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Newborn screening; Severe combined immunodeficiency; T-cell receptor excision circles Cribratge de nadons; Immunodeficiència combinada greu; Cercles d'excisió de receptors de cèl·lules T Cribado de recién nacidos; Inmunodeficiencia combinada grave; Círculos de escisión de receptores de células T Severe combined immunodeficiency (SCID), the most severe form of T-cell immunodeficiency, can be screened at birth by quantifying T-cell receptor excision circles (TRECs) in dried blood spot (DBS) samples. Early detection of this condition speeds up the establishment of appropriate treatment and increases the patient's life expectancy. Newborn screening for SCID started in January 2017 in Catalonia, the first Spanish and European region to universally include this testing. The results obtained in the first 2 years of experience are evaluated here. All babies born between January 2017 and December 2018 were screened. TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland). In 2018, the retest cutoff in the detection algorithm was updated based on the experience gained in the first year, and changed from 34 to 24 copies/μL. This decreased the retest rate from 3.34 to 1.4% (global retest rate, 2.4%), with a requested second sample rate of 0.23% and a positive detection rate of 0.02%. Lymphocyte phenotype (T, B, NK populations), expression of CD45RA/RO isoforms, percentage and intensity of TCR αβ and TCR γδ, presence of HLA-DR+ T lymphocytes, and in vitro lymphocyte proliferation were studied in all patients by flow cytometry. Of 130,903 newborns screened, 30 tested positive, 15 of which were male. During the study period, one patient was diagnosed with SCID: incidence, 1 in 130,903 births in Catalonia. Thirteen patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 10,069 newborns (43% of positive detections). Nine patients were considered false-positive cases because of an initially normal lymphocyte count with normalization of TRECs between 3 and 6 months of life, four infants had transient lymphopenia due to an initially low lymphocyte count with recovery in the following months, and three patients are still under study. The results obtained provide further evidence of the benefits of including this disease in newborn screening programs. Longer follow-up is needed to define the exact incidence of SCID in Catalonia.

The accuracy of the ALS procedure for fitting the CP decomposition is affected by incorrect model selection due to the properties of its objective function. A study on ALS performance is presented in order to show that for large data sets this occasional shortcoming becomes prevalent. This deficiency should warn off researchers from employing ALS unless the rank of the underlying trilinear structure can be established in advance. Multi-optimization provides a possible solution: ALS can be initialized with procedures insensitive to over-factoring such as SWATLD and ATLD. In this manner it is possible to overcome factorization issues and provide a gain in efficiency without relying on computationally expensive model selection procedures.

Compositional data are quantitative descriptions of the parts of some whole, conveying relative information. The relationship between two sets of compositional descriptors can be explored by use of Canonical Correlation analysis with a procedure based on Partial Least Squares (PLS). This method offers a way to deal with matrix singularity in an efficient fashion and presents the further advantage of being easy to interpret. In order to fully explore the potential of PLS for analyzing the relationships between two sets of compositions, the performances of the NIPALS, SIMPLS and Kernel algorithms are compared on simulated data.

The concept of functional food has evolved throughout the years. These days we define a food to be functional when it confers a benefit to human health. Lactic acid fermentation is one of the most important and used food processing technologies to produce this type of food. Fermentation of Lactobacillus Paracasei CBA L74 - a homofermentative, gram positive probiotic - on rice flour suspension has been proved to be a successful route to produce functional foods. However, the process was characterized by high energy consumption, low air sparging and complex expensive metabolite separation. A research program has been developed to carry out L. Paracasei fermentation using a low viscosity medium based on rice flour suspension. Fractionation of rice flour suspension provided a medium characterized by low amounts of solids and nutrients at concentration high that support the microorganism growth. Fermentations were carried in a 1L batch reactor equipped with an agitation systems designed to provide uniform mixing. The composition of the medium; cells, glucose, protein, pH, metabolite production as well as L. Paracasei’ growth trend was analysed throughout the process. Fermentation on supernatant obtained from rice flour and water suspension through centrifugation were possible to produce a potential probiotic functional food with a good bacterial charge.

