A Novel Tendon Injury Model, Induced by Collagenase Administration Combined with a Thermo-Responsive Hydrogel in Rats, Reproduces the Pathogenesis of Human Degenerative Tendinopathy.

Patellar tendinopathy is a common clinical problem, but its underlying pathophysiology remains poorly understood, primarily due to the absence of a representative experimental model. The most widely used method to generate such a model is collagenase injection, although this method possesses limitations. We developed an optimized rat model of patellar tendinopathy via the ultrasound-guided injection of collagenase mixed with a thermo-responsive Pluronic hydrogel into the patellar tendon of sixty male Wistar rats. All analyses were carried out at 3, 7, 14, 30, and 60 days post-injury. We confirmed that our rat model reproduced the pathophysiology observed in human patients through analyses of ultrasonography, histology, immunofluorescence, and biomechanical parameters. Tendons that were injured by the injection of the collagenase-Pluronic mixture exhibited a significant increase in the cross-sectional area (p < 0.01), a high degree of tissue disorganization and hypercellularity, significantly strong neovascularization (p < 0.01), important changes in the levels of types I and III collagen expression, and the organization and presence of intra-tendinous calcifications. Decreases in the maximum rupture force and stiffness were also observed. These results demonstrate that our model replicates the key features observed in human patellar tendinopathy. Collagenase is evenly distributed, as the Pluronic hydrogel prevents its leakage and thus, damage to surrounding tissues. Therefore, this model is valuable for testing new treatments for patellar tendinopathy.

Somatic Hypermutation and Framework Mutations of Variable Region Contribute to Anti-Zika Virus-Specific Monoclonal Antibody Binding and Function.

Zika virus (ZIKV) is a global public health concern due to its ability to cause congenital Zika syndrome and lack of approved vaccine, therapeutic, or other control measures. We discovered eight novel rabbit monoclonal antibodies (MAbs) that bind to distinct ZIKV envelope protein epitopes. The majority of the MAbs were ZIKV specific and targeted the lateral ridge of the envelope (E) protein domain III, while the MAb with the highest neutralizing activity recognized a putative quaternary epitope spanning E protein domains I and III. One of the non-neutralizing MAbs specifically recognized ZIKV precursor membrane protein (prM). Somatic hypermutation of immunoglobulin variable regions increases antibody affinity maturation and triggers antibody class switching. Negative correlations were observed between the somatic hypermutation rate of the immunoglobulin heavy-chain variable region and antibody binding parameters such as equilibrium dissociation constant, dissociation constant, and half-maximal effective concentration value of MAb binding to ZIKV virus-like particles. Complementarity-determining regions recognize the antigen epitopes and are scaffolded by canonical framework regions. Reversion of framework region amino acids to the rabbit germ line sequence decreased anti-ZIKV MAb binding activity of some MAbs. Thus, antibody affinity maturation, including somatic hypermutation and framework region mutations, contributed to the binding and function of these anti-ZIKV MAbs. IMPORTANCE ZIKV is a global health concern against which no vaccine or therapeutics are available. We characterized eight novel rabbit monoclonal antibodies recognizing ZIKV envelope and prM proteins and studied the relationship between somatic hypermutation of complementarity-determining regions, framework regions, mutations, antibody specificity, binding, and neutralizing activity. The results contribute to understanding structural features and somatic mutation pathways by which potent Zika virus-neutralizing antibodies can evolve, including the role of antibody framework regions.

Personalized diagnostic approach and indirect quantification of extravasation in human anaphylaxis.

