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Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17–3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk. [ABSTRACT FROM AUTHOR]

Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted in genetic variation underlying lipid levels, they mainly comprise individuals of European ancestry and thus their transferability to non-European populations is unclear. We performed genome-wide (GWAS) and imputed transcriptome-wide association studies of four lipid traits in the Hispanic Community Health Study/Study of Latinos cohort (HCHS/SoL, n = 11,103), replicated top hits in the Multi-Ethnic Study of Atherosclerosis (MESA, n = 3,855), and compared the results to the larger, predominantly European ancestry meta-analysis by the Global Lipids Genetics Consortium (GLGC, n = 196,475). In our GWAS, we found significant SNP associations in regions within or near known lipid genes, but in our admixture mapping analysis, we did not find significant associations between local ancestry and lipid phenotypes. In the imputed transcriptome-wide association study in multiple tissues and in different ethnicities, we found 59 significant gene-tissue-phenotype associations (P < 3.61×10−8) with 14 unique significant genes, many of which occurred across multiple phenotypes, tissues, and ethnicities and replicated in MESA (45/59) and in GLGC (44/59). These include well-studied lipid genes such as SORT1, CETP, and PSRC1, as well as genes that have been implicated in cardiovascular phenotypes, such as CCL22 and ICAM1. The majority (40/59) of significant associations colocalized with expression quantitative trait loci (eQTLs), indicating a possible mechanism of gene regulation in lipid level variation. To fully characterize the genetic architecture of lipid traits in diverse populations, larger studies in non-European ancestry populations are needed. [ABSTRACT FROM AUTHOR]

Background: Maternal iodine deficiency is related to high neonatal thyroid-stimulating hormone (TSH) values, with the threshold of 5 mIU/L recommended as an indicator of iodine nutrition status. The objective of this study was to analyse possible risk factors for increased TSH that could distort its validity as a marker of iodine status. The clinical relevance of this research question is that if the factors associated with iodine deficiency are known, iodine supplementation can be introduced in risk groups, both during pregnancy and in newborns. Methods: A case-control study was carried out in a sample of 46,622 newborns in 2002–2015 in Spain. Of these, 45,326 had a neonatal TSH value ≥5 mIU/L. The main variable was having TSH ≥5 mIU/L and the secondary variables were: sex, gestational age, day of sample extraction and maternal origin. Associated factors were analysed through a logistic regression model, calculating the odds ratio (OR). Results: The factors associated with this outcome were: male sex (OR = 1.34, 95% CI: 1.20–1.50, p<0.001), originating from an Asian/Oceanic country (OR = 0.80, 95% CI: 0.54–1.20, p = 0.536) or Europe (OR = 0.80, 95% CI: 0.66–0.96, p = 0.285) (including Spain, OR = 1) [p<0.001 for America (OR = 0.54, 95% CI: 0.44–0.68) and p = 0.025 for Africa (OR = 0.78, 95% CI: 0.62–0.97)] and fewer days from birth to sampling (OR = 0.80, 95% CI: 0.77–0.82, p<0.001). Conclusions: The risk of high neonatal TSH without congenital hypothyroidism is higher in males, decreases with a greater number of days from birth to extraction, and is dependent on maternal ethnicity but not on gestational age. [ABSTRACT FROM AUTHOR]

Linden (Tilia spp.), a profusely flowering temperate tree that provides bees with vital pollen and nectar, has been associated with bumble bee (Bombus spp.) mortality in Europe and North America. Bee deaths have been attributed, with inadequate evidence, to toxicity from mannose in nectar or starvation due to low nectar in late blooming linden. Here, we investigated both factors via untargeted metabolomic analyses of nectar from five T. cordata trees beneath which crawling/dead bumble bees (B. vosnesenskii) were observed, and of thoracic muscle of 28 healthy foraging and 29 crawling bees collected from linden trees on cool mornings (< 30°C). Nectar contained the pyridine alkaloid trigonelline, a weak acetylcholinesterase inhibitor, but no mannose. Principal component analysis of muscle metabolites produced distinct clustering of healthy and crawling bees, with significant differences (P<0.05) in 34 of 123 identified metabolites. Of these, TCA (Krebs) cycle intermediates were strongly represented (pathway analysis; P<0.01), suggesting that the central metabolism is affected in crawling bees. Hence, we propose the following explanation: when ambient temperature is low, bees with energy deficit are unable to maintain the thoracic temperature required for flight, and consequently fall, crawl, and ultimately, die. Energy deficit could occur when bees continue to forage on linden despite limited nectar availability either due to loyalty to a previously energy-rich source or trigonelline-triggered memory/learning impairment, documented earlier with other alkaloids. Thus, the combination of low temperature and nectar volume, resource fidelity, and alkaloids in nectar could explain the unique phenomenon of bumble bee mortality associated with linden. [ABSTRACT FROM AUTHOR]

