Background: A phase 3 trial, ADVANCE (NCT03777059), demonstrated that atogepant, an oral, CGRP receptor antagonist dosed once daily, results in clinically meaningful reductions in mean monthly migraine days. This open-label extension for ADVANCE trial completers evaluated long-term safety and tolerability of atogepant over 40-weeks. Methods: Participants in this trial (NCT03939312), rolled over from the ADVANCE trial, were treated with atogepant 60mg once daily for 40-weeks, with a 4-week safety follow-up. Only safety data were collected. Results: 685 participants took at least one dose of study drug, 74.6% completed the 40-week treatment period; mean age of 41.8 years, 88.2% female, 84.4% white, and mean BMI of 30.58 kg/m2. Mean (SD) treatment duration was 233.6 (89.32) days. 62.5% of participants experienced a treatment-emergent adverse event (TEAE), with 8.8% considered treatment-related by the investigator; serious adverse events (SAEs) occurred in 3.4% of participants, none were treatment-related. The most frequent AEs leading to discontinuation was nausea (0.4%, n=3); the most frequent TEAEs observed included upper respiratory tract infection (5.5%, n=38) and urinary tract infection (5.3%, n=36). No deaths or hepatic safety issues were observed. Conclusions: Safety results are consistent with known safety profile of atogepant and support long-term safety and tolerability of once daily dosing of atogepant 60mg.

Background: In phase 3 ADVANCE, atogepant 60mg reduced mean monthly migraine days (MMDs) from 7.8 days (baseline) to 3.0 (weeks 9-12; Δ=−4.7) in the overall episodic migraine population [treatment responders and nonresponders (i.e., marked benefit and minimal benefit)], which obscures information regarding magnitude of treatment effect in these populations. Here, magnitude of treatment effect in atogepant responders and nonresponders is characterized. Methods: Mean MMDs, acute medication use-days (MUDs), and Migraine-Specific Quality of Life-Role Function-Restrictive (MSQ-RFR) scores were calculated in treatment responders (based on MMD percentage reduction) and nonresponders from ADVANCE participants. Results: From baseline to weeks 9-12, ≥50% improvement was achieved by 71% (139/195) of participants. In these responders, MMDs reduced from 7.6 to 1.3 (Δ=−6.3). 50% (97/195) of participants achieved ≥75% response. In this group, MMDs reduced from 7.7 to 0.6 (Δ=−7.1). Atogepant 60mg nonresponders (<25% reduction in MMDs; 15% [30/195 participants]) showed MMD change from 7.7 to 9.1 (Δ=+1.4). Acute MUDs in ≥50% MMD responders decreased 7.1 to 1.6 (Δ=−5.5). In treatment-nonresponders, acute MUDs were 7.3 (baseline) and 7.2 (weeks 9-12; Δ=−0.1). Similar mean MSQ-RFR score changes were observed in both populations. Conclusions: Of participants who experienced ≥50% reduction in MMDs, 71% had substantial treatment effect (ΔMMD=−6.3), representing 83% reduction in MMDs.

Given the relatively small industry scale of cow-calf operations in New York to other regions of the country, little is known about differences in determinant values for feeder cattle. Using auction prices and quality characteristics over 7 years, differences in market, lot, and quality parameters suggest opportunities for improved marketing performance. A delta profit model is constructed to inform timing of marketing decisions for producers. The results indicate a relatively high potential for producers to increase farm returns by delaying sales of lighter-weight feeder cattle from the fall to spring auction months, given sufficient rates of gain and reasonable overwintering costs.