BACKGROUND: Anaphylaxis is the most acute and life-threatening manifestation of allergic disorders. Currently, there is a need to improve its medical management and increase the understanding of its molecular mechanisms. This study aimed to quantify the extravasation underlying human anaphylactic reactions and propose new theragnostic approaches. METHODS: Molecular determinations were performed in paired serum samples obtained during the acute phase and at baseline from patients presenting with hypersensitivity reactions. These were classified according to their severity as Grades 1, 2 and 3, the two latter being considered anaphylaxis. Tryptase levels were measured by ImmunoCAP, and serum protein concentration was quantified by Bradford assay. Human serum albumin (HSA) and haemoglobin beta subunit (HBB) levels were determined by Western blot and polyacrylamide gel electrophoresis, respectively. RESULTS: A total of 150 patients were included in the study. Of them, 112 had experienced anaphylaxis (83 and 29 with Grade 2 and 3 reactions, respectively). Tryptase diagnostic efficiency substantially improved when considering patients' baseline values (33%-54%) instead of the acute value threshold (21%). Serum protein concentration and HSA significantly decreased in anaphylaxis (p < .0001). HSA levels dropped with the severity of the reaction (6% and 15% for Grade 2 and 3 reactions, respectively). Furthermore, HBB levels increased during the acute phase of all hypersensitivity reactions (p < .0001). CONCLUSIONS: For the first time, the extravasation underlying human anaphylaxis has been evaluated based on the severity of the reaction using HSA and protein concentration measurements. Additionally, our findings propose new diagnostic and potential therapeutic approaches for this pathological event.

Interaction between Dietary Vitamin D3 and Vitamin K3 in Gilthead Seabream Larvae (Sparus aurata) in Relation to Growth and Expression of Bone Development-Related Genes.

Vitamins D and K are essential fat-soluble nutrients that intervene in bone development processes among other biological functions. The present study is aimed at investigating the potential combined effect of dietary supplementation with vitamin D3 (cholecalciferol) and vitamin K3 (menadione) in gilthead seabream (Sparus aurata) larvae. For that purpose, seabream diets were supplemented with different combinations of vitamin D3/vitamin K3 (mg/kg diet) as follows: 0.00/0, 0.06/70, 0.06/170, 0.13/70, 0.13/170, 0.40/70, and 0.40/170. Feeding gilthead seabream larvae (22 days post hatch) for 21 days with the diets supplemented with 0.06-0.13 mg/kg vitamin D3 and 70 mg/kg vitamin K3 (diets 0.06/70 and 0.13/70) led to the highest larval growth and survival and the highest expression of important biomarkers of both bone development and health, such as bmp2, osx, and mgp, and calcium homeostasis, such as pthrp and casr. However, the increased supplementation with both vitamins at 0.40 mg/kg vitamin D3 and 170 mg/kg vitamin K3 (diet 0.40/170) reduced larval growth and survival, downregulated bmp2 and pthrp expressions, and upregulated osx and mgp, causing an unbalance in the relative expression of these genes. The results of the present study have shown the interaction between vitamin D3 supplementation and vitamin K3 supplementation in larval performance and gene expression related to bone development and calcium homeostasis, denoting the significance of a correct balance between both vitamins in larval diets.

High Levels of Vitamin A in Plant-Based Diets for Gilthead Seabream (Sparus aurata) Juveniles, Effects on Growth, Skeletal Anomalies, Bone Molecular Markers, and Histological Morphology.

