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Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4–13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

Background and Objectives: To better understand the current use of simulation and barriers to its use in family medicine resident education, we surveyed US family medicine residency (FMR) program directors (PDs) about opinions and use of simulation-based medical education (SBME) in their programs. A number of specialties have incorporated or required simulation-based educational techniques in residency education over the past 10 years, but little is known about the current use of SBME in family medicine graduate medical education. We also evaluated associations between program characteristics and the use of SBME in FMR education. Methods: Questions were included on the 2019 Council of Academic Family Medicine Education Research Alliance (CERA) survey of US FMR PDs. The survey included questions regarding current use of SBME along with questions to identify barriers to its use in family medicine programs. Results: Thirty-nine percent (n=250) of PDs completed the survey; 84.5% reported using simulation. PDs reporting they did not use simulation were less likely to view simulation as valuable for education or assessment. Unexpectedly, residency program size was not associated with simulation use or access to a dedicated location for SBME. Discussion: Use of SBME in family medicine resident education has increased since 2011. PDs value simulation for education and remediation, and most programs have introduced some degree of simulation despite barriers. The results of this study can inform resources to support the continued integration of SBME into family medicine resident education.

Considering the field of application involving stent deployment simulations, the exploitation of a digital twin of coronary stenting that can reliably mimic the patient-specific clinical reality could lead to improvements in individual treatments. A starting step to pursue this goal is the development of simple, but at the same time, robust and effective computational methods to obtain a good compromise between the accuracy of the description of physical phenomena and computational costs. Specifically, this work proposes an approach for the development of a patient-specific artery model to be used in stenting simulations. The finite element model was generated through a 3D reconstruction based on the clinical imaging (coronary Optical Coherence Tomography (OCT) and angiography) acquired on the pre-treatment patient. From a mechanical point of view, the coronary wall was described with a suitable phenomenological model, which is consistent with more complex constitutive approaches and accounts for the in vivo pressurization and axial pre-stretch. The effectiveness of this artery modeling method was tested by reproducing in silico the stenting procedures of two clinical cases and comparing the computational results with the in vivo lumen area of the stented vessel.

Background and objectives: Infected cutaneous ulcers are major health problems for children living in rural areas of Papua New Guinea. The inaccessibility of affected populations and lack of access to basic healthcare, make a local plant-based therapy an attractive treatment option. We assessed Ficus septica exudate in biological assays relevant to wound healing. We then carried out a clinical trial to determine the exudate's efficacy in healing small cutaneous ulcers compared with Savlon antiseptic cream, and soap and water washing.\ud \ud Methods: Pre-clinical in vitro assessment of the exudate was carried out using assays to monitor the pro-inflammatory responses of M1 macrophages and neutrophils, antibacterial assays using known ulcer pathogens, an Ames test for mutagenicity and LC-MS chemical analysis of the exudate. An open label cluster-randomised clinical trial was performed, enrolling participants from three different clusters with skin lesions less than 1 cm in diameter. Each cluster comprising 50 participants was randomly assigned to one of three treatment arms namely topical exudate, topical Savlon antiseptic cream, and standard care (soap and water treatment), all administered daily for 2 days. The primary outcome was clinical healing/improvement measured at days 7 and 14, assessed by three dermatologists using blinded photographs. The primary analysis was assessed as non-inferiority of F. septica treatment based on the risk difference for healing/improvement.\ud \ud Results: In vitro, the exudate which is rich in the alkaloid ficuseptine, was found to be non-mutagenic whilst also inhibiting pro-inflammatory responses and exhibiting antibacterial activity. When administered to participants enrolled in the clinical trial, no significant differences were observed between the healing efficacy of F. septica exudate and the two comparator treatments (Savlon antiseptic cream and soap/water treatment). At day 14, but not at day 7, the efficacy of F. septica exudate for healing/improving the ulcers was non-inferior to Savlon antiseptic cream or water/soap treatment.\ud \ud Conclusions: F. septica exudate is non-mutagenic and has both bactericidal and anti-inflammatory properties. When applied topically to small cutaneous ulcers, the exudate has a healing effect that is non-inferior to Savlon antiseptic cream and standard treatment with soap and water at day 14. Our findings, which should be confirmed in larger clinical trials, have important public health implications.

