Cost-effectiveness of omalizumab for the treatment of severe pediatric allergic asthma-Results of a real-life study in Spain.

BACKGROUND: Severe pediatric allergic asthma (SPAA) induces a huge economic burden in terms of direct, indirect, and intangible costs. The use of omalizumab for the treatment of these patients has produced a significant improvement in several clinical outcomes, but at the same time, the cost for the management of the disease has also increased. The aim of this report was to evaluate whether the use of omalizumab is cost-effective. METHODS: A sample of 426 children with SPAA from the ANCHORS (Asthma iN CHildren: Omalizumab in Real-life in Spain) study was used to calculate the incremental cost-effectiveness ratio (ICER) for the avoidance of moderate-to-severe exacerbations (MSE) and also for the improvement in childhood Asthma Control Test (c-ACT) or the Asthma Control Questionnaire (ACQ5). We retrospectively collected data on health encounters and drug consumption before and up to 6 years after the beginning of the treatment with omalizumab. RESULTS: The ICER per avoided MSE was €2107 after 1 year, and it consistently decreased to €656 in those followed up to 6 years. Similarly, the ICER for the minimally important difference in control tests showed a decrease from €2059 to €380 per each 0.5 points of improvement in ACQ5 and from €3141 to €2322 per each 3 points improvement in c-ACT, at years 1 and 6, respectively. CONCLUSION: The use of OMZ is a cost-effective option for most children with uncontrolled SPAA, especially those who have frequent exacerbations; the costs are progressively reduced in successive years of treatment.

Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

BACKGROUND: Various studies have assessed omalizumab outcomes in the clinical practice setting but follow-up and/or number of patients included were limited. We aim to describe the long-term outcomes of pediatric patients with severe persistent allergic asthma receiving omalizumab in the largest real-life cohort reported to date. METHODS: ANCHORS was a multicenter, observational, retrospective cohort study conducted in 25 Pediatric Allergy and Pulmonology units in Spain. We collected data of patients < 18 years and initiating omalizumab between 2006 and 2018, from the year prior to omalizumab initiation to discontinuation or last available follow-up. The primary outcome was the evolution of the annual number of moderate-to-severe exacerbations compared with the baseline period. RESULTS: Of the 484 patients included, 101 (20.9%) reached 6 years of treatment. The mean ± standard deviation number of exacerbations decreased during the first year of treatment (7.9 ± 6.6 to 1.1 ± 2.0, P < .001) and remained likewise for up to 6 years. The other clinical parameters assessed also improved significantly during the first year and stabilized or continued to improve thereafter. The percentage of patients experiencing adverse events was consistently low, and the main reason for discontinuation was good disease evolution. CONCLUSION: In this large, long-term, observational study, moderate-to-severe exacerbations decreased significantly from the first year of treatment with omalizumab. The beneficial effect was maintained in the long term, along with a good safety profile. Our results position omalizumab as an effective long-term treatment in pediatric patients with severe persistent allergic asthma.

Extremity Tourniquet Training at High Seas.

BACKGROUND: Future navy officers require unique training for emergency medical response in the isolated maritime environment. The authors issued a workshop on extremity bleeding control, using four different commercial extremity tourniquets onboard a training sail ship. The purposes were to assess participants' perceptions of this educational experience and evaluate self-application simplicity while navigating on high seas. METHODS: A descriptive observational study was conducted as part of a workshop issued to volunteer training officers. A post-workshop survey collected their perceptions about the workshops' content usefulness and adequacy, tourniquet safety, self-application simplicity, and device preference. Tourniquet preference was measured by frequency count while the rest of the studied variables on a one-to-ten Likert scale. Frequencies and percentages were calculated for the studied variables, and application simplicity means compared using the ANOVA test (p < 0.05). RESULTS: Fifty-one Spanish training naval officers, aged 20 or 21, perceived high sea workshop content's usefulness, adequacy, and safety level at 8.6/10, 8.7/10, and 7.5/10, respectively. As for application simplicity, CAT and SAM-XT were rated equally with a mean of 8.5, followed by SWAT (7.9) and RATS (6.9), this one statistically different from the rest (p < 0.01). Windlass types were preferred by 94%. CONCLUSIONS: The training sail ship's extremity bleeding control workshop was perceived as useful and its content adequate by the participating midshipmen. Windlass types were regarded as easier to apply than elastic counterparts. They were also preferred by nine out of every ten participants.