Substitution of fish-based ingredients may alter the nutritional profile of the feeds, including the vitamin contents, ultimately leading to unbalanced vitamin supply. Vitamin A plays an essential role in epithelium preservation, cell differentiation, reproduction, and vision. It also intervenes in skeletogenesis through chondrocytes development. Therefore, low levels of vitamin A may cause poor growth and abnormal bone development among other symptoms. Besides, in gilthead seabream excess vitamin A altered bone structure and homeostasis, indicating that an upper level for vitamin A in feeds for this species must be defined. For this purpose, a practical plant-based diet (FM 10% and FO 6%) containing five increasing levels of vitamin A (24,000, 26,000, 27,000, 31,000, and 37,000 IU/kg) supplemented as retinyl acetate was formulated to identify the effects of high levels of vitamin A for gilthead seabream juveniles. The trial was conducted with 450 total fish distributed into 15 tanks, where each diet was tested in triplicates for 70 days. At the end of the trial, samples were taken for analyses of vitamin A-relevant markers. At the end of the trial the high levels of vitamin A supplementation did not cause a reduction in growth, whereas no significant effect was observed for the feed efficiency, specific growth rate, and feed convertion ratio. Although not significant, retinol content in liver showed a tendency to increase with the elevation of dietary vitamin A levels. Although minor, the highest level of vitamin A dietary content (37,000 IU/kg) caused a significant increase in caudal vertebrae partial fusion as well as caudal vertebrae malformations. Increasing dietary vitamin A was related to a reduction in the occurrence of microhemorrhages in the liver and a reduction in the presence of eosinophils associated to the pancreas. Overall, the results of the present study suggested that gilthead seabream juveniles fed a plant-based diet are able to tolerate very high levels of vitamin A supplementation when supplemented as retinyl acetate. Nevertheless, further supplementation should be avoided in order to reduce the prevalence of anomalies affecting the caudal vertebrae.

Development of a Novel Assay to Assess the Avidity of Dengue Virus-Specific Antibodies Elicited in Response to a Tetravalent Dengue Vaccine.

Antibody affinity maturation is a critical step in development of functional antiviral immunity; however, accurate measurement of affinity maturation of polyclonal serum antibody responses to particulate antigens such as virions is challenging. We describe a novel avidity assay employing biolayer interferometry and dengue virus-like particles. After validation using anti-dengue monoclonal antibodies, the assay was used to assess avidity of antibody responses to a tetravalent dengue vaccine candidate (TAK-003) in children, adolescents, and adults during two phase 2 clinical trials conducted in dengue-endemic regions. Vaccination increased avidity index and avidity remained high through 1 year postvaccination. Neutralizing antibody titers and avidity index did not correlate overall; however, a correlation was observed between neutralizing antibody titer and avidity index in those subjects with the highest degree of antibody affinity maturation. Therefore, vaccination with TAK-003 stimulates polyclonal affinity maturation and functional antibody responses, including neutralizing antibodies. CLINICAL TRIALS REGISTRATION: NCT01511250 and NCT02302066.

Specificity and Breadth of the Neutralizing Antibody Response to a Live-Attenuated Tetravalent Dengue Vaccine.

BACKGROUND: An effective dengue vaccine should ideally induce broadly neutralizing antibody (nAb) responses against all 4 dengue virus (DENV) serotypes. METHODS: We characterized the specificity and breadth of the nAb response to TAK-003, a live-attenuated tetravalent dengue vaccine, in serum samples from phase 2 and 3 clinical trials. RESULTS: Microneutralization tests using postvaccination serum showed comparable neutralization against diverse DENV-1-4 genotypes. Reporter virus particle neutralization assays after depletion of anti-DENV-2 nAbs demonstrated that the nAb response to DENV-1, -3, and -4 comprises both type-specific (TS) and cross-reactive (CR) nAbs. CONCLUSIONS: Therefore, TAK-003 induces broad tetravalent TS and CR nAb responses.

Validity and Reliability of a Nutritional Screening Tool (SCAN) in Children Newly Diagnosed with Cancer.

No standardized approach towards nutritional screening and assessment of pediatric oncology patients has been established. The nutrition screening tool for childhood cancer (SCAN) has been previously published as an effective screening method. This is an observational cross-sectional study to assess the validity and reliability of the SCAN tool, compare it to the detection of undernutrition using standard measures of assessment, and determine the overall prevalence of malnutrition and micronutrients alterations in our cohort. We included children newly diagnosed with cancer in a pediatric tertiary hospital in Madrid, Spain from August 2018 to May 2019. The following measurements were performed: SCAN questionnaire, anthropometric measurements, nutritional markers in blood, and micronutrient levels. A total of 49 patients were included. 22 patients (45%) were at risk of malnutrition according to the SCAN questionnaire. Four patients (8%) could be diagnosed with moderate undernutrition. These undernourished patients were distributed homogeneously among at-risk and not at-risk populations identified by the SCAN tool. Several micronutrient deficiencies were identified. We conclude that the SCAN questionnaire is an easy-to-use tool for everyday clinical practice. By not including anthropometric measurements it misses patients considered to be malnourished. Future data might help clarify if it is an effective tool in predicting a higher nutritional risk during the entire treatment course.

