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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Modern baleen whales (Mysticeti), the largest animals on Earth, arose from small ancestors around 36.4 million years ago (Ma). True gigantism is thought to have arisen late in mysticete history, with species exceeding 10 m unknown prior to 8 Ma. This view is challenged by new fossils from Seymour Island (Isla Marambio), Antarctica, which suggest that enormous whales once roamed the Southern Ocean during the Late Eocene (c. 34 Ma). The new material hints at an unknown species of the archaic mysticete Llanocetus with a total body length of up to 12 m. The latter is comparable to that of extant Omura's whales (Balaenoptera omurai Wada et al. 2003), and suggests that gigantism has been a re-occurring feature of mysticetes since their very origin. Functional analysis including sharpness and dental wear implies an at least partly raptorial feeding strategy, starkly contrasting with the filtering habit of living whales. The new material markedly expands the size range of archaic mysticetes, and demonstrates that whales achieved considerable disparity shortly after their origin.
Inappropriate use of antibiotics is contributing to a serious antimicrobial resistance problem in Asian hospitals. Despite resource constraints in the region, all Asian hospitals should implement antimicrobial stewardship (AMS) programs to optimize antibiotic treatment, improve patient outcomes, and minimize antimicrobial resistance. This document describes a consensus statement from a panel of regional experts to help multidisciplinary AMS teams design programs that suit the needs and resources of their hospitals. In general, AMS teams must decide on appropriate interventions (eg, prospective audit and/or formulary restriction) for their hospital, focusing on the most misused antibiotics and problematic multidrug-resistant organisms. This focus is likely to include carbapenem use with the goal to reduce carbapenem-resistant gram-negative bacteria. Rather than initially trying to introduce a comprehensive, hospital-wide AMS program, it would be practical to begin by pilot testing a simple program based on 1 achievable core intervention for the hospital. AMS team members must work together to determine the most suitable AMS interventions to implement in their hospitals and how best to put them into practice. Continuous monitoring and feedback of outcomes to the AMS teams, hospital administration, and prescribers will enhance sustainability of the AMS programs.
Ultrasound (US) detects synovitis more accurately than clinical examination (CE) in people with rheumatoid arthritis (RA). This review aimed to investigate the use of US, compared to CE alone, in treatment strategies for RA, and to estimate its potential to be cost-effective in making treatment decisions.
A systematic review was conducted of studies: investigating RA treatment response or strategies that compared US with CE-assessed synovitis; and of tapering RA treatment (1). A model was constructed to investigate the potential cost-effectiveness of US in (i) selecting patients suitable for treatment tapering; and (ii) avoiding treatment escalation (2).
Seven prospective cohort studies suggested US-detected synovitis was significantly associated with a treatment response or tapering failure, whereas in most cases clinical examination alone was not. Two randomized controlled trials (RCTs) identified suggested that US added to the Disease Activity Index (DAS)-based treatment strategies but did not significantly improve primary outcomes, but was associated with improved rate of DAS remission. The evidence showed that some patients (proportions varied widely) who had achieved low disease activity could have treatment tapered, with no, or little, short-term harm to the patient.
The model estimated that an average reduction of 2.5 percent in the costs of biological disease-modifying anti-rheumatic drug (bDMARDs) was sufficient to cover the costs of performing US every three months. This value increased to 4 percent and 13 percent for the costs of conventional disease-modifying anti-rheumatic drug (cDMARDs) depending on the assumed regimen.
Use of US to monitor synovitis could potentially be a cost-effective approach, given that low proportions of patients for whom clinicians consider amending treatment, would need to taper treatment, or remain on therapy without escalation. US could provide clinicians with more confidence in reducing the drug burden. However, there is considerable uncertainty in this conclusion due to lack of robust data relating to key parameters.