In fish, the circadian clock represents a key regulator of many aspects of biology and is controlled by combinations of abiotic and biotic factors. These environmental factors are frequently manipulated in fish farms as part of strategies designed to maximize productivity. The flatfish turbot, Scophthalmus maximus, represents one of the most important species within the aquaculture sector in Asia and Europe. Despite the strategic importance of this species, the function and regulation of the turbot circadian system remains poorly understood. Here, we have characterized the core circadian clock genes, clock1, per1, per2 and cry1 in turbot and have studied their daily expression in various tissues under a range of lighting conditions and feeding regimes. We have also explored the influence of light and feeding time on locomotor activity. Rhythmic expression of the four core clock genes was observed in all tissues studied under light dark (LD) cycle conditions. Rhythmicity of clock gene expression persisted upon transfer to artificial free running, constant conditions confirming their endogenous circadian clock control. Furthermore, turbot showed daily cycles of locomotor activity and food anticipatory activity (FAA) under LD and scheduled-feeding, with the activity phase as well as FAA coinciding with and being dependent upon exposure to light. Thus, while FAA was absent under constant dark (DD) conditions, it was still detected in constant light (LL). In contrast, general locomotor activity was arrhythmic in both constant darkness and constant light, pointing to a major contribution of light, in concert with the circadian clock, in timing locomotor activity in this species. Our data represents an important contribution to our understanding of the circadian timing system in the turbot and thereby the optimization of rearing protocols and the improvement of the well-being of turbot within fish farming environments. [ABSTRACT FROM AUTHOR]

Ceterach officinarum Willd is a plant widespread throughout Europe and used in southern Italy as a diuretic. Beliefs in the benefits of C. officinarum aqueous extract in the treatment of calcium oxalate kidney stones are widely held. Little is known, however, about the actual mechanism of its antilithiatic action. Our results in this in vitro study corroborate C. officinarum aqueous extract as a good source of antioxidants with a high antioxidant effects. Our results also demonstrate a major impact of C. officinarum aqueous extract on in vitro induced calcium oxalate crystallization kinetics and crystal morphology, showing its critical role in kidney stone formation and/or elimination. We show that progressively increasing doses of C. officinarum aqueous extract cause a sequence of effects. A powerful inhibitory action on calcium oxalate monohydrate (COM) growth and aggregation is first observed. C. officinarum aqueous extract also appears highly effective in stimulating nucleation increasing the number and reducing the size of COM crystals, which become progressively thinner, rounded and concave in a dose-dependent manner. These shape-modified COM crystals are known to be less adherent to renal tubular cells and more easily excreted through the urinary tract preventing kidney stone formation. Further, C. officinarum aqueous extract promotes the formation of calcium oxalate dihydrate (COD) rather than the monohydrate so that, at the highest concentrations used, only COD crystals are observed, in significant greater numbers with a clear reduction in their size, in a dose-dependent manner. Furthermore, AFM analyses allowed us to reveal the presence of C. officinarum component(s) on the surfaces of COD and modified COM crystals. The crystal surface adsorbed component(s) are shown to be similarly active as the total aqueous extract, suggesting a trigger factor which may direct crystal modification towards COD forms. In urolithiasis pathogenesis COD crystals are less dangerous than the COM forms due to their lower affinity for renal tubular cells. Our results are important in understanding the mechanisms which guide the modification induced by C. officinarum on the crystallization process. Based on these data, together with no adverse toxic effect being observed on the in vitro model of human intestinal enterocytes, C. officinarum aqueous extract could represent an attractive natural therapy for the treatment of urolithiasis. [ABSTRACT FROM AUTHOR]