A genome-wide association study of survival in patients with sepsis.

BACKGROUND: Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. METHODS: This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10-8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. FINDINGS: We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37-6.78], p = 4.92 × 10-8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. INTERPRETATION: We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.

A Mixed-Reality Tele-Operation Method for High-Level Control of a Legged-Manipulator Robot.

In recent years, legged (quadruped) robots have been subject of technological study and continuous development. These robots have a leading role in applications that require high mobility skills in complex terrain, as is the case of Search and Rescue (SAR). These robots stand out for their ability to adapt to different terrains, overcome obstacles and move within unstructured environments. Most of the implementations recently developed are focused on data collecting with sensors, such as lidar or cameras. This work seeks to integrate a 6DoF arm manipulator to the quadruped robot ARTU-R (A1 Rescue Tasks UPM Robot) by Unitree to perform manipulation tasks in SAR environments. The main contribution of this work is focused on the High-level control of the robotic set (Legged + Manipulator) using Mixed-Reality (MR). An optimization phase of the robotic set workspace has been previously developed in Matlab for the implementation, as well as a simulation phase in Gazebo to verify the dynamic functionality of the set in reconstructed environments. The first and second generation of Hololens glasses have been used and contrasted with a conventional interface to develop the MR control part of the proposed method. Manipulations of first aid equipment have been carried out to evaluate the proposed method. The main results show that the proposed method allows better control of the robotic set than conventional interfaces, improving the operator efficiency in performing robotic handling tasks and increasing confidence in decision-making. On the other hand, Hololens 2 showed a better user experience concerning graphics and latency time.

Increased miR-21-3p and miR-487b-3p serum levels during anaphylactic reaction in food allergic children.

BACKGROUND: Anaphylaxis is the most severe manifestation of allergic disorders. The poor knowledge of its molecular mechanisms often leads to under-diagnosis. MicroRNAs (miRNA) regulate physiologic and pathologic processes, and they have been postulated as promising diagnostic markers. The main objectives of this study were to characterize the human miRNA profile during anaphylaxis and to assess their capacity as diagnostic markers and determine their participation in the molecular mechanisms of this event. METHODS: The miRNA serum profiles from the acute and baseline phase of 5 oral food-challenged anaphylactic children (<18 years old) were obtained by next-generation sequencing (NGS). From the panel of statistically significant miRNAs obtained, several candidates were selected and analyzed in 19 anaphylactic children by qPCR. We performed system biology analysis (SBA) on their target genes to identify main functions and canonical pathways. A functional in vitro assay was carried out incubating endothelial cells (ECs) in anaphylactic conditions. RESULTS: The NGS identified 389 miRNAs among which 41 were significantly different between acute and baseline samples. The high levels of miR-21-3p (fold change = 2.28, P = .006) and miR-487b-3p (fold change = 1.04, P = .039) observed by NGS in acute serum samples were confirmed in a larger group of 19 patients. The SBA revealed molecular pathways related to the inflammation and immune system regulation. miR-21-3p increased intracellularly and in acute phase serum after EC stimulation. CONCLUSIONS: These findings provide, for the first time, some insights into the anaphylactic miRNA serum profile in children and point to miR-21-3p and miR-487b-3p as candidate biomarkers. Furthermore, the SBA revealed a possible implication of these molecules in the underlying molecular mechanisms. Moreover, ECs increased miR-21-3p intracellularly and released it to the environment in response to anaphylaxis.

The importance of phospholipids combined with long-chain PUFA in formulated diets for pikeperch (Sander lucioperca) larvae.

