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ObjectiveThe Early Treatment of Atrial Fibrillation for Stroke Prevention (EAST-AFNET4) trial showed a clinical benefit of early rhythm-control therapy in patients with recently diagnosed atrial fibrillation (AF). The generalisability of the results in the general population is not known.MethodsParticipants in the population-based UK Biobank were assessed for eligibility based on the EAST-AFNET4 inclusion/exclusion criteria. Treatment of all eligible participants was classified as early rhythm-control (antiarrhythmic drug therapy or AF ablation) or usual care. To assess treatment effects, primary care data and Hospital Episode Statistics were merged with UK Biobank data.Efficacy and safety outcomes were compared between groups in the entire cohort and in a propensity-matched data set.ResultsAF was present in 35 526/502 493 (7.1%) participants, including 8340 (988 with AF Eligible participants were older (70 years vs 63 years) and more likely to be female (42% vs 21%) compared with ineligible patients. Of 9004 participants with full primary care data, 874 (9.02%) received early rhythm-control. Safety outcomes were not different between patients receiving early rhythm-control and controls. The primary outcome of EAST-AFNET 4, a composite of cardiovascular death, stroke/transient ischaemic attack and hospitalisation for heart failure or acute coronary syndrome occurred less often in participants receiving early rhythm-control compared with controls in the entire cohort (HR 0.82, 95% CI 0.71 to 0.94, p=0.005). In the propensity-score matched analysis, early rhythm-control did not significantly decrease of the primary outcome compared with usual care (HR 0.87, 95% CI 0.72 to 1.04, p=0.124).ConclusionAround 80% of participants diagnosed with AF in the UK population are eligible for early rhythm-control. Early rhythm-control therapy was safe in routine care.

Nutraceuticals based on plant extracts rich in polyphenols, as well as dietary fibres, are new means to fight overweight/obesity and associated diseases. However, to understand the potential effects of polyphenols on health it is critical to study their bioavailability and metabolic fate. Consumption of a green coffee phenolic extract (GCPE) in combination with oat beta-glucan (BG) could affect the pharmacokinetic profile of the main polyphenols present in coffee (hydroxycinnamates). Moreover, the regular intake of the combination could also induce changes. Nine overweight men and women consumed a novel nutraceutical product containing 300 mg of green coffee hydroxycinnamic acids and 2.5 g of BG twice a day for 8 weeks. A pharmacokinetic study was carried out in blood and urine samples taken before (baseline) and at week 8 after the nutraceutical intervention, collecting samples at different times in a 0–24 h interval. Faecal samples were also obtained at 0 and 24 h after the intake of the nutraceutical at baseline and week 8. Phenolic metabolites were analysed by LC-MS-QToF. Results showed that polyphenols were differentially absorbed and extensively metabolized throughout the gastrointestinal tract. An apparent reduction in the excretion of small intestinal metabolites was accompanied by a tendency to increase colonic metabolites after sustained intake (p = 0.052). In conclusion, continued consumption of the GCPE/BG nutraceutical appears to enhance the absorption of hydroxycinnamates by increasing the colonic bioavailability of their derived metabolites compared to baseline, although the regular intake of the nutraceutical did not modify the metabolite profile in any of the biological samples., This research was funded by project AGL2015-69986-R from the Ministerio de Economía y Competitividad and grant PIE202070E184 funded by CSIC. MAS and JGC had predoctoral grants funded by Comunidad de Madrid (PEJD-2018-PRE/SAL-9104), respectively.

Obesity and its associated comorbidities are a major public health concern worldwide. Reduced energy intake and increased physical activity interventions have limited success in the long term. Nutraceuticals might be an alternative means to help lose weight and reduce obesity-associated cardiometabolic risk factors without changes in the habitual diet. The objective of the present study was to comparatively evaluate the efficiency of nutraceuticals based on the combination of a decaffeinated green coffee bean extract (GCBE) and two types of oat beta-glucans (BG) with different physiochemical properties on obesity related biomarkers in overweight/obese subjects. A randomized, dose–response, parallel, blind study was carried out in four groups of subjects (n = 15 each) who consumed for 6 weeks, twice a day, a nutraceutical containing 3 g d−1 or 5 g d−1 doses of 35% or 70% BG and a fixed amount of GCBE providing 600 mg d−1 of phenols. 35% BG showed a 10 and 100 times higher molecular weight and viscosity, respectively, compared to 70% BG. Food intake, anthropometry and different cardiometabolic markers were assessed at the beginning and end of the intervention. According to the general model of variance with repeated measure analysis, the intervention caused positive changes in the levels of total cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, haemoglobin A1c, insulin, systolic blood pressure (SBP), total body fat percentage (TBF%), visceral fat percentage, and waist and hip circumferences without differences among the treatments, except for SBP and TBF%. Looking into the rates of change [(end value − beginning value)/beginning value] of these parameters, 5 g – 70% BG was the treatment that lowered TBF% the most. In conclusion, 5 g – 70% BG may be more effective in helping to lose weight and additionally, it produced the least bloating according to participants’ subjective perception., This research was funded by project AGL2015-69986-R from the Ministerio de Economía y Competitividad. JGC had a predoctoral grant funded by Comunidad de Madrid (PEJD-2018-PRE/SAL-9104).

Coffee presents beneficial health properties, including antiobesity effects. However, its effects on inflammation are controversial. Hydroxycinnamic acids are the main coffee phenolic bioactive compounds. In human bioavailability studies carried out with coffee, among the most abundant compounds found in urine and plasma were the colonic metabolites, dihydrocaffeic (DHCA), dihydroferulic (DHFA), and hydroxyhippuric (HHA) acids. To understand the hepato-protective potential of these three compounds, we tested whether treatment with realistic concentrations (0.5–10 µM) were effective to counteract inflammatory process and oxidative status induced by tumor necrosis factor α (TNF-α). First, we established a novel model of inflammation/oxidation using TNF-α and HepG2 cells. Afterwards, we evaluated the activity of DHCA, DHFA, and HHA against the inflammatory/oxidative challenge through the determination of the inflammatory mediators, interleukins (IL)-6, and IL-8 and chemokines, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1, as well as the levels of biomarkers of oxidative stress, such as reactive oxygen species, reduced glutathione, and the antioxidant enzymes glutathione peroxidase and reductase. Results showed that all three compounds have a potential hepato-protective effect against the induced inflammatory/oxidative insult.

