OBJECTIVES/GOALS: Antibiotic treatment sets the stage for intestinal domination by Candida albicanswhich is necessary for development of invasive disease, but the resources driving this bloom remain poorly defined. We sought to determine these factors in order to design novel prophylaxis strategies for reducing gastrointestinal (GI) colonization. METHODS/STUDY POPULATION: We initially developed a generalizable framework, termed metabolic footprinting to determine the metabolites C. albicanspreferentially uses in the mouse GI tract. After identifying the metabolites C. albicansutilizes, we usedin vitro growth assays in the presence and absence of oxygen to validate out metabolomics findings. We next determined if a probiotic E. coli that utilizes oxygen would reduce C. albicanscolonization compared to a mutant E. coli that could not respire oxygen. Finding that oxygen was a necessary resource, we utilized germ-free mice to determine if Clostridiaspp. known to reduce GI oxygen would prevent C. albicanscolonization. Lastly, we sought to see if 5-aminosalicylic acid (5-ASA) could prevent C. albicanscolonization. RESULTS/ANTICIPATED RESULTS: We found that C. albicans preferentially utilizes simple carbohydrates including fructo-oligosaccharides (e.g., 1-kestose), disaccharides (e.g., β-gentiobiose), and alcoholic sugars (e.g., sorbitol) and is able to grow in vitro on minimal media supplemented with either of these nutrients. However, in the hypoxic environment that is found in the “healthy” colon, C. albicans cannot utilize these nutrients. We next found that pre-colonization in a mouse model with a probiotic E. coli significantly reduced C. albicanscolonization, but the mutant E. coli had no effect on colonization. We next showed that Clostridia supplementation restored GI hypoxia and reduced C. albicanscolonization. Remarkably, we found that 5-ASA significantly reduced GI colonization of C. albicans. DISCUSSION/SIGNIFICANCE: We have shown that C. albicans requires oxygen to colonize the GI tract. Importantly, we found that 5-ASA can prevent an antibiotic mediated bloom of C. albicans by restoring GI hypoxia, which warrants additional studies to determine if 5-ASA can be used as an adjunctive prophylactic treatment in high risk patients.

The presence of thermocapillary (Marangoni) convection in microgravity may help to enhance the heat transfer rate of phase change materials (PCMs) in space applications. We present a three-dimensional numerical investigation of the nonlinear dynamics of a melting PCM placed in a cylindrical container filled with n-octadecane and surrounded by passive air. The heat exchange between the PCM and ambient air is characterized in terms of the Biot number, when the air temperature has a linear profile. The effect of thermocapillary convection on heat transfer and the topology of the melting front is studied by varying the applied temperature difference between the circular supports and the heat transfer through the interface. The evolution of Marangoni convection during the PCM melting leads to the appearance of hydrothermal instabilities. A new mathematical approach for the nonlinear analysis of emerging hydrothermal waves (HTWs) is suggested. Being applied for the first time to the examination of PCMs, this procedure allows us to explore the nature of the coupling between HTWs and heat gain/loss through the interface, and how it changes over time. We observe a variety of dynamics, including standing and travelling waves, and determine their dominant and secondary azimuthal wavenumbers. Coexistence of multiple travelling waves with different wavenumbers, rotating in the same or opposite directions, is among the most fascinating observations.

We conducted the first taphonomic and paleoenvironmental study based on late Pleistocene–Holocene small mammal remains recovered from the famous Mylodon Cave (Cerro Benítez area, Última Esperanza, Chile). Most of the analyzed material came from the extensive excavations made by Earl Saxon in 1976. We also studied late Holocene small mammal samples of the neighboring rock shelter Dos Herraduras 1. Analyzed remains were mostly produced by owls, probably living inside the caves. In Mylodon Cave, the higher values of girdle bones are consistent with a windblown litter. We recorded nine species of rodents, seven cricetids, and two caviomorphs; almost all the identified taxa integrate recent local communities. Late Pleistocene–Holocene assemblages are characterized by the chinchilla rat Euneomys, indicating unforested areas around the caves under cold and moist climatic conditions. Middle Holocene amelioration is reflected by incremental rodent species richness, including the first record of taxa clearly associated with forest (e.g., Abrothrix lanosa). Late Holocene assemblages are markedly stable, indicating local conditions similar to the current (historical) environment. Quaternary rodents from Cerro Benítez area do not indicate abrupt environmental changes during middle–late Holocene, but a progressive trend towards forest increase.