The rich Mediterranean imports found in Early Celtic princely sites (7th-5th cent. BC) in Southwestern Germany, Switzerland and Eastern France have long been the focus of archaeological and public interest. Consumption practices, particularly in the context of feasting, played a major role in Early Celtic life and imported ceramic vessels have consequently been interpreted as an attempt by the elite to imitate Mediterranean wine feasting. Here we present the first scientific study carried out to elucidate the use of Mediterranean imports in Early Celtic Central Europe and their local ceramic counterparts through organic residue analyses of 99 vessels from Vix-Mont Lassois, a key Early Celtic site. In the Mediterranean imports we identified imported plant oils and grape wine, and evidence points towards appropriation of these foreign vessels. Both Greek and local wares served for drinking grape wine and other plant-based fermented beverage(s). A wide variety of animal and plant by-products (e.g. fats, oils, waxes, resin) were also identified. Using an integrative approach, we show the importance of beehive products, millet and bacteriohopanoid beverage(s) in Early Celtic drinking practices. We highlight activities related to biomaterial transformation and show intra-site and status-related differences in consumption practices and/or beverage processing. [ABSTRACT FROM AUTHOR]

Biophysical and biochemical data on hyaluronan (HA)-based dermal fillers strongly support their optimal use and design to meet specific requisites. Here, four commercially available (in Europe) HA “volumetric” fillers, among the most used in the clinical practice, have been characterized in vitro. Analyses revealed the highest amounts of water-soluble HA reported so far and provided hydrodynamic data for these soluble polymeric fractions. Volumetric gels exhibit a wide range of rigidity with most of them showing G’ values around 200-300Pa. They greatly differ in cohesivity. 1mL of gel hydrates up to 2.4–3.2mL. The products completely solubilize due to Bovine Testicular Hyaluronidase (BTH)’s action, thus predicting in vivo complete resorption. For the first time, filler degradation due to reactive oxygen species (ROS) was studied by rheological measurements and a rank in stability was established. Studies using Human Dermal Fibroblasts (HDF) indicated a positive biological response to the HA networks. Further, gel capacity to prompt collagen I, elastin and aquaporin3 synthesis was demonstrated, thus suggesting a positive effect on skin elasticity and hydration, besides the physical volumetric action. The findings are the first wide assessment of features for the volumetric class of HA-fillers and include first data on their resistance to degradation by ROS and biological effects on HDF. The study represents a valuable contribution to the understanding of HA-fillers, useful to optimize their use and manufacture. [ABSTRACT FROM AUTHOR]

