Actin Isoform Composition and Binding Factors Fine-Tune Regulatory Impact of Mical Enzymes.

Mical family enzymes are unusual actin regulators that prime filaments (F-actin) for disassembly via the site-specific oxidation of M44/M47. Filamentous actin acts as a substrate of Mical enzymes, as well as an activator of their NADPH oxidase activity, which leads to hydrogen peroxide generation. Mical enzymes are required for cytokinesis, muscle and heart development, dendritic pruning, and axonal guidance, among other processes. Thus, it is critical to understand how this family of actin regulators functions in different cell types. Vertebrates express six actin isoforms in a cell-specific manner, but MICALs' impact on their intrinsic properties has never been systematically investigated. Our data reveal the differences in the intrinsic dynamics of Mical-oxidized actin isoforms. Furthermore, our results connect the intrinsic dynamics of actin isoforms and their redox state with the patterns of hydrogen peroxide (H2O2) generation by MICALs. We documented that the differential properties of actin isoforms translate into the distinct patterns of hydrogen peroxide generation in Mical/NADPH-containing systems. Moreover, our results establish a conceptual link between actin stabilization by interacting factors and its ability to activate MICALs' NADPH oxidase activity. Altogether, our results suggest that the regulatory impact of MICALs may differ depending on the isoform-related identities of local actin networks.

Temperature variation in caves and its significance for subterranean ecosystems.

Climate change affects all ecosystems, but subterranean ecosystems are repeatedly neglected from political and public agendas. Cave habitats are home to unknown and endangered species, with low trait variability and intrinsic vulnerability to recover from human-induced disturbances. We studied the annual variability and cyclicity of temperatures in caves vis-à-vis surface in different climatic areas. We hypothesize that cave temperatures follow the average temperature pattern at the surface for each location with a slight delay in the signal, but we found three different thermal patterns occurring in caves: (1) high positive correlation and a similar thermal pattern to the surface, (2) low correlation and a slight thermal delay of the signal from the surface, and (3) high negative correlation with an extreme delay from the surface. We found daily thermal cycles in some caves, which may potentially control the circadian rhythms of cave organisms. Our results show that caves had lower thermal amplitude than the surface, and that thermal averages within caves approximately correspond to the to the annual average of surface temperature. Caves buffer external temperature and act as refugia for biota in extreme climatic events. Likewise, temperature increases at surface will lead to increment in caves, threatening subterranean biota and ecosystem services.

Phosphorus May Induce Phenotypic Transdifferentiation of Vascular Smooth Muscle Cells through the Reduction of microRNA-145.

Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney disease; however, it is not clear its effect in a population without kidney damage. The objective of this in vivo and in vitro study was to investigate the effect of high phosphorus exposure on the aortic and serum levels of miR-145 and its effect on vascular smooth muscle cell (VSMCs) changes towards less contractile phenotypes. The study was performed in aortas and serum from rats fed standard and high-phosphorus diets, and in VSMCs exposed to different concentrations of phosphorus. In addition, miR-145 silencing and overexpression experiments were carried out. In vivo results showed that in rats with normal renal function fed a high P diet, a significant increase in serum phosphorus was observed which was associated to a significant decrease in the aortic α-actin expression which paralleled the decrease in aortic and serum miR-145 levels, with no changes in the osteogenic markers. In vitro results using VSMCs corroborated the in vivo findings. High phosphorus first reduced miR-145, and afterwards α-actin expression. The miR-145 overexpression significantly increased α-actin expression and partially prevented the increase in calcium content. These results suggest that miR-145 could be an early biomarker of vascular calcification, which could give information about the initiation of the transdifferentiation process in VSMCs.

Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy.

Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.

Experimental Models to Study Diabetes Mellitus and Its Complications: Limitations and New Opportunities.

Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-iddm, as representative models of type 1 DM (DM-1); the Zucker diabetic fatty (ZDF) and Goto-kakizaki (GK) rats, as representative models of type 2 DM (DM-2); and other models induced by surgical, dietary and pharmacological-alloxan and streptozotocin-procedures. Given the variety of DM models in rats, as well as the non-uniformity in the protocols and the absence of all the manifestation of the long-term multifactorial complications of DM in humans, the researchers must choose the one that best suits the final objectives of the study. These circumstances, added to the fact that most of the experimental research in the literature is focused on the study of the early phase of DM, makes it necessary to develop long-term studies closer to DM in humans. In this review, a recently published rat DM model induced by streptozotocin injection with chronic exogenous administration of insulin to reduce hyperglycaemia has also been included in an attempt to mimic the chronic phase of DM in humans.

Mineral and bone metabolism markers and mortality in diabetic patients on haemodialysis.

BACKGROUND: Diabetic patients on haemodialysis have a higher risk of mortality than non-diabetic patients. The aim of this COSMOS (Current management of secondary hyperparathyroidism: a multicentre observational study) analysis was to assess whether bone and mineral laboratory values [calcium, phosphorus and parathyroid hormone (PTH)] contribute to this risk. METHODS: COSMOS is a multicentre, open-cohort, 3-year prospective study, which includes 6797 patients from 227 randomly selected dialysis centres in 20 European countries. The association between mortality and calcium, phosphate or PTH was assessed using Cox proportional hazard regression models using both penalized splines smoothing and categorization according to KDIGO guidelines. The effect modification of the association between the relative risk of mortality and serum calcium, phosphate or PTH by diabetes was assessed. RESULTS: There was a statistically significant effect modification of the association between the relative risk of mortality and serum PTH by diabetes (P = .011). The slope of the curve of the association between increasing values of PTH and relative risk of mortality was steeper for diabetic compared with non-diabetic patients, mainly for high levels of PTH. In addition, high serum PTH (>9 times the normal values) was significantly associated with a higher relative risk of mortality in diabetic patients but not in non-diabetic patients [1.53 (95% confidence interval 1.07-2.19) and 1.17 (95% confidence interval 0.91-1.52)]. No significant effect modification of the association between the relative risk of mortality and serum calcium or phosphate by diabetes was found (P = .2 and P = .059, respectively). CONCLUSION: The results show a different association of PTH with the relative risk of mortality in diabetic and non-diabetic patients. These findings could have relevant implications for the diagnosis and treatment of chronic kidney disease-mineral and bone disorders.

Role of Klotho and AGE/RAGE-Wnt/ß-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes.

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/ß-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-ß1, and Wnt/ß-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats.

Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Pancreatitis crónica: análisis de factores de progresión de la enfermedad / Chronic pancreatitis: analysis of disease progression factors

BACKGROUND: Alcohol and tobacco are important risk factors for chronic pancreatitis (CP). AIM: To analyze the effect of etiological factors such as tobacco and alcohol and pancreatic enzyme replacement therapy (PERT) in the progression of CP. MATERIAL AND METHODS: Patients with a diagnosis of CP were recruited and grouped according to variables such as tobacco, alcohol and PERT. They were followed for 18 months. Subsequently, different variables and analytical parameters involved in the progression of the disease were analyzed. RESULTS: A total of 50 patients diagnosed with CP were included. Of these, 28 patients underwent PERT, 39 were smokers and 33 were alcohol users. Compared with patients without PERT, those with PERT had a higher proportion of diabetes (64 and 32%, respectively), had a higher need for endoscopic treatment (25 and 0%, respectively) and a normal body mass index (71 and 27.3%, respectively. The smokers had higher calcium levels and increased lymphocytosis and leukocytosis. The alcohol consumption group had a higher mean age (p = 0.04) CONCLUSIONS: PERT may improve the nutritional status but does not reduce the need for endoscopic or surgical treatment. Smoking and alcohol consumption favored the progression of CP. Also, smoking induced a pro-inflammatory state.

Adverse events: an expensive and avoidable hospital problem.