Diets rich in antioxidant compounds are correlated to more favorable health outcomes. Carotenoids are powerful antioxidants, thanks to their effectiveness as scavengers of free radicals. The unique acrylic structure together with the presence of two additional double bonds make lycopene one of the most efficient carotenoids oxygen quenchers. Tomatoes (Solanum Lycopersicum, from which it takes its name) and their derivatives represent the major dietary source of lycopene. Other natural sources of lycopene are melons, guava and pink grapefruits. Cooking food can affect lycopene bioavailability that appears higher in heat-treated compared to raw products. Since lycopene is a lipophilic substance, its intestinal absorption and its distribution in body is related to the presence of lipids in diet and tissues, respectively. For this reason, plasma concentration of lycopene differs widely in individuals, as a result of the influence of different factors. In this review, we provide a complete and up-to-date overview of chemical, biochemical and metabolic properties, addressing the state of art on lycopene as protective molecule and the methods used to produce lycopene enriched foods and supplements from tomato industrial waste.

The PARAFAC-ALS algorithm is the most widely used procedure for approximating arrays with a trilinear structure because it provides least squares solutions and delivers consistent outputs. Nonetheless, it is particularly slow at converging especially under challenging conditions, i.e. data multicollinearity, high factors’ congruence and over-factoring. This shortcoming can be quite problematic when dealing with three-way arrays of large dimensions. More efficient procedures can be employed, such as ATLD, however they are far less reliable. As an alternative, ATLD and ALS can be combined in a multi-optimization procedure in order to increase efficiency without reducing accuracy. This novel approach has been carried out and tested on artificial and real data

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma arising from the skin. We aimed to review and deal with some of the most relevant controversial topics on the correct use of immunotherapy for the treatment of MCC. Methods: The primary search was carried out via PubMed, EMBASE, and the Cochrane Library (until 31st May, 2018), while other articles and guidelines were retrieved from related papers or those referenced in these papers. Additionally, we performed an extensive search on ClinicalTrials.gov to gather information on the ongoing clinical trials related to this specific topic. Results: We performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies evaluating these issues: Are there any predictive criteria of response to immunotherapy? What is the correct place of immunotherapy in the treatment algorithm of MCC? What is the best choice after immunotherapy failure? What to do with patients for whom immunotherapy is not been feasible or contraindicated? How long should immunotherapy be prolonged, and what follow-up should be offered after complete response? Conclusion: The therapeutic landscape of MCC is rapidly evolving: many open issues will probably be resolved, and many other questions are likely to arise in the next few years. The results of ongoing prospective clinical trials and of several other studies on these issues are eagerly awaited.

Esophageal Neuroendocrine tumors (NETs) are rare, aggressive and lacking specific symptoms. This causes a diagnostic delay, worsening the prognosis. Numerous cases are reported in literature, without a consensus on the management. Our aim was to clarify epidemiology, clinical presentation, diagnostic, therapeutic management of esophageal NETs. Extensive literature search identified a total of 226 articles. One hundred twenty-five articles (n = 1676) met the inclusion criteria, showing that: the incidence of esophageal NET varies geographically; men (60–70 years) are more affected; smoking and alcohol abuse are the major risk factors; dysphagia, weight loss, appetite loss are the most common clinical features. The histotypes include high-grade small and large cell esophageal carcinomas and low-grade carcinoid tumors. Mixed neuroendocrine/non-neuroendocrine neoplasms are the most common. Often the diagnosis occurs randomly on endoscopic examination. Circulating markers, functional combined with conventional imaging contributes to the diagnosis and management. Treatment depends on type, grade and stage of the tumor.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.

