A real life cohort of Mepolizumab treatment in severe eosinophilic asthma.

Summary: Background. Mepolizumab, a monoclonal antibody that interacts with IL-5, was the first anti-IL-5 approved for uncontrolled severe eosinophilic asthma. In several randomised, placebo-controlled trials, treatment with mepolizumab has shown a significant improvement in asthma symptoms and the need to use of oral corticosteroids (OCS). Several studies have correlated blood levels of eosinophil cationic protein (ECP) with the degree of eosinophilic inflammation, which could make it an indirect marker of eosinophilic activity. Methods. This was a single-centre retrospective study that included all patients diagnosed with severe eosinophilic asthma under treatment with mepolizumab. We recorded the number of exacerbations, daily prednisone intake, asthma control test scores and forced expiratory volume in the first second. Results. We followed 22 patients, 14 of whom were OCS-dependent with a mean daily dose of 15.85 ± 15.62 mg prednisone. After 12 months, only five continued taking OCS and the mean daily dose was reduced by up to 2.50 ± 3.84 mg (p less than 0.007). The exacerbation rate at baseline was 2.91 ± 2.27 and decreased to 0.82 ± 1.14 in the following year (p less than 0.001). ACT scores increased significantly from 16.00 ± 5.85 to 20.71 ± 4.45 after six months (p = 0.003). We also observed a decrease in ECP from 81.46 ± 43.99 µg/L to 19.12 ± 18.80 µg/L (p > 0.001). Conclusions. These real-life results are consistent with previous clinical trials demonstrating the efficacy and safety of mepolizumab in routine clinical practice for severe uncontrolled eosinophilic asthma. We observed a significant decrease in blood eosinophil counts and in ECP levels, suggesting a reduction in eosinophil activity following mepolizumab treatment.

Environmental risk assessment of petrogenic hydrocarbon spills in mangrove ecosystems: the Tumaco case study as a baseline, Colombian Pacific.

Petrogenic hydrocarbon spills (PHS) are harmful to mangrove ecosystems along tropical coastlines in the short and long term. The aim of this study was to assess the environmental risk of recurrent PHS on mangrove ecosystems in Tumaco municipality, Colombian Pacific. Mangrove characteristics and management aspects led to subdividing the study area into 11 units-of-analysis (UAs) for which threats, vulnerability, potential impacts, and risks were assessed based on environmental factors and the formulation and use of indicators in a rating scale with five categories, which are very low, low, moderate, high, and very high. The results showed that all UAs are highly (64%; 15,525 ha) or moderately (36%; 4,464 ha) threatened by PHS, highly (45%; 13,478 ha) or moderately (55%; 6,511 ha) vulnerable to this kind of pollution, and susceptible to high (73%; 17,075 ha) or moderate (27%; 2,914 ha) potential impacts. The environmental risk was high in 73% (17,075 ha) of the UAs, indicating likely irreversible damage to mangrove ecosystems by PHS, thus pointing to the need of urgent intervention by responsible authorities to ease their recovery and conservation. The methodology and results of this study become technical inputs that serve for environmental control and monitoring, which can be incorporated into contingency and risk management plans.

[Incidence of pressure ulcers due to prone position in patients admitted to the ICU for Covid-19]. / Incidencia de úlceras por presión secundarias al decúbito prono en pacientes ingresados en unidades de cuidados intensivos por SARS-CoV-2.