Improving radiation oncology through clinical audits: Introducing the IROCA project.

As radiotherapy practice and processes become more complex, the need to assure quality control becomes ever greater. At present, no international consensus exists with regards to the optimal quality control indicators for radiotherapy; moreover, few clinical audits have been conducted in the field of radiotherapy. The present article describes the aims and current status of the international IROCA "Improving Radiation Oncology Through Clinical Audits" project. The project has several important aims, including the selection of key quality indicators, the design and implementation of an international audit, and the harmonization of key aspects of radiotherapy processes among participating institutions. The primary aim is to improve the processes that directly impact clinical outcomes for patients. The experience gained from this initiative may serve as the basis for an internationally accepted clinical audit model for radiotherapy.

Different in vitro proliferation and cytokine-production inhibition of memory T-cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment.

Calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi) are the main immunosuppressants used for long-term maintenance therapy in transplant recipients to avoid acute rejection episodes. Both groups of immunosuppressants have wide effects and are focused against the T cells, although different impacts on specific T-cell subsets, such as regulatory T cells, have been demonstrated. A greater knowledge of the impact of immunosuppression on the cellular components involved in allograft rejection could facilitate decisions for individualized immunosuppression when an acute rejection event is suspected. Memory T cells have recently gained focus because they might induce a more potent response compared with naive cells. The impact of immunosuppressants on different memory T-cell subsets remains unclear. In the present study, we have studied the specific impact of CNI (tacrolimus) and mTORi (rapamycin and everolimus) over memory and naive CD4(+) T cells. To do so, we have analysed the proliferation, phenotypic changes and cytokine synthesis in vitro in the presence of these immunosuppressants. The present work shows a more potent effect of CNI on proliferation and cytokine production in naive and memory T cells. However, the mTORi permit the differentiation of naive T cells to the memory phenotype and allow the production of interleukin-2. Taken together, our data show evidence to support the combined use of CNI and mTORi in transplant immunosuppression.

Proteomic analysis through larval development of Solea senegalensis flatfish.

The post-embryonic development of the Senegalese sole, Solea senegalensis, a flatfish of growing interest in fisheries and aquaculture, is associated with drastic morpho-physiological changes during metamorphosis. Although in the last two decades knowledge on sole culture has notably increased, especially in Southern Europe, its progress was restricted due to lack of methods to control reproduction, improve larval quality and increase juvenile disease resistance. A limited knowledge of the physiological, molecular and genetic mechanisms involved is at the base of such limitation. A proteomic study was carried out to explore the molecular events that occur during S. senegalensis ontogenesis. Protein expression changes were monitored in larvae from 5 to 21 dph by combining 2DE and protein identification with de novo MS/MS sequencing. An average of 6177 ± 282 spots was resolved in 2DE gels. Hierarchical cluster analysis of the 705 selected spots grouped them in eight patterns. Thirty-four proteins were identified and assigned biological functions including structure, metabolism highlighting energy metabolism, transport, protein folding, stress response, chromatin organization and regulation of gene expression. These changes provide a sequential description of the molecular events associated with the biochemical and biological transformations that occur during sole larval development.

Molecular characterization and transcriptional regulation of the renin-angiotensin system genes in Senegalese sole (Solea senegalensis Kaup, 1858): differential gene regulation by salinity.