We present the Cosmological Double Radio Active Galactic Nuclei (CosmoDRAGoN) project: a large suite of simulated AGN jets in cosmological environments. These environments sample the intra-cluster media of galaxy clusters that form in cosmological smooth particle hydrodynamics (SPH) simulations, which we then use as inputs for grid-based hydrodynamic simulations of radio jets. Initially conical jets are injected with a range of jet powers, speeds (both relativistic and non-relativistic), and opening angles; we follow their collimation and propagation on scales of tens to hundreds of kiloparsecs, and calculate spatially-resolved synthetic radio spectra in post-processing. In this paper, we present a technical overview of the project, and key early science results from six representative simulations which produce radio sources with both core- (Fanaroff-Riley Type I) and edge-brightened (Fanaroff-Riley Type II) radio morphologies. Our simulations highlight the importance of accurate representation of both jets and environments for radio morphology, radio spectra, and feedback the jets provide to their surroundings., Comment: 25 pages, 20 figures. Accepted for publication in PASA

This case-study examines the release time of the everolimus drug from an experimental biodegrading coating of a Rontis corp. drug eluting stent (DES). The controlled drug release is achieved by the degradation of the coating, which consists of a mixture of polylactic co-glycolic acid (PLGA) and everolimus (55:45). In our analysis, we used the outcome of another study, which contains the geometry of an in-silico deployed Rontis corp. stent in a 3D reconstructed coney arterial segment. Using this geometry as input, the everolimus release was simulated using a computational model that includes: i) modeling of the blood flow dynamics, ii) modeling of PLGA degradation, and iii) modeling of the everolimus advection and diffusion towards both the lumen and the arterial wall. The results show the rapid release of everolimus. This is justified due to the high porosity of the coating, which is caused by the initial high concentration of everolimus in the coating.Clinical Relevance - The methodology presented in this work is an additional step towards predicting accurately drug release from DES. Also, the results of our work prove that high drug concentration in the coating causes its rapid release, which could be used as input in the design of new DES.

Kisspeptin is vital for the regulation of both fertility and metabolism. Kisspeptin receptor (Kiss1r) knockout (KO) mice exhibit increased adiposity and reduced energy expenditure in adulthood. Kiss1r mRNA is expressed in brown adipose tissue (BAT) and Kiss1r KO mice exhibit reduced Ucp1 mRNA in BAT and impaired thermogenesis. We hypothesised that mice with diminished kisspeptin signalling would exhibit reduced core body temperature (Tc) and altered dynamics of circadian and ultradian rhythms of Tc. Tc was recorded every 15-min over 14-days in gonadectomised wild-type (WT), Kiss1r KO, and also Kiss1-Cre (95% reduction in Kiss1 transcription) mice. Female Kiss1r KOs had higher adiposity and lower Ucp1 mRNA in BAT than WTs. No change was detected in Kiss1-Cre mice. Mean Tc during the dark phase was lower in female Kiss1r KOs versus WTs, but not Kiss1-Cre mice. Female Kiss1r KOs had a lower mesor and amplitude of the circadian rhythm of Tc than did WTs. In WT mice, there were more episodic ultradian events (EUEs) of Tc during the dark phase than the light phase, but this measure was similar between dark and light phases in Kiss1r KO and Kiss1-Cre mice. The amplitude of EUEs was higher in the dark phase in female Kiss1r KO and male Kiss1-Cre mice. Given the lack of clear metabolic phenotype in Kiss1-Cre mice, 5% of Kiss1 transcription may be sufficient for proper metabolic control, as was shown for fertility. Moreover, the observed alterations in Tc suggest that kisspeptin has a role in circadian and ultradian rhythm-driven pathways.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p&nbsp