Background: Extensive studies have been carried out over the years to determine the maximum acceptable weight that a worker is capable of lifting in a given situation among Occidental populations across Europe and US. Nonetheless, studies that place emphasis on using lifting frequency as the quantifying task parameter, especially in developing countries such as Malaysia, appear to be in scarcity. Hence, this study determined the maximum acceptable frequency of lift (MAFL) for combined manual material handling (MMH) tasks amongst Malaysian males. Method: Two lifting loads were considered in this study: 1 kg and 5 kg. Each subject adjusted his frequency of lifting using a psychophysical approach. The subjects were instructed to perform combined MMH task as fast as they could over a period of 45 minutes without exhausting themselves or becoming overheated. The physiological response energy expenditure was recorded during the experimental sessions. The ratings of perceived exertion (RPE) for four body parts (forearms, upper arm, lower back and entire body) were recorded after the subjects had completed the instructed task. Results: The mean frequencies of the MMH task had been 6.8 and 5.5 cycles/minute for lifting load of 1 and 5 kg, respectively, while the mean energy expenditure values were 4.16 and 5.62 kcal/min for 1 and 5 kg load, respectively. These displayed a significant difference in the Maximum Acceptable Frequency of Lift (MAFL) between the two loads, energy expenditure and RPE (p < 0.05) whereby the subjects appeared to work harder physiologically for heavier load. Conclusion: It can be concluded that it is significant to assess physiological response and RPE in determining the maximum acceptable lifting frequency at varied levels of load weight. The findings retrieved in this study can aid in designing tasks that do not exceed the capacity of workers in order to minimise the risk of WRMSDs. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance and related metabolic disturbances are major risk factors for the higher T2D risk and associated morbidity and mortality amongst South Asians. The contribution of physical activity to the increased prevalence of insulin resistance and related disturbances amongst South Asians is unknown. Methods: We recruited 902 South Asian and European men and women, aged 35–85 years from the ongoing LOLIPOP study. Clinical characterisation comprised standardised questionnaire and measurement of height, weight, waist and hip circumference and blood pressure. Fasting bloods were taken for assessment of glucose, insulin, lipids and HbA1c. Physical activity was quantified using a validated accelerometer, Actigraph GT3X+, worn for 7 days. Univariate and multivariate approaches were used to investigate the relationship between ethnicity, physical activity, insulin resistance and related metabolic disturbances. Results: Total physical activity was ~31% (P = 0.01) lower amongst South Asians compared to Europeans (Mean MET.minutes [SD]: 1505.2 [52] vs. 2050.9 [86.6], P<0.001). After adjusting for age and sex, total physical activity had a negative association with HOMA-IR (B [SE]: -0.18 [0.08], P = 0.04) and fasting glucose levels (B[SE]: -0.11 [0.04], P = 0.02). There was no association between physical activity and other glycemic and lipid parameters. Total physical activity per week contributed towards the differences in insulin resistance and associated metabolic disturbances between South Asians and Europeans. Conclusion: Lower levels of physical activity may contribute to the increased insulin resistance in South Asians compared to Europeans. Our results suggest that lifestyle modification through increased physical activity may help to improve glucose metabolism and reduce the burden of excess T2D and related complications amongst South Asians. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases (CVD) remain the most significant cause of death in low- and middle-income countries where the burden of CVD continues to rise due to the increasing incidence of CVD. The aim of this study was to assess the prevalence of ideal cardiovascular health (CVH) across sex and age groups and to analyze associations between demographic and socio-economic variables and ideal CVH metrics in the adult population of the Republic of Serbia. Methods: Information on demographic (age, sex, marital status, and type of settlement) and socio-economic characteristics (education, and wealth index), and the 7 ideal CVH metrics (smoking, physical activity, healthy diet, BMI, blood pressure, cholesterol, and glucose) was obtained for 13100 respondents aged 20 years and above, from the 2013 National Health Survey in the Republic of Serbia. According to the American Heart Association, the ideal CVH was defined as the simultaneous presence of 7 ideal CVH metrics. Results: Out of all ideal CVH metrics, the most prevalent components were ideal glucose (92.2%), ideal cholesterol (86.4%) and ideal smoking (63%), while the least prevalent ideal CVH component was ideal healthy diet (2.4%). Only 0.1% had all 7 CVH components at the ideal level. According to the multivariable logistic regression analysis the higher number of ideal CVH metrics was observed in women (OR = 4.46), younger people (OR = 7.12), people living without partner (OR = 1.70), more educated (OR = 2.51 for middle educated and OR = 3.57 for high educated), as well as among the rich (OR = 1.43). Conclusion: Our findings of existing age-specific, sex and socio-economic differences in the prevalence and number of ideal CVH metrics should serve for the development of appropriate CVD prevention policies tailored to fit specific needs of both sexes, all age groups and people with different socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated.Methods and Findings: We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991-1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19-0.29) adjusted for potential confounders and 0.37 (95% CI 0.27-0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding.Conclusions: A combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors. [ABSTRACT FROM AUTHOR]

Background: Postnatal corticosteroids (PNC) were widely used to treat and prevent bronchopulmonary dysplasia in preterm infants until studies showed increased risk of cerebral palsy and neurodevelopmental impairment. We aimed to describe PNC use in Europe and evaluate the determinants of their use, including neonatal characteristics and adherence to evidence-based practices in neonatal intensive care units (NICUs). Methods: 3917/4096 (95,6%) infants born between 24 and 29 weeks gestational age in 19 regions of 11 European countries of the EPICE cohort we included. We examined neonatal characteristics associated with PNC use. The cohort was divided by tertiles of probability of PNC use determined by logistic regression analysis. We also evaluated the impact of the neonatal unit’s reported adherence to European recommendations for respiratory management and a stated policy of reduced PNC use. Results: PNC were prescribed for 545/3917 (13.9%) infants (regional range 3.1–49.4%) and for 29.7% of infants in the highest risk tertile (regional range 5.4–72.4%). After adjustment, independent predictors of PNC use were a low gestational age, small for gestational age, male sex, mechanical ventilation, use of non-steroidal anti-inflammatory drugs to treat persistent ductus arteriosus and region. A stated NICU policy reduced PNC use (odds ratio 0.29 [95% CI 0.17; 0.50]). Conclusion: PNC are frequently used in Europe, but with wide regional variation that was unexplained by neonatal characteristics. Even for infants at highest risk for PNC use, some regions only rarely prescribed PNC. A stated policy of reduced PNC use was associated with observed practice and is recommended. [ABSTRACT FROM AUTHOR]