Schizophrenia and mood disorders -including unipolar depression and bipolar disorder-, are severe mental diseases with a highly heterogeneous symptomatology, among which cognitive dysfunction has progressively emerged as a key cornerstone. Patients suffering from these illnesses show significant deficits in different neurocognitive and social cognition domains. These deficits are evident during acute episodes, and in a high percentage of patients persist in periods of recovery, playing a decisive role on functional and clinical outcome. Nowadays, different pharmacological therapies have been tested, obtaining non-conclusive results. In this context, non-pharmacological strategies, such as neurocognitive remediation, have emerged as promising therapeutic intervention. Neurocognitive remediation comprises a program to rehabilitate cognitively impaired subjects, aiming either to restore their cognitive functioning or to compensate them in specific cognitive domains. One evolving approach, beginning to receive attention for its initial promising results, is computerized cognitive training. This technique employs tasks or games that exercise a particular brain function which target specific neural networks in order to improve cognitive functioning through neuroplasticity in a given neural circuit. In this scenario, we report our recent results with neuropersonaltrainer®-MH; a module for neurocognitive remediation consisting in a computerized telerehabilitation platform that enables cognitive remediation programs to be carried out in an intensive and personalized manner. Our group has applied NPTMH® in a pilot study treating patients with early onset psychotic disorder with positive and promising results, involving an improvement in functionality, neurocognition, and social cognition performance. Furthermore, new trials in bipolar disorder and major depressive disorder have been recently started.

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.

Introduction: Insufficient analgesia affects around 50% of emergency department patients. The use of a protocol helps to reduce the risk of oligoanalgesia in this context. Our objective was to describe the feasibility and efficacy of a multimodal analgesia protocol (combining paracetamol, oxycodone, and inhaled low-dose methoxyflurane) initiated by triage nurse. Methods: We performed a prospective, observational study in the emergency department at Grenoble Alpes University Hospital (Grenoble, France) between October 2017 and April 2018. Non severe adult trauma patients with a numerical pain rating scale (NRS) score ≥4 and receiving MEOF were included. The primary efficacy criterion was the proportion of patients with an NRS score ≤3 at 15min post-administration. Pain intensity was measured for 60 min as well as during radiography. Data on adverse events and satisfaction were also recorded. Data are presented as median [interquartile (IQR)] and were compared using non parametric tests. Results: A total of 200 adult patients were included (age: 32 [IQR: 23–49] years; 126 men (63%)). Patients presented at triage with a pain score of 7 [IQR: 6-8]. Sixty-six patients (33%) reported an NRS score ≤3 at 15 min post-administration. The time required to achieve a decrease of at least 2 points in the NRS score was 10 [IQR 5–20] min. The pain intensity was 4 [IQR: 2–5] before radiography and 4 [IQR: 2–6] during radiography. Adverse events were frequent (n = 128, 64%), mainly dizziness. No serious adverse events were reported and 89% of minor adverse events resolved at one hour. Both patients and health care providers reported good levels of satisfaction. Conclusion: The administration of a nurse-driven multimodal analgesia protocol combining paracetamol, oxycodone, and low-dose methoxyflurane was feasible on triage. It rapidly produced long-lasting analgesia in adult trauma patients.

