Clinical Heterogeneity of Pulmonary Arterial Hypertension Associated With Variants in TBX4

Background: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. Methods: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. Results: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. Conclusions: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.This project was founded by Project "Bases Gene´tico Moleculares de la Medicina de Precisio´n en la Hipertensio´n Arterial Pulmonar". Funder: Instituto Carlos III. Ministerio de Economı´a y Competitividad. https://www.isciii.es/Paginas/Inicio.aspx Award number: PI 18/01233 Grant Recipient: P E-

Effectiveness of a strategy that uses educational games to implement clinical practice guidelines among Spanish residents of family and community medicine (e-EDUCAGUIA project):A clinical trial by clusters

This study was funded by the Fondo de Investigaciones Sanitarias FIS Grant Number PI11/0477 ISCIII.-REDISSEC Proyecto RD12/0001/0012 AND FEDER Funding.Background: Clinical practice guidelines (CPGs) have been developed with the aim of helping health professionals, patients, and caregivers make decisions about their health care, using the best available evidence. In many cases, incorporation of these recommendations into clinical practice also implies a need for changes in routine clinical practice. Using educational games as a strategy for implementing recommendations among health professionals has been demonstrated to be effective in some studies; however, evidence is still scarce. The primary objective of this study is to assess the effectiveness of a teaching strategy for the implementation of CPGs using educational games (e-learning EDUCAGUIA) to improve knowledge and skills related to clinical decision-making by residents in family medicine. The primary objective will be evaluated at 1 and 6months after the intervention. The secondary objectives are to identify barriers and facilitators for the use of guidelines by residents of family medicine and to describe the educational strategies used by Spanish teaching units of family and community medicine to encourage implementation of CPGs. Methods/design: We propose a multicenter clinical trial with randomized allocation by clusters of family and community medicine teaching units in Spain. The sample size will be 394 residents (197 in each group), with the teaching units as the randomization unit and the residents comprising the analysis unit. For the intervention, both groups will receive an initial 1-h session on clinical practice guideline use and the usual dissemination strategy by e-mail. The intervention group (e-learning EDUCAGUIA) strategy will consist of educational games with hypothetical clinical scenarios in a virtual environment. The primary outcome will be the score obtained by the residents on evaluation questionnaires for each clinical practice guideline. Other included variables will be the sociodemographic and training variables of the residents and the teaching unit characteristics. The statistical analysis will consist of a descriptive analysis of variables and a baseline comparison of both groups. For the primary outcome analysis, an average score comparison of hypothetical scenario questionnaires between the EDUCAGUIA intervention group and the control group will be performed at 1 and 6months post-intervention, using 95% confidence intervals. A linear multilevel regression will be used to adjust the model. Discussion: The identification of effective teaching strategies will facilitate the incorporation of available knowledge into clinical practice that could eventually improve patient outcomes. The inclusion of information technologies as teaching tools permits greater learning autonomy and allows deeper instructor participation in the monitoring and supervision of residents. The long-term impact of this strategy is unknown; however, because it is aimed at professionals undergoing training and it addresses prevalent health problems, a small effect can be of great relevance. Trial registration: ClinicalTrials.gov: NCT02210442.Publisher PDFPeer reviewe

SARS-CoV-2 Infection in Multiple Sclerosis

To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal diseas

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

The role of calprotectin in vascular calcification associated with chronic kidney disease