The Deep Underground Neutrino Experiment (DUNE) is an international, world-class experiment aimed at exploring fundamental questions about the universe that are at the forefront of astrophysics and particle physics research. DUNE will study questions pertaining to the preponderance of matter over antimatter in the early universe, the dynamics of supernovae, the subtleties of neutrino interaction physics, and a number of beyond the Standard Model topics accessible in a powerful neutrino beam. A critical component of the DUNE physics program involves the study of changes in a powerful beam of neutrinos, i.e., neutrino oscillations, as the neutrinos propagate a long distance. The experiment consists of a near detector, sited close to the source of the beam, and a far detector, sited along the beam at a large distance. This document, the DUNE Near Detector Conceptual Design Report (CDR), describes the design of the DUNE near detector and the science program that drives the design and technology choices. The goals and requirements underlying the design, along with projected performance are given. It serves as a starting point for a more detailed design that will be described in future documents. Published version

Purpose The purpose of this paper is twofold: first, to evaluate the claim that consumers are willing to compromise on taste in order to obtain the potential health benefits from functional snacks; and second, to investigate the effect of expectations for the snacks, blind tasting and product information on hedonic judgments and willingness to pay (WTP). Design/methodology/approach A sample of 160 subjects was recruited to participate in a lab experiment that combined hedonic evaluations and a series of non-hypothetical second-price Vickrey auctions, under blind or informed tasting conditions. Participants were also asked to complete a questionnaire about consumer preferences, purchasing habits and demographics. Findings Results indicate that tasting and information have economically and statistically significant effects on overall food assessment with respect to prior product expectations. Provision of information regarding functional food components shortly before consumption makes consumers less strict on their taste evaluation and increases their WTP. This indicates that consumers are willing to partly sacrifice the pleasure of taste in order to improve the healthfulness of their diet. When information is provided after taste, it only exerts influence with respect to the carob-based snack. Furthermore, blind tasting has a negative effect on liking, irrespective of the product being evaluated. Finally, the econometric results reveal that older respondents tend to bid higher for functional snacks. Originality/value This study contributes to the existing literature not only on the basis of the novelty of results but also on the methodological front, since it showcases the combined use of hedonic tests and auctions with real monetary incentives as a state of the art technique on eliciting consumers’ overall assessment for functional snacks. It also highlights important elements in the toolkit that marketers can use to influence products’ perceived health benefits, and thus consumption choices.

Intravascular ultrasound (IVUS) imaging offers accurate cross-sectional vessel information. To this end, registering temporal IVUS pullbacks acquired at two time points can assist the clinicians to accurately assess pathophysiological changes in the vessels, disease progression and the effect of the treatment intervention. In this paper, we present a novel two-stage registration framework for aligning pairs of longitudinal and axial IVUS pullbacks. Initially, we use a Dynamic Time Warping (DTW)-based algorithm to align the pullbacks in a temporal fashion. Subsequently, an intensity-based registration method, that utilizes a variant of the Harmony Search optimizer to register each matched pair of the pullbacks by maximizing their Mutual Information, is applied. The presented method is fully automated and only required two single global image-based measurements, unlike other methods that require extraction of morphology-based features. The data used includes 42 synthetically generated pullback pairs, achieving an alignment error of 0.1853 frames per pullback, a rotation error 0.93° and a translation error of 0.0161 mm. In addition, it was also tested on 11 baseline and follow-up, and 10 baseline and post-stent deployment real IVUS pullback pairs from two clinical centres, achieving an alignment error of 4.3±3.9 for the longitudinal registration, and a distance and a rotational error of 0.56±0.323 mm and 12.4°±10.5°, respectively, for the axial registration. Although the performance of the proposed method does not match that of the state-of-the-art, our method relies on computationally lighter steps for its computations, which is crucial in real-time applications. On the other hand, the proposed method performs even or better that the state-of-the-art when considering the axial registration. The results indicate that the proposed method can support clinical decision making and diagnosis based on sequential imaging examinations.

On a P-poor, calcareous soil, three upland cotton (Gossypium hirsutum L.) cultivars (ST 402, ST 405, Zeta 2) were tested for 2 years under three P rates (0, 13.1, 26.2 kg P ha−1). Leaf traits (SPAD values; specific leaf area, SLA; carbon isotope discrimination, Δ; 15N natural abundance, δ15N) and elements (N, P, K, C, Na, Zn) along with arbuscular mycorrhizal (AM) colonisation were measured at first open flower, full bloom and first open boll stages. Phosphorus addition decreased yield, but had no effect on fibre quality, a response attributed to P-induced Zn deficiency, previously reported for cereals. The best-performing cv., ST 405, had high SPAD and SLA, but the lowest P, N and Zn concentrations, an indication of cultivar’s high use efficiency for these nutrients. At full bloom, SPAD was lowest, while SLA was highest. AM increased gradually with growth stages, while N, P, K and Zn concentrations showed an opposite trend, possibly due to a dilution effect. On Mediterranean calcareous soils, P fertilisation should take into account soil Zn levels in order to avoid P–Zn antagonistic relationships, which could impact negatively on yield.