This article presents the results of a program of radiocarbon dating and Bayesian modeling from the precontact Yup'ik site of Nunalleq (GDN-248) in subarctic southwestern Alaska. Nunalleq is deeply stratified, presenting a robust relative chronological framework of well-defined individual house floors abundant in ecofacts suitable for radiocarbon dating. Capitalizing on this potential, we present the results of one of the first applications of Bayesian statistical modeling of radiocarbon data from an archaeological site in the North American Arctic. Using these methods, we demonstrate that it is possible to generate robust, high-resolution chronological models from Arctic archaeology. Radiocarbon dates, procured prior to the program of dating and modeling presented here, suggested an approximately three-century duration of occupation at the site. The results of Bayesian modeling nuance this interpretation. While it is possible that there may have been activity for almost three centuries (beginning in the late fourteenth century), occupation of the dwelling complex, which dominates the site, was more likely to have endured for no more than a century. The results presented here suggest that the occupation of Nunalleq likely encompassed three generations beginning cal AD 1570–1630 before being curtailed by conflict around cal AD 1645–1675.

We consider a specific accumulation event that occurred in January 2002 in western Dronning Maud Land, Antarctica. Snow samples were obtained a few days after accumulation. We combine meteorological analyses and isotopic modelling to describe the isotopic composition of moisture during transport. Backward trajectories were calculated, based on European Centre for Medium-Range Weather Forecasts operational archive data so that the history of the air parcels transporting water vapour to the accumulation site could be reconstructed. This trajectory study showed that the air masses were not (super)saturated along most of the transport path, which is in contrast with assumptions in Lagrangian fractionation models and probably true for most precipitation events in Antarctica. The modelled fractionation along the trajectories was too limited to explain the measured isotopic content of the snow. It is shown that the observed isotopic composition of precipitation resulted from fractionation of initially more depleted water. This lower initial isotopic composition of water vapour might result from atmospheric mixing with more depleted air along the trajectory or from earlier condensation cycles, not captured by the trajectories. This is in accordance with isotope fields resulting from general circulation models, indicating a gradient in isotopic composition from the Equator to Antarctica.

Epidemiological evidence indicates that high consumption of tomatoes and tomato-based products reduces the risk of chronic diseases such as CVD and cancer. Such potential benefits are often ascribed to high concentrations of lycopene present in tomato products. Mainly from the results of in vitro studies, potential biological mechanisms by which carotenoids could protect against heart disease and cancer have been suggested. These include cholesterol reduction, inhibition of oxidation processes, modulation of inflammatory markers, enhanced intercellular communication, inhibition of tumourigenesis and induction of apoptosis, metabolism to retinoids and antiangiogenic effects. However, with regard to CVD, results from intervention studies gave mixed results. Over fifty human intervention trials with lycopene supplements or tomato-based products have been conducted to date, the majority being underpowered. Many showed some beneficial effects but mostly on non-established cardiovascular risk markers such as lipid peroxidation, DNA oxidative damage, platelet activation and inflammatory markers. Only a few studies showed improvement in lipid profiles, C reactive protein and blood pressure. However, recent findings indicate that lycopene could exert cardiovascular protection by lowering HDL-associated inflammation, as well as by modulating HDL functionality towards an antiatherogenic phenotype. Furthermore, in vitro studies indicate that lycopene could modulate T lymphocyte activity, which would also inhibit atherogenic processes and confer cardiovascular protection. These findings also suggest that HDL functionality deserves further consideration as a potential early marker for CVD risk, modifiable by dietary factors such as lycopene.

Documenting past changes in the East Antarctic surface mass balance is important to improve ice core chronologies and to constrain the ice-sheet contribution to global mean sea-level change. Here we reconstruct past changes in the ratio of surface mass balance (SMB ratio) between the EPICA Dome C (EDC) and Dome Fuji (DF) East Antarctica ice core sites, based on a precise volcanic synchronization of the two ice cores and on corrections for the vertical thinning of layers. During the past 216 000 a, this SMB ratio, denoted SMBEDC/SMBDF, varied between 0.7 and 1.1, being small during cold periods and large during warm periods. Our results therefore reveal larger amplitudes of changes in SMB at EDC compared with DF, consistent with previous results showing larger amplitudes of changes in water stable isotopes and estimated surface temperature at EDC compared with DF. Within the last glacial inception (Marine Isotope Stages, MIS-5c and MIS-5d), the SMB ratio deviates by up to 0.2 from what is expected based on differences in water stable isotope records. Moreover, the SMB ratio is constant throughout the late parts of the current and last interglacial periods, despite contrasting isotopic trends.