Purpose This study aimed to assess the effect of dietary consumption of olive pomace oil (OPO) on blood lipids (primary outcome) and other cardiovascular disease (CVD) risk factors (blood pressure, inflammation and endothelial function as secondary outcomes). Methods A randomized, controlled, blind, crossover intervention was carried out in healthy and at-risk (hypercholesterolemic) subjects. Participants consumed daily 45 g of OPO or high-oleic acid sunflower oil (HOSO) as control oil during 4 weeks. Results OPO significantly reduced low-density lipoprotein cholesterol (LDL-C; P = 0.003) and apolipoprotein B (Apo B; P = 0.022) serum concentrations, and LDL/HDL ratio (P = 0.027) in healthy and at-risk volunteers. These effects were not observed with HOSO. Blood pressure, peripheral artery tonometry (PAT), endothelial function and inflammation biomarkers were not affected. Conclusions Regular consumption of OPO in the diet could have hypolipidemic actions in subjects at cardiovascular risk as well as in healthy consumers, contributing to CVD prevention. Clinical trial registry NCT04997122, August 8, 2021, retrospectively registered.

This article belongs to the Special Issue Effects of Polyphenol-Rich Foods on Chronic Diseases., [Background]: olive pomace oil (OPO) is a nutritionally relevant fat due to its high oleic acid content (C18:1) and the presence of a wide range of minor bioactive components. Although numerous in vitro and preclinical studies have been developed to study some of its characteristic components, the health effect of prolonged OPO consumption is unknown., [Methods]: a randomised, blinded, cross-over, controlled clinical trial was carried out in 31 normocholesterolemic and 37 hypercholesterolemic subjects. Participants consumed 45 g/day of OPO or sunflower oil (SO) for 4 weeks, each preceded by a 3-week run-in/wash-out phase with corn oil (CO)., [Results]: regular consumption of OPO and SO had no statistically significant effect on any of the markers related to lipid profile, blood pressure, and endothelial function in both groups, except for eNOS levels, which were close to statistical significance due to the effect of oil (OPO and SO) (p = 0.083). A decrease in visceral fat (p = 0.028) in both groups was observed after OPO intake, accompanied by an increment of leptin (p = 0.017) in the hypercholesterolemic group., [Conclusion]: reducing visceral fat after prolonged OPO intake might contribute to improve cardiometabolic status, with a potentially positive effect on the vascular tone. Further clinical trials are needed to confirm the present results., Interprofesional del Aceite de Orujo de Oliva (ORIVA) financed the study (Ref. 20193239) and the predoctoral contract of S.G.R. (Ref. 20184930). The Community of Madrid partly financed the predoctoral contracts of M.A.S. (PEJD-2018-PRE/SAL-9104) and J.G.-C. (PEJD-2017-PRE/BIO-4225).

The well-known compound tetrakis(tert-butylammonium)-cyclo-tetrametavanadate (V), [(CH

Se estudia el nivel de implicación que tienen las 53 bibliotecas públicas estatales y las 76 bibliotecas universitarias de España con los colectivos multicultural y con diversidad funcional, utilizando como método el análisis detallado de sus cartas de servicio y de sus sedes web, con el fin de comprobar si se hace mención explícita a servicios y recursos especiales para los colectivos señalados y cómo se realiza dicha mención. Como resultado principal obtenemos que, tanto la multiculturalidad, como las personas con diversidad funcional, se encuentran muy poco representadas en las cartas de servicio de ambos tipos de bibliotecas, con porcentajes inferiores al 5 % en multiculturalidad y al 35 % en diversidad funcional, y si bien estos resultados resultan más elevados en las sedes web de las dos tipologías bibliotecarias, con porcentajes inferiores al 29 % para el colectivo multicultural y al 45 % en las personas con diversidad funcional, no podemos concluir favorablemente, ya que consideramos importante fomentar, desde el 100 % de las bibliotecas públicas y universitarias, la sensibilización social acerca de los valores positivos de ambos colectivos.

Obesity has reached pandemic proportions and has become a major health concern worldwide. Therefore, it is necessary to find new strategies against this condition and its associated comorbidities. Green coffee polyphenols (GCP) and oat beta-glucans (BGs) have proven their hypolipidaemic and hypoglycaemic effects. This study aimed to examine the effects of the long-term consumption of supplements containing GCP, BG or the novel GCP/BG combination on lipid and glucose metabolism biomarkers in overweight/obese subjects who maintained their dietary habits and physical activity, hence addressing the difficulty that this population faces in adapting to lifestyle changes. A randomised, crossover, blind trial was carried out in 29 volunteers who consumed either GCP (300 mg), BG (2.5 g) or GCP/BG (300 mg + 2.5 g) twice a day for 8 weeks. Blood samples were collected, and blood pressure and body composition were measured at the beginning and end of each intervention. Total cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), very low-density lipoprotein (VLDL-C) cholesterol, glycated haemoglobin, fasting glucose, insulin, aspartate transaminase, alanine transaminase and different hormones and adipokines were analysed. Only VLDL-C (p = 0.01) and diastolic blood pressure (p = 0.027) decreased after the intervention, especially with the BG supplement. There were no other significant changes in the analysed biomarkers. In conclusion, the regular intake of GCP, BG and GCP/BG without lifestyle changes is not an efficient strategy to improve lipid and glucose homeostasis in overweight/obese subjects., This research was funded by project AGL2015-69986-R from the Spanish Ministry of Economy and Competitivity. J.G.-C. had a predoctoral grant funded by Comunidad de Madrid (PEJD-2017-PRE_BIO-4225). M.A.S. had a predoctoral contract funded by Comunidad de Madrid (PEJD-2018-PRE/SAL-9104). S.G.-R. had a predoctoral contract funded by Interprofesional del Aceite de Orujo de Oliva (ORIVA).

The expansion of lithium-ion batteries from consumer electronics to larger-scale transport and energy storage applications has made understanding the many mechanisms responsible for battery degradation increasingly important. The literature in this complex topic has grown considerably; this perspective aims to distil current knowledge into a succinct form, as a reference and a guide to understanding battery degradation. Unlike other reviews, this work emphasises the coupling between the different mechanisms and the different physical and chemical approaches used to trigger, identify and monitor various mechanisms, as well as the various computational models that attempt to simulate these interactions. Degradation is separated into three levels: the actual mechanisms themselves, the observable consequences at cell level called modes and the operational effects such as capacity or power fade. Five principal and thirteen secondary mechanisms were found that are generally considered to be the cause of degradation during normal operation, which all give rise to five observable modes. A flowchart illustrates the different feedback loops that couple the various forms of degradation, whilst a table is presented to highlight the experimental conditions that are most likely to trigger specific degradation mechanisms. Together, they provide a powerful guide to designing experiments or models for investigating battery degradation.

