 185 exacerbations according to daily records in the app whereas only 64 exacerbations were recalled during medical visits. Perception became more accurate for severe exacerbations (kappa 0.6577), although we found no factors that predicted poor recall. The proportion of 72.5% patients were classified as unstable if the exacerbations captured by Prevexair were used to define stability, versus 47.8% if the exacerbations recall in visit was used. Two-thirds of the exacerbations recorded in the Prevexair application were not reported to doctors during their clinical visits. Almost half were treated with oral corticosteroids and/or antibiotics and more than one-quarter of the exacerbations treated did not seek medical attention. CONCLUSION: The findings of this cohort study confirm that patients do not always remember the exacerbations suffered during their medical visit. The prevexair application is useful in monitoring COPD patients at high risk, in order to a better assessment of exacerbations of COPD during medical visits. Further research must be carried out to evaluate this strategy in clinical practice.

[Residency training of European respiratory medicine specialists: The HERMES project]. / La formación especializada en neumología en Europa. El proyecto HERMES.

Given the movement of medical specialists across borders in recent years, and the changes in legislation affecting the structure and operation of boards responsible for the various medical specialties, the task of harmonizing the training of respiratory medicine residents across the European Union has become crucial. The project for Harmonized Education in Respiratory Medicine for European Specialists (HERMES) is a collective response to this need. After 3 years of work toward building consensus, HERMES is entering its second phase. The Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) has the aim of informing our resident trainees, their instructors, and others concerned with postgraduate education in respiratory medicine in Spain about this undeniably difficult task of harmonization.

[Positron emission tomography for the study of solitary pulmonary nodules]. / La tomografía por emisión de positrones en el estudio del nódulo pulmonar solitario.

Solitary pulmonary nodules are a major clinical challenge for all doctors involved in their study. The aim is always to avoid missing malignant lesions but also to avoid performing unnecessary diagnostic tests. The most recent research suggests that in the near future chest computed tomography will become even more widely used for the early detection of lung cancer. If this occurs, there is likely to be a marked increase in the number of solitary pulmonary nodules detected, making it essential to develop techniques that enable us to manage this problem with an optimal risk-benefit ratio. We review the underlying principles of positron emission tomography and the advances that have been made in its use for the study of solitary pulmonary nodules. In addition, we discuss the possible causes of false positives and negatives in this technique and the strategies aimed at increasing diagnostic yield.

[Effect of AM3 on health-related quality of life in patients with chronic obstructive pulmonary disease belonging to risk groups]. / Efecto de AM3 en la calidad de vida de pacientes con enfermedad pulmonar obstructiva crónica en subgrupos de riesgo.

BACKGROUND AND OBJECTIVE: AM3 is an immunomodulator that significantly improves the quality of life of patients with chronic obstructive pulmonary disease (COPD). This study examined the effect of AM3 on the quality of life of patients in different risk groups and identified the factors associated with change in this variable. PATIENTS AND METHOD: This was a randomized, double-blind, placebo-controlled trial involving parallel groups of patients. The duration of the trial was 6 months. The study involved 253 patients with a mean (standard deviation) age of 67.7 (8.1) years and a mean forced expiratory volume in one second (FEV1) of 49.7% (10.2%). RESULTS: Only 121 patients (47.8%) suffered at least one exacerbation during the 6 months period. At the end of the study period, the improvement in St. George's Respiratory Questionnaire (SGRQ) score in those patients who suffered an exacerbation but who received AM3 was significantly greater than that experienced by similar placebo-treated patients (-8.10 compared to -2.5 units; p=0.034). Patients treated with inhaled corticoids also improved more with AM3 than with placebo (-9.17 compared to -4.44; p=0.035). In the 108 patients with an FEV1 of <50%, the improvements were not significantly different (-9.57 vs. -6.57; p=0.23). The factors influencing the change in SGRQ score were baseline SGRQ (p<0.001), exacerbations (p<0.008), an FEV1 of <50% (p<0.032) and treatment with AM3 (p<0.004). CONCLUSIONS: Among the patients who experienced exacerbations, treatment with AM3 helped prevent the deterioration of their quality of life. Along with AM3 treatment, the factors that independently influenced the change in SGRQ score were suffering from an exacerbation and poorer pulmonary function.

Treatment with AM3 restores defective T-cell function in COPD patients.

