Background Folate and other one-carbon metabolism nutrients are essential to enable DNA methylation to occur, but the extent to which their dietary intake influences methylation in adulthood is unclear. Objective We assessed associations between dietary intake of these nutrients and DNA methylation in peripheral blood, overall and at specific genomic locations. Design We conducted a cross-sectional study using baseline data and samples from 5186 adult participants in the Melbourne Collaborative Cohort Study (MCCS). Nutrient intake was estimated from a food-frequency questionnaire. DNA methylation was measured by using the Illumina Infinium HumanMethylation450 BeadChip array (HM450K). We assessed associations of intakes of folate, riboflavin, vitamins B-6 and B-12, methionine, choline, and betaine with methylation at individual cytosine-guanine dinucleotides (CpGs), and with median (genome-wide) methylation across all CpGs, CpGs in gene bodies, and CpGs in gene promoters. We also assessed associations with methylation at long interspersed nuclear element 1 (LINE-1), satellite 2 (Sat2), and Arthrobacter luteus restriction endonuclease (Alu) repetitive elements for a subset of participants. We used linear mixed regression, adjusting for age, sex, country of birth, smoking, energy intake from food, alcohol intake, Mediterranean diet score, and batch effects to assess log-linear associations with dietary intake of each nutrient. In secondary analyses, we assessed associations with low or high intakes defined by extreme quintiles. Results No evidence of log-linear association was observed at P < 10-7 between the intake of one-carbon metabolism nutrients and methylation at individual CpGs. Low intake of riboflavin was associated with higher methylation at CpG cg21230392 in the first exon of PROM1 (P = 5.0 × 10-8). No consistent evidence of association was observed with genome-wide or repetitive element measures of methylation. Conclusion Our findings suggest that dietary intake of one-carbon metabolism nutrients in adulthood, as measured by a food-frequency questionnaire, has little association with blood DNA methylation. An association with low intake of riboflavin requires replication in independent cohorts. This study was registered at http://www.clinicaltrials.gov as NCT03227003.

BackgroundMutations in the X-linked gene filamin A (FLNA), encoding the actin-binding protein FLNA, cause a wide spectrum of connective tissue, skeletal, cardiovascular and/or gastrointestinal manifestations. Males are typically more severely affected than females with common pre- or perinatal death.Case presentationWe provide a genotype- and phenotype-oriented literature overview of FLNA hemizygous mutations and report on two live-born male FLNA mutation carriers. Firstly, we identified a de novo, missense mutation (c.238C > G, p.(Leu80Val)) in a five-year old Indian boy who presented with periventricular nodular heterotopia, increased skin laxity, joint hypermobility, mitral valve prolapse with regurgitation and marked facial features (e.g. a flat face, orbital fullness, upslanting palpebral fissures and low-set ears). Secondly, we identified two cis-located FLNA mutations (c.7921C > G, p.(Pro2641Ala); c.7923delC, p.(Tyr2642Thrfs*63)) in a Bosnian patient with Ehlers-Danlos syndrome-like features such as skin translucency and joint hypermobility. This patient also presented with brain anomalies, pectus excavatum, mitral valve prolapse, pulmonary hypertension and dilatation of the pulmonary arteries. He died from heart failure in his second year of life.ConclusionsThese two new cases expand the list of live-born FLNA mutation-positive males with connective tissue disease from eight to ten, contributing to a better knowledge of the genetic and phenotypic spectrum of FLNA-related disease.

An adequately functionally located traffic infrastructure is an important factor in the mobility of people because it affects the quality of traffic, safety and efficiency of carrying out transportation activities. Locating a roundabout on an urban network is an imperative for road engineering to address traffic problems such as reduction of traffic congestion, enhancement of security and sustainability, etc. Therefore, this paper evaluates potential locations for roundabout construction using Rough BWM (Best Worst Method) and Rough WASPAS (Weighted Aggregated Sum Product Assessment) models. Determination of relative criterion weights on the basis of which the potential locations were evaluated was carried out using the Rough BWM method. In this paper, in order to enable the most precise consensus for group decision-making, a Rough Hamy aggregator has been developed. The main advantage of the Hamy mean (HM) operator is that it can capture the interrelationships among multi-input arguments and can provide DMs more options. Until now, there is no research based on HM operator for aggregating imprecise and uncertain information. The obtained indicators are described through eight alternatives. The results show that the fifth and sixth alternatives are the locations that should have a priority in the construction of roundabouts from the perspective of sustainable development, which is confirmed throughout changes of parameter k and with comparing to other methods in the sensitivity analysis.