Background The prognostic value of myocardial trabecular complexity in patients with hypertrophic cardiomyopathy (HCM) is unknown. Purpose To explore the prognostic value of myocardial trabecular complexity using fractal analysis in participants with HCM. Materials and Methods The authors prospectively enrolled participants with HCM who underwent 3.0-T cardiovascular MRI from August 2011 to October 2017. The authors also enrolled 100 age- and sex-matched healthy participants to form a comparison group. Trabeculae were quantified with fractal analysis of cine slices to estimate the fractal dimension (FD). Participants with HCM were divided into normal and high FD groups according to the upper limit of normal reference value from the healthy group. The primary end point was defined as all-cause mortality and aborted sudden cardiac death. The secondary end point was the composite of the primary end point and readmission to the hospital owing to heart failure. Internal validation was performed using the bootstrapping method. Results A total of 378 participants with HCM (median age, 50 years; age range, 40-61 years; 207 men) and 100 healthy participants (median age, 46 years; age range, 36-59 years; 55 women) were included in this study. During the median follow-up of 33 months ± 18 (standard deviation), the increased maximal apical FD (≥1.325) had a higher risk of the primary and secondary end points than those with a normal FD (

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.

This article belongs to the Special Issue Effects of Polyphenol-Rich Foods on Chronic Diseases., Knowledge on the bioavailability of coffee (poly)phenols mostly come from single dose postprandial studies. This study aimed at investigating the effects of regularly consuming a green coffee phenolic extract (GCPE) on the bioavailability and metabolism of (poly)phenols. Volunteers with overweight/obesity consumed a decaffeinated GCPE nutraceutical containing 300 mg hydroxycinnamates twice daily for two months. Plasma and urinary pharmacokinetics, and fecal excretion of phenolic metabolites were characterized by LC-MS-QToF at weeks 0 and 8. Fifty-four metabolites were identified in biological fluids. Regular consumption of the nutraceutical produced certain changes: reduced forms of caffeic, ferulic and coumaric acids in urine or 3-(3′-hydroxypenyl)propanoic, and 3,4-dihydroxybenzoic acids in feces significantly increased (p < 0.05) after 8 weeks; in contrast, coumaroylquinic and dihydrocoumaroylquinic acids in urine decreased (p < 0.05) compared to baseline excretion. The sum of intestinal and colonic metabolites increased after sustained consumption of GCPE, without reaching statistical significance, suggesting a small overall effect on (poly)phenols’ bioavailability., This research was funded by project AGL2015-69986-R from the Spanish Ministry of Science and Innovation and project PIE 202070E184 funded by CSIC. MAS and JGC had predoctoral grants funded by Comunidad de Madrid (PEJD-2018-PRE/SAL-9104) and (PEJD-2017-PRE_BIO-4225), respectively.

[EN] The well-known compound tetrakis(tert-butylammonium)-cyclo-tetrametavanadate (V), [(CH3)3CNH3]4[V4O12] (1h_RT), which crystallizes in the tetragonal I4/m space group, undergoes an irreversible solid state transformation upon heating, constituting one of the few examples in which the initial and the final stages are structurally characterized by sc-XRD. Now, we observed the ability of the same compound to undergo an additional single-crystal-to-single-crystal (SCSC) transformation upon thermal stimuli, but this time at low temperatures (153 K). Compound 1h_RT contains a discrete unprotonated [V4O12]4− tetrahedral anion in which V and O bridging atoms are coplanar. In both phases, these tetrameric anions are linked through tert-butylammonium cations in an extensive network of hydrogen bonds, but at low temperatures, this phase loses its characteristic O-V-O coplanarity, with the resulting rearrangement of the crystal packing and hydrogen-bond network which provide its reversibility at low temperatures. Again, the initial and final stages have been characterized structurally by sc-XRD. This research was funded by IT1722-22, KK-2022/00045 and MCIN, grant MAT2017-89553-P.

This study aimed to compare the antinociceptive effects of tramadol 5% and lidocaine 2% on mental nerve block in horses of the Brazilian Pony breed. Eight adult non-pregnant mares were used in this study. The ponies were tranquilized with acepromazine (5 µg kg

The "MIcro-Surgical Anastomose Workflow recognition on training sessions" (MISAW) challenge provided a data set of 27 sequences of micro-surgical anastomosis on artificial blood vessels. This data set was composed of videos, kinematics, and workflow annotations described at three different granularity levels: phase, step, and activity. The participants were given the option to use kinematic data and videos to develop workflow recognition models. Four tasks were proposed to the participants: three of them were related to the recognition of surgical workflow at three different granularity levels, while the last one addressed the recognition of all granularity levels in the same model. One ranking was made for each task. We used the average application-dependent balanced accuracy (AD-Accuracy) as the evaluation metric. This takes unbalanced classes into account and it is more clinically relevant than a frame-by-frame score. Six teams, including a non-competing team, participated in at least one task. All models employed deep learning models, such as CNN or RNN. The best models achieved more than 95% AD-Accuracy for phase recognition, 80% for step recognition, 60% for activity recognition, and 75% for all granularity levels. For high levels of granularity (i.e., phases and steps), the best models had a recognition rate that may be sufficient for applications such as prediction of remaining surgical time or resource management. However, for activities, the recognition rate was still low for applications that can be employed clinically. The MISAW data set is publicly available to encourage further research in surgical workflow recognition. It can be found at www.synapse.org/MISAW, Comment: MICCAI2020 challenge report, 36 pages including 15 for supplementary material (complet results for each participating teams), 17 figures

