Profibrotic Role of Inducible Heat Shock Protein 90α Isoform in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-ß, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.

Clinical management and acute exacerbations in patients with idiopathic pulmonary fibrosis in Spain: results from the OASIS study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with decline in lung function and poor prognosis entailing significant impairment in quality of life and high socioeconomic burden. The aim of this study was to characterize clinical management and resources utilization of patients with IPF in Spain, according to predicted forced vital capacity (FVC) % at baseline. METHODS: Prospective, non-interventional, multicentric real-world data study in patients with IPF in Spain with 12-months follow-up. Clinical management and resources utilization during study period were recorded and compared between groups. FVC decline and acute exacerbations occurrence and associated healthcare resource use were also analysed. FVC decline after 12 months was estimated as relative change. RESULTS: 204 consecutive patients with IPF were included and divided according to baseline FVC % predicted value. At baseline, patients with FVC < 50% received significantly more pharmacological and non-pharmacological treatments, and more help from caregiver. During the 12-months follow-up, patients with FVC < 50% required more specialized care visits, emergency visits, hospitalizations, pulmonary functions tests, non-health resource use (special transportation), and pharmacological treatments (p < 0.05 for all comparisons). Moreover, patients with FVC < 50% at baseline experienced more AE-IPF (p < 0.05), requiring more health-related resources use (primary care visits, p < 0.05). FVC decline was observed in all groups over the 12 months. FVC decreased on average by 2.50% (95% CI: - 5.98 to 0.98) along the year. More patients experienced an FVC decline > 10% in the more preserved lung function groups than in the FVC < 50% group, because of their already deteriorated condition. CONCLUSIONS: We observed a significantly higher annual IPF-related resource use in patients with more impaired lung function at baseline. Since FVC decreases irrespective of FVC% predicted at baseline, slowing IPF progression to maintain patients at early disease stages is relevant to improve IPF management and to optimize resource use. TRIAL REGISTRATION: EU PAS register number EUPAS19387 [June 01, 2017].

Demographic, exposure and clinical characteristics in a multinational registry of engineered stone workers with silicosis.

OBJECTIVES: To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry. METHODS: With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher's exact tests and logistic regression. RESULTS: Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity. CONCLUSIONS: Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers.

Epigenetic alterations of TGFß and its main canonical signaling mediators in the context of cardiac fibrosis.

Cardiac fibrosis is a pathological process that presents a continuous overproduction of extracellular matrix (ECM) components in the myocardium, which negatively influences the progression of many cardiac diseases. Transforming growth factor ß (TGFß) is the main ligand that triggers the production of pro-fibrotic ECM proteins. In the cardiac fibrotic process, TGFß and its canonical signaling mediators are tightly regulated at different levels as well as epigenetically. Cardiac fibroblasts are one of the most important TGFß target cells activated after cardiac injury. TGFß-driven fibroblast activation is subject to epigenetic modulation and contributes to the progression of cardiac fibrosis, mainly through the expression of pro-fibrotic molecules implicated in the disease. In this review, we describe epigenetic regulation related to canonical TGFß signaling in cardiac fibroblasts.

Mapping IPF helps identify geographic regions at higher risk for disease development and potential triggers.

BACKGROUND AND OBJECTIVE: The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis (IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross-analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development. METHODS: This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data. RESULTS: In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent. CONCLUSION: In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.

Long-term outcomes in chronic hypersensitivity pneumonitis.

INTRODUCTION: The objective of this study was to analyze mortality, possible predictors of long-term survival, and health-related quality of life of a large chronic hypersensitivity pneumonitis (CHP) patient sample. METHODS: Longitudinal study in patients diagnosed with CHP during 2004-2013, followed for at least 1 year. Patients remaining alive and consenting to participate had a follow-up visit during 2015, including a complete pulmonary function study and the EuroQol-5D and Beck Depression and Anxiety Inventories. RESULTS: Out of the 160 patients finally included, 87 remained alive. Seventy-three had died or underwent lung transplantation at the time of the study with a median survival of 7.0 (4.4-14.5) years. A Cox proportional risk model showed that factors associated with lower survival were as follows: increased age, a low percentage of lymphocytes in bronchoalveolar lavage (BAL), a decreased transfer factor of the lung for carbonmonoxide (DLCO), presence of honeycomb in the high-resolution chest scan (HRCT), and the usual interstitial pneumonia (UIP) histologic pattern. At follow-up, all patients presented an EuroQol-5D score <0.8 and 21(50%) and 9(28.6%) subjects presented a probable anxiety and depressive syndrome, respectively. CONCLUSION: CHP is a severe disease with a bad mid-term prognosis. Lymphocyte values in BAL and DLCO values at baseline, presence of honeycomb in HRCT, and UIP histologic pattern were found to be predictors of survival. Early accurate diagnosis of the disease is fundamental for prompt initiation of antigen avoidance.