Introduction: The Prehospital Evidence-Based Practice (PEP) program is an online, freely accessible, continuously updated Emergency Medical Services (EMS) evidence repository. This summary describes the research evidence for the identification and management of adult patients suffering from sepsis syndrome or septic shock. Methods: PubMed was searched in a systematic manner. One author reviewed titles and abstracts for relevance and two authors appraised each study selected for inclusion. Primary outcomes were extracted. Studies were scored by trained appraisers on a three-point Level of Evidence (LOE) scale (based on study design and quality) and a three-point Direction of Evidence (DOE) scale (supportive, neutral, or opposing findings based on the studies’ primary outcome for each intervention). LOE and DOE of each intervention were plotted on an evidence matrix (DOE x LOE). Results: Eighty-eight studies were included for 15 interventions listed in PEP. The interventions with the most evidence were related to identification tools (ID) (n = 26, 30%) and early goal directed therapy (EGDT) (n = 21, 24%). ID tools included Systematic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA) and other unique measures. The most common primary outcomes were related to diagnosis (n = 30, 34%), mortality (n = 40, 45%) and treatment goals (e.g. time to antibiotic) (n = 14, 16%). The evidence rank for the supported interventions were: supportive-high quality (n = 1, 7%) for crystalloid infusion, supportive-moderate quality (n = 7, 47%) for identification tools, prenotification, point of care lactate, titrated oxygen, temperature monitoring, and supportive-low quality (n = 1, 7%) for vasopressors. The benefit of prehospital antibiotics and EGDT remain inconclusive with a neutral DOE. There is moderate level evidence opposing use of high flow oxygen. Conclusion: EMS sepsis interventions are informed primarily by moderate quality supportive evidence. Several standard treatments are well supported by moderate to high quality evidence, as are identification tools. However, some standard in-hospital therapies are not supported by evidence in the prehospital setting, such as antibiotics, and EGDT. Based on primary outcomes, no identification tool appears superior. This evidence analysis can guide selection of appropriate prehospital therapies.

Disentangling trophic interactions among species is important for elucidating mechanisms underlying ecosystem functioning and services. Carabid beetles are an important guild of predators that may regulate pest populations in arable landscapes, but their generalist feeding behavior hinders predictions about their actual contribution to pest control. In order to assess carabids’ potential for pest control, we simultaneously analyzed the carbon and nitrogen stable isotope ratios of a community of 45 co-occurring species in wheat and oilseed rape fields. With the expectation to identify distinct trophic groups based on the mean and the variance of carabid isotopic signatures, we observed a high degree of overlap in trophic positions between species. However, we also observed that species could be successfully categorized into two groups according to whether or not their carbon signatures varied independently from variations in the crop baseline. We interpret these results as differential primary resource uptake or by differential mobility aptitude in foraging. Accordingly, we propose that the isotopic signal can inform us on the presence/absence of links between generalist predators and cultivated plants through the trophic networks they belong to, and consequently on their potential role as pest natural enemies. We therefore suggest the complementarity of stable isotope analysis for obtaining a time-integrated assessment of carabid trophic behavior that may be combined with more direct molecular diet analysis allowing the simultaneous quantification of specific trophic links within agricultural landscapes.

Yield maps are a powerful tool with regard to managing upcoming crop productions but can contain a large amount of defective data that might result in misleading decisions. The objective of this work is to help improve and compare yield data filtering algorithms by generating simulated datasets as if they had been acquired directly in the field. Two stages were implemented during the simulation process (i) the creation of spatially correlated datasets and (ii) the addition of known yield sources of errors to these datasets. A previously published yield filtering algorithm was applied on these simulated datasets to demonstrate the applicability of the methodology. These simulated datasets allow results of yield data filtering methods to be compared and improved.

This paper presents a lake-level record established for the last millennium at Lake Saint-Point in the French Jura Mountains. A comparison of this lake-level record with a solar irradiance record supports the hypothesis of a solar forcing of variations in the hydrological cycle linked to climatic oscillations over the last millennium in west-central Europe, with higher lake levels during the solar minimums of Oort (around AD 1060), Wolf (around AD 1320), Spörer (around AD 1450), Maunder (around AD 1690), and Dalton (around AD 1820). Further comparisons of the Saint-Point record with the fluctuations of the Great Aletsch Glacier (Swiss Alps) and a record of Rhône River floods from Lake Bourget (French Alps) give evidence of possible imprints of proxy sensitivity on reconstructed paleohydrological records. In particular, the Great Aletsch record shows an increasing glacier mass from AD 1350 to 1850, suggesting a cumulative effect of the Little Ice Age cooling and/or a possible reflection of a millennial-scale general cooling until the mid-19th century in the Northern Hemisphere. In contrast, the Saint-Point and Bourget records show a general trend toward a decrease in lake levels and in flood magnitude anti-correlated with generally increasing solar irradiance.

