Comparative characterization of the infant gut microbiome and their maternal lineage by a multi-omics approach.

The human gut microbiome establishes and matures during infancy, and dysregulation at this stage may lead to pathologies later in life. We conducted a multi-omics study comprising three generations of family members to investigate the early development of the gut microbiota. Fecal samples from 200 individuals, including infants (0-12 months old; 55% females, 45% males) and their respective mothers and grandmothers, were analyzed using two independent metabolomics platforms and metagenomics. For metabolomics, gas chromatography and capillary electrophoresis coupled to mass spectrometry were applied. For metagenomics, both 16S rRNA gene and shotgun sequencing were performed. Here we show that infants greatly vary from their elders in fecal microbiota populations, function, and metabolome. Infants have a less diverse microbiota than adults and present differences in several metabolite classes, such as short- and branched-chain fatty acids, which are associated with shifts in bacterial populations. These findings provide innovative biochemical insights into the shaping of the gut microbiome within the same generational line that could be beneficial in improving childhood health outcomes.

Allergy-associated biomarkers in early life identified by Omics techniques.

The prevalence and severity of allergic diseases have increased over the last 30 years. Understanding the mechanisms responsible for these diseases is a major challenge in current allergology, as it is crucial for the transition towards precision medicine, which encompasses predictive, preventive, and personalized strategies. The urge to identify predictive biomarkers of allergy at early stages of life is crucial, especially in the context of major allergic diseases such as food allergy and atopic dermatitis. Identifying these biomarkers could enhance our understanding of the immature immune responses, improve allergy handling at early ages and pave the way for preventive and therapeutic approaches. This minireview aims to explore the relevance of three biomarker categories (proteome, microbiome, and metabolome) in early life. First, levels of some proteins emerge as potential indicators of mucosal health and metabolic status in certain allergic diseases. Second, bacterial taxonomy provides insight into the composition of the microbiota through high-throughput sequencing methods. Finally, metabolites, representing the end products of bacterial and host metabolic activity, serve as early indicators of changes in microbiota and host metabolism. This information could help to develop an extensive identification of biomarkers in AD and FA and their potential in translational personalized medicine in early life.

Circulating serum profile of small non-coding RNAs in patients with anaphylaxis beyond microRNAs.

Introduction: Anaphylaxis is the most severe manifestation of allergic disorders. Currently, an increasing number of cells, pathways and molecules involved in the etiopathogenesis of anaphylaxis are being discovered. However, there are no conclusive biomarkers to confirm its diagnosis. Small non-coding RNAs (sncRNAs) are 18-200 nucleotide molecules that can be divided into: microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), transference RNA derived fragments (tRFs) and YRNA derived fragments (YRFs). These molecules participate in cell-cell communication modulating various physiological processes and have been postulated as non-invasive biomarkers of several pathologies. Therefore, in this study we characterized the serum circulating profile of other sncRNA beyond miRNAs in two populations of 5 adults and 5 children with drug- and food-mediated anaphylaxis, respectively. Methods: Samples were obtained from each patient under two different conditions: during anaphylaxis and 14 days after the reaction (control). The sncRNA analysis was carried out by Next Generation Sequencing (NGS). Results: A total of 671 sncRNAs (3 piRNAs, 74 snoRNAs, 54 snRNAs, 348 tRFs and 192 YRFs) were identified in adults with drug-induced anaphylaxis, while 612 sncRNAs (2 piRNAs, 73 snoRNAs, 52 snRNAs, 321 tRFs and 164 YRFs) were characterized in children with food-mediated anaphylaxis. However, only 33 (1 piRNA, 4 snoRNAs, 1 snRNAs, 7 tRFs and 20 YRFs) and 80 (4 snoRNAs, 6 snRNAs, 54 tRFs and 16 YRFs) of them were statistically different between both conditions, respectively. Among them, only three (Y_RNA.394, Y_RNA.781 and SCARNA2) were common to both adults and children analysis. Discussion: This study provides a differential profile of circulating serum sncRNAs beyond miRNAs in patients with anaphylaxis, postulating them as candidate biomarkers for this pathological event and as novel mediators of the reaction.