p-SMAD2/3 and DICER promote pre-miR-21 processing during pressure overload-associated myocardial remodeling.

Transforming growth factor-ß (TGF-ß) induces miR-21 expression which contributes to fibrotic events in the left ventricle (LV) under pressure overload. SMAD effectors of TGF-ß signaling interact with DROSHA to promote primary miR-21 processing into precursor miR-21 (pre-miR-21). We hypothesize that p-SMAD-2 and -3 also interact with DICER1 to regulate the processing of pre-miR-21 to mature miR-21 in cardiac fibroblasts under experimental and clinical pressure overload. The subjects of the study were mice undergoing transverse aortic constriction (TAC) and patients with aortic stenosis (AS). In vitro, NIH-3T3 fibroblasts transfected with pre-miR-21 responded to TGF-ß1 stimulation by overexpressing miR-21. Overexpression and silencing of SMAD2/3 resulted in higher and lower production of mature miR-21, respectively. DICER1 co-precipitated along with SMAD2/3 and both proteins were up-regulated in the LV from TAC-mice. Pre-miR-21 was isolated bound to the DICER1 maturation complex. Immunofluorescence analysis revealed co-localization of p-SMAD2/3 and DICER1 in NIH-3T3 and mouse cardiac fibroblasts. DICER1-p-SMAD2/3 protein-protein interaction was confirmed by in situ proximity ligation assay. Myocardial up-regulation of DICER1 constituted a response to pressure overload in TAC-mice. DICER mRNA levels correlated directly with those of TGF-ß1, SMAD2 and SMAD3. In the LV from AS patients, DICER mRNA was up-regulated and its transcript levels correlated directly with TGF-ß1, SMAD2, and SMAD3. Our results support that p-SMAD2/3 interacts with DICER1 to promote pre-miR-21 processing to mature miR-21. This new TGFß-dependent regulatory mechanism is involved in miR-21 overexpression in cultured fibroblasts, and in the pressure overloaded LV of mice and human patients.

Hypersensitivity Pneumonitis: Challenges in Diagnosis and Management, Avoiding Surgical Lung Biopsy.

This review presents an update of the currently available information related to hypersensitivity pneumonitis, with a particular focus on the contribution of several techniques in the diagnosis of this condition. The methods discussed include proper elaboration of a complete medical history, targeted auscultation, detection of specific immunoglobulin G antibodies against the most common antigens causing this disease, skin tests, antigen-specific lymphocyte activation assays, bronchoalveolar lavage, and cryobiopsy. Special emphasis is placed on the relevant contribution of specific inhalation challenge (bronchial challenge test). Surgical lung biopsy is presented as the ultimate recourse, to be used when the diagnosis cannot be reached through the other methods covered.

Is lack of antibiotic usage affecting udder health status of organic dairy cattle?

This research communication aimed to compare somatic cell count (SCC), the main marker of udder health status, in organic farms not using antibiotics (O, n = 6), organic farms using antibiotics (OA, n = 7) and conventional farms (CA, n = 5) using antibiotic treatments, all of them at pasture. SCC was statistically significantly higher in O (173780) compared to CA (93325) and OA (107152). Milk yield had a significant diluting effect on SCC and differences between groups increased with parities. Stratified analysis of SCC depending on lactation number and % of monthly SCC test with different linear scores (LS) indicated that there is no difference in udder health in the primiparous heifers from the three groups of farms, but it deteriorates in older cows because of chronic infections in O (possibly due to lack of antibiotic use). Our results suggest that the non-use of antibiotics had an effect in udder health leading to higher occurrence of clinical and subclinical mastitis. Therefore, preventive management practices for mastitis control are essential in organic farms.

Use of homeopathy in organic dairy farming in Spain.