INTRODUCTION: Adverse healthcare-related events (AE) entail reduced patient safety. Estimating their frequency, characteristics, avoidability and impact is a means to identify targets for improvement in the quality of care. METHODS: This was a descriptive observational study conducted within the Patient Safety Incident Study in Hospitals in the Community of Madrid (ESHMAD). The study was conducted in a high-complexity hospital in May 2019 through a two-phase electronic medical record review: (1) AE screening and epidemiological and clinical data collection and (2) AE review and classification and analysis of their impact, avoidability, and associated costs. RESULTS: A total of 636 patients were studied. The prevalence of AE was 12.4%. Death during the stay was associated with the presence of AE (OR [CI95%]: 2.15 [1.07 to 4.52]) versus absence and emergency admission (OR [CI95%]: 17.11[6.63 to 46.26]) versus scheduled. A total of 70.2% of the AEs were avoidable. Avoidable AEs were associated with the presence of pressure ulcers (OR [CI95%]: 2.77 [1.39 to 5.51]), central venous catheter (OR [CI95%]: 2.58 [1.33 to 5.00]) and impaired mobility (OR [CI95%]: 2.24[1.35 to 3.71]), versus absences. They were associated too with the stays in the intensive care unit (OR [CI95%]: 2.75 [1.07 to 7.06]) versus medical service. AEs were responsible for additional costs of €909,716.8 for extra days of stay and €12,461.9 per patient with AE. CONCLUSIONS: The prevalence of AEs was similar to that found in other studies. AEs led to worse patient outcomes and were associated with the patient's death. Although avoidable AEs were less severe, their higher frequency produced a greater impact on the patient and healthcare system.Key messagesAdverse events are one of the main problems in healthcare delivery and patients who suffer from at least one AE are double as likely to die during hospitalization.Avoidable adverse events are the most frequent in health care and they are a good target where achieve improvement areas that allow getting optimal patient safety and quality of care levels.Patients hospitalized in the ICU, with the previous presence of pressure ulcers, central venous catheter, or impaired mobility were associated with the development of avoidable AE, so optimal management of these patients would reduce the impact of AE.

Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients.

Salmonella enterica subsp. enterica serotypes isolated for the first time in feral cats: The impact on public health.

Stray cat populations can represent a significant threat of the transmission of zoonotic diseases such as salmonellosis. The objective of this study was to assess Salmonella carriage by free-living cats in Gran Canaria island and the Salmonella serovars involved, in order to inform to those responsible for the colonies about the possible risk factors. One hundred rectal swabs of feral cats were taken. Salmonella strains were serotyped in accordance with Kauffman-White-Le-Minor technique. Of a total of 100 animals under study, 19% were found to be positive to Salmonella spp. This is the first report that described the zoonotic serovars S. Nima, S. Bredeney, S. Grancanaria and S. Kottbus in cats. The present study demonstrates that feral cats may represent a source of risk for the spread of different Salmonella zoonotic serovars. It has been reported that there is a certain correlation between Salmonella isolates from pets and wild animals. Further studies are needed from other animal species and environmental sources to make this correlation.

A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D-a randomised multicentre international clinical trial.

BACKGROUND: Vitamin D status has been implicated in COVID-19 disease. The objective of the COVID-VIT-D trial was to investigate if an oral bolus of cholecalciferol (100,000 IU) administered at hospital admission influences the outcomes of moderate-severe COVID-19 disease. In the same cohort, the association between baseline serum calcidiol levels with the same outcomes was also analysed. METHODS: The COVID-VIT-D is a multicentre, international, randomised, open label, clinical trial conducted throughout 1 year. Patients older than 18 years with moderate-severe COVID-19 disease requiring hospitalisation were included. At admission, patients were randomised 1:1 to receive a single oral bolus of cholecalciferol (n=274) or nothing (n=269). Patients were followed from admission to discharge or death. Length of hospitalisation, admission to intensive care unit (ICU) and mortality were assessed. RESULTS: In the randomised trial, comorbidities, biomarkers, symptoms and drugs used did not differ between groups. Median serum calcidiol in the cholecalciferol and control groups were 17.0 vs. 16.1 ng/mL at admission and 29.0 vs. 16.4 ng/mL at discharge, respectively. The median length of hospitalisation (10.0 [95%CI 9.0-10.5] vs. 9.5 [95%CI 9.0-10.5] days), admission to ICU (17.2% [95%CI 13.0-22.3] vs. 16.4% [95%CI 12.3-21.4]) and death rate (8.0% [95%CI 5.2-12.1] vs. 5.6% [95%CI 3.3-9.2]) did not differ between the cholecalciferol and control group. In the cohort analyses, the highest serum calcidiol category at admission (>25ng/mL) was associated with lower percentage of pulmonary involvement and better outcomes. CONCLUSIONS: The randomised clinical trial showed the administration of an oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve the outcomes of the COVID-19 disease. A cohort analysis showed that serum calcidiol at hospital admission was associated with outcomes. TRIAL REGISTRATION: COVID-VIT-D trial was authorised by the Spanish Agency for Medicines and Health products (AEMPS) and registered in European Union Drug Regulating Authorities Clinical Trials (EudraCT 2020-002274-28) and in ClinicalTrials.gov ( NCT04552951 ).