The appearance of pressure ulcers (PU) is one of the frequent complications of prone position (PP), due to prolonged pressure and shear forces. Objectives: To compare the incidence of pressure ulcers secondary to prone position and describe their location among four Intensive Care Units (ICU) of public hospitals. Methods: Multicenter descriptive and retrospective observational study. The population consisted of patients admitted to the ICU between February 2020 and May 2021, diagnosed with Covid-19 who required prone decubitus. The variables studied were sociodemographic, days of admission to the ICU, total hours on PP, PU prevention, location, stage, frequency of postural changes, nutrition and protein intake. Data collection was carried out through the clinical history of the different computerized databases of each hospital. Descriptive analysis and association between variables were performed using SPSS vs.20.0. Results: A total of 574 patients were admitted for Covid-19, 43.03% were pronated. 69.6% were men, median age was 66 (IQR 55-74) and BMI 30.7 (RIC 27-34.2). Median ICU stay was 28 days (IQR 17-44.2), median hours on PD per patient 48 h (IQR 24-96). The incidence of PU occurrence was 56.3%, 76.2% of patients presented a PU, the most frequent location was the forehead (74.9%). There were significant differences between hospitals in terms of PU incidence (p = 0.002), location (p < 0.001) and median duration of hours per PD episode (p = 0.001). Conclusions: The incidence of pressure ulcers due to the prone position was very high. There is great variability in the incidence of pressure ulcers between hospitals, location and average duration of hours per episode of prone position.

Role of bimetallic Au-Ir subnanometer clusters mediating O2 adsorption and dissociation on anatase TiO2 (101).

A comprehensive computational study on the oxygen molecule (O2) adsorption and activation on bimetallic Au-Ir subnanometer clusters supported on TiO2(101)- up to five atoms in size-is performed. A global optimization density functional theory-based basin-hopping algorithm is used to determine putative global minima configurations of both mono- and bimetallic clusters supported on the metal oxide surface for all sizes and compositions. Our results indicate a strong cluster-oxide interaction for monometallic Ir clusters with calculated adsorption energy (Eads) values ranging from -3.11 to -5.91 eV. Similar values are calculated for bimetallic Au-Ir clusters (-3.21 up to -5.69 eV). However, weaker Eads values are calculated for Au clusters (ranging from -0.66 to -2.07 eV). As a general trend, we demonstrate that for supported Au-Ir clusters on TiO2(101), those Ir atoms preferentially occupy cluster-oxide interface positions while acting as anchor sites for the Au atoms. The overall geometric arrangements of the putative global minima configurations define O2 adsorption and dissociation, particularly involving the monometallic Au5 and Ir5 as well as the bimetallic Au2Ir3 and Au3Ir2 supported clusters. Spontaneous O2 dissociation is observed on both Ir5 and on the Ir-metallic part of Au3Ir2 and Au2Ir3 supported clusters. This is in sharp contrast with supported Au5, where a large activation energy is needed (1.90 eV). Interestingly, for Au5, we observe that molecular O2 adsorption is favorable at the cluster/oxide interface, followed by a smaller dissociation barrier (0.71 eV). From a single cluster catalysis point of view, our results have strong implications in the ongoing understanding of oxide supported bimetallic while providing a useful first insight into the continuous in silico design of novel subnanometer catalysts.

Lung disease in patients with common variable immunodeficiency.

BACKGROUND: Common Variable Immunodeficiency (CVID) is characterized by an impaired antibody production and a higher susceptibility to encapsulated bacterial infections. Lung disease is considered to be the most important cause of morbidity and mortality. METHODS: We analyzed clinical, radiological and functional characteristics in 80 patients with CVID assisted in the Unidad Inmunologia e Histocompatibilidad at Durand Hospital from 1982 to 2018. RESULTS: Of the 80 patients, 55 showed pathologic lung Computed Tomography (CT). Twenty of them (36.4%) showed bronchiectasis; 26 (47.3%) interstitial involvement associated with nodules and adenopathies called GLILD (granulomatous-lymphocytic interstitial lung disease); and nine patients (16.3%) showed other lesions. Nine percent of patients with lung disease showed CT progression; none of them had spirometry worsening. GLILD patients had normal and restrictive patterns in lung function tests, in equal proportions. Two patients - one with GLILD and the other one with bronchiectasis - had an increase in spirometric pattern severity without CT progression. Lung biopsy was performed in 19% of GLILD patients, all of whom had histopathologic diagnosis of Lymphoid Interstitial Pneumonia (LIP). CONCLUSIONS: GLILD is the major cause of lung disease in CVID. Computed tomography is useful for diagnosis but not necessary in follow-up, in which functional tests should have better correlation with clinical evolution, reducing radiation exposure. Biopsy should be indicated when the clinical diagnosis is unclear. Treatment should be considered whenever there is clear evidence of disease progression.

