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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.
Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.
Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.
Polygenic risk showed a dose–response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.
Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion – an index of perceived support and morale – was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.
Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507–519)
The fluorescent excitation of long-wavelength X-ray spectra is reviewed with respect to X-ray tube target element, inherent filtration, and optimum kilovoltage. A demountable X-ray tube vacuum spectrograph designed for the determination of the light elements is described. Operation of this instrument with both secondary and combined primary—secondary excitation is evaluated. Examples from the literature are cited to show the feasibility of direct electron excitation of longwavelength spectra.
The purpose of this investigation was to develop a rapid, accurate method of analysis for small amounts of calcium in wolframite concentrates. This analysis is necessary to determine if wolframite concentrates meet the U. S. National Stockpile Specification P-57R2, which limits the calcium content to 0.2 per cent.
Because of the small depth of sample analyzed in fluorescent x-ray spectrography the calcium Kα line intensity was found to be a function of the chemical composition of the calcium-bearing particle as well as the matrix composition. This particle-conn position effect was particularly important in this analysis because the calcium may be present as a carbonate, tungstate, phosphate, etc. Three methods of sample preparation were found to eliminate the variation of calcium Kα intensity with mineralogical occurrences: (1) Reduction in particle size by extensive grinding, (2) chemical fusion wtli sodium carbonate, and (3) solution of the calcium by an add.
Determinations by all three procedures are believed to be accurate to within ± 5 per cent for more than 0.30 per cent calcium and ± 10 per cent at the 0.1-per cent level. The lower limit of detectability is in the order of 0.005-0.01 per cent.
The operating characteristics of a gas-flow proportional counter used in conjunction with a pulse-height analyzer were studied in detail. This detector was found to have a high counting efficiency for calcium Ka radiation, to have a low counting efficiency for overlapping higher order radiation and to have counting stability equivalent to Geiger tubes.
The Bureau of Mines purchased the electron optics, vacuum system, and sample stage assembly for the electron-probe X-ray spectrograph and designed and built the two reflection and two transmission scanning curved-crystal spectrometers. The reflection spectrometers were placed in a vacuum chamber for measurements of long-wavelength X-radiation. Operational characteristics of this spectrograph were determined. A low-alloy stainless-steel sample containing 5 wt. % depleted uranium and a stainless-steel sample containing 20 wt. % gadolinium were analyzed.
A number of procedures for fluorescent X-ray analysis have been introduced to accommodate the samples that are produced from research on the recovery of values from secondary metal sources. For some applications, standards are conveniently available such as those that can be purchased from the National Bureau of Standards. For other applications, secondary standards must be prepared and analyzed by independent methods. The sample preparation procedures vary considerably. For monitoring process efficiency, sample preparation is often kept at a minimum such as simply pouring loose powders into disposable cups. For the most accurate analyses, sample preparatton requires casting the alloys and finishing the surfaces. Matrix correction procedures are employed where concentrations of major constituents vary over wide ranges.
X-ray fluorescence induced by charged particles has been employed in trace element analysis of both animal and human blood, tissue and bone samples. Preparation techniques included microtome slicing and wet digestion in nitric acid, internal chemical standards being used in the latter case.
Most of the specimens arose from a study of interactions between the toxic elements lead and zinc in growing foals; this was motivated by reports of sickness and death in foals raised near lead-zinc smelters. The cause of toxicity in animals from environmental pollution is often attributed to Single factors, whereas in reality interactions among many factors, including a variety of toxic and nutrient trace elements, should be considered.
A variety of spectra are presented and elemental concentrations derived. Agreement between the X-ray data and atomic absorption spectrophotometry is encouraging. The results demonstrate the potential of particle-excited X-ray fluorescenee as a broad-range analytical technique for the study of trace element interactions.