European beech forests growing on marginal calcareous soils have been proposed to be vulnerable to decreased soil water availability. This could result in a large-scale loss of ecological services and economical value in a changing climate. In order to evaluate the potential consequences of this drought-sensitivity, we investigated potential species range shifts for European beech forests on calcareous soil in the 21st century by statistical species range distribution modelling for present day and projected future climate conditions. We found a dramatic decline by 78% until 2080. Still the physiological or biogeochemical mechanisms underlying the drought sensitivity of European beech are largely unknown. Drought sensitivity of beech is commonly attributed to plant physiological constraints. Furthermore, it has also been proposed that reduced soil water availability could promote nitrogen (N) limitation of European beech due to impaired microbial N cycling in soil, but this hypothesis has not yet been tested. Hence we investigated the influence of simulated climate change (increased temperatures, reduced soil water availability) on soil gross microbial N turnover and plant N uptake in the beech-soil interface of a typical mountainous beech forest stocking on calcareous soil in SW Germany. For this purpose, triple 15N isotope labelling of intact beech seedling-soil-microbe systems was combined with a space-for-time climate change experiment. We found that nitrate was the dominant N source for beech natural regeneration. Reduced soil water content caused a persistent decline of ammonia oxidizing bacteria and therefore, a massive attenuation of gross nitrification rates and nitrate availability in the soil. Consequently, nitrate and total N uptake of beech seedlings were strongly reduced so that impaired growth of beech seedlings was observed already after one year of exposure to simulated climatic change. We conclude that the N cycle in this ecosystem and here specifically nitrification is vulnerable to reduced water availability, which can directly lead to nutritional limitations of beech seedlings. This tight link between reduced water availability, drought stress for nitrifiers, decreased gross nitrification rates and nitrate availability and finally nitrate uptake by beech seedlings could represent the Achilles’ heel for beech under climate change stresses. [ABSTRACT FROM AUTHOR]

Introduction: There is evidence that greater neighbourhood walkability (i.e., neighbourhoods with more amenities and well-connected streets) is associated with higher levels of total walking in Europe and in Asia, but it remains unclear if this association holds in the Canadian context and in chronic disease populations. We examined the relationships of different walkability measures to biosensor-assessed total walking (i.e., steps/day) in adults with type 2 diabetes living in Montreal (QC, Canada). Materials and Methods: Participants (60.5±10.4 years; 48.1% women) were recruited through McGill University-affiliated clinics (June 2006 to May 2008). Steps/day were assessed once per season for one year with pedometers. Neighbourhood walkability was evaluated through participant reports, in-field audits, Geographic Information Systems (GIS)-derived measures, and the Walk Score®. Relationships between walkability and daily steps were estimated using Bayesian longitudinal hierarchical linear regression models (n = 131). Results: Participants who reported living in the most compared to the least walkable neighbourhoods completed 1345 more steps/day (95% Credible Interval: 718, 1976; Quartiles 4 versus 1). Those living in the most compared to the least walkable neighbourhoods (based on GIS-derived walkability) completed 606 more steps per day (95% CrI: 8, 1203). No statistically significant associations with steps were observed for audit-assessed walkability or the Walk Score®. Conclusions: Adults with type 2 diabetes who perceived their neighbourhoods as more walkable accumulated more daily steps. This suggests that knowledge of local neighborhood features that enhance walking is a meaningful predictor of higher levels of walking and an important component of neighbourhood walkability. [ABSTRACT FROM AUTHOR]