Vibrio cholerae is a microorganism that causes acute diarrheal diseases and cholera, one of the leading causes of global morbidity and mortality, especially in children under five years old. It is present in many regions and has been isolated from diverse sources such as water, soil and food. Surveillance of this microorganism in Cuba from 1985 through June 1997 showed circulation of non-epidemic non-O1/non-O139 serogroups, but surveillance continued to identify distribution of V. cholerae serotypes and serogroups in the different geographic regions of the country during the following years, due to the risk of introducing cholera-causing serogroups that provoked cholera epidemics in other countries of the region.Describe the temporal‒spatial distribution of serogroups and serotypes of V. cholerae in Cuba.A cross-sectional study was conducted that included isolates from passive surveillance of V. cholerae in 16 hygiene and epidemiology centers throughout Cuba from July 1997 through December 2019, submitted to the National Reference Laboratory for Acute Diarrheal Diseases of the Pedro Kourí Tropical Medicine Institute in Havana, Cuba. The timeline was subdivided into three five-year periods and one eight-year period. The centers submitting isolates were grouped into three geographical regions: western, central and eastern Cuba. A total of 1060 V. cholerae isolates were studied, from the 1438 samples sent from 15 Provincial Hygiene, Epidemiology and Microbiology Centers and the Municipal Hygiene, Epidemiology and Microbiology Center of the Isle of Youth Special Municipality. Genus, species and serotype of all specimens were studied and reviewed in the context of the outbreaks of acute diarrheal diseases reported in the country.All 1060 isolates were confirmed as V. cholerae. In the distribution by time period and region, the highest percentage occurred in the 2012‒2019 period, and the eastern region contributed the most isolates in all periods. Approximately 63.9% (677/1060) were from outbreaks, and in the 2012‒2019 period, the most epidemic-causing isolates came from the western region. Approximately 52.8% (560/1060) were identified as non-O1/non-O139 V. cholerae, and 47.2% (500/1060) as O1 V. cholerae; of these, 96.4% (482/500) corresponded to Ogawa serotype and 3.6% (18/500) to Inaba. Circulation of non-O1/non-O139 V. cholerae occurred throughout the entire period. The O1 serogroup began to circulate in 2012 and continued through 2016; however, since 2017, it has not been identified again. In the western region, there were smaller percentages of isolates of non-O1/non-O139 V. cholerae in all periods, except 2012‒2019. In that period, V. cholerae O1 was identified to a lesser degree in the central region.Vibrio cholerae circulated in all three Cuban regions during the years studied, with a higher percentage of isolates of the non-O1/non-O139 serogroup, which caused outbreaks or sporadic cases of diarrhea in the eastern region, with the exception of the 2012‒2019 period, when epidemic outbreaks of the O1 serogroup (which causes cholera) occurred in all three regions, with higher percentages in the western region.

Massive molecular testing for COVID-19 has been pointed out as fundamental to moderate the spread of the pandemic. Pooling methods can enhance testing efficiency, but they are viable only at low incidences of the disease. We propose Smart Pooling, a machine learning method that uses clinical and sociodemographic data from patients to increase the efficiency of informed Dorfman testing for COVID-19 by arranging samples into all-negative pools. To do this, we ran an automated method to train numerous machine learning models on a retrospective dataset from more than 8,000 patients tested for SARS-CoV-2 from April to July 2020 in Bogotá, Colombia. We estimated the efficiency gains of using the predictor to support Dorfman testing by simulating the outcome of tests. We also computed the attainable efficiency gains of non-adaptive pooling schemes mathematically. Moreover, we measured the false-negative error rates in detecting the ORF1ab and N genes of the virus in RT-qPCR dilutions. Finally, we presented the efficiency gains of using our proposed pooling scheme on proof-of-concept pooled tests. We believe Smart Pooling will be efficient for optimizing massive testing of SARS-CoV-2.

Observational and experimental evidence has linked chronotype to both psychological and cardiometabolic traits. Recent Mendelian randomization (MR) studies have investigated direct links between chronotype and several of these traits, often in isolation of outside potential mediating or moderating traits. We mined the EpiGraphDB MR database for calculated chronotype–trait associations (p-value &lt, 5 × 10−8). We then re-analyzed those relevant to metabolic or mental health and investigated for statistical evidence of horizontal pleiotropy. Analyses passing multiple testing correction were then investigated for confounders, colliders, intermediates, and reverse intermediates using the EpiGraphDB database, creating multiple chronotype–trait interactions among each of the the traits studied. We revealed 10 significant chronotype–exposure associations (false discovery rate &lt, 0.05) exposed to 111 potential previously known confounders, 52 intermediates, 18 reverse intermediates, and 31 colliders. Chronotype–lipid causal associations collided with treatment and diabetes effects, chronotype–bipolar associations were mediated by breast cancer, and chronotype–alcohol intake associations were impacted by confounders and intermediate variables including known zeitgebers and molecular traits. We have reported the influence of chronotype on several cardiometabolic and behavioural traits, and identified potential confounding variables not reported on in studies while discovering new associations to drugs and disease.

Olive-pomace oil is rich in oleic acid, and thus it can be an interesting dietary fat alternative as it can allow reaching the recommendation of consuming 20% of total diet energy in the form of monounsaturated fatty acids. In addition, olive-pomace oil also contains a wide range of minor components that may contribute to its healthy properties. The major components identified with healthy properties are triterpenic dialcohols and acids, squalene, tocopherols, sterols, fatty alcohols and phenolic compounds. The refining process, that the crude pomace-oil must undergo for commercial purposes, significantly reduces the content of phenolic compounds, while the other minor components remain at concentrations which can induce positive health effects, especially on cardiovascular health, outstanding pentacyclic triterpenes and aliphatic fatty alcohols in olive-pomace oil. Numerous in vitro and preclinical studies support that mainly the pure compounds, or extracts isolated from plant sources, play an important role in preventing cardiovascular disease and risk factors. Likewise, tocopherols, squalene and phytosterols, in addition to the minor fraction of phenolic compounds, have shown high biological activity with particular association to the cardiovascular function. In the light of the foregoing, and taking into consideration the absence of clinical studies with olive-pomace oil, it would be of great interest to develop randomized, crossover, controlled, double-blind studies to extend the knowledge and understanding on the health effects of olive-pomace olive., The authors thank ORIVA (Interprofesional del Aceite de orujo de Oliva) for finanacial support (Projects-References 20175429 and 20185194).

Más que simples textos y viñetas sobre escenas cotidianas para entretener a las niñas de la postguerra, los cómics femeninos de los 50 son un símbolo de la propaganda político-socio-moral que desde altos cargos morales buscaba hacer efecto en el comportamiento sexual de las chicas españolas. Mediante un análisis temático, iconográfico y lingüístico es posible comprender cómo estas inocentes representaciones habían pasado por la criba moral de la censura franquista, retratando un modelo ideal de mujer, futura madre y esposa.