The presence of mutations in PRF1, UNC13D, STX11 and STXBP2 genes in homozygosis or compound heterozygosis results in immune deregulation. Most such cases lead to clinical manifestations of haemophagocytic lymphohistiocytosis (HLH). In the present study, we analyzed degranulation and cytotoxicity in a pediatric patient with a late presentation of HLH associated with Epstein-Barr virus infection. Remarkably, the results of the degranulation assay showed reduction of CD107a median fluorescence intensity (MFI) and absent cytotoxicity. Genetic analysis identified compound heterozygous mutations in STXBP2 gene: a previously reported splicing defect in exon 15 (c.1247-1G>C, p.V417LfsX126) and a novel missense mutation in exon 9 (c.728T>G, p.L243R). Transfection experiments of STXBP2-L243R or STXBP2-WT constructs showed an undetectable protein expression of the STXBP2-L243R mutation. The residue L243 is highly preserved evolutionarily; moreover, computational analysis of its structure revealed its participation in the rich network of interactions that stabilizes domains 2 and 3 of the protein. Altogether, we demonstrated by molecular and in silico analysis that the new L243R mutation in STXBP2 plays a pathogenic role that, together with the p.Val417Leufsc mutation, shows the synergistic negative effect of these two mutations on STXBP2 function, leading to a decrease of degranulatory activity in vivo.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

El bloque administrativo en la planta Dow Química Cartagena cuenta con un equipo de climatización obsoleto, que presenta un sin fin de inconvenientes en el momento de realizar mantenimiento, así como también pérdidas económicas asociadas al bajo rendimiento energético. Es por eso que este proyecto se fundamenta en el diseño de un sistema de climatización en la planta de Dow Química Cartagena, garantizando un sistema que cumpla las condiciones climáticas mínimas deseadas por el cliente, siendo confiable y eficiente, que están a su vez regidas por las normativas colombianas de sistemas de aire acondicionado ACAIRE. El diseño del sistema tiene en cuenta todas las consideraciones de diseños tantos ambientales como económicas, en el que de describen a su vez el tratamiento del aire y el tratamiento del agua. La alternativa desarrollada cuenta con dos sistemas, un sistema de tuberías y un sistema de ducteria, los cuales están diseñado siguiendo los estándares de los handbooks de diseño, Finalmente se realiza el diseño detallado térmicamente de un intercambiador de calor de tubos escalonados aletados. The administrative building of Dow Química Cartagena has an obsolete and inefficient air conditioning system, which presents endless inconveniences at the time of maintenance, as well as economic losses associated with low energy efficiency. That is why this project is based mainly on the design of an air conditioning system for Dow Quimica Cartagena plant, guaranteeing a system that meets the minimum desired climatic conditions require for the client, being reliable and efficient, which are in turn governed by the Colombian regulations of ACAIRE air conditioning systems. The system design takes into account all considerations of both environmental and economic designs, in which they describe in turn the treatment of air and the treatment of water. The developed alternative has two systems, a pipe system and a ductwork system, which are designed following the standards of the design handbooks. Finally, the thermally detailed design of a finned staggered tube heat exchanger is carried out.

Herein, joint recommendations for diagnosis and treatment of vulvo-vaginal atrophy (VVA) in women in the peri- and post-menopausal phases from the Societa Italiana per la Menopausa (SIM) and the Societa Italiana della Terza Eta (SIGiTE) are presented. The recommendations are aimed at all healthcare personnel caring for women in the menopausal transition or postmenopausal phase, and are also intended to raise awareness of VVA. Recent data clearly indicate VVA is a highly prevalent condition among postmenopausal women, and that the vast majority of women with VVA are not adequately treated. In reality, diagnosis of VVA is simple and largely clinical. Many types of treatments are available for VVA, ranging from preventive education measures to local non-hormonal therapies, local agents that modulate hormonal receptors and systemic as well as laser therapy and radiofrequency. Regardless of the therapeutic approach adopted, greater communication between the physician and the woman with VVA should be actively encouraged. This is also in light of the difficulty of talking about the VVA and related disorders. Greater communication also encourages adequate therapy and thus minimizes the impact of VVA on the quality of life of the woman and her partner.