Dietary phosphoglycerides and n-3 long-chain PUFA (LC-PUFA) play important functions in the development of pikeperch (Sander lucioperca) larvae. This study aimed to determine optimal dietary levels of soyabean lecithin (SBL)-derived phospholipids (PL) in starter feeds for pikeperch larvae 10-30 d post-hatch (DPH) and examine performance and ontogeny by additional supplementation of n-3 LC-PUFA in the form of Algatrium DHA 70 (glyceride product; 660-700 mg/g DHA; EPA 60-75 mg/g). In total, six isoproteic and isoenergetic extruded diets were formulated with increasing levels of PL (3·7, 8·3 or 14·5 % wet weight (w.w.), respectively); however, three of the diets were supplemented with three levels of Algatrium DHA 70 (0·6, 2·0 or 3·4 %, respectively). Liver proteomic analyses of larvae at 30 DPH were included for effects of PL and primarily DHA on performance, physiological expression and interactions in larval proteins. In addition, bone anomalies, digestive enzymatic activity, candidate gene expression and skeleton morphogenesis were examined. Results confirmed the importance of dietary PL levels of at least 8·2 % w.w., and an additional beneficiary effect of supplementation with DHA plus EPA. Thus, combined supplementation of SBL (up to 14·51 % w.w. PL) and n-3 LC-PUFA (1·004 % DM DHA and 0·169 % DM EPA) in the form of TAG resulted in highest growth and lowest incidence of anomalies, improved digestive enzyme activity and had differential effect on liver proteomics. The results denote that essential fatty acids can be supplemented as TAG to have beneficial effects in pikeperch larvae development.

A Web-Based Telemanagement System for Improving Disease Activity and Quality of Life in Patients With Complex Inflammatory Bowel Disease: Pilot Randomized Controlled Trial.

BACKGROUND: The reported efficacy of telemedicine in patients with inflammatory bowel disease (IBD) is inconsistent among studies, and data for complex IBD are lacking. OBJECTIVE: We aimed to evaluate the impact of remote monitoring using a Web system-Telemonitorización de la Enfermedad de Crohn y Colitis Ulcerosa or Telemonitoring of Crohn's Disease and Ulcerative Colitis (TECCU)-as compared to standard care and telephone care on health outcomes and health care in patients with complex IBD. METHODS: We performed a 3-arm randomized controlled trial. Adult patients with IBD who received immunosuppressants and biological agents were recruited from the IBD Unit of a tertiary university hospital. The patients were randomized into groups to receive remote monitoring (G_TECCU), nurse-assisted telephone care (G_NT), or standard care with in-person visits (G_control). All patients completed the study visits at baseline and at 12 and 24 weeks in addition to each type of intervention. The primary outcome was the percentage of patients in remission at 24 weeks. Secondary health outcomes were quality of life, medication adherence, adverse effects, satisfaction, and social activities. Data on the number of outpatient visits and telephone calls, emergency visits, hospitalizations, IBD-related surgeries, and corticosteroid courses were also collected. RESULTS: A total of 63 patients were selected (21 patients in each group). During the study, 90.5% (19/21) of patients in G_control, 95.2% (20/21) in G_NT, and 85.7% (18/21) in G_TECCU were compliant to the intervention. After 24 weeks, the percentage of patients in remission was higher in G_TECCU (17/21, 81%) than in G_NT (14/21, 66.7%) and G_control (15/21, 71.4%). A higher improvement in disease activity was observed in G_TECCU than in G_control in terms of the Harvey-Bradshaw/Mayo (odds ratio=0.12, 95% CI=0.003-2.162, P=.19) and Harvey-Bradshaw/Walmsley (odds ratio=0.11, 95% CI=0.004-1.55, P=.13) indexes. Improvement in disease activity was associated with a larger reduction in fecal calprotectin values in G_TECCU compared to G_control (estimated intervention effect: odds ratio=-0.90; 95% CI=-1.96 to 0.16, P=.11). All completers adhered to treatment in G_TECCU. In addition, the quality of life, social activities, and satisfaction improved in all 3 groups. Although the number of outpatient visits and telephone calls was lower in G_TECCU than in G_NT and G_control, the safety profile was similar in all 3 groups. CONCLUSIONS: This pilot clinical trial suggests that the TECCU Web-based system is a safe strategy for improving health outcomes in patients with complex IBD and reducing the use of health care resources. TRIAL REGISTRATION: ClinicalTrials.gov NCT02943538; https://clinicaltrials.gov/ct2/show/NCT02943538 (Archived by WebCite at http://www.webcitation.org/746CRRtDN).