In this work, the complete cDNA sequence encoding angiotensinogen (agt) in the euryhaline flatfish Senegalese sole was obtained. Additionally, putative coding sequences belonging to other renin-angiotensin system (RAS) genes including renin (ren), angiotensin-converting enzyme (ace), angiotensin-converting enzyme 2 (ace2), as well as angiotensin II receptor type I (agtr1) and type II (agtr2), were also identified. In juvenile tissues, agt transcripts were mainly detected in liver, ren in kidney, ace and ace2 in intestine, agtr1 in kidney and brain, and agtr2 in liver and kidney. Expression analysis of the six RAS genes after a salinity shift revealed a clear increase of agt mRNA abundance in liver just after transferring soles to high salinity water (60 ppt) with a peak at 48 h. Moreover, gene expression analysis in gills showed transcriptional regulation of ace and agtr1 at 48 h and agtr2 at 96 h after transferring soles to 60 ppt. Incubation of larvae before mouth opening (until 3 days post hatch; dph) at low salinity (10 ppt) resulted in a coordinated transcriptional up-regulation of RAS genes. Nevertheless, no differences in mRNA abundance between salinities were observed when larvae were cultivated to low salinity after mouth opening. Whole-mount in situ hybridization (WISH) signal for agt and ace in 3 dph larvae incubated at 10 ppt and 35 ppt confirmed that the former gene was mainly expressed in liver whereas the later gene was mainly located in pharynx and posterior gut, without pronounced differences in intensity between salinities. Possible physiological significance of all these results is discussed.

Ultra-high performance liquid chromatography coupled to ion mobility quadrupole time-of-flight mass spectrometry for the identification of non-volatile compounds migrating from 'natural' dishes.

Although most new biomaterials for food industry applications are labelled '100% natural fabrication' and 'chemical-free', certain compounds may migrate from those materials to the food, compromising the organoleptic characteristics and safety of the product. In this work, the degree of compound migration from dishes made with four different biomaterials: bamboo, palm leaf, wood and wheat pulp was investigated. Migration tests were carried out using three food simulants, 10% ethanol (simulant A), 3% acetic acid (simulant B), and 95% ethanol (simulant D2). Unequivocal identification of non-intentionally added substances (NIAS) is challenging even when using high-resolution mass spectrometry techniques however, a total of 25 different non-volatile compounds from the migration tests were identified and quantified using Ultra-high performance liquid chromatography coupled to ion mobility quadrupole time-of-flight mass spectrometry (UPLC-IMS-MS). In the bamboo samples three oligomers, cyclic diethylene glycol adipate, 3,6,9,16,19,22-hexaoxabicyclo[22.3.1]-octacosa-1(28),24,26-triene-2,10,15,23-tetrone and 1,4,7,14,17,20-hexaoxacyclohexacosane-8,13,21,26-tetrone exceeded the specified limits of migration.

A matter of fat: insulin resistance and oxidative stress.

BACKGROUND: Obesity is linked to insulin resistance (IR), which can lead to type 2 diabetes mellitus. Oxidative stress present in early obesity may favor the progression to comorbid conditions. OBJECTIVE: To examine the relationship between oxidative stress biomarkers and the severity of IR in a group of obese children. METHODS: Forty obese children with a body mass index (BMI) Z-score ≥ 2 were divided into two groups using the median obtained for the homeostasis model assessment of IR (HOMA-IR). Anthropometric parameters (including body fat composition by bioelectrical impedance) and biochemical parameters were assessed. The following biomarkers of oxidative stress were measured: malondialdehyde (MDA), carbonyl groups (CG), reduced glutathione, oxidized low-density lipoprotein, and vitamin E. Comparisons were adjusted for gender and Tanner stage. RESULTS: Children with high values of HOMA-IR were more likely to have high body fat percentage and waist circumferences. However, the BMI Z-score did not correlate to the level of IR. Children with higher values of HOMA-IR presented increased levels of markers of oxidative stress in lipids (MDA, p = 0.005) and proteins (CG, p = 0.015). Moreover, MDA increased with increasing levels of HOMA-IR (r = 0.50, p = 0.002), suggesting that lipoperoxidation increases as IR worsens. In a multivariate regression model, only HOMA-IR was predictive of MDA values, irrespective of adiposity parameters and other metabolic risk factors (r2 = 0.22, p = 0.002). CONCLUSIONS: Oxidative stress increases in obese children according to the severity of IR, which could be linked to the development of comorbidities.

Analysis of potential migration compounds from silicone molds for food contact by SPME-GC-MS.