BACKGROUND: Lymphocyte alterations have been associated with an increased prevalence of acute respiratory infections in COPD patients. AM3 is an oral immunomodulator that normalizes the defective functions of peripheral blood natural killer and phagocytic cells in COPD patients and improves their health-related quality of life. OBJECTIVES: To characterize putative systemic abnormalities of the T-cell compartment in COPD patients, and to investigate whether AM3 can restore such abnormalities. DESIGN: The study was a randomized, prospective, double-blind, placebo-controlled trial in a cohort of COPD patients. The results were also compared to those of nonsmoker and ex-smoker healthy control subjects. SETTING: Outpatient departments of four hospitals. PATIENTS: Seventy COPD patients were randomized to receive either AM3 or a placebo orally for 90 consecutive days. Populations of 36 healthy nonsmokers and 36 healthy ex-smokers were used as control subjects. MEASUREMENTS: Peripheral blood mononuclear cell (PBMC) proliferation and production of interleukin (IL)-2, IL-4, IL-12p40, tumor necrosis factor-alpha, and interferon (IFN)-gamma proteins in response to the T-cell polyclonal mitogens were assessed at baseline and at the end of treatment. RESULTS: The proliferative response was significantly decreased in COPD patients. Decreased production of IFN-gamma was the only defect in the profiles of the cytokine measures, and was selectively observed in COPD patients, but not in nonsmoker and ex-smoker healthy control subjects. Treatment with AM3 significantly restored the PBMC proliferative response to polyclonal mitogens and significantly promoted stimulated IFN-gamma production in these patients. The normalization of these proliferative responses was not related to significant variations in the numbers of peripheral blood monocytes, CD3+, CD4+, CD8+ cells or of any major naïve/memory/activated T-cell subset. The increased IFN-gamma production in the AM3 study arm was associated with an increase in the mean of number of IFN-gamma molecules produced per CD8+ T cells. CONCLUSIONS: PBMCs of COPD patients showed clear functional T-lymphocyte abnormalities that are rescued by AM3 treatment.

Chronic respiratory symptoms, spirometry and knowledge of COPD among general population.

RATIONALE: Infradiagnosis of chronic obstructive pulmonary disease (COPD) may be related to the lack of knowledge about the disease and/or the scarce use of diagnostic procedures. This study analyses the frequency of respiratory symptoms and the knowledge about COPD in the general population, together with the use of spirometry in individuals at risk of COPD. POPULATION AND METHOD: A telephone survey was carried out in 6758 subjects older than 40 years, stratified by age, habitat (urban or rural) and region, screened by random-digit dialling. RESULTS: Up to 24% reported having at least one chronic respiratory symptom and 20.9% had a self-reported respiratory diagnosis. A total of 19.2% were active smokers and 40% had never tried to quit. Only 60% of the individuals with chronic symptoms had consulted a physician and, of them, only 45% had undergone spirometry. Spirometry was mentioned more frequently by subjects attended by pulmonologists than by GPs (67.6 vs. 28.6%; P<0.001). The term COPD was identified only by 8.6% of the participants. CONCLUSIONS: Many individuals with respiratory symptoms do not request medical attention and do not attempt to quit smoking. There is a lack of knowledge about COPD. Physicians should more actively inform about the disease and increase the use of spirometry for early detection.

Health literacy and health outcomes in chronic obstructive pulmonary disease.

BACKGROUND: There is little information worldwide about the impact of health literacy (HL) on clinical outcomes of COPD. Our aim was to quantify inadequate HL in Spain, as measured by the Short Assessment of Health Literacy for Spanish Adults questionnaire, and to examine the associations between HL and both COPD outcomes and health status. METHODS: 296 COPD patients of 68(SD = 9) years and a FEV1%predicted of 53%(SD = 18%) were enrolled and followed-up for one year. 59% showed "inadequate" HL. RESULTS: Individuals with inadequate HL were older (70[SD = 9] vs 65[SD = 8] years; p < 0.001) and had less knowledge of their disease, as measured by the low HL-COPD questionnaire, (6.9[SD = 2.3] vs 7.5[SD = 1.9]; p < 0.001). While their lung function was no different, they reported significant differences in mMRC (1.6[SD = 1] vs 1.4[SD = 1]; p < 0.001), CAT (19.2[SD = 8.1] vs 18.3[SD = 7.5]; p = 0.049), and EQ-5 (3.1[SD = 2.2] vs 2.3[SD = 1.9]; p < 0.00). Those with inadequate HL had also higher risk of having ≥2 comorbidities (OR = 1.87; 95%CI = 1.14-3.08), need of assistance (OR = 2.5; 95%CI = 1.5-4.2), anxiety/depression (OR = 1.9; 95%CI = 1.2-3.0), admissions or visits to the emergency department (OR = 1.70; 95%CI = 1.1-2.7), and all-cause deaths in the following year (3.8% (SE = 1.1%) vs 0%; p = 0.051). CONCLUSIONS: Inadequate HL is prevalent among COPD patients and it is related to health status and relevant clinical outcomes of the disease. HL needs to be considered when planning the care for COPD patients.