Not Described Variant of Notch3 Gen for Cadasil Disease.

Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein.

Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile.

Conventional treatment of obstetric antiphospholipid syndrome fails in approximately 20-30% of pregnant women without any clearly identified risk factor. It is important to identify risk factors that are associated with these treatment failures. This study aimed to assess the impact of risk factors on pregnancy outcomes in women with obstetric antiphospholipid syndrome treated with conventional treatment. We carefully retrospectively selected 106 pregnancies in women with obstetric antiphospholipid syndrome treated with heparin + aspirin. Pregnancy outcomes were evaluated according to the following associated risk factors: triple positivity profile, double positivity profile, single positivity profile, history of thrombosis, autoimmune disease, more than four pregnancy losses, and high titers of anticardiolipin antibodies and/or anti-ßeta-2-glycoprotein-I (aß2GPI) antibodies. To establish the association between pregnancy outcomes and risk factors, a single binary logistic regressions analysis was performed. Risk factors associated with pregnancy loss with conventional treatment were: the presence of triple positivity (OR = 5.0, CI = 1.4-16.9, p = 0.01), high titers of aß2GPI (OR = 4.4, CI = 1.2-16.1, p = 0.023) and a history of more than four pregnancy losses (OR = 3.5, CI = 1.2-10.0, p = 0.018). The presence of triple positivity was an independent risk factor associated with gestational complications (OR = 4.1, CI = 1.2-13.9, p = 0.02). Our findings reinforce the idea that triple positivity is a categorical risk factor for poor response to conventional treatment.

Virulence and antimicrobial resistance of Klebsiella pneumoniae isolated from passerine and psittacine birds.

Klebsiella pneumoniae is considered one of the most important Gram-negative opportunistic pathogens. The contact between humans and birds poses health risks to both. The aim of this study was to investigate the resistance and virulence of K. pneumoniae isolates from psittacines and passerines, seized from illegal trade in Brazil. We analysed 32 strains isolated from birds of the orders Psittaciformes and Passeriformes by polymerase chain reaction (PCR) for virulence factor genes. Antibiotic resistance was assessed by disk diffusion assay and PCR. The results indicated that fimH (100%), uge (96.8%), kfu (81.2%) and irp-2 (68.7%) were the most common virulence genes, followed by kpn (46.8%), K2 (43.7%), mrkD (34.3%) and iroN (15.6%). The combination of virulence genes resulted in a great diversity of genotypes and the heterogeneity of the strains is also confirmed in the analysis by amplified fragment length polymorphism. The susceptibility profiles of the K. pneumoniae showed 25% of multiple antibiotic resistance strains. We identified seven strains that presented non-extended spectrum beta lactamase blaSHV variants SHV-1 and SHV-11 and one strain positive to the blaTEM-1 gene. Plasmid-mediated quinolone resistance was present in 10 strains (10/32). The data obtained in this study reveal the pathogenic potential of this pathogen and highlight the need for surveillance and monitoring.

Mercury Accumulation, Structural Damages, and Antioxidant and Immune Status Changes in the Gilthead Seabream (Sparus aurata L.) Exposed to Methylmercury.

In aquatic systems, mercury (Hg) is an environmental contaminant that causes acute and chronic damage to multiple organs. In fish, practically all of the organic Hg found is in the form of methylmercury (MeHg), which has been associated with animal and human health problems. This study evaluates the impact of waterborne-exposure to sublethal concentrations of MeHg (10 µg L(-1)) in gilthead seabream (Sparus aurata). Hg was seen to accumulate in liver and muscle, and histopathological damage to skin and liver was detected. Fish exposed to MeHg showed a decreased biological antioxidant potential and increased levels of the reactive oxygen molecules compared with the values found in control fish (nonexposed). Increased liver antioxidant enzyme activities (superoxide dismutase and catalase) were detected in 2 day-exposed fish with respect to the values of control fish. However, fish exposed to MeHg for 10 days showed liver antioxidant enzyme levels similar to those of the control fish but had increased hepato-somatic index and histopathological alterations in liver and skin. Serum complement levels were higher in fish exposed to MeHg for 30 days than in control fish. Moreover, head-kidney leukocyte activities increased, although only phagocytosis and peroxidase activities showed a significant increase after 10 and 30 days, respectively. The data show that 30 days of exposure to waterborne MeHg provokes more significant changes in fish than a short-term exposure of 2 or 10 days.