Chemsex: are we prepared? / Chemsex: ¿estamos preparados?

It was with great interest that we read the article published by Dolengevich-Segal (Dolengevich-Segal et al., 2017), which provides an interesting review of the emerging phenomenon known as chemsex and the different drugs used in this type of practice.We would like to highlight the importance and usefulness of this paper, given the progressive increase in the prevalence of drug use in the context of sexual activity among men who have sex with men (MSM) in Western Europe (Fernández-Dávila et al,. 2016). This situation raises the need to launch epidemiological studies to assess the phenomenon - not only, however, from the point of view of mental health, but also from the field of infectious diseases and toxicology. We must not forget that this type of practice involves an increase in the risk of infection by sexually transmitted diseases and the problems that drug use can cause from the toxicological point of view. Both are causes of emergency room (ER) consultation, and more training in how to tackle the problems arising from chemsex should be provided.

Hemos leído con gran interés el artículo publicado por Dolengevich-Segal (Dolengevich-Segal et al., 2017) donde se hace una interesante revisión sobre un fenómeno emergente como es el chemsex, y las diferentes drogas que se utilizan en este tipo de prácticas. Nos gustaría poner de manifiesto la importancia y utilidad de la publicación, por el progresivo incremento en la prevalencia del consumo de drogas en el contexto de la actividad sexual en hombres que mantienen sexo con hombres (HSH) en Europa Occidental (Fernández-Dávila et al,. 2016). Esto conduce a la necesidad de poner en marcha estudios epidemiológicos que evalúen el fenómeno, pero no solo desde el punto de vista de salud mental, sino también desde el campo de las enfermedades infecciosas y de la toxicología. No debemos olvidar que este tipo de prácticas suponen un incremento en el riesgo de infección por enfermedades de transmisión sexual y los problemas desde el punto de vista toxicológico al que pueden dar lugar el consumo de drogas. Ambos constituyen motivos de consulta en los servicios de urgencias (SU), donde debería incrementarse la formación necesaria para abordar los problemas derivados del chemsex.

Histochemical localization of zinc in the retina cells of gilthead sea bream (sparus aurata) fed different presentations of zinc.

To describe the distribution of zinc in the retina of a representative marine fish species and to determine whether the intracellular deposition amount correlates with the presentation of the zinc included in the practical diets (organic, inorganic, encapsulated, fish meal, and Control diet), we examined the precise localization of endogenous zinc in the gilthead sea bream (Sparus aurata) retina by autometallography. As observed by light microscopy, reaction products were widely distributed throughout the retina, including the outer segments of photoreceptors, except in the nuclear layers. Differing from other species previously studied, zinc depositions were not different between the outer and inner retina, and the retinal ganglion cell layer showed reaction products with a characteristic disposition surrounding the neuronal soma. An additional finding in this species was the rich disposition around photoreceptors, so abundant that it outlines the shape of the rods and cones. With regards to the diet, the zinc organic formulation was able to produce a higher amount of precipitates, followed by fish meal and encapsulated zinc diets. The inorganic and the Control diet produced a basal zinc deposition in the same layers above mentioned although less evident and similar to that determined in other species fed with non-supplemented diets.

Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis.