Meltwater intrusions of glacial origin complicate the operation of a coalmine situated approximately 200 m below the bed of Gruvefonna ice cap, Svalbard. The magnitude of this water input is expected to increase with the intended enlargement of the mine. The current praxis, evacuation of the water by pumping, is an expensive undertaking and prompts the investigation of alternative solutions. The evaluation of different options requires reliable values of the total volume and the input rate of the water to be drained. To quantify the melt rate at the glacier surface, we applied a distributed temperature-index model. The model parameters were calibrated using mass-balance measurements performed at Gruvefonna during the 2003 ablation season. The water discharge in the mine during the same period was derived from records of the pump rate. Comparing the records of modelled melt and measured discharge reveals an efficient hydraulic connection between the glacier surface and the mine. The total discharge volume in the mine over the 2003 melt season was about 2.8 × 106m3, exceeding significantly the total melt- and rainwater production on the glacier surface directly above the mine (1.2 × 106m3). This implies that the mine discharge receives contributions from a larger surface area. Based on the distribution of hydraulic potential at the glacier bed, we estimate this contributing area. In a number of scenarios, we calculate the amount of meltwater intrusions for several steps of the planned mine enlargement.
Conventional and reference-surface mass-balance data from Gulkana and Wolverine Glaciers, Alaska, USA, are used to address the questions of how rapidly these glaciers are adjusting (or ‘responding’) to climate, whether their responses are stable, and whether the glaciers are likely to survive in today’s climate. Instability means that a glacier will eventually vanish, or at least become greatly reduced in volume, if the climate stabilizes at its present state. A simple non-linear theory of response is presented for the analysis. The response of Gulkana Glacier is characterized by a timescale of several decades, but its stability and therefore its survival in today’s climate are uncertain. Wolverine seems to be responding to climate more slowly, on the timescale of one to several centuries. Its stability is also uncertain, but a slower response time would make it more susceptible to climate changes.
Information about glacier volume and ice thickness distribution is essential for many glaciological applications, but direct measurements of ice thickness can be difficult and costly. We present a new method that calculates ice thickness via an estimate of ice flux. We solve the familiar continuity equation between adjacent flowlines, which decreases the computational time required compared to a solution on the whole grid. We test the method on Columbia Glacier, a large tidewater glacier in Alaska, USA, and compare calculated and measured ice thicknesses, with favorable results. This shows the potential of this method for estimating ice thickness distribution of glaciers for which only surface data are available. We find that both the mean thickness and volume of Columbia Glacier were approximately halved over the period 1957–2007, from 281 m to 143 m, and from 294 km3 to 134 km3, respectively. Using bedrock slope and considering how waves of thickness change propagate through the glacier, we conduct a brief analysis of the instability of Columbia Glacier, which leads us to conclude that the rapid portion of the retreat may be nearing an end.
A mass-balance model using upper-air meteorological data for input was calibrated with surface mass balance measured mainly during 1977–78 at 67 sites on Columbia Glacier, Alaska, between 135 and 2645 m a.s.l. Root-mean-square error, model vs measured, is 1.0 m w.e. a−1, with r2 = 0.88. A remarkable result of the analysis was that both precipitation and the factor in the positive degree-day model used to estimate surface ablation were constant with altitude. The model was applied to reconstruct glacier-wide components of surface mass balance over 1948–2007. Surface ablation, 4 km3 ice eq. a−1 (ice equivalent), has changed little throughout the period. From 1948 until about 1981, when drastic retreat began, the surface mass balance was positive but changes in glacier geometry were small, so the positive balance was offset by calving, ∼0.9 km3 ice eq. a−1 . During retreat, volume loss of the glacier accounted for 92% of the iceberg production. Calving increased to ∼4.3 km3 ice eq. a−1 from 1982 to 1995, and after that until 2007 to ∼8.0 km3 ice eq. a−1, which was about twice the loss by surface ablation, whereas prior to retreat it was only about a quarter as much. Calving is calculated as the difference between glacier-wide surface mass balance and geodetically determined volume change.
Glaciers on King George Island, Antarctica, have shown retreat and surface lowering in recent decades, concurrent with increasing air temperatures. A large portion of the glacier perimeter is ocean-terminating, suggesting possible large mass losses due to calving and submarine melting. Here we estimate the ice discharge into the ocean for the King George Island ice cap. L-band synthetic aperture radar images covering the time-span January 2008 to January 2011 over King George Island are processed using an intensity-tracking algorithm to obtain surface velocity measurements. Pixel offsets from 40 pairs of radar images are analysed and inverted to estimate a weighted average surface velocity field. Ice thicknesses are derived from simple principles of ice flow mechanics using the computed surface velocity fields and in situ thickness data. The maximum ice surface speeds reach >225 m a-1, and the total ice discharge for the analysed flux gates of King George Island is estimated to be 0.720 ± 0.428 Gt a−1, corresponding to a specific mass loss of 0.64 ± 0.38 m w.e. a-1 over the area of the entire ice cap (1127 km2).