A sufficient and balanced maternal diet is critical to meet the nutritional demands of the developing fetus and to facilitate deposition of fat reserves for lactation. Multiple adaptations occur to meet these energy requirements, including reductions in energy expenditure and increases in maternal food intake. The central nervous system plays a vital role in the regulation of food intake and energy homeostasis and responds to multiple metabolic and nutrient cues, including those arising from the gastrointestinal tract. This review describes the nutrient requirements of pregnancy and the impact of over- and undernutrition on the risk of pregnancy complications and adult disease in progeny. The central and peripheral regulation of food intake is then discussed, with particular emphasis on the adaptations that occur during pregnancy and the mechanisms that drive these changes, including the possible role of the pregnancy-associated hormones progesterone, estrogen, prolactin, and growth hormone. We identify the need for deeper mechanistic understanding of maternal adaptations, in particular, changes in gut-brain axis satiety signaling. Improved understanding of food intake regulation during pregnancy will provide a basis to inform strategies that prevent maternal under- or overnutrition, improve fetal health, and reduce the long-term health and economic burden for mothers and offspring.

Background: coronary computed tomography angiography (CCTA) is a first line non-invasive imaging modality for detection of coronary atherosclerosis. Computational modeling with lipidomics analysis can be used for prediction of coronary atherosclerotic plaque progression. Methods: 187 patients (480 vessels) with stable coronary artery disease (CAD) undergoing CCTA scan at baseline and after 6.2 ± 1.4 years were selected from the SMARTool clinical study cohort (Clinicaltrial.gov Identifiers NCT04448691) according to a computed tomography (CT) scan image quality suitable for three-dimensional (3D) reconstruction of coronary arteries and the absence of implanted coronary stents. Clinical and biohumoral data were collected, and plasma lipidomics analysis was performed. Blood flow and low-density lipoprotein (LDL) transport were modeled using patient-specific data to estimate endothelial shear stress (ESS) and LDL accumulation based on a previously developed methodology. Additionally, non-invasive Fractional Flow Reserve (FFR) was calculated (SmartFFR). Plaque progression was defined as significant change of at least two of the morphological metrics: lumen area, plaque area, plaque burden. Results: a multi-parametric predictive model, including traditional risk factors, plasma lipids, 3D imaging parameters, and computational data demonstrated 88% accuracy to predict site-specific plaque progression, outperforming current computational models. Conclusions: Low ESS and LDL accumulation, estimated by computational modeling of CCTA imaging, can be used to predict site-specific progression of coronary atherosclerotic plaques.

Instability to Tollmien–Schlichting waves is one of the primary routes to transition to turbulence for two-dimensional boundary layers in quiet disturbance environments. Cancellation of Tollmien–Schlichting waves using surface heating was first demonstrated in the experiments of Liepmann et al. (J. Fluid Mech., vol. 118, 1982, pp. 187–200) and Liepmann & Nosenchuck (J. Fluid Mech., vol. 118, 1982, pp. 201–204). Here we consider a similar theoretical formulation that includes the effects of localised (unsteady) wall heating/cooling. The resulting problem is closely related to that of Terent'ev (Prikl. Mat. Mekh., vol. 45, 1981, pp. 1049–1055; Prikl. Mat. Mekh., vol. 48, 1984, pp. 264–272) on the generation of Tollmien–Schlichting waves by a vibrating ribbon, but with thermal effects. The nonlinear receptivity problem based on triple-deck scales is formulated and the linearised version solved both analytically as well as numerically. The most significant result is that the wall heating/cooling function can be chosen such that there is no pressure response to the disturbance, meaning there is no generation of Tollmien–Schlichting waves. Numerical calculations substantiate this with an approximation based on the exact analytical result. Previous numerical studies of the unsteady triple-deck equations have shown difficulties in capturing the convective wave packet that develops in the initial-value problem and we show that these arise from the choice of time steps as well as the range of the Fourier modes taken.