Four commercially available silicone cupcake molds have been studied. An evaluation of the post-cure treatment applied to the silicone molds was carried out and the loss of volatile organic compounds after cure treatment was quantified. The two higher quality molds showed losses at the 0.5% (w/w) (recommended by BfR standard), while the two lower quality molds exceeded this limit. The migration studies were carried out using Tenax® as a solid food simulant. The volatile compounds that migrate were identified and quantified using SPME-GC-MS. Up to fourteen silicone oligomers were quantified. When the molds were subjected to post-cure treatment, none of them exceeded the global migration of 10 mg/dm2; while those lower quality molds showed migrations higher than 10 mg/dm2, so their use in contact with food is not recommended.

How bilastine is used to treat allergic rhinitis and urticaria in children.

Management guidelines for allergic rhinitis and urticaria recommend oral second-generation antihistamines as first-line treatment. The efficacy and safety of bilastine, the newest nonsedating second-generation antihistamine, are well established in adolescents/adults with these allergic conditions. The bilastine development program for pediatric use (2-<12 years) followed EMA-authorized processes. Pharmacokinetic/pharmacodynamic simulation and modeling and a pharmacokinetic study were conducted to identify and confirm the pediatric dose (10 mg/day). A Phase III, multicenter, double-blind, randomized, placebo-controlled, parallel-group study was performed to confirm the safety of bilastine 10 mg/day in children. In this article, evidence is reviewed for use of bilastine in children with allergic rhinoconjunctivitis or urticaria. Several cases are presented which demonstrate its role in routine clinical practice.

Cystatin C, cardiometabolic risk, and body composition in severely obese children.

The aim of this study was to assess the relationship between cystatin C (CysC), cardiometabolic risk factors (CMRFs), and body composition in severely obese children. We evaluated 117 children aged 7-14 years old. Seventy-nine of these were severely obese (body mass index z-score ranging from 2.1 to 8.4), and 38 were children with normal nutrition state. CysC was determined by immunonephelometry. CMRFs (glucose, insulin, high-density lipoprotein cholesterol, triglycerides, homocysteine, uric acid, alanine aminotransferase, and high-sensitivity C-reactive protein) were measured by standard biochemical methods. Blood pressure was evaluated at the clinical examination. Renal function was estimated using the glomerular filtration rate (eGFR) based upon creatinine levels, and body weight (Léger formula). Body composition was assessed by segmental bioelectrical impedance. Obese children at the highest tertile of CysC values were characterized by their aggregation of CMRFs. CysC concentration was associated with insulin resistance, alanine aminotransferase, uric acid, and homocysteine after adjusting for age, gender, and eGFR. CysC values were also correlated with the fat-free mass and specifically with skeletal muscle mass. CysC levels were correlated with CMRFs factors independently of renal function, and affected by skeletal muscle mass in severely obese children, although they are less influenced by this than is creatinine.

Migration of volatile compounds from natural biomaterials and their safety evaluation as food contact materials.

The concern for environmental conservation is increasing, and a very important factor to consider is the search for alternatives to the use of plastics in the food packaging industry. A good option is the manufacture of containers of biodegradable materials, such as the so-called biomaterials made of vegetable fibre such as wheat, wood, bamboo or palm leaf pulp. The migration of compounds from food packaging can cause alterations in food safety and acceptability. Therefore, their control through studies of specific migration is definitely important in the food industry. Specific migration has been studied in two types of dishes (wheat pulp and wood) in contact with three liquid simulants (ethanol 10%, acetic acid 3% and ethanol 95%). The analysis of migration extracts have been carried out by solid-phase microextraction coupled to gas chromatography (SPME-GC-MS) in the most suitable working conditions. In addition, those identified compounds considered of interest according to existing legislation have been quantified in order to assess whether exceed or not the migration limits established for some of them. The results obtained show that the quantified compounds are well below the specific migration limits (SML) set by the legislation, thereby showing the safety in use of this type of biodegradable dishes.

Predicting the antioxidant capacity and total phenolic content of bearberry leaves by data fusion of UV-Vis spectroscopy and UHPLC/Q-TOF-MS.