This paper deals with the Differential Evolution (DE) based method for identification of the heat equation parameters applied for the estimation of a bare overhead conductor`s temperature. The parameters are determined in the optimization process using a dynamic model of the conductor; the measured environmental temperature, solar radiation and wind velocity; the current and temperature measured on the tested overhead conductor; and the DE, which is applied as the optimization tool. The main task of the DE is to minimise the difference between the measured and model-calculated conductor temperatures. The conductor model is relevant and suitable for the prediction of the conductor temperature, as the agreement between measured and model-calculated conductor temperatures is exceptional, where the deviation between mean and maximum measured and model-calculated conductor temperatures is less than 0.03 °C.

Introduction: Juvenile systemic sclerosis is an orphan disease. Currently, the majority of juvenile systemic sclerosis cohort studies are retrospective in design without standardized assessment. This study was conducted prospectively to investigate the difference in manifestations of limited cutaneous juvenile systemic sclerosis and diffuse cutaneous juvenile systemic sclerosis subtypes. An additional aim was to compare these data to other juvenile systemic sclerosis cohorts and a large adult systemic sclerosis cohort. Methods: Patients fulfilling the Paediatric Rheumatology European Society juvenile systemic sclerosis classification criteria were included. Clinical characteristics and patient-related outcomes were assessed. Results: In all, 88 patients with a mean disease duration of 3.5 years were enrolled, 72.5% with diffuse cutaneous juvenile systemic sclerosis with a mean modified Rodnan Skin score of 18 and 27.5% with limited cutaneous juvenile systemic sclerosis with mean modified Rodnan Skin score of 9. The mean age at the onset of Raynaud’s and first non-Raynaud’s symptoms was similar in both groups, approximately 9 and 10.5 years. Active digital tip ulcerations were present in 29% diffuse cutaneous juvenile systemic sclerosis and none in the limited cutaneous juvenile systemic sclerosis subjects (p = 0.005). Of those with cardiopulmonary testing, 3% of diffuse cutaneous juvenile systemic sclerosis and 23% of limited cutaneous juvenile systemic sclerosis group had cardiac involvement (p = 0.015), and 41% diffuse cutaneous juvenile systemic sclerosis and 22% of the limited cutaneous juvenile systemic sclerosis group had pulmonary involvement (p = 0.009). Physician global disease damage assessment was higher in the diffuse cutaneous juvenile systemic sclerosis group compared to the limited cutaneous juvenile systemic sclerosis group: 35 and 15 (p = 0.021). Discussion: The majority of this international juvenile systemic sclerosis cohort had diffuse cutaneous juvenile systemic sclerosis (72.5%) with more frequent vascular and pulmonary involvement compared to the limited cutaneous group, who had increased cardiac involvement. Our cohort reflects prior findings of published juvenile systemic sclerosis cohorts and emphasizes a difference in the presentation compared to adult-onset systemic sclerosis.

Production of biogas and utilization of the resulting digestates as fertilizers has been increasing in Europe in the last few decades. Depending on the feedstock used for the anaerobic digestion process, these organic fertilizers may be a source of different pollutants, such as trace metals. When applied to soils, digestates may influence the natural metal content and enhance the release of metals to the environment since they can be rich in different trace metals and are usually rich in dissolved organic matter. This study focused on investigating metal presence, seasonal variability of their soluble forms and crop uptake in a two-year field experiment, using two different biogas digestates as fertilizers. The use of digestates as fertilizers was compared to cattle manure, mineral fertilizer and a control without fertilizer addition, with respect to the presence and distribution of the trace metals Cd, Cu, Zn, Ni, Cr, Mn and Mo, as well as Al in the soil and plant. The results of the study showed that both biogas digestates have caused a 10 to 20 % increase in the total soil concentration of Ni, Cd and Cr compared to control plots without fertilizer addition. Application of biogas digestates had only a minor effect on metal uptake in plants. Overall, the selected application rate of 100 kg/ha of plant available nitrogen has had little effect on plant metal uptake and crop quality and the use of biogas digestates was comparable to the use of animal manure.

Along with exciting visions for 5G communications and the Tactile Internet, the networking requirement of attaining extremely low end-to-end latency has appeared. While network devices are typically equipped with buffers to counteract packet loss caused by short-lived traffic bursts, the more those buffers get filled, the more delay is added to every packet passing through. In this paper, we develop congestion avoidance methods that harness the power of fully programmable data-planes. The corresponding programmable switches, through languages such as P4, can be programmed to gather and react to important packet meta-data, such as queue load, while the data packets are being processed. In particular, we enable P4 switches to (1) track processing and queuing delays of latency-critical flows and (2) react immediately in the data-plane to congestion by rerouting the affected flows. Through a proof-of-concept implementation in emulation and on real hardware, we demonstrate that a data-plane approach reduces average and maximum delay, as well as jitter, when compared to non-programmable approaches.