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy.

In the recent years, Bioresorbable Vascular Scaffolds (BVS) for the treatment of atherosclerosis have been introduced. InSilc is a cloud based in silico clinical trial (ISCT) platform for drug-eluting BVS. The platform integrates multidisciplinary and multiscale models predicting the BVS performance. In this study, we present a use case scenario and demonstrate the functioning of the individual modules and of the whole pipeline and the ability to predict BVS short, medium, long-term outcomes.

Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic–pituitary–gonadal (HPG) axis. Kisspeptin is produced by two major populations of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC). These neurons project to and activate gonadotrophin-releasing hormone (GnRH) neurons (acting via the kisspeptin receptor, Kiss1r) in the hypothalamus and stimulate the secretion of GnRH. Gonadal sex steroids stimulate kisspeptin neurons in the RP3V, but inhibit kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC kisspeptin neurons act as the GnRH pulse generator. Due to kisspeptin’s profound effect on the HPG axis, a focus of recent research has been on afferent inputs to kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition. Alternatively, evidence is building for a direct role for kisspeptin in regulating energy balance and metabolism. Kiss1r-knockout (KO) mice exhibit increased adiposity and reduced energy expenditure. Although the mechanisms underlying these observations are currently unknown, Kiss1r is expressed in adipose tissue and potentially brown adipose tissue (BAT) and Kiss1rKO mice exhibit reduced energy expenditure. Recent studies are now looking at the effects of kisspeptin signalling on behaviour, with clinical evidence emerging of kisspeptin affecting sexual behaviour, further investigation of potential neuronal pathways are warranted.

Aim: Current dietary assessment methods are prone to subjective bias, highlighting the demand for an objective marker of fruit and vegetable (F/V) intake. Carotenoids from F/V consumption deposit in skin and adipose tissue, contributing to changes in skin colour. Results from research in females have highlighted positive associations between skin colour assessed by reflectance spectroscopy and F/V intake. The aim of this study was to determine the relationship between (i) F/V intake, (ii) carotenoid intake and skin colour in young Caucasian men. Methods: In this cross-sectional study reflectance spectroscopy was used to quantify skin colour in young Caucasian men. Skin colour was assessed at eight sun-exposed and unexposed body locations. A food frequency questionnaire was administered to assess F/V intake over the past month. Partial correlations were done to assess the associations between skin yellowness, F/V intake (grams) and carotenoid intake (milligrams), both with and without controlling for skin lightness. Results: Carotenoid intake was strongly associated with F/V intake (r = 0.8, p

Climate change affects the Mediterranean region stressing lentil crops during flowering and seed set. Early maturation and drought tolerance are desirable traits in these conditions. Phosphorus (P) is considered to enhance early flowering, maturity and thus yields. Four P rates (0, 30, 60, 90 kg P2O5 ha−1) were applied on four cultivars (Samos, Thessaly, Flip, Ikaria) during two seasons. Growing degree-days (GDD) were calculated for vegetative (V4–5, V7–8) and reproductive stages (R1, R2, R4, R6, R8). At R2 (full bloom) carbon isotope discrimination (Δ) was used to assess water-use efficiency. At R8 (full maturity), the seed weight (SW) was determined by harvest. Cultivars, P and the P × cultivar and P × growth season interactions affected the earliness in reproductive stages; P had no effect on GDD of vegetative stages. Phosphorus both induced earliness (Flip, Thessaly) and delayed maturity (Samos, Ikaria). GDD and SW were negatively correlated for the P × cultivar interaction at R1 (first bloom), R2, R4 (flat pod) and R6 (full pod filling) stages; being the strongest at R1. Negative correlations were evident for the P × growth season interaction at R2, R4 and R6 stages; being the strongest at R4. Cultivars and P did not affect Δ. A proper combination of cultivar and P rate can mitigate lentil yield losses under changing Mediterranean climate.