La finalidad de este trabajo es observar y distinguir en un marco de dificultades para el acceso a la información, las mayores o menores aproximaciones que se presentan entre las normativas vigentes sobre el trabajo rural y las circunstancias que condicionan para que las mismas se cumplan o no, con las implicancias que ello puede tener sobre los trabajadores rurales en la horticultura platense. Las relaciones laborales en la actividad agropecuaria están presentes de manera permanente y en virtud de tratarse de relaciones asimétricas, la intervención o regulación de los vínculos que se establecen entre empleado y empleador es imprescindible. De esta manera el rol que juega el Estado y las políticas que se implementen determina la manera en que estas relaciones se den. Para ello, es parte constitutiva el marco normativo que acompaña las medidas de gobierno. Es indisoluble la relación entre los actores (empleador/empleado) que comprende la actividad agropecuaria, las políticas públicas y la normativa que regula esos vínculos. De tal manera, se estima conveniente relevar someramente cómo se fueron gestando en el devenir histórico estas cuestiones para comprender los procesos actuales en materia laboral en el sector agrario. La construcción socionormativa de parte del estado ha variado, pero se puede adelantar que la regulación y control para esta actividad es compleja, por las diversas producciones que se realizan y los territorios diversos que dificultan por lo menos el contralor necesario por parte del estado. El marco teórico que propone Zurbriggen (2006) para el estudio de las políticas públicas, se tomará como guía para la búsqueda de explicaciones, junto a aportes de Martínez Nogueira (1995). La investigación se realizó, tomando como soporte a la corriente cualitativa (secuencia de procesos), comprendiendo un trabajo de campo en el que se entrevistaron 10 agentes que cumplen acciones en el territorio hortícola platense. La temática del trabajo hortícola platense, está caracterizada por una profunda informalidad, destacando, que esta característica se sostiene a lo largo de toda la cadena hortícola. Las relaciones-acuerdos entre trabajadores y empleadores son diversas y en la mayoría de los casos difusas en lo que refiere a obligaciones y derechos delimitados por los mencionados acuerdos. Resulta necesario dar mejor difusión a los derechos establecidos en el Estatuto del Peón Rural; así como también desarrollar mecanismos que permitan la aplicación de la misma, considerando la heterogeneidad de establecimientos que conforman la horticultura platense., The purpose of this work is to observe and distinguish in a framework of difficulties for access to information, the greater or lesser approximations that are presented between the regulations in force on rural work and the circumstances that condition them so that they are met or not, with the implications that this may have on rural workers in the platense horticulture. The labor relations in the agricultural activity are present permanently and by virtue of being asymmetric relations, the intervention or regulation of the links established between employee and employer is essential. In this way, the role played by the State and the policies that are implemented determine the manner in which these relationships occur. For this, the regulatory framework that accompanies the government measures is constitutive. The relationship between the actors (employer / employee) that includes agricultural activity, public policies and the regulations that regulate these links is inseparable. In this way, it is considered convenient to summarize briefly how these issues were gestating in the historical evolution to understand the current labor processes in the agrarian sector. The socionormativa construction of part of the state has varied, but it can be anticipated that the regulation and control for this activity is complex, for the diverse productions that are made and the diverse territories that hinder at least the necessary control by the state. The theoretical framework proposed by Zurbriggen (2006) for the study of public policies will be taken as a guide for the search for explanations, together with contributions by Martínez Nogueira (1995). The research was carried out, taking as support the qualitative stream (sequence of processes), comprising fieldworks in which 10 agents were interviewed who carry out actions in the platense horticultural territory. The thematic of the platense horticultural work, is characterized by a deep informality, emphasizing, that this characteristic is sustained along all the horticultural chain. The relationships-agreements between workers and employers are diverse and in most cases diffuse in what refers to obligations and rights defined by the aforementioned agreements. It is necessary to give better diffusion to the rights established in the Statute of the Rural Pawn; as well as develop mechanisms that allow the application of the same, considering the heterogeneity of establishments that make up the platense horticulture., Facultad de Ciencias Agrarias y Forestales

Resumen: Objetivos: Determinar la validez de la ecografía en Atención Primaria (AP) para detección de aneurisma de aorta abdominal (AAA) en varones de 65 a 75 años y la concordancia interobservador en el diagnóstico entre médicos de AP y el referente del área (Cirugía Vascular). Estimar la prevalencia de AAA en dicha población y su relación con factores de riesgo. Diseño: Estudio descriptivo transversal. Emplazamiento: Centros de Salud Coto y Calzada II (Gijón). Participantes: Varones nacidos entre el 1/1/1939 y el 31/12/1950. Intervención: De 2.511 varones se seleccionaron 407 mediante muestreo aleatorizado estratificado. Se realizó medición ecográfica del diámetro aórtico. Se derivaron para segunda medida en Cirugía Vascular a aquellos con ≥3 cm y un 20% de los

Cooling electrical tabs of the cell instead of the lithium ion cell surfaces has shown to provide better thermal uniformity within the cell, but its ability to remove heat is limited by the heat transfer bottleneck between tab and electrode stack. A two-dimensional electro-thermal model was validated with custom made cells with different tab sizes and position and used to study how heat transfer for tab cooling could be increased. We show for the first time that the heat transfer bottleneck can be opened up with a single modification, increasing the thickness of the tabs, without affecting the electrode stack. A virtual large-capacity automotive cell (based upon the LG Chem E63 cell) was modelled to demonstrate that optimised tab cooling can be as effective in removing heat as surface cooling, while maintaining the benefit of better thermal, current and state-of-charge homogeneity. These findings will enable cell manufacturers to optimise cell design to allow wider introduction of tab cooling. This would enable the benefits of tab cooling, including higher useable capacity, higher power, and a longer lifetime to be possible in a wider range of applications.

In this chapter we discuss the past, present and future of clinical biomarker development. We explore the advent of new technologies, paving the way in which health, medicine and disease is understood. This review includes the identification of physicochemical assays, current regulations, the development and reproducibility of clinical trials, as well as, the revolution of omics technologies and state-of-the-art integration and analysis approaches.

Multimorbidity, frequently associated with aging, can be operationally defined as the presence of two or more chronic conditions. Predicting the likelihood of a patient with multimorbidity to develop a further particular disease in the future is one of the key challenges in multimorbidity research. In this paper we are using a network-based approach to analyze multimorbidity data and develop methods for predicting diseases that a patient is likely to develop. The multimorbidity data is represented using a temporal bipartite network whose nodes represent patients and diseases and a link between these nodes indicates that the patient has been diagnosed with the disease. Disease prediction then is reduced to a problem of predicting those missing links in the network that are likely to appear in the future. We develop a novel link prediction method for static bipartite network and validate the performance of the method on benchmark datasets. By using a probabilistic framework, we then report on the development of a method for predicting future links in the network, where links are labelled with a time-stamp. We apply the proposed method to three different multimorbidity datasets and report its performance measured by different performance metrics including AUC, Precision, Recall, and F-Score.