INTRODUCTION: The purpose of this study was to investigate whether common variants across the nuclear factor erythroid 2-like 2 (NFE2L2) gene contribute to the development of the acute respiratory distress syndrome (ARDS) in patients with severe sepsis. NFE2L2 is involved in the response to oxidative stress, and it has been shown to be associated with the development of ARDS in trauma patients. METHODS: We performed a case-control study of 321 patients fulfilling international criteria for severe sepsis and ARDS who were admitted to a Spanish network of post-surgical and critical care units, as well as 871 population-based controls. Six tagging single-nucleotide polymorphisms (SNPs) of NFE2L2 were genotyped, and, after further imputation of additional 34 SNPs, association testing with ARDS susceptibility was conducted using logistic regression analysis. RESULTS: After multiple testing adjustments, our analysis revealed 10 non-coding SNPs in tight linkage disequilibrium (0.75 ≤ r (2) ≤ 1) that were associated with ARDS susceptibility as a single association signal. One of those SNPs (rs672961) was previously associated with trauma-induced ARDS and modified the promoter activity of the NFE2L2 gene, showing an odds ratio of 1.93 per T allele (95 % confidence interval, 1.17-3.18; p = 0.0089). CONCLUSIONS: Our findings support the involvement of NFE2L2 gene variants in ARDS susceptibility and reinforce further exploration of the role of oxidant stress response as a risk factor for ARDS in critically ill patients.

A hierarchical method for whole-brain connectivity-based parcellation.

In modern neuroscience there is general agreement that brain function relies on networks and that connectivity is therefore of paramount importance for brain function. Accordingly, the delineation of functional brain areas on the basis of diffusion magnetic resonance imaging (dMRI) and tractography may lead to highly relevant brain maps. Existing methods typically aim to find a predefined number of areas and/or are limited to small regions of grey matter. However, it is in general not likely that a single parcellation dividing the brain into a finite number of areas is an adequate representation of the function-anatomical organization of the brain. In this work, we propose hierarchical clustering as a solution to overcome these limitations and achieve whole-brain parcellation. We demonstrate that this method encodes the information of the underlying structure at all granularity levels in a hierarchical tree or dendrogram. We develop an optimal tree building and processing pipeline that reduces the complexity of the tree with minimal information loss. We show how these trees can be used to compare the similarity structure of different subjects or recordings and how to extract parcellations from them. Our novel approach yields a more exhaustive representation of the real underlying structure and successfully tackles the challenge of whole-brain parcellation.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

BACKGROUND: Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. METHODS: We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. RESULTS: MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. CONCLUSIONS: MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. CLINICAL TRIALS REGISTRATION: NCT00565929.

Photocatalytic Activity of Ag Nanoparticles Deposited on Thermoexfoliated g-C3N4.

The limited access to fresh water and the increased presence of emergent pollutants (EPs) in wastewater has increased the interest in developing strategies for wastewater remediation, including photocatalysis. Graphitic carbon nitride (g-C3N4) is a 2D non-metal material with outstanding properties, such as a 2.7 eV bandgap and physicochemical stability, making it a promising photocatalyst. This work reports the process of obtaining high-surface-area (SA) g-C3N4 using the thermal-exfoliation process and the posterior effect of Ag-nanoparticle loading over the exfoliated g-C3N4 surface. The photocatalytic activity of samples was evaluated through methylene blue (MB) degradation under visible-light radiation and correlated to its physical properties obtained by XRD, TEM, BET, and UV-Vis analyses. Moreover, 74% MB degradation was achieved by exfoliated g-C3N4 compared to its bulk counterpart (55%) in 180 min. Moreover, better photocatalytic performances (94% MB remotion) were registered at low Ag loading, with 5 wt.% as the optimal value. Such an improvement is attributed to the synergetic effect produced by a higher SA and the role of Ag nanoparticles in preventing charge-recombination processes. Based on the results, this work provides a simple and efficient methodology to obtain Ag/g-C3N4 photocatalysts with enhanced photocatalytic performance that is adequate for water remediation under sunlight conditions.