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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: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Metal–insulator–metal (MIM) resonant absorbers comprise a conducting ground plane, a thin dielectric, and thin separated metal top-surface structures. The dielectric SiO2 strongly absorbs near 9 µm wavelength and has correspondingly strong long-wave-infrared (LWIR) dispersion for the refractive index. This dispersion results in multiple absorption resonances spanning the LWIR, which can enhance broad-band sensitivity for LWIR bolometers. Similar considerations apply to silicon nitride Si3N4. TiO2 and AlN have comparatively low dispersion and give simple single LWIR resonances. These dispersion-dependent features for infrared MIM devices are demonstrated by experiment, electrodynamic simulation, and an analytic model based on standing waves.
Coastal ecosystems have been increasingly subjected to poor water quality. Remote sensing has been used to monitor water quality, but few studies have integrated remotely sensed data with compositional and/or abundance data of coral reef taxa. In the present study, fish biomass was assessed along the Jakarta Bay Thousand Island reef system and variation in the biomass of selected fish families related to substrate cover and remotely sensed data. Overall, fish biomass and the biomass of each of the families Acanthuridae, Apogonidae, Caesionidae, Chaetodontidae, Ephippidae, Pomacentridae, Labridae and the subfamily Scaridae were much higher mid- and offshore than inshore. Substrate cover and chlorophyll-a concentrations proved to be significant predictors of spatial variation in fish biomass, suggesting an important impact of reef degradation and eutrophication on reef fish abundance.
Ternary lead chalcogenides, such as PbSxSe1-x, offer the possibility of room-temperature infrared detection with engineered cut-off wavelengths within the important 3-5 micron mid-wave infrared (MWIR) wavelength range. We present growth and characterization of aqueous spray-deposited thin films of PbSSe. Complexing agents in the aqueous medium suppress unwanted homogeneous reactions so that growth occurs only by the heterogeneous reaction on the hydrophilic substrate. The strongly-adherent films are smooth with a mirror-like finish. The films comprise densely packed grains with tens of nm dimensions and a total film thickness of ∼400-500 nm. Measured optical constants reveal absorption out to at least 4.5 μm wavelength and a ∼0.3 eV bandgap intermediate between those of PbS and PbSe. The semiconducting films are p-type with resistivity ∼1 and 85 Ohm-cm at 300 and 80 K, respectively. Sharp x-ray diffraction peaks identify the films as Clausthalite-Galena solid-state solution with a lattice constant that indicates an even mixture of PbS and PbSe. The photoconductive response is observed at both nitrogen and room temperature up to at least 2 kHz chopping frequency.
Established methods of recruiting population controls for case–control studies to investigate gastrointestinal disease outbreaks can be time consuming, resulting in delays in identifying the source or vehicle of infection. After an initial evaluation of using online market research panel members as controls in a case–control study to investigate a Salmonella outbreak in 2013, this method was applied in four further studies in the UK between 2014 and 2016. We used data from all five studies and interviews with members of each outbreak control team and market research panel provider to review operational issues, evaluate risk of bias in this approach and consider methods to reduce confounding and bias. The investigators of each outbreak reported likely time and cost savings from using market research controls. There were systematic differences between case and control groups in some studies but no evidence that conclusions on the likely source or vehicle of infection were incorrect. Potential selection biases introduced by using this sampling frame and the low response rate are unclear. Methods that might reduce confounding and some bias should be balanced with concerns for overmatching. Further evaluation of this approach using comparisons with traditional methods and population-based exposure survey data is recommended.
In August 2015, Public Health England detected an outbreak of Shiga toxin-producing Escherichia coli (STEC) serotype O157:H7 caused by contaminated salad leaves in a mixed leaf prepacked salad product from a national retailer. The implicated leaves were cultivated at five different farms and the zoonotic source of the outbreak strain was not determined. In March 2016, additional isolates from new cases were identified that shared a recent common ancestor with the outbreak strain. A case–case study involving the cases identified in 2016 revealed that ovine exposures were associated with illness (n = 16; AOR 8·24; 95% CI 1·55–39·74). By mapping the recent movement of sheep and lambs across the United Kingdom, epidemiological links were established between the cases reporting ovine exposures. Given the close phylogenetic relationship between the outbreak strain and the isolates from cases with ovine exposures, it is plausible that ovine faeces may have contaminated the salad leaves via untreated irrigation water or run-off from fields nearby. Timely and targeted veterinary and environmental sampling should be considered during foodborne outbreaks of STEC, particularly where ready to eat vegetables and salads are implicated.
