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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.
The dairy industry has continued to innovate to meet the needs of the consumers' specification of milk at a low price, of good hygienic quality and with rising expectations of animal welfare. The introduction of robotic milking offers the opportunity for the cost effective deployment of novel sensors for a variety of milk analytes. Traditional methods of monitoring health changes in animals are based entirely on the human senses. However, in modern milking systems humans rarely have enough time to see the cows to observe for signs of ill health, the extreme case is that of robotic milking. Novel sensors will allow closed loop control systems where the early detection of deviations from optimal performance will enable the farm manager to make management decisions before damage to potential milk yields is irreversible. Where a biological model already exists, for example, in the prediction of ovulation with milk progesterone analysis, rapid progress is being made towards an automated prediction system. Integrated management systems for dairy cows will not only have the traditional goals of efficient milk production but can also be tuned to reduce polluting outputs of ammonia, phosphorus and methane. The main metabolic markers in milk to be monitored are urea, fat, ketones and protein. The detection of mastitis can be achieved by the development of sensor systems to detect enzyme markers of inflammatory response such as Nagase. Multi-disciplinary research is needed to develop integrated management systems drawing all the different elements of dairy cow management into a single system. The major cause of death in dairy cows is dystocia and monitoring systems are needed to ensure that parturition is better managed.
Sampling for analysis of milk constituents (fat and protein) is a routine procedure on commercial dairy farms. It is assumed that for this procedure a representative sample of whole milk is taken, either as a fractionated sample from the milk meter or as a thoroughly mixed milk sample taken after the milk has been agitated with air in the recording jar. The use of on-line sensors for milk analysis will provide real-time data on which nutritional management decisions can be made according to milk composition. However, there is no recommendation as to the optimum sampling time in an on-line system to obtain a representative sample during the milking process. Ideally sampling should be carried out as early as possible for the analysis to be completed before the milking system is needed for the next cow. It is important to establish within milking variation of milk constituents for an on-line sensing system, especially since fat increases significantly throughout milking. The aims of this study were to determine the within milking variation of urea, acetone, fat and protein and to specify the most appropriate time of sampling within milking to obtain representative concentrations of these constituents and analytes.
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.
Accurate astrometric and photometric calibrations of all-sky photographic surveys, such as the Palomar Quick-V survey and the UK SERC-J survey, digitised for the construction of the Hubble Space Telescope Guide Star Catalog, are of extreme astrophysical value. Their wide range of applications includes, for example, galactic structure, stellar populations, extragalactic studies, and deep sky catalogs for mission planning and telescope operations. The Guide Star Photometric Catalog (GSPC-I, Lasker et al. 1988) provides stellar calibration sequences, placed approximately in the center of each survey plate, with a limiting magnitude of V = 15 mag. The goal of our program is to extend these calibrators to V = 20 mag in the Johnson-Kron-Cousins B, V and R passbands, with an accuracy of 0.05 mag. This is accomplished by taking CCD frames centered on the faintest star of each GSPC-I sequence. Typically, both long and short exposures are acquired in each field in order to link the bright and faint ends of the sequence.
Measurements of precise positions of optical counterparts of extra-galactic radio-sources, with the aim to compare them with VLBI positions, is in progress at Torino Observatory. The Carlsberg Automatic Meridian Circle Catalogue (CAMC) is used for plate reductions. Presently, about 40% of the plate material required to complete the project has been taken and some significant improvements have been made both in the material and the reduction methods. Improvements are also due to the publication of a new volume of the CAMC catalogue that significantly increases the number of stars in the fields.
Ajdovska Jama (The Pagan's Cave) in southeast Slovenia lies within the catchment of the River Sava, a major tributary of the Danube. The site is well known for its Neolithic burials and has been excavated to a high standard on various occasions since 1884. The human remains at the site occurred as distinct clusters of mainly disarticulated bones belonging to at least 31 individuals. Hitherto, dating of the burials has been based on the associated archaeological finds, including a few low-precision radiometric radiocarbon measurements on charred plant material. In the present study, bones from 15 individuals were subsampled for accelerator mass spectrometry (AMS) and stable isotope analyses. These comprised adults and children from 3 of the clusters. The results of the study indicate that the burials all belong to a relatively short time interval, while the stable isotope data indicate a mixed diet based on C3 plant and animal food sources. These interpretations differ somewhat from those of previous researchers. The AMS 14C and stable isotope analyses form part of a wider investigation of dietary and demographic change from the Mesolithic to the Iron Age in the Danube Basin.
The observations by the Compton Gamma Ray Observatory (CGRO) have shown that highly variable and radio-loud quasars emit a significant fraction of their energy in the γ band. According to the Inverse Compton model, the γ-ray emission is due to upscattering of soft (IR-optical-UV) photons by high energy particles. Optical monitoring is thus of great value in providing information on the mechanisms that rule the production of the seed photons for the γ-ray radiation and on the γ-ray emission itself. In particular, detection of variability correlations between optical and γ-ray emissions would be a crucial test for the theoretical predictions.
Since July 1996, 815 new names on features on bodies in the Solar System have been assigned by the WGPSN and approved at the IAU General Assembly in Kyoto in 1997. Of these names, 666 were for Venus, 17 for Mars, 3 for the Moon, 125 for the Galilean satellites, 3 for the Uranian satellite Miranda, and 1 for the minor planet Ida. 71 additional names mostly on Venus have been selected and have been given or are awaiting provisional approval by the IAU Executive Committee (EC). These names are up for final approval at the next IAU General Assembly.
It is with great sadness that we have to report the death on 24 August 1990 of the WG’s President, Harold Masursky, at the age of 66. Dr. Masursky is known for his many contributions in planetary science and for his many years of dedicated work in planetary nomenclature. During the interim until the next IAU General Assembly the IAU Executive Committee has appointed K. Aksnes as Acting President of the WG.
The TOCAMM (TOrino CAgliari Measuring Machine) project undertaken jointly between Torino and Cagliari Astronomical Observatories aimed to convert the old measuring machine ASCORECORD into an automatic and impersonal one. This program is intended to contribute to the link of the HIPPARCOS Catalogue to the ICRS through the determination of precise position of optical counterparts of 80 extragalactic radiosources taken from the IERS list and to investigate the astrometric accuracy of the Guide Star Catalog (version 1 and 2). The calibration test phase, carried out first at the Astronomical Observatory of Torino and after at Cagliari Observatory, where the machine has been now installed, indicate that the available positional accuracy is about 0.5 microns in both x and y coordinates.
We present new X-ray data with an improved position for the supersoft X-ray source RXJ0537.6–7033, and propose a candidate for the optical identification.
The source was initially designated as RXJ0537.7–7034 because there was a high uncertainty in the position, at the edge of the field of the ROSAT PSPC (Orio & Ögelman 1993). It was later observed three more times by the ROSAT PSPC at intervals of approximately 6 months, from the beginning of 1992 to the end of 1993. The change of the name is due to the new, more precise position obtained in these observations. The count rate was 0.021 ± 0.005 count s−1 in the first 1992 observation and remained at the same level in the second 1992 observation. The source was not detected in the first half of 1993, with an upper limit of 0.002 count s−1; finally in 1993 December it was detected with only 0.0035±0.0007 count s−1. It seems therefore to be very variable.
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.