This paper re-examines the problem of the flow of a fluid of finite depth over two Gaussian-shaped obstructions on the stream bed. A weakly nonlinear analysis in the form of the Korteweg–de Vries equation is used to compare with the results of the fully nonlinear problem. The main focus is to find waveless subcritical solutions, and contours showing the obstruction height and separation values that result in waveless solutions are found for different Froude numbers and different obstruction widths.
Oxyspirura petrowi is a heteroxenous parasitic nematode that has been reported in high prevalences from birds in the Order Galliformes experiencing population declines in the USA. There is a paucity of information regarding the natural history O. petrowi, including the life cycle and effects of infection on wild bird populations. In order to study the life cycle of this parasite, we collected plains lubber grasshoppers (Brachystola magna) from a field location in Mitchell County, Texas. We found third-stage larvae (L3) in 37.9% (66/174) B. magna. We determined that they were O. petrowi through morphological comparison of L3 from experimentally infected Acheta domesticus and by sequence analysis. Then, we showed that B. magna are a potential intermediate hosts for O. petrowi infections in northern bobwhites (Colinus virginianus) in a laboratory setting by experimental infection. We first detected shedding of eggs in feces using a fecal float technique 52 days post infection. In addition, we recovered 87 O. petrowi from experimentally infected northern bobwhites. Although we detected shedding in feces, recovery of eggs was low (>5 eggs/g). Future work is needed to understand shedding routes and shedding patterns of northern bobwhites infected with O. petrowi.
We examine a problem in which a line sink causes a disturbance to an otherwise uniform flowing stream of infinite depth. We consider the fully non-linear problem with the inclusion of surface tension and find the maximum sink strength at which steady solutions exist for a given stream flow, before examining non-unique solutions. The addition of surface tension allows for a more thorough investigation into the characteristics of the solutions. The breakdown of steady solutions with surface tension appears to be caused by a curvature singularity as the flow rate approaches the maximum. The non-uniqueness in solutions is shown to occur for a range of parameter values in all cases with non-zero surface tension.
The excavation of a large circular dished earthwork near Carnforth,
North Lancashire, in 1982, has revealed a substantial Bronze Age funerary
monument. The earliest structure was a sub-rectangular enclosure of
limestone boulders dated to c. 1740–1640 BC cal. and
associated with parts of two poorly preserved inhumation burials lying on
the previously cleared ground surface. Both burials were accompanied by
typologically early metalwork. The central inhumation was associated with
a flat axe and dagger, suggesting an individual of high status as well as
providing an important link between the early stages of development of
both bronze types. The subsequent overlying cairn of smaller stones
included eleven fairly discrete concentrations of inhumed bone, and seven
of cremated bone and pottery. All this material was extremely
fragmentary, and was probably derived from later re-use of the
There are insufficient data from nationwide surveys on the prevalence of specific psychotic disorders and associated co-morbidities.
The 2010 Australian national psychosis survey used a two-phase design to draw a representative sample of adults aged 18–64 years with psychotic disorders in contact with public treatment services from an estimated resident population of 1 464 923 adults. This paper is based on data from 1642 participants with an International Classification of Diseases (ICD)-10 psychotic disorder. Its aim is to present estimates of treated prevalence and lifetime morbid risk of psychosis, and to describe the cognitive, physical health and substance use profiles of participants.
The 1-month treated prevalence of psychotic disorders was 3.10 cases per 1000 population aged 18–64 years, not accounting for people solely accessing primary care services; lifetime morbid risk was 3.45 per 1000. Mean premorbid intelligence quotient was approximately 0.5 s.d.s below the population mean; current cognitive ability (measured with a digit symbol coding task) was 1.6 s.d.s below the population mean. For both cognitive tests, higher scores were significantly associated with better independent functioning. The prevalence of the metabolic syndrome was high, affecting 60.8% of participants, and pervasive across diagnostic groups. Of the participants, two-thirds (65.9%) were current smokers, 47.4% were obese and 32.4% were sedentary. Of the participants, half (49.8%) had a lifetime history of alcohol abuse/dependence and 50.8% lifetime cannabis abuse/dependence.