Comparative Genomics Within the Bacillus Genus Reveal the Singularities of Two Robust Bacillus amyloliquefaciens Biocontrol Strains.

Bacillus amyloliquefaciens CECT 8237 and CECT 8238, formerly known as Bacillus subtilis UMAF6639 and UMAF6614, respectively, contribute to plant health by facing microbial pathogens or inducing the plant's defense mechanisms. We sequenced their genomes and developed a set of ad hoc scripts that allowed us to search for the features implicated in their beneficial interaction with plants. We define a core set of genes that should ideally be found in any beneficial Bacillus strain, including the production of secondary metabolites, volatile compounds, metabolic plasticity, cell-to-cell communication systems, and biofilm formation. We experimentally prove that some of these genetic elements are active, such as i) the production of known secondary metabolites or ii) acetoin and 2-3-butanediol, compounds that stimulate plant growth and host defense responses. A comparison with other Bacillus genomes permits us to find differences in the cell-to-cell communication system and biofilm formation and to hypothesize variations in their persistence and resistance ability in diverse environmental conditions. In addition, the major protection provided by CECT 8237 and CECT 8238, which is different from other Bacillus strains against bacterial and fungal melon diseases, permits us to propose a correlation with their singular genetic background and determine the need to search for additional blind biocontrol-related features.

Involvement of the -420C>G RETN polymorphism in myocardial fibrosis in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis. HCM is an autosomal-dominant disease caused by more than 400 mutations in sarcomeric genes. Changes in nonsarcomeric genes contribute to its phenotypic heterogeneity. Cardiac fibrosis can be studied using late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We evaluated the potential role of two polymorphisms in nonsarcomeric genes on interstitial fibrosis in HCM. MATERIALS AND METHODS: Two polymorphisms in nonsarcomeric genes [ACE (deletion of 287 bp in the 16th intron) and RETN (-420C>G)] were analysed in 146 HCM patients. Cardiac fibrosis was assessed using LGE to determine the number of affected segments. RESULTS: Allelic frequencies in ACE and RETN polymorphisms were consistent with the Hardy-Weinberg equilibrium (both P > 0.05). We found that the presence of the polymorphic allele in the -420C>G RETN polymorphism was independently associated with the number of affected segments of LGE (P = 0.038). Increased circulating resistin concentration, measured by enzyme-linked immunosorbent assay, was associated with a higher degree of cardiac fibrosis. Myocardial fibrosis, assessed by Masson's trichrome staining, was associated with the -420C>G RETN polymorphism in 46 tissue samples obtained by septal myectomy (P = 0.044). CONCLUSIONS: The -420C>G RETN polymorphism was independently associated with the degree of cardiac fibrosis, assessed by LGE, in patients with HCM. In addition, there was an association between the polymorphism and the circulating resistin levels as well as with myocardial fibrosis in tissues obtained by myectomy. Investigating the physiological implication of the RETN polymorphism in HCM in combination with the use of imaging technologies might help to establish the severity of disease in patients with HCM.

Does airway hyperresponsiveness monitoring lead to improved asthma control?