Indigenous women and children experience some of the most profound health disparities globally. These disparities are grounded in historical and contemporary trauma secondary to colonial atrocities perpetuated by settler society. The health disparities that exist for chronic diseases may have their origins in early-life exposures that Indigenous women and children face. Mechanistically, there is evidence that these adverse exposures epigenetically modify genes associated with cardiometabolic disease risk. Interventions designed to support a resilient pregnancy and first 1000 days of life should abrogate disparities in early-life socioeconomic status. Breastfeeding, prenatal care and early child education are key targets for governments and health care providers to start addressing current health disparities in cardiometabolic diseases among Indigenous youth. Programmes grounded in cultural safety and co-developed with communities have successfully reduced health disparities. More works of this kind are needed to reduce inequities in cardiometabolic diseases among Indigenous women and children worldwide.
Infants with prenatally diagnosed CHD are at high risk for adverse outcomes owing to multiple physiologic and psychosocial factors. Lack of immediate physical postnatal contact because of rapid initiation of medical therapy impairs maternal–infant bonding. On the basis of expected physiology, maternal–infant bonding may be safe for select cardiac diagnoses.
This is a single-centre study to assess safety of maternal–infant bonding in prenatal CHD.
In total, 157 fetuses with prenatally diagnosed CHD were reviewed. On the basis of cardiac diagnosis, 91 fetuses (58%) were prenatally approved for bonding and successfully bonded, 38 fetuses (24%) were prenatally approved but deemed not suitable for bonding at delivery, and 28 (18%) were not prenatally approved to bond. There were no complications attributable to bonding. Those who successfully bonded were larger in weight (3.26 versus 2.6 kg, p<0.001) and at later gestation (39 versus 38 weeks, p<0.001). Those unsuccessful at bonding were more likely to have been delivered via Caesarean section (74 versus 49%, p=0.011) and have additional non-cardiac diagnoses (53 versus 29%, p=0.014). There was no significant difference regarding the need for cardiac intervention before hospital discharge. Infants who bonded had shorter hospital (7 versus 26 days, p=0.02) and ICU lengths of stay (5 versus 23 days, p=0.002) and higher survival (98 versus 76%, p<0.001).
Fetal echocardiography combined with a structured bonding programme can permit mothers and infants with select types of CHD to successfully bond before ICU admission and intervention.
Background: When measuring young Duchenne Muscular Dystrophy (DMD) patients’ health-related quality of life (HRQoL), parent-proxy reports are heavily relied on. Therefore, it is imperative that the relationship between parent-proxy and child self-report HRQoL is understood. This study examined the level of agreement between children and their parent-proxy rating of the child’s HRQoL. Methods: We used FOR-DMD clinical trial baseline data. HRQoL, measured using the PedsQL inventory, was reported by 178 parent and child (ages 4 to 7 years) dyads. Intracorrelation coefficients (ICC) measured absolute agreement while paired t-tests determined differences in the average HRQoL ratings between groups. Results: The level of agreement between child and parent-proxy ratings of HRQoL was poor for the generic PedsQL scale (ICC: 0.29) and its subscales; and, similarly low for the neuromuscular disease module (ICC:0.16). On average, parents rated their child’s HRQoL as poorer than the children rated themselves in all scales except for psychosocial and school functioning. Conclusions: Child and parent-proxy HRQoL ratings are discordant in this study sample, as occurs in other chronic pediatric diseases. This should be taken into account when interpreting clinical and research HRQoL findings in this population. Future studies should examine reasons for parents’ perception of poorer HRQoL than that reported by their children.
Prevalence of skin sores and scabies in remote Australian Aboriginal communities remains unacceptably high, with Group A Streptococcus (GAS) the dominant pathogen. We aim to better understand the drivers of GAS transmission using mathematical models. To estimate the force of infection, we quantified the age of first skin sores and scabies infection by pooling historical data from three studies conducted across five remote Aboriginal communities for children born between 2001 and 2005. We estimated the age of the first infection using the Kaplan–Meier estimator; parametric exponential mixture model; and Cox proportional hazards. For skin sores, the mean age of the first infection was approximately 10 months and the median was 7 months, with some heterogeneity in median observed by the community. For scabies, the mean age of the first infection was approximately 9 months and the median was 8 months, with significant heterogeneity by the community and an enhanced risk for children born between October and December. The young age of the first infection with skin sores and scabies reflects the high disease burden in these communities.