Novel mediator in anaphylaxis: decreased levels of miR-375-3p in serum and within extracellular vesicles of patients.

Introduction: Anaphylaxis is among the most severe manifestations of allergic disorders, but its molecular basis remains largely unknown and reliable diagnostic markers are not currently available. MicroRNAs (miRNAs) regulate several pathophysiological processes and have been proposed as non-invasive biomarkers. Therefore, this study aims to evaluate their involvement in anaphylactic reaction and their value as biomarkers. Methods: Acute (anaphylaxis) and baseline (control) serum samples from 67 patients with anaphylaxis were studied. Among them, 35 were adults with drug-induced anaphylaxis, 13 adults with food-induced anaphylaxis and 19 children with food-induced anaphylaxis. The circulating serum miRNAs profile was characterized by next-generation sequencing (NGS). For this purpose, acute and baseline samples from 5 adults with drug-induced anaphylaxis were used. RNA was extracted, retrotranscribed, sequenced and the readings obtained were mapped to the human database miRBase_20. In addition, a system biology analysis (SBA) was performed with its target genes and revealed pathways related to anaphylactic mediators signaling. Moreover, functional and molecular endothelial permeability assays were conducted with miR-375-3p-transfected cells in response to cAMP. Results: A total of 334 miRNAs were identified, of which 21 were significant differentially expressed between both phases. Extracellular vesicles (EVs) were characterized by Western blot, electron microscopy and NanoSight. A decrease of miR-375-3p levels was determined by qPCR in both serum and EVs of patients with anaphylaxis (****p<.0001). Precisely, the decrease of miR-375-3p correlated with the increase of two inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1) and granulocyte macrophage colony-stimulating factor (GM-CSF). On the other hand, functional and molecular data obtained showed that miR-375-3p partially blocked the endothelial barrier maintenance and stabilization by disassembly of cell-cell junctions exhibiting low Rac1-Cdc42 levels. Discussion: These findings demonstrate a differential serum profile of circulating miRNAs in patients with anaphylaxis and exhibit the miR-375-3p modulation in serum and EVs during drug- and food-mediated anaphylactic reactions. Furthermore, the in silico and in vitro studies show a negative role for miR-375-3p/Rac1-Cdc42 in the endothelial barrier stability.

Further Insights into the Gut Microbiota of Cow's Milk Allergic Infants: Analysis of Microbial Functionality and Its Correlation with Three Fecal Biomarkers.

Cow's milk allergy (CMA) is one of the most prevalent food allergies in children. Several studies have demonstrated that gut microbiota influences the acquisition of oral tolerance to food antigens at initial stages of life. Changes in the gut microbiota composition and/or functionality (i.e., dysbiosis) have been linked to inadequate immune system regulation and the emergence of pathologies. Moreover, omic sciences have become an essential tool for the analysis of the gut microbiota. On the other hand, the use of fecal biomarkers for the diagnosis of CMA has recently been reviewed, with fecal calprotectin, α-1 antitrypsin, and lactoferrin being the most relevant. This study aimed at evaluating functional changes in the gut microbiota in the feces of cow's milk allergic infants (AI) compared to control infants (CI) by metagenomic shotgun sequencing and at correlating these findings with the levels of fecal biomarkers (α-1 antitrypsin, lactoferrin, and calprotectin) by an integrative approach. We have observed differences between AI and CI groups in terms of fecal protein levels and metagenomic analysis. Our findings suggest that AI have altered glycerophospholipid metabolism as well as higher levels of lactoferrin and calprotectin that could be explained by their allergic status.

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.

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.