The total phenolic content (TPC) and antioxidant capacity have been considered as important quality parameters for plant extracts. In this study, bearberry leaves were regarded as studied subject and a reliable method was established to predict the TPC and antioxidant capacity of bearberry leaves. Ultraviolet-visible spectrometry (UV-Vis) and ultra high pressure liquid chromatography coupled to time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) were used to provide spectral fingerprinting and metabolomic profiling. The data obtained (separately and merged) were used to build partial least squares (PLS) regression model. The PLS model built by using ultraviolet-visible spectra provided a satisfactory prediction result. Mid-level data fusion using the scores significantly improved the performance of PLS regression model, the residual predictive deviations (RPDs) for TPC and α, α-diphenyl-ß-picrylhydrazyl (DPPH) were 6.258 and 6.699, respectively, showing an excellent predictive ability. This study proved the potential of combination of UV-Vis spectrometry and UHPLC/Q-TOF-MS in the prediction of TPC and antioxidant capacity of plant extracts.

Phenolic Compounds Content and Genetic Diversity at Population Level across the Natural Distribution Range of Bearberry (Arctostaphylos uva-ursi, Ericaceae) in the Iberian Peninsula.

Bearberry (Arctostaphylos uva-ursi) is a medicinal plant traditionally employed for the treatment of urinary tract infections due to high contents of arbutin (hydroquinone ß-D-glucoside), which is now mainly used as a natural skin-whitening agent in cosmetics. Bearberry has also been proposed as a natural antioxidant additive due to the high contents of phenolic compounds in leaves. We studied the variation on phenolic compounds in 42 wild populations of bearberry, aiming to elucidate if intrinsic biological, climatic, and/or geographic factors affect phenolic contents across its natural distribution in the Iberian Peninsula. Bearberry leaves were collected during autumn over a three-year period (2014-2016) in populations across a latitude and altitude gradient. Methanolic extracts showed a wide range of variation in total phenols content, and different phenolic profiles regarding arbutin (levels of this major constituent varied from 87 to 232 mg/g dr wt), but also catechin and myricetin contents, which were affected by geographic and climatic factors. Moderate levels of variation on genome size-assessed by flow cytometry-and on two plastid DNA regions were also detected among populations. Genetic and cytogenetic differentiation of populations was weakly but significantly associated to phytochemical diversity. Elite bearberry genotypes with higher antioxidant capacity were subsequently identified.

2-D DIGE analysis of Senegalese sole (Solea senegalensis) testis proteome in wild-caught and hormone-treated F1 fish.

In the farmed flatfish Senegalese sole, F1 males reared in captivity often show lower sperm production and fertilization capacity than wild-caught males. To gain insights into the molecular mechanisms that may be altered in the F1 testis, we used 2-D DIGE to compare the protein profiling of the testis of wild-caught males at the spermiation stage with that of F1 males showing different stages of germ cell development after hormone treatment in vivo. The abundance of 58 out of 1014 protein spots was found to differ significantly between the groups. De novo identification of these proteins by MS/MS revealed that proteins implicated in oxidoreductase activity, protein catabolism, formation of the zona pellucida receptor, cytoskeleton organization, and lipid binding and metabolism, were regulated in the F1 testes as germ cell development progressed. However, distinct isoforms or PTMs of some of these proteins, as well as of proteins involved in iron and glucose metabolism and ATP production, were expressed at lower levels in the testes of F1 males than in wild fish regardless of the hormone treatment. These results contribute to identifying proteins associated with spermatogenesis not previously described in teleosts, and suggest potential mechanisms that may be involved in the poor reproductive performance of Senegalese sole F1 males.

New insights into molecular pathways associated with flatfish ovarian development and atresia revealed by transcriptional analysis.