The Molonglo Observatory Synthesis Telescope (MOST) is an 18000 m2 radio telescope located 40 km from Canberra, Australia. Its operating band (820–851 MHz) is partly allocated to telecommunications, making radio astronomy challenging. We describe how the deployment of new digital receivers, Field Programmable Gate Array-based filterbanks, and server-class computers equipped with 43 Graphics Processing Units, has transformed the telescope into a versatile new instrument (UTMOST) for studying the radio sky on millisecond timescales. UTMOST has 10 times the bandwidth and double the field of view compared to the MOST, and voltage record and playback capability has facilitated rapid implementaton of many new observing modes, most of which operate commensally. UTMOST can simultaneously excise interference, make maps, coherently dedisperse pulsars, and perform real-time searches of coherent fan-beams for dispersed single pulses. UTMOST operates as a robotic facility, deciding how to efficiently target pulsars and how long to stay on source via real-time pulsar folding, while searching for single pulse events. Regular timing of over 300 pulsars has yielded seven pulsar glitches and three Fast Radio Bursts during commissioning. UTMOST demonstrates that if sufficient signal processing is applied to voltage streams, innovative science remains possible even in hostile radio frequency environments.
The class of radio transients called Fast Radio Bursts (FRBs) encompasses enigmatic single pulses, each unique in its own way, hindering a consensus for their origin. The key to demystifying FRBs lies in discovering many of them in order to identity commonalities – and in real time, in order to find potential counterparts at other wavelengths. The recently upgraded UTMOST in Australia, is undergoing a backend transformation to rise as a fast transient detection machine. The first interferometric detections of FRBs with UTMOST, place their origin beyond the near-field region of the telescope thus ruling out local sources of interference as a possible origin. We have localised these bursts to much better than the ones discovered at the Parkes radio telescope and have plans to upgrade UTMOST to be capable of much better localisation still.
It is well known that some giant extragalactic star-forming regions contain WR stars. D'Odorico, Massey, Rosa and coworkers found many examples in nearby galaxies of giant HII regions whose spectra show that they contain WN, and occasionally, WC stars. The dwarf emission-line galaxies He 2–10 (Allen et al. 1976) and Tol 3 (Kunth & Sargent 1981) have a strong broad emission feature near HeII 4686Å; in the latter object ∼150 WN stars are required to explain the observed equivalent width.
The geodetic IRIS-network is a transatlantic 5-station VLBI-array dedicated to monitor variations of the earth's rotation (e.g. Carter et al., 1985). In a 5 day cycle 14 extragalactic radio sources are observed in regular intervals, covering a GST-range of up to 24 hours, using the MkIII-system in Mode C at 3.6cm (X-band) and 13cm (S-band) wavelength. As this database provides a great potential to monitor source structures and their changes with mas-resolution (the sample contains at least 7 “superluminals”), we have initiated a project to obtain radio maps at both frequencies and to determine, how accurate physical parameters like component flux densities and separations can be measured. Early results are published in Schalinski (1985) and Schalinski et al. (1986). In addition to astrophysical applications, we investigate the influence of structure phases on phase- and group-delay corrections (s. Campbell et al., this vol.).
Side-looking airborne radar (SLAR) imagery obtained in April-May 1974 from the North Slope of Alaska between Barrow and Harrison Bay indicates that tundra lakes can be separated into two classes based on the strength of the radar returns. Correlations between the areal patterns of the returns, limited ground observations on lake depths and water compositions, and information obtained from LANDSAT imagery strongly suggest that areas of fresh-water lakes giving weak returns are frozen completely to the bottom while areas giving strong returns are not. This is a reasonable interpretation inasmuch as the reflection coefficient associated with the high-dielectric-contrast ice-water interface would be roughly twelve times that associated with the low-contrast ice-soil interface. Brackish lakes also give weak returns even when they are not completely frozen. This is the result of the brine present in the lower portion of the ice cover limiting the penetration of the X-band radiation into the ice. The ability to separate tundra lakes rapidly and easily into these two classes via SLAR should be useful in understanding a wide variety of problems.