[Chronic pancreatitis: analysis of disease progression factors]. / Pancreatitis crónica: análisis de factores de progresión de la enfermedad.

BACKGROUND: Alcohol and tobacco are important risk factors for chronic pancreatitis (CP). AIM: To analyze the effect of etiological factors such as tobacco and alcohol and pancreatic enzyme replacement therapy (PERT) in the progression of CP. MATERIAL AND METHODS: Patients with a diagnosis of CP were recruited and grouped according to variables such as tobacco, alcohol and PERT. They were followed for 18 months. Subsequently, different variables and analytical parameters involved in the progression of the disease were analyzed. RESULTS: A total of 50 patients diagnosed with CP were included. Of these, 28 patients underwent PERT, 39 were smokers and 33 were alcohol users. Compared with patients without PERT, those with PERT had a higher proportion of diabetes (64 and 32%, respectively), had a higher need for endoscopic treatment (25 and 0%, respectively) and a normal body mass index (71 and 27.3%, respectively. The smokers had higher calcium levels and increased lymphocytosis and leukocytosis. The alcohol consumption group had a higher mean age (p = 0.04) Conclusions: PERT may improve the nutritional status but does not reduce the need for endoscopic or surgical treatment. Smoking and alcohol consumption favored the progression of CP. Also, smoking induced a pro-inflammatory state.

Recommendations for prevention of infection in systemic autoimmune rheumatic diseases.

OBJECTIVES: To develop recommendations for the prevention of infection in adult patients with systemic autoimmune rheumatic diseases (SARD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of experts selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network criteria. Specific recommendations were made. RESULTS: Five questions were selected, referring to prevention of infection by Pneumocystis jirovecii with trimethoprim/sulfamethoxazole, primary and secondary prophylactic measures against hepatitis B virus, vaccination against human papillomavirus, vaccination against Streptococcus pneumoniae and vaccination against influenza virus, making a total of 18 recommendations, structured by question, based on the evidence found for the different SARD and/or expert consensus. CONCLUSIONS: There is enough evidence on the safety and efficacy of vaccinations and other prophylactic measures against the microorganisms reviewed in this document to specifically recommend them for patients with SARD.

Survival with low- and high-flux dialysis.

BACKGROUND: Besides advances in haemodialysis (HD), mortality rates are still high. The effect of the different types of HD membranes on survival is still a controversial issue. The aim of this COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis was to survey, in HD patients, the relationship between the use of conventional low- or high-flux membranes and all-cause and cardiovascular mortality. METHODS: COSMOS is a multicentre, open-cohort, 3-year prospective study, designed to evaluate mineral and bone disorders in the European HD population. The present analysis included 5138 HD patients from 20 European countries, 3502 randomly selected at baseline (68.2%), plus 1636 new patients with <1 year on HD (31.8%) recruited to replace patients who died, were transplanted, switched to peritoneal dialysis or lost to follow-up by other reasons. Cox-regression analysis with time-dependent variables, propensity score matching and the use of an instrumental variable (facility-level analysis) were used. RESULTS: After adjustments using three different multivariate models, patients treated with high-flux membranes showed a lower all-cause and cardiovascular mortality risks {hazard ratio (HR) = 0.76 [95% confidence interval (CI) 0.61-0.96] and HR = 0.61 (95% CI 0.42-0.87), respectively}, that remained significant after matching by propensity score for all-cause mortality (HR = 0.69, 95% CI 0.52-0.93). However, a facility-level analysis showed no association between the case-mix-adjusted facility percentage of patients dialysed with high-flux membranes and all-cause and cardiovascular mortality. CONCLUSIONS: High-flux dialysis was associated with a lower relative risk of all-cause and cardiovascular mortality. However, dialysis facilities using these dialysis membranes to a greater extent did not show better survival.