Organic farming principles promote the use of unconventional therapies as an alternative to chemical substances (which are limited by organic regulations), with homeopathy being the most extensive. Traditionally, Spain has had little faith in homeopathy but its use in organic farming is growing. Fifty-six Spanish organic dairy farmers were interviewed to obtain what we believe to be the first data on the use of homeopathy in organic dairy cattle in Spain. Only 32% of farms use some sort of alternative therapy (16.1% homeopathy, 10.7% phytotherapy and 5.3% using both therapies) and interestingly, a clear geographical pattern showing a higher use towards the East (similar to that in the human population) was observed. The main motivation to use homeopathy was the need to reduce chemical substances promoted by organic regulations, and the treatment of clinical mastitis being the principle reason. The number of total treatments was lower in farms using homeopathy compared with those applying allopathic therapies (0.13 and 0.54 treatments/cow/year respectively) and although the bulk SCC was significantly higher (p < 0.001) in these farms (161,826 and 111,218 cel/ml, respectively) it did not have any negative economical penalty for the farmer and milk quality was not affected complying with the required standards; on the contrary homeopathic therapies seems to be an alternative for reducing antibiotic treatments, allowing farmers to meet the organic farming principles.

BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-ß signaling.

Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-ß (TGF-ßs) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-ß signaling. The present study tests the hypothesis that BAMBI plays a protective role during the adverse LV remodeling under pressure overload. The subjects of the study were BAMBI knockout mice (BAMBI(-/-)) undergoing transverse aortic constriction (TAC) and patients with severe aortic stenosis (AS). We examined LV gene and protein expression of remodeling-related elements, histological fibrosis, and heart morphology and function. LV expression of BAMBI was increased in AS patients and TAC-mice and correlated directly with TGF-ß. BAMBI deletion led to a gain of myocardial TGF-ß signaling through canonical (Smads) and non-canonical (TAK1-p38 and TAK1-JNK) pathways. As a consequence, the remodeling response to pressure overload in BAMBI(-/-) mice was exacerbated in terms of hypertrophy, chamber dilation, deterioration of long-axis LV systolic function and diastolic dysfunction. Functional remodeling associated transcriptional activation of fibrosis-related TGF-ß targets, up-regulation of the profibrotic micro-RNA-21, histological fibrosis and increased metalloproteinase-2 activity. Histological remodeling in BAMBI(-/-) mice involved TGF-ßs. BAMBI deletion in primary cardiac fibroblasts exacerbated TGF-ß-induced profibrotic responses while BAMBI overexpression in NIH-3T3 fibroblasts attenuated them. Our findings identify BAMBI as a critical negative modulator of myocardial remodeling under pressure overload. We suggest that BAMBI is involved in negative feedback loops that restrain the TGF-ß remodeling signals to protect the pressure-overloaded myocardium from uncontrolled extracellular matrix deposition in humans and mice.

Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis.

Reliable methods are needed to diagnose hypersensitivity pneumonitis. The aim of the study was to establish the diagnostic yield of specific inhalation challenge (SIC) in patients with hypersensitivity pneumonitis. All patients with suspected hypersensitivity pneumonitis in whom SIC was performed (n=113) were included. SIC was considered positive when patients showed a decrease of >15% in forced vital capacity (FVC) or >20% in diffusing capacity of the lung for carbon dioxide, or a decrease of 10% to 15% in FVC accompanied by a temperature increase of 0.5°C within 24 h of inhalation of the antigen. SIC was positive to the agents tested in 68 patients: 64 received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-positive in the remaining four patients. In the SIC-negative group (n=45), 24 patients received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-negative, and 21 patients were diagnosed with other respiratory diseases. The sensitivity and specificity of the test were 72.7% and 84%, respectively. Having hypersensitivity pneumonitis caused by an antigen other than birds or fungi predicted a false-negative result (p=0.001). In hypersensitivity pneumonitis, positive SIC testing virtually confirms the diagnosis, whereas negative testing does not rule it out, especially when the antigenic sources are not birds or fungi.

Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study.

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤ 24 h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose >200mg versus ≤ 200 mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended.

Bronchial inflammation in hypersensitivity pneumonitis after antigen-specific inhalation challenge.