Controlling physical machinery and processes is at the core of production automation. However, challenged by inflexibility, automation and control is evaluating to outsource this control to resourceful cloud environments. While this enables to derive better control through a plethora of measurements, it challenges the control quality through delay introduced through networks. In this paper, we show how to unify control and communication by offloading delay sensitive control tasks from the cloud to local network elements --- a previously unexplored area for in-network processing --- enabling both, ultra-high quality-of-control and scalable orchestration through cloud environments. Our implementation demonstrates how we combine state of the art control with communication. We achieve this by expressing the control and the datapath in P4 which we synthesize to BPF programs that we execute in XDP environments on Netronome SmartNICs. Further, we highlight the demands of control towards communication to build more involved and complex in-network controllers.

While traffic signals, signs, and road markings provide explicit guidelines for those operating in and around the roadways, some decisions, such as determinations of “who will go first,” are made by implicit negotiations between road users. In such situations, pedestrians are today often dependent on cues in drivers’ behavior such as eye contact, postures, and gestures. With the introduction of more automated functions and the transfer of control from the driver to the vehicle, pedestrians cannot rely on such non-verbal cues anymore. To study how the interaction between pedestrians and automated vehicles (AVs) might look like in the future, and how this might be affected if AVs were to communicate their intent to pedestrians, we designed an external vehicle interface called automated vehicle interaction principle (AVIP) that communicates vehicles’ mode and intent to pedestrians. The interaction was explored in two experiments using a Wizard of Oz approach to simulate automated driving. The first experiment was carried out at a zebra crossing and involved nine pedestrians. While it focused mainly on assessing the usability of the interface, it also revealed initial indications related to pedestrians’ emotions and perceived safety when encountering an AV with/without the interface. The second experiment was carried out in a parking lot and involved 24 pedestrians, which enabled a more detailed assessment of pedestrians’ perceived safety when encountering an AV, both with and without the interface. For comparison purposes, these pedestrians also encountered a conventional vehicle. After a short training course, the interface was deemed easy for the pedestrians to interpret. The pedestrians stated that they felt significantly less safe when they encountered the AV without the interface, compared to the conventional vehicle and the AV with the interface. This suggests that the interface could contribute to a positive experience and improved perceived safety in pedestrian encounters with AVs – something that might be important for general acceptance of AVs. As such, this topic should be further investigated in future studies involving a larger sample and more dynamic conditions.

Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), are affecting a huge percentage of the world’s population with mortality rates exceeding those of lung cancer and breast cancer combined. The major challenge is the number of patients who are incorrectly diagnosed. To address this, we developed an expert diagnostic system that can differentiate among patients with asthma, COPD or a normal lung function based on measurements of lung function and information about patient’s symptoms. To develop accurate classification algorithms, data from 3657 patients were used and then independently verified using data from 1650 patients collected over a period of two years. Our results demonstrate that the expert diagnostic system can correctly identify patients with asthma and COPD with sensitivity of 96.45% and specificity of 98.71%. Additionally, 98.71% of the patients with a normal lung function were correctly classified, which contributed to a 49.23% decrease in demand for conducting additional tests, therefore decreasing financial cost.

Abstract Orchiectomy is often employed in zootechnical activities with the main objective of carcass improvement; therefore, the search for alternatives that minimize surgical trauma, operative time and mainly decrease operating costs is pertinent. The nylon clamp is a tensile strength device, well tolerated by the body and inexpensive. It has been used as a hemostatic method in several surgical procedures. The aim of this study was to evaluate the operability and functionality of this device for the preliminary hemostasis of the spermatic cord in the open orchiectomy, comparing it to the surgical nylon thread. Twenty male pigs were divided into 2 experimental groups: GI (clamp - 10 animals) and GII (surgical nylon thread - 10 animals). The surgical time, the degree of hemostasis, the size of the incision, the presence or absence of edema and secretions, besides the weight gain were evaluated. For analysis of inflammatory response, fibrinogen was assessed. Compared to surgical nylon, the clamps presented advantages over surgical time and blood loss. It was concluded that the use of nylon clamps for hemostasis of the spermatic cords of pigs submitted to orchiectomies reduced the total time of surgeries, as well as hemorrhages, when compared to hemostasis with nylon thread. Furthermore, weight gain and induction of inflammatory response were not influenced by the hemostasis method used.