Motivated by a lack of sufficient local and national computing facilities for computational fluid dynamics simulations, the Affordable Systems Computing Unit (ASCU) was established to investigate low cost alternatives. The options considered have all involved cluster computing, a term which refers to the grouping of a number of components into a managed system capable of running both serial and parallel applications. The present work aims to demonstrate the utility of commodity processors for dedicated batch processing. The performance of the cluster has proved to be extremely cost effective, enabling large three dimensional flow simulations on a computer costing less than £25k sterling at current market prices. The experience gained on this system in terms of single node performance, message passing and parallel performance will be discussed. In particular, comparisons with the performance of other systems will be made. Several medium-large scale CFD simulations performed using the new cluster will be presented to demonstrate the potential of commodity processor based parallel computers for aerodynamic simulation.

We examined the role of the environment in the development of Parkinson's disease (PD). A group of 42 parkinsonians have been compared with a group of 84 matched controls. The epidemiological study (1987-1989) covered the territory of the Community Health Department of Valleyfield, in southern Quebec (Canada). Odds ratio adjusted for age and sex were calculated for seven environmental factors. A decreased risk for PD was associated with residence in rural areas (OR: 0.31; p ≤ 0.05) and residence near industry or mining (OR: 0.15; p ≤ 0.05). An increased risk for PD seems to be associated with occupational exposure to the three metals Mn, Fe and Al (OR: 2.28; p = 0.07) especially when the duration of exposure is longer than 30 years (OR: 13.64; p ≤ 0.05). Other environmental factors not found to be associated with PD were: pesticides manipulation, farm work, industrial work and well water consumption.

The effects of plerocercoids of the cestode Triaenophorus nodulosus infecting the livers of native Eurasian perch Perca fluviatilis and non-native pumpkinseed Lepomis gibbosus was investigated in 17 sites along the Moselle watershed. With a single exception, infected individuals were not observed in the main channel whether or not northern pike Esox lucius, a final host, was present. In ponds where the pike was present, the prevalence of T. nodulosus averaged 86% in Eurasian perch and 15% in pumpkinseed. The parasite was not present at all in ponds when pike were absent. Parasite load, hepatosomatic index (HSI), gonadosomatic index (GSI) and body condition index (CI) were compared between hosts in one site where parasite prevalence and fish abundance was highest. HSI in infected perch was significantly higher than in uninfected perch, whereas no differences in HSI were detected between infected and uninfected pumpkinseed. While perch were more frequently infected and had a greater average parasite load than pumpkinseed, there were no significant differences in either indicator between the two species. Furthermore, no significant differences in GSI or CI were observed between infected and uninfected fish in either species, by either gender or maturity stage. We hypothesize that pumpkinseed is more resistant to the parasite or less likely to feed upon infected copepods than perch.

Since early detection of pathogens and their virulence factors contribute to intervention and control strategies, we assessed the enteropathogens in diarrhoea disease and investigated the link between toxigenic strains of Escherichia coli from stool and drinking-water sources; and determined the expression of toxin genes by antibiotic-resistant E. coli in Lagos, Nigeria. This was compared with isolates from diarrhoeal stool and water from Wisconsin, USA. The new Luminex xTAG GPP (Gastroplex) technique and conventional real-time PCR were used to profile enteric pathogens and E. coli toxin gene isolates, respectively. Results showed the pathogen profile of stool and indicated a relationship between E. coli toxin genes in water and stool from Lagos which was absent in Wisconsin isolates. The Gastroplex technique was efficient for multiple enteric pathogens and toxin gene detection. The co-existence of antibiotic resistance with enteroinvasive E. coli toxin genes suggests an additional prognostic burden on patients.