La ingeniería y la matemática se han retroalimentado desde sus inicios. La ingeniería como la aplicación del conocimiento científico a la invención práctica y la matemática como el conocimiento científico en sí mismo. Este artículo se sitúa en el germen del desarrollo de la física-matemática como herramienta clave en la ingeniería, a través del problema de la cuerda vibrante, con un final envuelto en “armonías”.

This conceptual paper examines the philanthropic value of alumni mentorship programmes. Through the review of literature on alumni mentorship, this paper argues that participation in alumni mentoring provides a bridge to philanthropic awareness and giving on a corporate and individual level. Co-operative strategies between graduate employers, higher education institutions (HEIs) and alumni mentors create an environment of multiple beneficiaries to alumni mentorship. Alongside student or recent alumni mentees who benefit from career advice and mentorship, mentoring schemes normalize giving back to one’s alma mater. Alumni mentors benefit by building their own professional development and leadership skills. Industry partners, who encourage alumni to become mentors, benefit from developing mentoring and early coaching skills within their graduate employees while enhancing their corporate social responsibility (CSR) profile. HEIs also benefit by building affinity, re-engaging alumni in the institution and translating alumni engagement into support for the institutional goals. This project seeks early conceptual underpinning for a future research project to explore alumni mentorship contributing to an employment and educational environment that promotes philanthropy.

International audience; Natural and artificial directional selection in cosmopolitan and autochthonous livestock and wild relative populations have shaped their genomes defining the level of variability and determining selective sweeps as final adaptation to different environmental conditions and production systems. In this study we analyzed the genetic variability and selection signatures in 19 European local pig breeds sampled from 7 countries (Croatia, France, Germany, Italy, Lithuania, Portugal, Serbia, Slovenia and Spain) (Alentejana, Apulo-Calabrese, Basque, Bísara, Majorcan Black, Black Slavonian, Casertana, Cinta Senese, Gascon, Krskopolje, Lithuanian indigenous wattle, Lithuanian White Old Type, Mora Romagnola, Moravka, Nero Siciliano, Sarda, Schwäbisch-Hällisches Schwein, Swallow-Bellied Mangalitsa and Turopolje), 3 cosmopolitan Italian breeds (Large White, Landrace and Duroc) and Italian wild boars. For each population, we prepared DNA pools using equimolar DNA from 30 to 35 animals. Whole-genome 150-bp paired-end sequencing was carried out on an Illumina HiSeq machine. More than 18.4 billion of reads were obtained and mapped on the Sscrofa11.1 genome version with BWA, obtaining a mean depth of sequencing of 42X, respectively. CRISP, coupled to an ad hoc bioinformatic pipeline, was used to detect more than 30 million of high-quality variants (18% not included in dbSNP yet). Variant annotation, carried out with VEP, highlighted that the 0.34% of the autosomal SNPs impacted genes at the protein level. Selection signature analyses (Fst and the Pooled Heterozygosity) highlighted more than 400 sweep regions distributed along the 18 porcine autosomes and scaffolds. Some of these genome regions harboured major genes affecting body shape/size (e.g., NR6A1, PLAG1, LCORL and CASP10), coat color (e.g., KIT, MC1R) and growth/fatness (e.g., MC4R), providing a first global variability analysis of European Sus scrofa populations. This study has been funded by European Union’s H2020 RIA program (grant agreement No 634476).

Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

SUMMARYThe prompt availability of reliable epidemiological information on emerging pandemics is crucial for public health policy-makers. Early in 2013, a possible new H1N1 epidemic notified by an intensive care unit (ICU) to GiViTI, the Italian ICU network, prompted the re-activation of the real-time monitoring system developed during the 2009–2010 pandemic. Based on data from 216 ICUs, we were able to detect and monitor an outbreak of severe H1N1 infection, and to compare the situation with previous years. The timely and correct assessment of the severity of an epidemic can be obtained by investigating ICU admissions, especially when historical comparisons can be made.