The present work aimed at understanding gut microbiota bioconversion of phenolic compounds (PC) and organic acids in predigested Hibiscus sabdariffa (Hb) calyces and the mixture of Hb and Agave (Agave tequilana Weber) fructans (AF). With this purpose, dried Hb and Hb/AF were predigested with enzymatic treatment, and then fermented in a dynamic in vitro model of the human colon (TIM-2). After HPLC-ESI-QToF-MS analysis of samples taken at 0, 24, 48 and 72 h of fermentation, it was observed that hydroxycinnamic acids, flavanols, flavonols, and anthocyanins were mainly transformed into derivatives of hydroxyphenylpropionic, hydroxyphenylacetic and hydroxybenzoic acids. Moreover, organic acids, such as hydroxycitric and hibiscus acids, were formed along with unidentified lactones and reduced compounds. Interestingly, no differences were observed between microbial-derived metabolites formed after the fermentation of Hb and Hb/AF. In conclusion, colonic fermentation of polyphenol-rich Hb yields a wide range of microbial phenolic metabolites with potential effects on health., RMB and SGSA acknowledge to Science and Technology for Development Program (CYTED) through the Ibero-American Network of Underutilized Autonomous Foods (ALSUB-CYTED, 118RT0543). SGSA acknowledges CONACYT-Mexico for the sabbatical grant 260935. The Spanish Ministry of Science, Innovation and Universities (Project AGL2015-69986-R) is also acknowledged. This research has been made possible with the support of the Dutch Province of Limburg.

Substance P (SP) is a tachykinin that regulates airway mucous secretion in both health and disease. Our study aimed to determine whether overexpression of SP without pre‐existing inflammation was sufficient to induce changes in mucin secretion and transport in small airways. Utilizing porcine precision‐cut lung slices, we measured the impact of AAV‐mediated overexpression of SP on airway physiology ex vivo. Immunofluorescence signal intensity for MUC5AC was significantly increased in SP‐overexpressed precision‐cut lung slices compared to GFP controls. No difference in MUC5B signal intensity between treatments was detected. SP‐overexpressed precision‐cut lung slices also exhibited decreased IL10 mRNA, an important inhibitor of mucous cell metaplasia. Overt deficits in mucociliary transport were not noted, though a trend for decreased mean transport speed was detected in methacholine‐challenged airways overexpressing SP compared to GFP controls. Pharmacologic inhibition of the NF‐kβ pathway abrogated the effects of overexpression of SP on both MUC5AC and IL10. Collectively, these data suggest that overexpression of SP in the absence of existing inflammation increases MUC5AC via activation of the NF‐kβ pathway. Thus, these data further highlight SP as a key driver of abnormal mucous secretion and underscore NF‐kβ signaling as a pathway of potential therapeutic intervention., Overexpression of Substance P increased MUC5AC in porcine small airways in the absence of inflammation. The effect was mitigated by the inhibition of the NF‐KB pathway.

Resumen del póster presentado a la 1st International E-Conference on Antioxidants in Health and Disease, celebrada del 1 al 15 de diciembre de 2020., Mango byproducts are a relevant source of phenolic compounds that have already been shown to display a multitud e of health beneficial properties. The biological activity of a compound is determined by its absorption and metabolism. Considering the low bioavailability of polyphenols at small intestinal level, it is important to study the biotransformation of mango peel polyphenols bythe gut microbiota to determine the chemical structure of the potential bioactive microbial·derived metabolites. Thus, gut microbiota bioconversion of polyphenols in predigested mango 'Ataulfo' peel was studied using a validated, dynamic in vitro human colon model (TIM·2) with faecal microbial inoculum. Driel peels were predigested with enzymatic treatment, followed by TIM·2 fermentation (72h). Samples were taken at O, 24, 48 and 72h and a nelyzed by HPLC·QToF. Derivatives of hydroxyphenylpropionic, hydroxyphenylacetic and hydroxybenzoic acids, as well as pyrogallol were the main polyphenols identified. These metabolites might derive from the biotrasnsformation of flavonoids (flavanols and flavonols), gel lates and gallotannins in mango peel. Despite the high content of ellagic acid, low amounts were detected in TIM·2 samples due to trasnsformation mainly into urolithins A and C. Xanthone and benzophenone derivatives, specific to mango, remained after the colonic biotransformation, contrary to flavonoids, which completely disappeared. In conclusion, microbiel derived metabolites, especially xanthone and benzophenone derivatives, are partially stable after colonic fermentation, and thus have the potential to contribute to mango peel bioactivity.

We present the first experimental framework for segmenting instruments in surgical scenes guided by natural language descriptions. Previous approaches rely exclusively on visual cues, thus ignoring the fine-grained nature of the problem. We exploit the rich domain knowledge of function by introducing structured descriptions. Our method, the Language-Guided Instrument (LGI) Segmentation network, merges three levels of information to compute the probability of an object candidate belonging to each surgical instrument category: context information (the image’s features), local information (the candidate’s features) and language information (a sentence per class), in which we include the differentiating details of each instrument type. We perform a comprehensive experimental evaluation over the standard benchmarks for the task and we show that LGI enhances the performance of different backbone instance segmentation methods, obtaining a significant improvement over the state-of-the-art. To the best of our knowledge, we propose the first experimental framework for jointly applying vision and language to a high-impact global healthcare problem.

In this chapter we discuss the past, present and future of clinical biomarker development. We explore the advent of new technologies, paving the way in which health, medicine and disease is understood. This review includes the identification of physicochemical assays, current regulations, the development and reproducibility of clinical trials, as well as, the revolution of omics technologies and state-of-the-art integration and analysis approaches.

Rosmarinus officinalis L. is a widespread aromatic plant commonly consumed as a tea in traditional cuisine and in folk medicine to treat various illnesses due to its therapeutic properties. To the best of our knowledge, there are no reports on the bioavailability and metabolism of R. officinalis tea polyphenols in humans. This study was aimed at assessing the bioavailability and nutrikinetics of R. officinalis phenolic compounds in healthy humans for the first time. Forty-eight compounds were identified in plasma and urine. Few un-metabolized compounds were detected since rosemary polyphenols were extensively metabolized into phase II conjugates, with rapid appearance and clearance in plasma, pointing to small intestinal absorption. Phase II derivatives of caffeic acid showed kinetics compatible with both intestinal and colonic hydrolysis of rosmarinic acid yielding free caffeic and 3,4-dihydroxyphenyl-lactic acids, which were absorbed and metabolized into phase II derivatives. These metabolites, along with reduced forms of caffeic acid and their phase II metabolites, and those of hydroxyphenylpropionic, hydroxylphenylacetic, benzoic and hippuric acids, highlight the importance of colonic absorption. Total urinary excretion of the phenols added up to 235 µmol, corresponding to 22.3% of the ingested amount (1055 µM). In conclusion, rosemary tea polyphenols are partially bioavailable and extensively metabolized, mainly by the colonic microbiota., We acknowledge financial support received from the Tunisian Ministry of Higher Education and Scientific Research, and from the Spanish Ministry of Economy, Industry and Competitivity (project AGL2015-69986-R).