Since a few years, a new wind measurement instrument has been competing with standard cupanemometers: the LiDAR. The performances of this instrument over complex terrain are stilla matter of debate and this is mainly due to the flow homogeneity assumption made by theinstrument. In this work, the error caused by this hypothesis was evaluated with the helpof OpenFOAM 1.7, MeteoDyn WT 4.0 and WAsP Engineering for a LiDAR deployed on a complexsite covered with dense forest. The assessment of the CFD model firstly revealed thesignificant impact of both the location and nature of the inlet boundary condition.Despite the presence of terrain complexity within a radius of 340 m around the remotesensor, an averaged error of less than 3% was observed, suggesting that the LiDAR is onlyaffected by topographic variations in the immediate vicinity of the scanned volume.

Defect structures in Rubidium Titanyl Phosphate (RTP) crystals (non-doped and doped) grown by the Top Seeded Solution Growth (TSSG) method were characterized using Synchrotron White Beam X-ray Topography. Main defects observed in non-doped crystals are growth sector boundaries while both growth sector boundaries and growth striations are observed in the Nb single doped and (Nb,Yb)-codoped crystals with relatively few linear defects such as dislocations. Results show that the overall crystalline quality is lowered as more doping elements are incorporated. Details of defect distributions are correlated with the growth process to facilitate high quality growth of doped RTP.

For a better understanding of the physical phenomena associated with the appearance of defects in laser welding, a heat and fluid flow model is developed using Comsol Multiphysics®. This first step of the project is focused on the modeling of a static laser shot on a sample of steel. This 2D axially-symmetric configuration is used to study the main physical phenomena related to the creation of the keyhole. This model takes into account the three phases of the matter: the vaporized metal, the liquid phase and the solid base. To track the evolution of these three phases, coupled equations of energy and momentum are solved. The liquid/vapor interface is tracked using the Level-Set method. The calculated velocity and free surface deformation are analyzed. Melt pool shapes are compared with experimental macrographs and the influence of some parameters such as laser power is discussed.

Sampling of the fish community was carried out for 20 years in the Mirgenbach reservoir, in North-Eastern France. The prevalence and the mean intensity of Ligula intestinalis (Cestoda) were analysed in roach (Rutilus rutilus) and silver bream (Blicca bjoerkna) populations, the main two infected species. The aim of this study was to investigate the host switch from roach to silver bream and the consequences of L. intestinalis infestation in silver bream, which is an unusual host for this parasite as Ligula parasitism in silver bream appears to be rare. We analysed in detail the relationships between parasitism index (PI), gonadosomatic index (GSI), perivisceral fat abundance (PFA) and condition index (CI) in the silver bream population. In 1998, prevalence of L. intestinalis highlighted a clear host switch from roach to silver bream. In the silver bream population, young fish were the most severely infected and the impact of plerocercoids appeared to be different depending on the host sex. In male silver bream, plerocercoids drew energy from fat reserves even if GSI was also slightly impacted. On the contrary, in females energy was diverted from gonad maturation rather than from perivisceral fat reserves. No significant difference was observed in terms of CI in either sex.

Magnetic flux emergence as the mechanism leading to the formation of magnetized structures in the solar atmosphere plays a key role in the dynamic of the Sun. Observed as a whole, emerging flux regions show clear signs of twisted structure, bearing the magnetic free energy necessary to power active events. The high resolution observations of the recent solar observatories (e.g. Hinode, SDO) have revealed how intermittent the magnetic field appears and how various active events induced by flux emergence are. Magnetic field reconstructions methods show that the topology of the field in interspot regions presents a serpentine structure, i.e. field lines having successive U and Ω parts. Associated with the appearance of magnetic polarities, a tremendous number of brief small scale brightening are observed in different photospheric and chromospheric lines, e.g. Ellerman Bombs, along with small scale jet-like structures. These events are believed to be the observational signatures of the multiple magnetic reconnections which enable the magnetic field to emerge further up and magnetically structure the corona above active region. Meanwhile a world-wide effort to numerically model the emergence of magnetic field forming solar active region is been carried on. Using different types of physical paradigm – e.g. idealized magnetohydrodynamic model, advanced treatment of the physical equations, data-driven simulations – these numerical experiments highlight how electric currents can build-up during flux emergence, lead to reconnection and thus explain the formation of the different observed transients.