BACKGROUND: The Senegalese sole (Solea senegalensis) is a marine flatfish of increasing commercial interest. However, the reproduction of this species in captivity is not yet controlled mainly because of the poor knowledge on its reproductive physiology, as it occurs for other non-salmonid marine teleosts that exhibit group-synchronous ovarian follicle development. In order to investigate intra-ovarian molecular mechanisms in Senegalese sole, the aim of the present study was to identify differentially expressed genes in the ovary during oocyte growth (vitellogenesis), maturation and ovarian follicle atresia using a recently developed oligonucleotide microarray. RESULTS: Microarray analysis led to the identification of 118 differentially expressed transcripts, of which 20 and 8 were monitored by real-time PCR and in situ hybridization, respectively. During vitellogenesis, many up-regulated ovarian transcripts had putative mitochondrial function/location suggesting high energy production (NADH dehydrogenase subunits, cytochromes) and increased antioxidant protection (selenoprotein W2a), whereas other regulated transcripts were related to cytoskeleton and zona radiata organization (zona glycoprotein 3, alpha and beta actin, keratin 8), intracellular signalling pathways (heat shock protein 90, Ras homolog member G), cell-to-cell and cell-to-matrix interactions (beta 1 integrin, thrombospondin 4b), and the maternal RNA pool (transducer of ERBB2 1a, neurexin 1a). Transcripts up-regulated in the ovary during oocyte maturation included ion transporters (Na+-K+-ATPase subunits), probably required for oocyte hydration, as well as a proteinase inhibitor (alpha-2-macroglobulin) and a vesicle calcium sensor protein (extended synaptotagmin-2-A). During follicular atresia, few transcripts were found to be up-regulated, but remarkably most of them were localized in follicular cells of atretic follicles, and they had inferred roles in lipid transport (apolipoprotein C-I), chemotaxis (leukocyte cell-derived chemotaxin 2,), angiogenesis (thrombospondin), and prevention of apoptosis (S100a10 calcium binding protein). CONCLUSION: This study has identified a number of differentially expressed genes in the ovary that were not previously found to be regulated during ovarian development in marine fish. Specifically, we found evidence, for the first time in teleosts, of the activation of chemoattractant, angiogenic and antiapoptotic pathways in hypertrophied follicular cells at the onset of ovarian atresia.

Determination the set-off migration of ink in cardboard-cups used in coffee vending machines.

The set-off migration from printing inks can cause alterations in the safety and acceptability of food. Therefore, its control in the food industry is of special importance. The aim of this study was the determination of the migration of compounds coming from different types of cardboard-cups used in coffee vending machines. The volatile compounds present in cardboard-cups were studied and specific migration studies were carried out by solid phase microextraction with headspace coupled to gas chromatography (HS-SPME-GC-MS). The migration of compounds from the cardboard-cups manufacturing material, plastic coating (LDPE) and printing inks were identified and quantified. Those migrants listed in the Regulation No. 10/2011 presented values lower than the specific migration limit (SML), although a series of non-listed and non-authorized compounds were identified. From the results obtained the risk assessment of the vending cups from two different companies has been done.

Spanish traditional tomato. Effects of genotype, location and agronomic conditions on the nutritional quality and evaluation of consumer preferences.

Traditional tomatoes are highly valued for their organoleptic quality and cultural links with a territory. At present, strong competition has put these crops at risk, and it is necessary to differentiate the local cultivars and improve their nutritional value. This work focused on the nutritional study of four selected lines of a local tomato grown in two locations and in two agronomic conditions to nutritionally characterize the tomatoes and to study the effect of location and cultivation on nutritional parameters. Data on nutritional characterization revealed significant effects of location and treatment in most compounds. Tomatoes grown in traditional areas showed a significantly higher concentration of some phenolic acids and beta-carotene. Lycopene contents were not location dependent. The open field test showed significant differences in all the components. Regarding the best nutritional genotypes, all the components were dependent on lines, and significant differences were confirmed between them.

Antioxidant and antimicrobial markers by UPLC®-ESI-Q-TOF-MSE of a new multilayer active packaging based on Arctostaphylos uva-ursi.

49 different non-volatile compounds were determined in Spanish Arctostaphylos uva-ursi leaves using UPLC®-ESI-Q-TOF with MSE technology. Both positive and negative electrospray ionization were applied. MarkerLynx® was proposed as a powerful tool to distinguish samples from eight wild populations of Spain by determining their non-volatile markers. Development of HRMS methods let to analysis of metabolites in plants. Antioxidant and antimicrobial capacities of different extracts were evaluated. Plant extract with the strongest antioxidant and simultaneous good antimicrobial capacity (Lierta) was chosen and incorporated in a multilayer packaging. Then, antioxidant capacity of the new packaging was evaluated and the efficient free radical scavenging properties were demonstrated.