Chez les patients atteints de maladie rénale chronique (MRC), la morbidité et la mortalité dues aux maladies cardiovasculaires augmentent avec le déclin de la fonction rénale. La calcification vasculaire, via une rigidité artérielle et une insuffisance cardiaque, est un facteur de risque majeur de mortalité chez les patients souffrants de MRC. Favorisée par le trouble du métabolisme minéral et osseux et l'inflammation systémique chez ces patients, la calcification vasculaire est un mécanisme complexe caractérisé par le dépôt anormal de cristaux de calcium et de phosphate dans la paroi vasculaire. Malgré les efforts de recherche intensifs de ces dernières années, les traitements disponibles ont un effet limité et demeurent insuffisants pour reverser la pathologie. Par conséquent, l'objectif de cette thèse était de découvrir de nouveaux acteurs moléculaires associés aux complications cardiovasculaires et à la calcification vasculaire dans la MRC afin de fournir de nouveaux agents thérapeutiques potentiels. À l'aide d'une analyse protéomique et d'une validation par ELISA, nous avons identifié que la calprotectine, une protéine circulante associée à l’inflammation, était associé de manière significative et indépendante à la survenue de complications cardiovasculaires et à la mortalité chez 112 patients MRC (stade 3 et 4) et 171 patients dialysés. Ensuite, dans une cohorte indépendante de 213 patients MRC (stade 5), nous avons démontré qu'une augmentation de la calprotectine sérique était associée à une calcification vasculaire accrue. Le rôle pro-inflammatoire de la calprotectine via l'activation des récepteurs TLR4 (Toll-like receptor 4) et RAGE (Receptor for Advanced Glycation End-Products) a été rapporté dans plusieurs maladies inflammatoires, mais jamais dans la calcification vasculaire. Ainsi, nous avons mis en évidence qu’un traitement par la calprotectine exacerbait la calcification in vitro, en utilisant des cellules musculaires lisses vasculaires primaires humaines et ex vivo, en utilisant des anneaux aortiques de souris. A l’aide d’études mécanistiques, nous avons démontré une implication de RAGE et TLR4 dans cet effet. De manière intéressante, l'utilisation d'un inhibiteur spécifique de la calprotectine, le paquinimod, atténuait l'effet pro-calcifiant de la calprotectine in vitro. Enfin, le rôle protecteur du paquinimod sur la calcification vasculaire a été confirmé in vivo dans deux modèles de souris : le modèle de néphrectomie subtotale et chez des souris âgées ApoE-/-. En conclusion, cette thèse montre que (i) la calprotectine est associée au développement de complications cardiovasculaires, à la mortalité et à l'état de calcification chez les patients atteints de MRC, (ii) la calprotectine favorise la calcification vasculaire (iii) le paquinimod est un nouvel agent thérapeutique efficace sur la calcification vasculaire.In patients with chronic kidney disease (CKD), the risk of cardiovascular disease and mortality steadily increases as kidney function declines. Vascular calcification, leading to aortic stiffening and heart failure, is a decisive risk factor for cardiovascular mortality in patients with CKD. Promoted by bone mineral disorder and systemic inflammation in CKD patients, vascular calcification is a complex mechanism characterised by the abnormal deposition of calcium and phosphate salts in the vascular wall. Despite intensive research efforts in recent years, available treatments still have limited effect. Therefore, the aim of this thesis was to unravel new molecular changes associated to cardiovascular morbid-mortality in CKD and to decipher the role of novel candidates on vascular calcification to provide potential new therapeutic agents. Using serum proteomic analysis and further validation through ELISA, we identified that calprotectin, a circulating damage-associated molecular pattern, was significantly and independently associated with cardiovascular outcome and mortality in 112 CKD3-4 and 171 CKD5 patients on dialysis. Next, in an independent cohort of 213 CKD5 patients, we demonstrated that higher serum calprotectin was associated with increased vascular calcification. The pro-inflammatory role of calprotectin through activation of TLR4 (Toll-like receptor 4) and RAGE (Receptor for Advanced Glycation End-Products), has been reported in several inflammatory disorders, but never in vascular calcification. For this reason, we next evaluated the role of calprotectin in vitro, using human primary vascular smooth muscle cells and ex vivo, using mouse aortic rings. Calprotectin exacerbated calcification in both approaches increasing calcium content and alkaline phosphatase activity. Furthermore, mechanistic studies demonstrated an involvement of RAGE and TLR4 on this effect. Interestingly, the use of a specific inhibitor of calprotectin, named paquinimod, attenuated the pro-calcifying effect of calprotectin in vitro and ex vivo. The protective role of paquinimod on vascular calcification was further demonstrated in two mice models: 5/6 subtotal nephrectomy mice model and in old ApoE-/- mice. To conclude, this thesis shows that (i) calprotectin is associated with cardiovascular outcome, mortality and calcification status in CKD patients, (ii) calprotectin promotes vascular calcification (iii) paquinimod is an effective novel therapeutic agent on vascular calcification

Péptidos bioactivos identificados en hidrolizados enzimáticos de caseínas lácteas y procedimiento de obtención

Péptidos bioactivos identificados en hidrolizados enzimáticos de caseínas lácteas y procedimiento de obtención. La invención consiste en la producción de productos bioactivos derivados de las proteínas lácteas para producción de lactoproductos bioactivos derivados de proteínas de lacteas en especial caseinas. Los diez péptidos objeto de la patente se pueden obtener químicamente, biotecnológicamente o por tratamiento enzimático a partir de proteínas que los contengan y dan lugar a péptidos con actividad antimicrobiana, inhibidora de la enzima convertidora de la anqiotensina in vitro y/o actividad antihipertensiva y/o actividad antioxidante. Estos productos nutraceúticos, ya sea como hidrolizado o como péptido biactivos, son tanto útiles para la industria alimentaria como para la farmacéutica.Consejo Superior de Investigaciones Científicas (España)B1 Patente con informe sobre el estado de la ténic

Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE−/−) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis

Clinical heterogeneity of pulmonary arterial hypertension associated with variants in TBX4

Background The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. Methods Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. Results Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. Conclusions Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate managementInstituto de Salud Carlos III | Ref. PI 18/0123