Husk tomato (Physalis ixocarpa Brot. ex. Horm) is mainly used in the preparation of many Mexican sauces due to its unique and slightly acidic flavor, both in raw and cooked forms. These sauces also usually contain Serrano hot pepper (Capsicum annuum L), onion (Allium cepa L.), garlic (Allium sativum L.), coriander (Coriandrum sativum L.) and salt. Mexican sauces are a pre-Hispanic staple food, yet there is scarce knowledge on the phenolic compounds (PC) that reach the colon bound to the indigestible fraction (IF) after intestinal digestion. Thus, the aim of the present work was to evaluate the indigestible fraction of two types of Mexican sauces made with cooked and raw husk tomato: cooked green sauce (CGS) and raw green sauce (RGS). IF of CGS and RGS were fermented in the in vitro model of the human colon (TIM-2) to investigate the PC bioconversion by the gut microbiota after 24, 48 and 72 h. PC of the original sauces and their predigested fractions, as well as the formed metabolites were identified and monitored by HPLC-ESI-QToF-MS. Cooking husk tomato significantly increased the total indigestible fraction (TIF), mainly due to its insoluble indigestible fraction (IIF), and diminished PC. Flavonoids (flavonols and flavones) were the most abundant phenolic group in digested sauces followed by capsaicinoids (a characteristic group derived from hot pepper), hydroxycinnamic acids, and hydroxybenzoic acids. The metabolites 3-(ρ-hydroxyphenyl) propionic acid, 3-(3-hydroxyphenyl) propionic acid and 4-hydroxyphenylacetic acid were the most abundant colonic metabolites identified, which are thought to be derived from the biotransformation of flavonoids and hydroxycinnamates. These results are the first obtained on in vitro colonic fermentation of Mexican sauces and should be considered in future studies on the health effects related to consuming this staple food., The Spanish Ministry of Science, Innovation and Universities (Project AGL2015-69986-R) is also acknowledged. Alicia Paulina Cárdenas Castro thanks CONACYT-Mexico for the financial support, grant registration number: 662703 and Koen Venema acknowledges the support of the Dutch Province of Limburg.

espanolDurante los ultimos anos se ha incrementado la incidencia de casos de sobrepeso/obesidad entre la poblacion, afectando en ciertas partes del mundo a mas de la mitad de la poblacion adulta. La obesidad lleva asociada comorbilidades como la diabetes de tipo 2, la esteatosis hepatica no alcoholica y las enfermedades cardiovasculares entre otras muchas, que la han convertido en la segunda causa de muerte evitable en el mundo, solo por detras del tabaquismo. Ante esta nueva realidad se hace necesaria la busqueda de nuevas estrategias para combatir el sobrepeso/obesidad y sus patologias asociadas. Los nutraceuticos o suplementos dieteticos se han convertido en una herramienta dietetica de sumo interes gracias a su composicion de compuestos bioactivos beneficiosos para la salud. De entre estos compuestos bioactivos, este estudio abordara en profundidad dos de ellos: una fibra soluble, los β-glucanos procedentes de la avena, y un tipo de compuesto fenolico, los hidroxicinamatos. Ambos tipos de compuestos presentan efectos complejos y multifactoriales al actuar como agentes hipolipemiantes, hipoglucemiantes, antioxidantes, prebioticos o saciantes. Ejercen su efecto modulando diferentes vias metabolicas que afectan tanto a la absorcion como al metabolismo de los lipidos y los glucidos, reduciendo el dano oxidativo, promoviendo la proliferacion de especies bacterianas beneficiosas y reduciendo la ingesta dietetica. Se puede concluir que tanto los beta-glucanos como los hidroxicinamatos presentan potencial como herramienta nutricional en el manejo de distintas disfunciones metabolicas asociadas a la obesidad. EnglishOver the last few years the prevalence of overweight and obesity has increased, affecting in certain parts of the World to more than half of the adult population. Obesity has been related to disorders such as type-2 diabetes, non-alcoholic fatty liver disease, and cardiovascular diseases, among others, which has made obesity the second cause of preventable death, only behind smoking. Bearing this in mind, it is necessary to find new strategies to overcome overweight/obesity and its associated pathologies. In this context, nutraceuticals and dietary supplements have become interesting tools thanks to their composition, rich in bioactive compounds beneficial to health. Among bioactive compounds, this study will focus on β-glucans, a type of soluble dietary fiber, and hydroxycinnamic acids, a group of phenols. Both types of compounds show complex and multifactorial effects, acting as hypolipemic, hypoglycemic, antioxidant, prebiotic and satiating agents. They act by modulating different metabolic pathways, affecting the absorption and metabolism of lipids and carbohydrates, reducing oxidative damage, promoting the proliferation of beneficial bacterial species, and reducing dietary intake. It may be concluded that both beta-glucans and hydroxycinnamates have potential as nutritional tools for the management of obesity and its associated metabolic dysfunctions.

The Lithium-ion battery (LIB) is an important technology for the present and future of energy storage, transport, and consumer electronics. However, many LIB types display a tendency to ignite or release gases. Although statistically rare, LIB fires pose hazards which are significantly different to other fire hazards in terms of initiation route, rate of spread, duration, toxicity, and suppression. For the first time, this paper collects and analyses the safety challenges faced by LIB industries across sectors, and compares them to the research contributions found in all the review papers in the field. The comparison identifies knowledge gaps and opportunities going forward. Industry and research efforts agree on the importance of understanding thermal runaway at the component and cell scales, and on the importance of developing prevention technologies. But much less research attention has been given to safety at the module and pack scales, or to other fire protection layers, such as compartmentation, detection or suppression. In order to close the gaps found and accelerate the arrival of new LIB safety solutions, we recommend closer collaborations between the battery and fire safety communities, which, supported by the major industries, could drive improvements, integration and harmonization of LIB safety across sectors.