This paper presents a probability density function (PDF) form of the population balance equation (PBE) for polysized and polyshaped droplets and solid particles in turbulent flows. A key contribution of this paper lies in the inclusion of an explicit consideration of the inertial effects and the shape of particles in the PDF-PBE formulation. The number density is taken as a function of droplet or particle size (volume) and shape as well as space and time. Potentially, other particle properties could also be included in the formulation. Inertial effects are quantified through the Stokes number, leading to accurate modelling of the different trajectories that are followed by droplets and/or particles with different sizes and shapes. To treat these effects, a new affordable approach is proposed and referred to as the method of Stokes binning. Here, the inertial dispersed elements are accelerated due to fluid dynamic forces associated with an averaged Stokes number in each bin. The model is validated against two data sets. The first data set includes a series of numerical test cases involving the injection of polyshaped droplets ranging in size from 1 to 50
into a turbulent jet resulting in inlet Stokes numbers ranging from 0.03 to 75.2. The second data set consists of an experimental case focusing on the dispersion of 60 and 90
spherical droplets in a turbulent round jet, resulting in inlet Stokes numbers of 53 and 122, respectively. The results confirm the ability of the approach to accurately model the polysized and polyshaped droplet dispersion using as few as eight Stokes bins. This approach has the potential to greatly reduce the computational cost of modelling the evolution of inertial droplets and particles in turbulent flows.
Addition of wavelength selective absorbers on microbolometers tends to increase their thermal mass and slow their infrared response times. Making the bolometric material an integral part of the absorber and minimizing layer thicknesses is one possible way to maintain high detector speeds. Here, we study experimentally the effect on permittivity of adding a layer of semiconducting VOx between two layers of SiO2. Additionally, we investigate theoretically the effect on resonance wavelength of thinning the metal in metal-insulator-metal plasmonic resonant absorbers.
Fifteen confirmed cases and 15 possible cases of Shiga toxin-producing Escherichia coli (STEC) O157 phage type 21/28 were linked to direct contact with lambs at a ‘Lambing Live’ event in the North West of England between 29 March and 21 April 2014. Twenty-one (70%) of the cases were female, 23 (77%) were children aged <16 years, of whom 14 (46%) were in the 0–5 years age group. Five children developed haemolytic uraemic syndrome. Multilocus variable number tandem repeat analysis (MLVA) profiles on 14 human cases were indistinguishable, and 6/10 animal isolates had a MLVA profile identical to the outbreak profile. Whole-genome sequencing analysis revealed that all isolates, both human and animal, fell within a 5-single nucleotide polymorphism cluster indicating the isolates belonged to the same point source. On inspection of the premises, extensive and uncontrolled physical contact between visitors and animals was occuring within the animal pens and during bottle-feeding. Public areas were visibly contaminated with animal faeces. Information to visitors, and the infection control awareness demonstrated by staff, was inadequate. Managing the risk to visitors of STEC O157 infection at animal petting events and open farms requires implementation of stringent control measures by the operator, as outlined in the industry code of practice. Enforcement action is sometimes required to prevent high-risk activities taking place at both permanent and temporary attractions.
A southern sky survey of Hiin the velocity range − 340 km s−1 to + 380 km s−1 has shown that a long filament of H iextends from the Small Magellanic Cloud (SMC) region down to the South Galactic Pole and connects with the long Hifilament discovered recently by Wannier and Wrixon (1972) and van Kuilenberg (1972). There is also some evidence that this continues on the other side of the Magellanic Clouds and crosses the galactic plane at l = 306°. This filament, which follows very closely a great circle over its entire 180° arc across the sky, is given the name ‘The Magellanic Stream’. It may have been produced by gravitational interaction between the SMC and the Galaxy during a close passage (20 kpc) of the SMC some 5 × 108 yr ago, although it is impossible to account for the observed radial velocities along the Stream unless some force other than gravity is invoked to act on the Stream as well.
A southern sky survey of H I in the velocity range — 340 km s−1 to +380 km s−1 has shown that a long filament of H I extends from the Small Magellanic Cloud (SMC) region down to the South Galactic Pole and connects with the long H I filament discovered recently by Wannier and Wrixon (1972) and van Kuilenburg (1972). There is also some evidence that the feature continues on the other side of the Magellanic Clouds and crosses the galactic plane at l = 306°. The whole filament, which follows very closely a great circle over its entire 180° length, is given the name ‘The Magellanic Stream’. It may have been produced by gravitational interaction between the SMC and the Galaxy during a close passage (20 kpc) of the SMC some 5 × 108 yr ago although it is impossible to account for the observed radial velocities along the Stream unless some force other than gravity is invoked to act on the Stream as well.
Transparent conducting thin-films of SnO2: F were grown on preheated glass, Al2O3 coated glass, and quartz substrates by Streaming Process for Electrodeless Electrochemical Deposition (SPEED). Stannic chloride (SnCl4) and ammonium fluoride (NH4F) dissolved in a mixture of deionized water and organic solvents were used as precursors. The preheated substrate temperature was varied between 440 and 500 °C. High quality SnO2:F films were grown at all the substrate temperatures studied. The resulting typical film thickness was 250 nm. X-ray diffraction shows that the grown films are polycrystalline SnO2 with a tetragonal crystal structure. The average optical transmission of the films was around 93% throughout the wavelength range 400 to 1000 nm. The lowest electrical resistivity achieved was 6 × 10-4 Ω-cm. The Hall measurements showed that the film is an n-type semiconductor, with carrier mobility of 8.3 cm2/V-s, and carrier concentration of 1 × 1021 cm-3. The direct bandgap was determined to be 4.0 eV from the transmittance spectrum.