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

BACKGROUND: Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. METHODS: OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. RESULTS: Data derived from 58 patients aged 10.3 years (IQR 6.3-13.2) and median milk-specific IgE 100 kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000 mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000 mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P = .013) and anaphylaxis (P = .001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500 mg; 33.3% ≥6000 mg). CONCLUSION: Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.

Urban environment and dietary behaviours as perceived by residents living in socioeconomically diverse neighbourhoods: A qualitative study in a Mediterranean context.

Scholars have determined that low socioeconomic status (SES) is associated with unhealthy dietary behaviours and that local food environments shape food inequality. Less is known about how residents' perceptions of their food environment affect their dietary behaviours. We conducted 37 semistructured interviews and 29 focus groups in three socioeconomically distinct neighbourhoods in Madrid. We identified the following main categories related to social and physical food environments: (a) perceptions of healthy and unhealthy dietary behaviours, (b) children's relationships with food, (c) precariousness and (d) residential food retailer types. Older adults were perceived as healthier consumers, whereas younger people were identified as fast-food consumers. In the low- and middle-SES neighbourhoods, residents saw home-cooked legume-based stews as healthy food. In the high-SES neighbourhood, television cooking programs were highlighted as a positive influence. In the low- and middle-SES neighbourhoods, grandparents played an essential role in the transmission of healthy eating habits to their grandchildren. In the high-SES neighbourhood, children's diets at home were determined by school menus. In the low- and middle-SES neighbourhoods, participants talked about a black market where food could be purchased. Food retailers with low-quality foods were also highlighted. In all neighbourhoods, residents missed traditional food stores, and in the low- and middle-SES neighbourhoods, immigrant-run food stores were not well accepted. Our study presents the concepts shaping how neighbourhood SES differences affect dietary behaviours according to residents of a large Mediterranean city.

Changing Neighborhoods and Residents' Health Perceptions: The Heart Healthy Hoods Qualitative Study.

Cities, and therefore neighborhoods, are under constant change. Neighborhood changes may affect residents' health in multiple ways. The Heart Healthy Hoods (HHH) project studies the association between neighborhood and residents' health. Focusing on a middle⁻low-socioeconomic neighborhood in Madrid (Spain), our aim was to describe qualitatively its residents' perceptions on the urban changes and their impacts on health. We designed a qualitative study using 16 semi-structured interviews including adult residents and professionals living or working in the area. Firstly, we described the perceived main social and neighborhood changes. Secondly, we studied how these neighborhood changes connected to residents' health perceptions. Perceived major social changes were new demographic composition, new socio⁻cultural values and economic changes. Residents' negative health perceptions were the reduction of social relationships, increase of stress and labor precariousness. Positive health perceptions were the creation of supportive links, assimilation of self-care activities and the change in traditional roles. Neighborhood changes yielded both negative and positive effects on residents' health. These effects would be the result of the interrelation of different elements such as the existence or absence of social ties, family responsibilities, time availability, economic resources and access and awareness to health-promoting programs. These qualitative research results provide important insight into crafting urban health policies that may ultimately improve health outcomes in communities undergoing change.

Spatial and temporal patterns of pesticide concentrations in streamflow, drainage and runoff in a small Swedish agricultural catchment.

A better understanding of the dominant source areas and transport pathways of pesticide losses to surface water is needed for targeting mitigation efforts in a more cost-effective way. To this end, we monitored pesticides in surface water in an agricultural catchment typical of one of the main crop production regions in Sweden. Three small sub-catchments (88-242ha) were selected for water sampling based on a high-resolution digital soil map developed from proximal sensing methods and soil sampling; one sub-catchment had a high proportion of clay soils, another was dominated by coarse sandy soils while the third comprised a mix of soil types. Samples were collected from the stream, from field drains discharging into the stream and from within-field surface runoff during spring and early summer in three consecutive years. These samples were analyzed by LC-MS/MS for 99 compounds, including most of the polar and semi-polar pesticides frequently used in Swedish agriculture. Information on pesticide applications (products, doses and timing) was obtained from annual interviews with the farmers. There were clear and consistent differences in pesticide occurrence in the stream between the three sub-catchments, with both the numbers of detected compounds and concentrations being the largest in the area with a high proportion of clay soils and with very few detections in the sandy sub-catchment. Macropore flow to drains was most likely the dominant loss pathway in the studied area. Many of the compounds that were detected in drainage and stream water samples had not been applied for several years. This suggests that despite the predominant role of fast flow pathways in determining losses to the stream, long-term storage along the transport pathways also occurs, presumably in subsoil horizons where degradation is slow.