SummaryBackgroundCOVID-19 is an acute respiratory illness caused by the novel coronavirus SARS-CoV-2. The disease has rapidly spread to most countries and territories and has caused 14·2 million confirmed infections and 602,037 deaths as of July 19th 2020. Massive molecular testing for COVID-19 has been pointed as fundamental to moderate the spread of the disease. Pooling methods can enhance testing efficiency, but they are viable only at very low incidences of the disease. We propose Smart Pooling, a machine learning method that uses clinical and sociodemographic data from patients to increase the efficiency of pooled molecular testing for COVID-19 by arranging samples into all-negative pools.MethodsWe developed machine learning methods that estimate the probability that a sample will test positive for SARS-Cov-2 based on complementary information from the sample. We use these predictions to exclude samples predicted as positive from pools. We trained our machine learning methods on samples from more than 8,000 patients tested for SARS-Cov-2 from April to July in Bogotá, Colombia.FindingsOur method, Smart Pooling, shows efficiency of 306% at a disease prevalence of 5% and efficiency of 107% at disease a prevalence of up to 50%, a regime in which two-stage pooling offers marginal efficiency gains compared to individual testing (see Figure 1). Additionally, we calculate the possible efficiency gains of one- and two-dimensional two-stage pooling strategies, and present the optimal strategies for disease prevalences up to 25%. We discuss practical limitations to conduct pooling in the laboratory.InterpretationPooled testing has been a theoretically alluring option to increase the coverage of diagnostics since its proposition by Dorfmann during World War II. Although there are examples of successfully using pooled testing to reduce the cost of diagnostics, its applicability has remained limited because efficiency drops rapidly as prevalence increases. Not only does our method provide a cost-effective solution to increase the coverage of testing amid the COVID-19 pandemic, but it also demonstrates that artificial intelligence can be used complementary with well-established techniques in the medical praxis.FundingFaculty of Engineering, Universidad de los Andes, Colombia.1Research in contextEvidence before this studyThe acute respiratory illness COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) labeled COVID-19 as a pandemic in March 2020. Reports from February 2020 indicated the possibility of asymptomatic transmission of the virus, which has called for molecular testing to identify carriers of the disease and prevent them from spreading it. The dramatic rise in the global need for molecular testing has made reagents scarce. Pooling strategies for massive diagnostics were initially proposed to diagnose syphilis during World War II, but have not yet seen widespread use mainly because their efficiency falls even at modest disease prevalence.We searched PubMed, BioRxiv, and MedRxiv for articles published in English from inception to July 15th 2020 for keywords “pooling”, “testing” AND “COVID-19”, AND “machine learning” OR “artificial intelligence”. Early studies for pooled molecular testing of SARS-CoV-2 revealed the possibility of detecting single positive samples in dilutions of samples from up to 32 individuals. The first reports of pooled testing came in March from Germany and the USA. These works suggested that it was feasible to conduct pooled testing as long as the prevalence of the disease was low. Numerous theoretical works have focused only on finding or adapting the ideal pooling strategy to the prevalence of the disease. Nonetheless, many do not consider other practical limitations of putting these strategies into practice. Reports from May 2020 indicated that it was feasible to predict an individual’s status with machine learning methods based on reported symptoms.Added value of this studyWe show how artificial intelligence methods can be used to enhance, but not replace, existing well-proven methods, such as diagnostics by qPCR. We show that in this fashion, pooled testing can yield efficiency gains even as prevalence increases. Our method does not compromise the sensitivity or specificity of the diagnostics, as these are still given by the molecular test. The artificial intelligence models are simple, and we make them free to use. Remarkably, artificial intelligence methods can continuously learn from every set of samples and thus increase their performance over time.Implications of all the available evidenceUsing artificial intelligence to enhance rather than replace molecular testing can make pooling testing feasible, even as disease incidence rises. This approach could make pooled testing an effective tool to tackle the disease’s progression, particularly in territories with limited resources.

New findings What is the central question of this study? What is the impact of airway cholinergic history on the properties of airway mucus secretion in a cystic fibrosis-like environment? What is the main finding and its importance? Prior cholinergic challenge slightly modifies the characteristics of mucus secretion in response to a second cholinergic challenge in a diminished bicarbonate and chloride transport environment. Such modifications might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease. Abstract Viral infections precipitate exacerbations in many airway diseases, including asthma and cystic fibrosis. Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance in response to a second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secretion is regulated by the cholinergic nervous system and that abnormal airway mucus contributes to exacerbations of airway disease, we hypothesized that prior cholinergic challenge would also modify subsequent mucus responses to a secondary cholinergic challenge. Using our established cholinergic challenge-rechallenge model in pigs, we atomized the cholinergic agonist bethanechol or saline control to pig airways. Forty-eight hours later, we removed tracheas and measured mucus secretion properties in response to a second cholinergic stimulation. The second cholinergic stimulation was conducted in conditions of diminished chloride and bicarbonate transport to mimic a cystic fibrosis-like environment. In pigs previously challenged with bethanechol, a second cholinergic stimulation produced a mild increase in sheet-like mucus films; these films were scarcely observed in animals originally challenged with saline control. The subtle increase in mucus films was not associated with changes in mucociliary transport. These data suggest that prior cholinergic history might modify mucus secretion characteristics with subsequent stimulation in certain environmental conditions or disease states. Such modifications and/or more repetitive stimulation might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.

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PurposeMucus abnormalities are central to the pathophysiology of several chronic airway diseases. Mucus secretion and clearance are regulated, in part, by cholinergic innervation. Prolonged cholinergic stimulation may contribute to mucus abnormalities in disease. Thus, we tested the hypothesis that prolonged cholinergic stimulation gives rise to lasting mucus abnormalities in airways.MethodsWe delivered aerosolized bethanechol, a cholinergic agonist, to pig airways. Forty-eight hours later, we measured mucus secretion and mucociliary transport in tracheal segments ex vivo. Tracheal and bronchoalveolar lavage concentrations of the major secreted mucus glycoproteins, mucin5B (MUC5B) or mucin5AC (MUC5AC), were measured with ELISA and antibody labeling. Pig airway epithelia were cultured at the air-liquid interface and treated with bethanechol for forty-eight hours. Stimulated fluid secretion was measured with reflected microscopy and Ussing chambers were used to measure ion transport.ResultsAirways from bethanechol-challenged pigs exhibited sheet-like mucus films, which were not associated with a greater abundance of MUC5AC or MUC5B. Epithelia treated with bethanechol had diminished fluid secretion and decreased Cl- transport. However, mucus and fluid alterations were not associated with impaired mucociliary transport.ConclusionsThese data suggest that cholinergic transmission induces sustained alterations in airway mucus properties. Such defects might compound and/or contribute to persistent mucus phenotypes found after the resolution of airway inflammation.