Sponge-related research in Taiwan has primarily focused on natural product exploration. This research has, however, been hampered by a lack of fundamental work on sponge taxonomy and ecology. In the present study, subtidal sponges were photo-recorded in situ and collected by scuba diving at a depth range of 2–20 m from 2009 to 2012 in 16 different sites surrounding the Penghu Archipelago, Taiwan. Sponge samples were identified to the lowest taxonomic level based on skeletal morphology and spicules. A total of 53 species belonging to 24 families and 10 orders were identified in this study. The number of sponge species per site ranged from 0 to 24. The most widely distributed sponge species was Callyspongia (Euplacella) cf. communis (Carter, 1881) followed by Haliclona (Gellius) cymaeformis (Esper, 1794), and Aaptos suberitoides (Brøndsted, 1934). At one location, Chipeiyu, no sponges were observed. Non-metric multidimensional scaling (NMDS) ordination revealed relatively low similarity among most sampling sites. Large- and small-scale hydrological and habitat features are probably responsible for compositional variation of sponge assemblages among groups of sampling sites. Our richness analyses suggest that many more sponge species remain to be discovered in the Penghu Archipelago.
In September 2010, an outbreak of cryptosporidiosis affected members of a swimming club. A cohort study was undertaken to identify the number affected and risk factors for infection. Of 101 respondents, 48 met the case definition for probable cryptosporidiosis. Multivariate analysis demonstrated a strong and highly significant association between illness and attendance at a training session on 13 September 2010 (adjusted odds ratio 28, P < 0·0001). No faecal incidents were reported and pool monitoring parameters were satisfactory. The competitive nature of club swimming requires frequent training and participation in galas, potentially facilitating contamination into other pools and amplification of outbreaks among wider groups of swimmers. There was a lack of awareness of the 2-week exclusion rule among swimmers and coaches, and a high level of underreporting of illness. The study demonstrates the benefits of rapid field epidemiology in identifying the true burden of illness, the source of infection and limiting spread.
A compact spectrometer-on-a-chip featuring a plasmonic molecular interaction region has been conceived, designed, modeled, and partially fabricated. The silicon-on-insulator (SOI) system is the chosen platform for the integration. The low loss of both silicon and SiO2 between 3 and 4 μm wavelengths enables silicon waveguides on SiO2 as the basis for molecular sensors at these wavelengths. Important characteristic molecular vibrations occur in this range, namely the bond stretching modes C-H (Alkynes), O-H (monomeric alcohols, phenols) and N-H (Amines), as well as CO double bonds, NH2, and CN. The device consists of a broad-band infrared LED, photonic waveguides, photon-to-plasmon transformers, a molecular interaction region, dispersive structures, and detectors. Photonic waveguide modes are adiabatically converted into SPPs on a neighboring metal surface by a tapered waveguide. The plasmonic interaction region enhances optical intensity, which allows a reduction of the overall device size without a reduction of the interaction length, in comparison to ordinary optical methods. After the SPPs propagate through the interaction region, they are converted back into photonic waveguide modes by a second taper. The dispersing region consists of a series of micro-ring resonators with photodetectors coupled to each resonator. Design parameters were optimized via electro-dynamic simulations. Fabrication was performed using a combination of photo- and electron-beam-lithography together with standard silicon processing techniques.
Potential transmission of organisms from the environment to patients is a concern, especially in enclosed settings, such as operating rooms, in which there are multiple and frequent contacts between patients, provider's hands, and environmental surfaces. Therefore, adequate disinfection of operating rooms is essential. We aimed to determine the change in both the thoroughness of environmental cleaning and the proportion of environmental surfaces within operating rooms from which pathogenic organisms were recovered.
Prospective environmental study using feedback with UV markers and environmental cultures.
A 1,500-bed county teaching hospital.
Environmental service personnel, hospital administration, and medical and nursing leadership
The proportion of UV markers removed (cleaned) increased from 0.47 (284 of 600 markers; 95% confidence interval [CI], 0.42-0.53) at baseline to 0.82 (634 of 777 markers; 95% CI, 0.77-0.85) during the last month of observations (P < .0001). Nevertheless, the percentage of samples from which pathogenic organisms (gram-negative bacilli, Staphylococcus aureus, and Enterococcus species) were recovered did not change throughout our study. Pathogens were identified on 16.6% of surfaces at baseline and 12.5% of surfaces during the follow-up period (P = .998). However, the percentage of surfaces from which gram-negative bacilli were recovered decreased from 10.7% at baseline to 2.3% during the follow-up period (P = .015).
Feedback using Gram staining of environmental cultures and UV markers was successful at improving the degree of cleaning in our operating rooms.