Recommendations for prevention of infection in systemic autoimmune rheumatic diseases. / Recomendaciones SER sobre prevención de infección en enfermedades reumáticas autoinmunes sistémicas.

OBJECTIVES: To develop recommendations for the prevention of infection in adult patients with systemic autoimmune rheumatic diseases (SARD). METHODS: Clinical research questions relevant to the objective of the document were identified by a panel of experts selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network criteria. Specific recommendations were made. RESULTS: Five questions were selected, referring to prevention of infection by Pneumocystis jirovecii with trimethoprim/sulfamethoxazole, primary and secondary prophylactic measures against hepatitis B virus, vaccination against human papillomavirus, vaccination against Streptococcus pneumoniae and vaccination against influenza virus, making a total of 18 recommendations, structured by question, based on the evidence found for the different SARD and/or expert consensus. CONCLUSIONS: There is enough evidence on the safety and efficacy of vaccinations and other prophylactic measures against the microorganisms reviewed in this document to specifically recommend them for patients with SARD.

Multicenter Study of Secukinumab Survival and Safety in Spondyloarthritis and Psoriatic Arthritis: SEcukinumab in Cantabria and ASTURias Study.

Objectives: We aimed to evaluate the drug retention rate and safety of secukinumab (SEC) in patients with axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA) in a real clinical setting. Methods: This multicenter retrospective observational study included all AxSpA and PsA patients who received at least one dose of SEC. Adverse events (AE) and the drug retention rate were the main study outcomes. Drug survival was analyzed by Kaplan-Meier curves while predictive factors of discontinuation were evaluated using a Cox regression analysis. The weight of these associations was estimated by hazard ratio (HR) values. Results: We included 154 patients (59 PsA and 95 AxSpA). Mean disease duration was 6.5 years (IQR 2-8). Sixty-one percent of patients were treated with two or more biologics prior to SEC. The 1 and 2-year retention rates for SEC were 66 and 43%, respectively. The main causes of discontinuation were inefficacy (59%) and AE (36%). The factors associated with lower risk of discontinuation were male gender (HR 0.54, 95% CI 0.38-0.78 p = 0.001), obesity (HR 0.53, 95% CI 0.30-0.93 p = 0.027), hypertension (HR 0.55, 95% CI 0.30-0.93 p = 0.008), and diabetes (HR 0.42 95% CI 0.18-0.99 p = 0.047) while number of previous biologics and depression were predictors of discontinuation (HR 1.18, 95% CI 1.04-1.34 p = 0.011 and HR 2.53, 95% CI 1.61-3.96 p < 0.001). Conclusions: SEC showed a good retention rate in a population previously exposed to several biological therapies. As a novelty, cardiometabolic comorbidities were associated with better drug survival.

Predictive and diagnosis models of stroke from hemodynamic signal monitoring.

This work presents a novel and promising approach to the clinical management of acute stroke. Using machine learning techniques, our research has succeeded in developing accurate diagnosis and prediction real-time models from hemodynamic data. These models are able to diagnose stroke subtype with 30 min of monitoring, to predict the exitus during the first 3 h of monitoring, and to predict the stroke recurrence in just 15 min of monitoring. Patients with difficult access to a CT scan and all patients that arrive at the stroke unit of a specialized hospital will benefit from these positive results. The results obtained from the real-time developed models are the following: stroke diagnosis around 98% precision (97.8% sensitivity, 99.5% specificity), exitus prediction with 99.8% precision (99.8% Sens., 99.9% Spec.), and 98% precision predicting stroke recurrence (98% Sens., 99% Spec.). Graphical abstract depicting the complete process since a patient is monitored until the data collected is used to generate models.

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences.

Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.