La figura docente del profesor contratado doctor vinculado: situación actual en España y la experiencia de Andalucía / The figure of the tenure-eligible lecturer: current situation Spain and experience in Andalusia

En este documento se refieren las bases legales nacionales y, más en concreto, las autonómicas andaluzas que dan respaldo a la figura del profesor contratado doctor vinculado y a la posibilidad de convocar las plazas correspondientes en las facultades de medicina de las universidades públicas españolas. Se exponen, asimismo, las características asistenciales y académicas que deben darse para llevar a cabo la convocatoria pública de dichas plazas. Se resume, a continuación, cuál es la situación actual existente en relación con dicha figura del profesorado en las facultades de medicina españolas. Se analizan también las ventajas y las posibles limitaciones que actualmente se derivan de contar con profesores contratados doctores vinculados y ello tanto para los médicos especialistas eventualmente interesados en optar a una de estas plazas como para el centro sanitario y la facultad de medicina correspondientes. Finalmente, se reseña la posible utilidad del documento elaborado por la Conferencia Nacional de Decanos de Facultades de Medicina de España (CNDFME) en la Asamblea General que se celebró en la Facultad de Medicina de Oviedo del 17 al 19 de mayo del 2018 y actualizado en marzo de 2020

A discussion is presented on the national legal foundations, and more specifically, those of Andalusia, that support the figure of the tenure-eligible lecturer and the possibility of filling the corresponding positions in the faculties of medicine in Spanish public universities are discussed. The clinical and academic characteristics that they must have in order to fill those public positions are also presented. The current situation as regards such a figure as a lecturer in Spanish faculties of medicine is then summarised. An analysis is made of the advantages and the possible limitations arising from having a tenure-eligible lecturer, and how this affects both the medical specialists possibly interested in opting for one of these positions, as well as for the corresponding health centres and faculties of medicine. Finally, mention is made of the possible use of the document prepared by the National Conference of Medical Faculty Deans (CNDFME) in the General Assembly held in the Oviedo Faculty of Medicine from 17 to 19 May 2018, and updated in March 2020

The general public's knowledge of chronic obstructive pulmonary disease and its determinants: current situation and recent changes.

BACKGROUND: The objective of this study was to determine the level of knowledge about chronic obstructive pulmonary disease (COPD) and its determinants in the general population of Spain, and to compare it with a similar survey conducted in 2002. METHODS: We conducted a cross-sectional, observational, epidemiological study in September 2011 by means of a telephone interview with a representative sample of individuals aged 40-80 years living in all 17 regions of Spain. RESULTS: A total of 6,528 responses were obtained (response rate of 13.1%), 53% of respondents were females with a mean age of 59.8 years. Regarding tobacco use, 19.4% were current smokers while 27.9% reported being former smokers. Only 17.0% spontaneously recognized the term «COPD¼. Valencia was the region with the highest degree of ignorance regarding COPD (91%), while Aragon had the lowest (73.7%). Nevertheless, COPD is considered a severe disease, following angina pectoris in severity. Upon comparing these results with the previous survey from 2002, we observed significant improvements in the knowledge and understanding of COPD (8.6% vs. 17.0%), with a marked variability between the regions (P<.05). Currently, only 4.7% of the Spanish population knows that there is a National Strategy for COPD, although 86.0% have a favorable or very favorable opinion about the new Anti-tobacco Law. CONCLUSION: The lack of knowledge about COPD and its determinants in the general population remains high compared to 2002; thus, more and better educational and awareness programs are necessary.

La enseñanza de la práctica clínica en la Facultad de Medicina de la Universidad Complutense de Madrid / Teaching of clinical practice in the Faculty of Medicine of the Complutense University of Madrid

Se describe la metodología de instrucción y evaluación en práctica clínica y el grado de implicación del profesorado en esta tarea en la Unidad Docente del Hospital 12 de Octubre (Facultad de Medicina, Universidad Complutense de Madrid). A pesar de algunas disfunciones curriculares, nuestros estudiantes alcanzan un buen nivel de competencia clínica al final del grado. Algunos profesores tienen un conocimiento limitado de los roles docentes que pueden asumir, por lo que deberían recibir formación específica. Idealmente, la enseñanza clínica ha de implicar a todos los profesionales que cuidan del paciente en el contexto extra- e intrahospitalario

We describe the methodology for instruction and assessment of clinical practice and analyze the profile and teaching roles of faculty at the Teaching Unit of the Hospital 12 de Octubre (Faculty of Medicine, Complutense University of Madrid). Despite some structural limitations in curriculum development our students reach a good final level of clinical competence. The need for trainers to understand the different roles they can assume, improving faculty development and involving all the professionals taking care of the patient in the teaching process are emphasized