BACKGROUND AND OBJECTIVE: The aim of this study is to compare the inflammatory profile before and after specific inhalation challenge (SIC) in induced sputum from patients with hypersensitivity pneumonitis (HP) and to investigate whether different causal antigens define the resulting profile. METHODS: A prospective study was conducted in 27 patients with HP: 15 patients due to exposure to birds (BHP) and 12 due to exposure to fungi (FHP), confirmed by SIC. Induced sputum was obtained before and/or 24 h after SIC. Cell types were determined by differential cell count using optical microscopy. Interferon-γ, interleukin (IL)-12p70, IL-2, IL-10, IL-8, IL-6, IL-4, IL-5, IL-1ß, tumour necrosis factor (TNF)-α and TNF-ß levels were measured in the supernatants. RESULTS: Following SIC, higher sputum neutrophilia levels (P = 0.048) and an increase in IL-8 levels (P = 0.017) were found in patients with FHP than in those with BHP. FHP patients also showed increased IL-1ß, IL12-p70 and IL5 levels (P = 0.011, P = 0.036 and P = 0.018, respectively) after SIC. In BHP, a trend towards increases in sputum eosinophils and TH2 cytokines (IL4, IL5) was seen following SIC (P = 0.059, P = 0.068 and P = 0.075 respectively). CONCLUSIONS: This study shows that bronchial inflammation is present in patients with HP evidenced by increases in sputum neutrophils and eosinophils following exposure to the offending antigen during SIC.

Fibroblast-derived extracellular vesicles as trackable efficient transporters of an experimental nanodrug with fibrotic heart and lung targeting.

The discovery of extracellular vesicles (EVs) as efficient exogenous biotransporters of therapeutic agents into cells across biological membranes is an exciting emerging field. Especially the potential of EVs as targeted delivery systems for diseases with selective treatments, such as fibrosis, whose treatment causes side effects in other organs not involved in the disease. Methods: In this study, we collected embryonic fibroblast-derived EVs from two different centrifugation fractions, 10 K g and 100 K g fractions from a NIH-3T3 cell line loaded with an experimental drug. Mice with fibrotic hearts and lungs were obtained by administration of angiotensin II. We generated fluorescent EVs and bioluminescent drug to observe their accumulation by colocalization of their signals in fibrotic heart and lung. The biodistribution of the drug in various organs was obtained by detecting the Au present in the drug nanostructure. Results: The drug-loaded EVs successfully reduced fibrosis in pathological fibroblasts in vitro, and modified the biodistribution of the experimental drug, enabling it to reach the target organs in vivo. We described the pre-analytical characteristics of EVs related to physical variables, culture and harvesting conditions, crucial for their in vivo application as nanotransporters using a previously validated protein-based antifibrotic drug. The results showed the colocalization of EVs and the experimental drug in vivo and ex vivo and the efficient reduction of fibrosis in vitro. This work demonstrates that 10K-EVs and 100K-EVs derived from fibroblasts can act as effective biotransporters for targeted drug delivery to profibrotic fibroblasts, lungs, or heart. Conclusion: We observed that fibroblast-derived 10K-EVs and 100K-EVs are useful biotransporters encapsulating a new generation drug leading to a reduction of fibrosis in profibrotic fibroblasts in vitro. In addition, drug containing EVs were shown to reach fibrotic heart and lungs in vivo, enhancing free drug biodistribution.

Long-term effect of tocilizumab on mortality, readmissions, persistent symptoms and lung function in SARS-CoV-2 patients 1 year after hospital discharge: A matched cohort study.

BACKGROUND: Tocilizumab is presumed to be an effective and safe treatment for severe SARS-Cov-2, but its usefulness has not been investigated yet for long-term outcomes. This study aimed to evaluate the influence of tocilizumab on mortality in patients with SARS-CoV-2 throughout the year following discharge. METHODS: A retrospective observational analysis was performed on electronic medical records of patients with SARS-CoV2 who were discharged from our hospital after surviving the first wave in March-April 2020. Logistic regression was used to analyse the effect of tocilizumab on mortality, as the main outcome, and propensity-score analysis to further validate their effect. Secondary outcomes were readmissions, persistent symptoms and lung function evolution. Patients were selected by matching their individual propensity for receiving therapy with tocilizumab, conditional on their demographic and clinical variables. RESULTS: A total of 405 patients were included in the mortality study (33.6 % were treated with tocilizumab) and 390 were included in the assessment of persistent symptoms. After propensity-score analysis, no association between tocilizumab use and 1-year overall mortality was found (HR= 2.05, 95 % CI: 0.21-19.98). No differences regarding persistent symptoms (OR= 1.01 95 %CI 0.57-1.79), nor lung function parameters (forced vital capacity: coefficient -0.16 95 %CI -0.45 to 0.14) were found throughout the year follow-up between control and tocilizumab group. CONCLUSIONS: The administration of tocilizumab in patients with SARS-CoV-2 did not show any effect on long-term mortality. Identically, no association were found regarding readmissions, persistent symptoms or lung function evolution and tocilizumab administration in our cohort of patients after 1 year follow-up.