Free and total valproic acid (VPA) pharmacokinetic evaluation was carried out at steady state in six young epileptics who were also receiving other anticonvulsants. Subjects received their usual morning dose of VPA after an overnight fast. Blood samples for free and total VPA were taken prior to the dose and frequently thereafter for 12 hours. The calculated pharmacokinetic parameters for total VPA and free VPA were: half-lives of 7.5 ± 1.6 hours and 5.0 ± 1.5 hours, volumes of distribution of 0.189 ± 0.038 l/kg and 1.51 ± 0.98 l/kg, and clearances of 0.30 ± 0.06 and 3.6 ± 2.0 ml/min/kg., respectively. There was a strong correlation between percent free VPA and total VPA (r = 0.81) but marked inter- and intra-subject variations were seen. Studies attempting to correlate VPA levels to clinical response must take such data into account.

The standard model of intertemporal choice assumes risk neutrality towards the length of life: under additivity of lifetime utility and expected utility assumptions, agents are not sensitive to a mean preserving spread in the length of life. Using a survey fielded in the RAND American Life Panel, this paper provides empirical evidence on possible deviation from risk neutrality with respect to longevity in the US population. The questions we ask allow to find the distribution as well as to quantify the degree of risk aversion with respect to the length of life in the population. We find evidence that roughly 75% of respondents were not neutral with respect to longevity risk. Hence, there is a little empirical support for the joint use of the expected utility and additive lifetime utility assumptions in life-cycle models. Higher income households are more likely to be risk averse towards the length of life. We do not find evidence that the degree of risk aversion varies with age or education.

The last report on pertussis seroprevalence in Belgium concerned samples collected during 1993–1994. In the context of the Eupert-Labnet WP6 seroprevalence study (comparing sera from 16 European member states), 1500 anonymized leftover diagnostic samples were collected randomly during the second semester of 2012 by the clinical chemistry laboratories of six participating Belgian centres, distributed equally between Flanders, Wallonia and Brussels Capital Region. As suggested by the WP6 organizers, a total of 750 samples (125/centre) were selected from subjects in the 20–29 years age group and 750 samples (125/centre) from subjects in the 30–39 years age group. Anti-PT IgG levels were measured using Virion-Serion ELISA and analysed using predefined cut-off levels. Sixty-one (4%) sera were indicative of an infection in the past 2 years (between 50 and 100 IU/ml) and another 61 (4%) sera had anti-PT IgG antibodies reflecting acute infection (>100 IU/ml). These results highlight the presence of a Bordetella pertussis reservoir in the adult ‘healthy’ Belgian population.

The reliability of reverse transcription quantitative real-time PCR (RT-qPCR) depends on normalising the mRNA abundance using carefully selected, stable reference genes. Our aim was to propose sets of reference genes for normalisation in bovine or caprine adipose tissue (AT), mammary gland, liver and muscle. All of these tissues contribute to nutrient partitioning and metabolism and, thus, to the profitability of ruminant productions (i.e. carcasses, meat and milk). In this study, eight commonly used reference genes that belong to different functional classes (CLN3, EIF3K, MRPL39, PPIA, RPLP0, TBP, TOP2B and UXT) were analysed using the geNorm procedure to determine the most stable reference genes in bovine and/or caprine tissues. Abundances and rankings of reference genes varied between tissues, species and the combination of tissues and/or species. Therefore, we proposed 29 sets of reference genes that differed depending on the tissue and/or species. As examples of the 29 sets, EIF3K, TOP2B and UXT were proposed as the most stable reference genes in bovine AT; UXT, EIF3K and RPLP0 were the most stable reference genes in bovine and caprine AT. The optimal number of reference genes for data normalisation was 3 for 27 of the proposed 29 sets. In two of the 29 sets, four to five reference genes were necessary for data normalisation when the number of studied tissues was increased. For example, UXT, EIF3K, TBP, TOP2B and CLN3 were required for data normalisation in bovine mammary gland, AT, muscle and liver. We have evaluated some of our proposed sets of reference genes for the normalisation of CD36 gene expression. Normalisation using the three most stable reference genes has revealed downregulation of CD36 gene expression in bovine mammary gland by a concentrate-based diet that is supplemented with sunflower oil and upregulation of CD36 gene expression in caprine liver by including a rapidly degradable starch in the diet. The dietary regulation of the gene expression of CD36 has been erased by normalisation with the least stable reference genes, which may result in misinterpretation of CD36 gene regulation. To conclude, our results provide valuable reference gene sets for other studies that aim to measure tissue and/or species-specific mRNA abundance in ruminants.