Understanding the local food environment: A participatory photovoice project in a low-income area in Madrid, Spain.

There is a need to partner between researchers, practitioners and residents to increase our understanding of environmental influences on dietary behaviors. We used the participatory method of Photovoice to understand key determinants of the local food environment influencing residents' diets. This project was conducted in Villaverde, a low-income area located in Madrid, Spain. From February to May 2015, 24 residents working in four Photovoice groups, took photographs related to their local food environment. Each group analyzed and critically discussed their photographs in small group sessions. Through a consensus-building process, participants identified 30 emerging categories, which followed five conceptual themes related to their food environment: 1) eating in moderation, 2) cultural diversity, 3) food stores, 4) social relationships and 5) economic crisis and poverty. Participants, researchers and practitioners successfully collaborated in analyzing, writing, disseminating the project results, and directly informing local policy-makers, media, and other residents. The project results may guide community-generated interventions for promoting a healthier food environment.

Population cardiovascular health and urban environments: the Heart Healthy Hoods exploratory study in Madrid, Spain.

BACKGROUND: Our aim is to conduct an exploratory study to provide an in-depth characterization of a neighborhood's social and physical environment in relation to cardiovascular health. A mixed-methods approach was used to better understand the food, alcohol, tobacco and physical activity domains of the urban environment. METHODS: We conducted this study in an area of 16,000 residents in Madrid (Spain). We obtained cardiovascular health and risk factors data from all residents aged 45 and above using Electronic Health Records from the Madrid Primary Health Care System. We used several quantitative audit tools to assess: the type and location of food outlets and healthy food availability; tobacco and alcohol points of sale; walkability of all streets and use of parks and public spaces. We also conducted 11 qualitative interviews with key informants to help understanding the relationships between urban environment and cardiovascular behaviors. We integrated quantitative and qualitative data following a mixed-methods merging approach. RESULTS: Electronic Health Records of the entire population of the area showed similar prevalence of risk factors compared to the rest of Madrid/Spain (prevalence of diabetes: 12 %, hypertension: 34 %, dyslipidemia: 32 %, smoking: 10 %, obesity: 20 %). The food environment was very dense, with many small stores (n = 44) and a large food market with 112 stalls. Residents highlighted the importance of these small stores for buying healthy foods. Alcohol and tobacco environments were also very dense (n = 91 and 64, respectively), dominated by bars and restaurants (n = 53) that also acted as food services. Neighbors emphasized the importance of drinking as a socialization mechanism. Public open spaces were mostly used by seniors that remarked the importance of accessibility to these spaces and the availability of destinations to walk to. CONCLUSION: This experience allowed testing and refining measurement tools, drawn from epidemiology, geography, sociology and anthropology, to better understand the urban environment in relation to cardiovascular health.

Surface Runoff of Pesticides from a Clay Loam Field in Sweden.