The current guidelines recommend an approach to asthma management based on asthma control, rather than asthma severity. Although several specific questionnaires have been developed and control criteria have been established based on clinical guidelines, the evaluation of asthma control is still not optimal. In general, these indicators provide adequate assessment of current control, but they are more limited when estimating future risk. There is much evidence demonstrating the persistence of airway inflammation and airway hyperresponsiveness (AHR) in patients with total control. Therefore, the objective of this review was to analyse the possible role of AHR monitoring as an instrument for assessing asthma control. We will evaluate its capacity as an indicator for future risk, both for estimating the possibility of clinical deterioration and loss of lung function or exacerbations. Furthermore, its relationship with inhaled corticosteroid treatment will be analysed, while emphasizing its capacity for predicting response and adjusting dosage, as well as information about the capability of AHR for monitoring treatment. Last of all, we will discuss the main limitations and emerging opportunities of AHR as an assessment instrument for asthma control.

Sputum periostin in patients with different severe asthma phenotypes.

BACKGROUND: Identifying inflammatory phenotypes is relevant in severe uncontrolled asthma. The aim of this study was to identify the different clinical, inflammatory, functional, and molecular phenotypes in patients with severe asthma and to investigate the potential role of sputum periostin as a biomarker of severe asthma phenotypes. PATIENTS AND METHODS: Sputum induction was performed in 62 patients diagnosed with severe asthma. Skin prick testing, lung function tests, exhaled nitric oxide, hematimetry, and total serum IgE were performed. Periostin was measured in sputum supernatants. RESULTS: Patients with asthma were phenotyped and 80% had late-onset asthma, 50% had fixed airflow obstruction, and 66% showed a Th2-high phenotype. With respect to inflammatory phenotypes, 71% were eosinophilic and 25% mixed granulocytic. Periostin levels were higher in patients with fixed as compared to variable airflow limitation (69.76 vs 43.84 pg/ml, P < 0.05) and in patients with eosinophilic as compared to mixed granulocytic phenotype (61.58 vs 37.31 pg/ml, P < 0.05). There was an inverse correlation between postbronchodilator FEV1 /FVC and periostin levels (-0.276, P < 0.05). CONCLUSION: This study demonstrates the utility of periostin in phenotyping severe asthma. Periostin levels in sputum are associated with persistent airflow limitation in asthma patients with airway eosinophilia despite treatment with high-dose inhaled corticosteroids.

Bees explain floral variation in a recent radiation of Linaria.

The role of pollinators in floral divergence has long attracted the attention of evolutionary biologists. Although abundant studies have reported the effect of pollinators on flower-shape variation and plant speciation, the influence of pollinators on plant species differentiation during rapid radiations and the specific consequences of shifts among similar pollinators are not well understood. Here, we evaluate the association between pollinators and floral morphology in a closely related and recently diversifying clade of Linaria species (sect. Supinae subsect. Supinae). Our approach combined pollinator observations, functional floral morphometric measures and phylogenetic comparative analyses. The fauna visiting Linaria species was determined by extensive surveys and categorized by a modularity algorithm, and the size and shape of flowers were analysed by means of standard and geometric morphometric measures. Standard measures failed to find relationships between the sizes of representative pollinators and flowers. However, discriminant function analyses of geometric morphometric data revealed that pollination niches are finer predictors of flower morphologies in Linaria if compared with phylogenetic relationships. Species with the most restrictive flowers displayed the most slender spurs and were pollinated by bees with larger proboscides. These restrictive flower shapes likely appeared more than once during the evolutionary history of the study group. We show that floral variation can be driven by shifts between pollinators that have been traditionally included in a single functional group, and discuss the consequences of such transitions for plant species differentiation during rapid radiations.

Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial.

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.

Light-emitting-diodes based on ordered InGaN nanocolumns emitting in the blue, green and yellow spectral range.

The growth of ordered arrays of InGaN/GaN nanocolumnar light emitting diodes by molecular beam epitaxy, emitting in the blue (441 nm), green (502 nm), and yellow (568 nm) spectral range is reported. The device active region, consisting of a nanocolumnar InGaN section of nominally constant composition and 250 to 500 nm length, is free of extended defects, which is in strong contrast to InGaN (planar) layers of similar composition and thickness. Electroluminescence spectra show a very small blue shift with increasing current (almost negligible in the yellow device) and line widths slightly broader than those of state-of-the-art InGaN quantum wells.