Our findings highlight the need for comprehensive, integrative models of recovery to maximize the potential for good health and quality of life for people with psychotic illness.
The subcritical flow of a stream over a bottom obstruction or depression is considered with particular interest in obtaining solutions with no downstream waves. In the linearised problem this can always be achieved by superposition of multiple obstructions, but it is not clear whether this is possible in a full nonlinear problem. Solutions computed here indicate that there is an effective nonlinear superposition principle at work as no special shape modifications were required to obtain wave-cancelling solutions. Waveless solutions corresponding to one or more trapped waves are computed at a range of different Froude numbers and are shown to provide a rather elaborate mosaic of solution curves in parameter space when both negative and positive obstruction heights are included.
In this paper we report on the fabrication and characterization of GaN diodes (Schottky and p-n junctions) grown by plasma assisted MBE. We observed that Schottky diodes improve both in reverse as well as forward bias when deposited on 5 μm thick HVPE n+-GaN/sapphire instead of bare sapphire substrates. These improvements are attributed to the reduction of disloctions in the MBE homoepitaxially grown GaN. Similar benefits are observed in the reverse bias of the p-n junctions which according to EBIC measurements are attributed to the reduction of etch pits in the MBE grown p-GaN.
Potential crop yield loss due to early-season weed competition is an important risk associated with postemergence weed management programs. WeedSOFT is a weed management decision support system that has the potential to greatly reduce such risk. Previous research has shown that weed emergence time can greatly affect the accuracy of corn yield loss predictions by WeedSOFT, but our understanding of its predictive accuracy for soybean yield loss as affected by weed emergence time is limited. We conducted experiments at several sites across the Midwestern United States to assess accuracy of WeedSOFT predictions of soybean yield loss associated with mixed-species weed communities established at emergence (VE), cotyledon (VC), first-node (V1), or third-node (V3) soybean. Weed communities across research sites consisted mostly of annual grass species and moderately competitive annual broadleaf species. Soybean yield loss occurred in seven of nine site-years for weed communities established at VE soybean, four site-years for weed communities established at VC soybean, and one site-year for weed communities established at V1 soybean. No soybean yield loss was associated with weed communities established at the V3 stage. Nonlinear regression analyses of predicted and observed soybean yield data pooled over site-years showed that predicted yields were less than observed yields at all soybean growth stages, indicating overestimation of soybean yield loss. Pearson correlation analyses indicated that yield loss functions overestimated the competitive ability of high densities of giant and yellow foxtail with soybean, indicating that adjustments to competitive index values or yield loss function parameters for these species may improve soybean yield loss prediction accuracy and increase the usefulness of WeedSOFT as a weed management decision support system.
We have investigated by x-ray diffraction defect structures in 6H-SiC after neutron irradiation with different fluences and followed by different annealing procedures. An interpretation along a model of Klimanek [1, 4–6] shows, that higher fluences lead to a stronger than linear reduction of the correlation length, whereas higher annealing temperatures correlate with a better recovery of the correlation length. In addition defects of 1st kind created by irradiation are reduced by annealing. We find that annealing changes the character of the defects and it accentuates a defect structure already present in the original samples.
Low energy plasma enhanced chemical vapour deposition (LEPECVD) is a deposition technique developed for the epitaxy of Si and SiGe at ultra-high deposition rates. Due to a high current plasma discharge composed of low energy particles, a high plasma enhancement can be obtained without any accompanying plasma induced damage of the wafer surface. The most important application of LEPECVD so far is for compositionally graded relaxed SiGe buffer layers. Such relaxed buffer layers are demonstrated with end composition up to pure Ge and with a growth time below 1 hour. A p-type hetero-MOSFET formed in a SiGe channel compressively strained to a Si0.5Ge0.5 relaxed buffer layer, is demonstrated as one example where the high growth rates of LEPECVD allows the synthesis of devices which cannot be produced with an acceptable throughput with conventional deposition methods. The room temperature effective hole mobility of 760 cm2/Vs obtained on such devices demonstrates a high structural and electrical quality of the LEPECVD material.