Economic Burden of Idiopathic Pulmonary Fibrosis in Spain: A Prospective Real-World Data Study (OASIS Study).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease associated with dyspnoea, cough and impaired quality of life affecting around 7500 patients in Spain. OBJECTIVE: Our aim was to estimate the economic impact of IPF according to forced vital capacity (FVC) % predicted level in adult patients. METHODS: We conducted a prospective, observational, multicentric study of patients with confirmed IPF in Spain. Total annual IPF-related costs were estimated per patient, and categorised according to the FVC% predicted value (FVC < 50%, FVC 50-80%, FVC > 80%) and total sample. Incurred direct health- and non-health-related costs and indirect costs were calculated considering the IPF-related healthcare resource use and the corresponding unitarian costs. Results were updated to 2023 euros. RESULTS: Two hundred and four consecutive patients with IPF were included: 77% male, average age (standard deviation) 70.8 (7.6) years. At baseline, FVC% was < 50%, 50-80% and > 80% of predicted value in 10.8%, 74.5% and 14.7% of patients, respectively. The final cost-evaluable population included 180 subjects. The mean (standard deviation) total annual IPF-related cost was €26,997 (17,555), with statistically significant differences (p = 0.0002) between groups: €44,412 (33,389) for the FVC < 50%, €25,803 (14,688) for the FVC 50-80% and €23,242 (13,642) for the FVC > 80%. Annual direct health costs had the greatest weight and included pharmacological treatments [€22,324 (13,773)] and hospitalisation days [€1659 (7362)]. 14 patients had ≥ 1 acute exacerbation of IPF during the study; mean total cost of an acute exacerbation of IPF was €10,372. According to the multivariate analysis, an impaired lung function (FVC < 50%) and use of antifibrotic treatment were determinants of cost (p < 0.0001 both). CONCLUSIONS: We observed a significantly higher annual IPF-related cost at a lower level of predicted FVC%, the direct cost having the greatest weight to the total costs. Maintaining patients at early disease stages by slowing IPF progression is relevant to reduce the economic impact of IPF. CLINICAL TRIAL REGISTRATION: EU PAS register number EUPAS19387 (1 June, 2017).

Assessment of Individualized Mean Perfusion Pressure Targets for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury-The PrevHemAKI Randomized Controlled Trial.

BACKGROUND: Retrospective studies support that mean perfusion pressure (MPP) deficit in cardiac surgery patients is associated with a higher incidence of acute kidney injury (CS-AKI). The aim of our study was to apply an algorithm based on MPP in the postoperative period to determine whether management with an individualized target reduces the incidence of CS-AKI. METHODS: Randomized controlled trial of patients undergoing cardiac surgery with extracorporeal circulation. Adult patients submitted to valve replacement and/or bypass surgery with a high risk of CS-AKI evaluated by a Leicester score >30 were randomized to follow a target MPP of >75% of the calculated baseline or a standard hemodynamic management during the first postoperative 24 h. RESULTS: Ninety-eight patients with an eGFR of 54 mL/min were included. There were no differences in MAP and MPP in the first 24 h between the randomized groups, although a higher use of noradrenaline was found in the intervention arm (38.78 vs. 63.27, p = 0.026). The percentage of time with MPP < 75% of measured baseline was similar in both groups (10 vs. 12.7%, p = 0.811). MAP during surgery was higher in the intervention group (73 vs. 77 mmHg, p = 0.008). The global incidence of CS-AKI was 36.7%, being 38.6% in the intervention group and 34.6% in the control group (p = 0.40). There were no differences in extrarenal complications between groups as well. CONCLUSION: An individualized hemodynamic management based on MPP compared to standard treatment in cardiac surgery patients was safe but did not reduce the incidence of CS-AKI in our study.