Nymphs and adults of Podisus maculiventris (Say), reared on four sizes (diet levels) of live larvae of Galleria mellonella (L.), captured prey, consumed food, and grew at rates varying with the size of larvae supplied. For nymphs, a direct linear relationship was obtained between rate of food consumption and daily growth and rate of food consumption and daily development. For adults, male and female, age did not affect food intake significantly, but for females alone, food intake differed significantly at different diet levels. A significant difference was also obtained for both sexes between body weight and diet level. Males and females lived longest on diet 1, apparently because of reduced metabolic activity.The number of eggs laid by each female corresponded to its food consumption for the first 35 days but decreased thereafter with age. The mean dry weights for fertile and infertile eggs at different diet levels did not differ significantly irrespective of the amount of food consumed by egg-laying females.For each nymph in each of instars 2 to 5 and for adults, the consumption quotient, an index of metabolic activity, increased as the rate of food consumption increased. For nymphs, the quotient decreased during ontogeny at each diet level, and for adults, decreased with age at diet levels 2, 3, and 4. The quotient remained constant for adults of both sexes at diet level 1.Results show that nymphs and adults of P. maculiventris can survive and mature satisfactorily for extended periods on small prey but needs larger prey to accelerate development, increase growth, and maintain a high reproductive potential.

Based on bomb calorimeter determinations, the calorific values of four sizes of larvae of Galleria mellonella (L.) fed to nymphs and adults of the predator Podisus maculiventris (Say) increased with increase in larval size. Correspondingly, these values for P. maculiventris nymphs in fourth and fifth instars and adults, male and female, increased when the predator fed on larger larvae. Increases in energy consumption resulted in increases in energy loss due to respiration and egestion for nymphs and adults of the predator. For unfed males and females, calorific values decreased with age, i.e., as initial body energy reserves were used up.No significant differences in mean calorific values were observed for fertile and infertile eggs laid by females reared at each of the four diet levels. This suggests that the amount of energy utilized by females in the production of eggs is fairly constant, irrespective of the amount of energy consumed at each diet level.Energy budgets for nymphs of P. maculiventris showed that gross efficiency of growth for second- and third-instar nymphs was inversely proportional to energy consumed; however, no such relationship was observed for fourth and fifth instars. For males, energy budgets showed that at all diet levels little growth took place during adult fife, with gross efficiency at diet levels 1 to 4 ranging from 0.88 to 2.20%. For females, some growth occurred at all levels of diet during the first 35 days of adult life, mainly as a result of the production of eggs. Gross efficiency during this period ranged from 5.5 to 13.6%. Efficiency of reproduction at diet levels 1 to 4 ranged from 37.26 to 45.35% during the first 35 days of adult life and from 39.46 to 51.16% for the next 20 days.

Experiments were carried out to determine the effect of age on the functional response of the pentatomid predator Podisus maculiventris (Say), reared in a simple glass jar universe on different prey sizes of Galleria mellonella (L.). Holling’s (1959) ’disc’ equation accurately described the predator’s response at all prey sizes up to 50 days of life. For nymphs, the calculated ’rate of discovery’, a, increased as the predator age increased, but the time of handling prey, b, decreased; for both adult males and females, these calculated values increased gradually up to the 50th day. The relationship between predator age and numbers of prey killed, and predator age and amount of prey body contents consumed (food consumption), was linear at all prey sizes, but mainly negatively so. Prey size was an important component of the predation process for all stages of the predator.It is concluded that ’hunger’ is an important parameter of the attack model since the degree of predator satiation bears directly on b-type activities which in turn affects a-type activities. These findings indicate that under field conditions P. maculiventris will kill more small-sized lepidopterous prey larvae than large-sized ones, and that, because of the greater prey defense of the latter, their survival from predator attacks will increase. These actions may be of considerable importance in the survival of lepidopterous host species.

This is a report on a program to sample the European corn borer, Ostrinia nubilalis (Hbn.), with the object of obtaining reliable statistics for life tables (see e.g. Morris, 1955; LeRoux and Reimer, 1959).