Pesticides stored at or close to the soil surface after field application can be mobilized and transported off the field when surface runoff occurs. The objective of our study was to quantify the potential pesticide losses in surface runoff from a conventionally managed agricultural field in a Swedish climate. This was achieved by measuring surface runoff volumes and concentrations in runoff of six spring-applied pesticides and autumn-applied glyphosate and its metabolite aminomethylphosphonic acid (AMPA). Measurements were performed for 3 yr both during the growing seasons and during intervening winter snowmelt periods on a clay loam field close to Uppsala. During growing seasons, surface runoff was generated on only five occasions during one 25-d period in 2012 when the infiltration capacity of the soil may have been reduced by structural degradation due to large cumulative rainfall amounts after harrowing. Concentrations in surface runoff exceeded Swedish water quality standards in all samples during this growing season for diflufenican and pirimicarb. Surface runoff was generated during three snowmelt periods during the winter of 2012-2013. All of the applied pesticides were found in snowmelt samples despite incorporation of residues by autumn plowing, degradation, and leaching into the soil profile during the period between spraying and sampling. Concentrations of glyphosate ranged from 0.12 to 7.4 µg L, and concentrations of AMPA ranged from 0 to 2.7 µg L. Our results indicate that temporal changes in hydraulic properties during the growing season and when the soil freezes during winter affect pesticide losses through surface runoff.

Bloqueo trifascicular paroxístico secundario a endocarditis infecciosa sobre válvula tricúspide / Transient trifascicular block secondary to tricuspid valve endocarditis

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Desigualdades de género y diabetes mellitus tipo 2: la importancia de la diferencia / Gender inequalities and type 2 diabetes: the importance of the difference

Fundamentos: La diabetes mellitus tipo 2 (DM2) afecta de manera diferente a hombres y mujeres, y habría que distinguir si estas diferencias son debidas a la expresión de riesgos dispares ligados al sexo y/o relacionados con desigualdades de género. El objetivo del presente trabajo es sintetizar los estudios que presentan desigualdades de sexo respecto a la prevalencia, incidencia, complicaciones y mortalidad en la DM2. Material y métodos: Se realizó una búsqueda sistemática en la base de datos de PubMed de la Librería Nacional de Medicina de Estados Unidos y en Elsevier. Se acotó la búsqueda a los artículos sobre DM2 que estaban publicados entre enero de 1999 y diciembre de 2009, en inglés o español. Se incluyeron los artículos que presentaban entre sus objetivos analizar tres temáticas principales: «prevalencia e incidencia», «control y complicaciones» y «mortalidad». Resultados: De los 22 artículos encontrados, 6 demostraban diferencias significativas en cuanto a prevalencia, 8 en cuanto al control y las complicaciones, y 8 respecto a la mortalidad. En la mayoría de los artículos no se distinguían los efectos atribuibles a factores biológicos ligados al sexo de los atribuibles a factores relacionados con el género. Conclusiones: A pesar de que hay diferentes resultados en salud entre hombres y mujeres con DM2, las desigualdades de género no están suficientemente explicadas en los artículos en los que hay diferencias significativas por sexo. Para profundizar en las causas de estas diferencias, sería necesario incluir en los estudios indicadores que incorporaran la perspectiva de género(AU)

Background: Type 2 Diabetes mellitus (T2DM) affects men and women differently, and it needs to be determined whether these differences are due to expression of disparate sex-linked risks and/or related to gender inequalities. The aim of this paper is to summarise the studies presenting gender inequalities regarding the prevalence, incidence, complications and mortality in T2DM. Material and methods: We conducted a systematic review in the National Library of Medicine's PubMed database and Elsevier database. The search was refined to those diabetes articles that were published between January 1999 and December 2009 in English or Spanish. We included those articles that had among their objectives to discuss three main themes: «prevalence and incidence», «control and complications» and «mortality». Results: Of the 22 articles, 6 found significant differences in prevalence, 8 in the control and the complications, and 8 with respect to mortality. Most of the articles did not differentiate between the effects attributable to biological factors linked to the sex and those attributable to gender-related factors. Conclusions: Although there are different health outcomes between men and women with T2DM, gender inequalities are not sufficiently explained in the articles in which there are significant sex differences. To understand the causes of these differences, indicators that incorporate gender perspectives should be included in studies(AU)