The deformation of a strain triangle (≈6 km × 8 km × 11 km) located on first-year ice in the Beaufort Sea was observed over a two-week period in March 1971. Significant strain events (≈ 1.5%) were observed to occur during short (≈6 h) time periods. The long-term (one day or more) divergence rate varied between 0.04 and 0.08 × 10−3 h−1. Short-term divergence rates showed values as high as 0.29 × 10−3 h−1. The observed shearing motion indicated that the floes to the east were moving to the south relative to the floes to the west. This agrees with the shear pattern that might be expected considering the location of the station in the Pacific Gyre. Studies of fracture (lead and crack) orientations in the vicinity of the strain triangle indicate reasonable correlations with the orientation of the strain-rate ellipse. A qualitative relation is suggested between the fracture density and the long-term divergence rate. Correlations were also observed between the divergence of the wind field as computed from the surface pressure field and the ice divergence.
A numerical model for three-dimensional, time-dependent glacier flow (Campbell and Rasmussen, 1970) treated the ice as a Newtonian viscous fluid and related its dynamics to two large-scale bulk parameters: the viscosity v determining the ice-to-ice friction, and a basal friction parameter A determining the ice-to-rock friction. The equations were solved using the relatively simple flow law of Bodvarsson (1955) in which the basal shear stress is proportional to volume transport. Recent research suggests that a more realistic basal flow law is one in which the basal shear stress to some lower power (1–3) is either proportional to the vertically averaged velocity (Glen, 1958; Nye, 1960, 1963[a], [b], [c], 1965[a], [b], [c]) or to the ratio of the vertically averaged velocity to glacier thickness (Budd and Jenssen, in press).
In the present study a generalized flow law incorporating all of the above bulk basal flow laws is applied to the Campbell–Rasmussen momentum equation to form a generalized two-dimensional transport equation, which, when combined with the continuity equation, yields a numerically tractable set of equations for three-dimensional, time-dependent glacier flow. Solutions of the model are shown for steady-state flow and surge advance and recovery for a typical valley glacier bed for powers 1, 2, and 3 for each of the basal flow laws for a steady-state climate input and a given ice-to-ice viscosity parameter.
A history of the idea of transporting large icebergs to arid regions to provide a fresh-water source is presented and the problem is considered in four main parts: (1) Location of a supply of icebergs. Only in the Antarctic are supplies of large tabular icebergs available. Data on the size distribution of these icebergs are reviewed and it is concluded that icebergs of almost any desired size can readily be located. (2) Towing. Steady-state towing velocities of different sized icebergs are calculated based on estimates of the drag of the icebergs and the bollard pull of tugs. Because drag increases with velocity squared, large icebergs can only be towed at very slow velocities (<c. 0.5 m/s). However, tugs that can be built within the capabilities of current technology are capable of towing extremely large icebergs. (3) Melting in transit. Calculations of melting indicate that, although melting losses are significant and may be excessive for small icebergs, when large icebergs are towed, large amounts of ice are left when the iceberg arrives at its destination. Towing trajectories, travel times, and ice delivery rates are calculated for optimum routes between the Amery Ice Shelf and Western Australia (A–A) and the Ross Ice Shelf and the Atacama Desert (R–A). Forces included in these calculations are towing, air, water, gradient current and Coriolis. Transit times exceed 107 d (A–A) and 145 d (R–A) with over 50% of the initial ice delivered. (4) Economic feasibility. After total towing charges are paid, it is possible to deliver ice to Western Australia for 1.3 mills/m3 of water and to the Atacama Desert region for 1.9 mills/m3. These costs are appreciably less than the expected price of water delivered at these locations (8 mills/m3). The water delivered by the operation of one super-tug alone would irrigate 16 000 km2. Problems related to both iceberg transport and processing are reviewed and although substantial problems do exist, they appear to be within the capabilities of current technology.
It is suggested that the overall idea is indeed feasible and should be explored further by specific groups of experts.