Basic studies on factors determining abundance of the European corn borer are few, some of the most notable having been carried out by Barber (1926), Huber et al. (1928), Thompson and Parker (1928), Stirrett (1938), Vance (1943), Baker et al. (1949), Bigger and Petty (1953), Everett et al. (1958) and Chiang and Hodson (1959). None of these studies was a thorough study of mortality factors in development of the European corn borer from endemic to epidemic levels. A number of specific factors known to be important in the epidemiology of this species have been investigated by Arbuthnot (1949), Neiswander (1952), Goleman (1954), Chiang and Holdaway (1955), and Chiang (1959), and the application of biometric techniques to the sampling of corn borer populations has been studied by Beard (1943), McGuire (1954), and Bankcroft and Brindley (1956). None of the latter authors have, however, investigated sampling techniques relating to the development of life tables for this species.

The main aim of the present study was to examine the effects of long-term supplementing diets with saturated or unprotected polyunsaturated fatty acids from two different plant oils rich in either n-3 or n-6 fatty acids (FAs) plus docosahexaenoic acid (DHA)-rich algae on mammary gene expression and milk fat composition in lactating dairy cows. Gene expression was determined from mammary tissue and milk epithelial cells. Eighteen primiparous German Holstein dairy cows in mid-lactation were randomly assigned into three dietary treatments that consist of silage-based diets supplemented with rumen-stable fractionated palm fat (SAT; 3.1% of the basal diet dry matter, DM), or a mixture of linseed oil (2.7% of the basal diet DM) plus DHA-rich algae (LINA; 0.4% of the basal diet DM) or a mixture of sunflower oil (2.7% of the basal diet DM) plus DHA-rich algae (SUNA; 0.4% of the basal diet DM), for a period of 10 weeks. At the end of the experimental period, the cows were slaughtered and mammary tissues were collected to study the gene expression of lipogenic enzymes. During the last week, the milk yield and composition were determined, and milk was collected for FA measurements and the isolation of milk purified mammary epithelial cells (MECs). Supplementation with plant oils and DHA-rich algae resulted in milk fat depression (MFD; yield and percentage). The secretion of de novo FAs in the milk was reduced, whereas the secretion of trans-10,cis-12-CLA and DHA were increased. These changes in FA secretions were associated in mammary tissue with a joint down-regulation of mammary lipogenic enzyme gene expression (stearoyl-CoA desaturase, SCD1; FA synthase, FASN) and expression of the regulatory element binding transcription factor (SREBF1), whereas no effect was observed on lipoprotein lipase (LPL) and glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM). A positive relationship between mammary SCD1 and SREBF1 mRNA abundances was observed, suggesting a similar regulation for these genes. Such data on mammary gene expression in lactating cows presenting MFD contribute to strengthen the molecular mechanisms that govern milk fat synthesis in the mammary glands. In purified MEC, the dietary treatments had no effect on gene expressions. Differences between mammary tissue and milk purified MEC gene expression were attributed to the effect of lipid supplements on the number of milk purified MEC and its RNA quality, which are determinant factors for the analysis of gene expression using milk cells.

The potential benefits on human health have prompted an interest in developing nutritional strategies for reducing saturated and increasing specific unsaturated fatty acids (FA) in ruminant milk. The impact of the level and type of starchy concentrate added to diets supplemented with sunflower-seed oil on caprine milk FA composition and on mammary, omental and perirenal adipose, and liver lipid metabolism was examined in fourteen Alpine goats in a replicated 3 × 3 Latin square with 21 d experimental periods. Treatments were a grass hay-based diet with a high level of forage (F) or a high level of concentrate with either maize grain (CM) or flattened wheat (CW) as source of starch and supplemented with 130 g/d sunflower-seed oil. Milk yield was enhanced (P < 0·01) and milk fat content was decreased on the CM and CW diets compared with the F diet, resulting in similar milk fat secretion. Both high-concentrate diets increased (P < 0·05) milk yield of 10 : 0-16 : 0 and decreased trans-9,11-18 : 1 and cis-9, trans-11-18 : 2. The CW diet decreased (P < 0·05) the output of Σ C18 and Σ cis-18 : 1 and increased (P < 0·05) the output of trans-10-18 : 1 in milk. The expression and/or activity of fourteen proteins involved in the major lipogenic pathways in mammary tissues and of lipogenic genes in adipose and liver tissues were similar among treatments. In conclusion, high starch concentrates alter milk FA yield via mechanisms independent of changes in mammary, liver or adipose tissue lipogenic gene expression. Furthermore, data provided indications that mammary lipogenic responses to starch-rich diets differ between caprine and bovine ruminants.