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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.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
Methods
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Results
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Conclusions
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
Early individualized interventions for informal dementia caregivers can prevent overburdening in the later stages. However, the needs of early-stage dementia caregivers (EDC) remain largely unknown. This study aimed to explore the needs and wishes and need for care of EDC to maximize the benefit of potential programs for EDC and tailor interventions accordingly.
Methods:
Four focus group interviews with 28 informal caregivers of people with dementia (PwD) were analyzed using inductive content analysis. Both EDC and caregivers in the later stages were included to compare perceived EDC needs from different points in the caregiver career.
Results:
Four themes were identified: the early-stage needs paradox, barriers in acceptance, facilitators in acceptance, and a transition from loss to adaptation. The retrospective view provided by later-stage caregivers differed from the view of EDC; EDC struggled with acknowledging needs due to fear of stigma and low acceptance. EDC stressed the importance of acceptance as a prerequisite for adequate adaptation, but were hindered by lack of knowledge, difficulty acknowledging changes, and focus on loss. In contrast, better understanding of the disease, increasing personal time, structuring ones day, and using appropriate humor can reduce negative communication, increase positive encounters and caregiver-confidence, contributing to positive interaction with the care recipient and an increase in well-being.
Conclusions:
Early therapeutic interventions could help caregivers identify their needs, increase knowledge about changes in roles and relationship reciprocity, and focus on enhancement of the positive, intact experiences to prevent caregiver burden.
In the past 15 years, stretchable electronic circuits have emerged as a new technology in the domain of assembly, interconnections, and sensor circuit technologies. In the meantime, a wide variety of processes using many different materials have been explored in this new field. In the current contribution, we present an approach inspired by conventional rigid and flexible printed circuit board (PCB) technology. Similar to PCBs, standard packaged, rigid components are assembled on copper contact pads using lead-free solder reflow processes. Stretchability is obtained by shaping the copper tracks as horseshoe-shaped meanders. Elastic materials, predominantly polydimethylsiloxanes, are used to embed the conductors and the components, thus serving as a circuit carrier. We describe mechanical modeling, aimed at optimizing the build-up toward maximum mechanical reliability of the structures. Details on the production process, reliability assessment, and a number of functional demonstrators are described.
EURECA (European Underground Rare Event Calorimeter Array) is an
astro-particle physics facility aiming to directly detect galactic dark
matter. The Laboratoire Souterrain de Modane has been selected as host
laboratory. The EURECA collaboration unites CRESST, EDELWEISS and the
Spanish-French experiment ROSEBUD, thus concentrating and focussing effort
on cryogenic detector research in Europe into a single facility. EURECA will
use a target mass of up to one ton, enough to explore WIMP – nucleon scalar
scattering cross sections in the region of 10-9 – 10-10 picobarn.
A major advantage of EURECA is the planned use of more than just one target
material (multi target experiment for WIMP identification).
We compared the prevalence of human and animal methicillin-resistant Staphylococcus aureus (MRSA) at pig farms in The Netherlands, and related this to individual and farm-level characteristics. More than half of the farms investigated (28/50) had MRSA in pigs or stable dust and about one third (15/50) of person(s) were identified as MRSA carriers. Human carriage was found only on farms with MRSA-positive pigs or dust. MRSA strains in human samples were the same spa-type as found in pigs and all were not typable by pulsed-field gel electrophoresis (NT-MRSA). Multivariate analyses showed that risk factors for human MRSA carriage were: working in pig stables (OR 40, 95% CI 8–209) and the presence of sows and finishing pigs (OR 9, 95% CI 3–30). Veterinary sample collectors sampling the pigs showed transient MRSA carriage only during the day of the farm visit. Working in pig stables with MRSA-positive pigs poses a high risk for acquiring MRSA, increasingly so when contact with live pigs is more intensive or long lasting.
This paper describes the modelling of the toner behaviour in the development nip of the Océ Direct Imaging print process. The dynamic motion of and mechanical interactions between toner particles are explicitly modelled. The mechanical interactions are due to collisions, friction, adhesion, and electromagnetic forces. The discrete element method (DEM) is used as the simulation tool for a quantitative description of the system. The interaction rules are determined for the toner particles and the surfaces of the development rollers. The model is validated with print quality results. It is shown that it is possible to achieve quantitative agreement between DEM simulations and experimental print quality results.
This paper discusses two techniques that have, at first sight, completely
different applications: photon emission microscopy (PEM) and micro-Raman
spectroscopy (μRS). We explain the principles of these techniques,
their application domain, and we will show that they can in some cases offer
complementary information, and be applied to common or similar problems.
In advanced CMOS technology nodes one may achieve further enhancement of device performance by carrier mobility modification in the transistor channel. The carrier mobility enhancement can be realized by formation of strained silicon layers on a Si1−xGex strain relaxed buffer. Formation of source and drain extensions on such structures need to satisfy one additional requirement, the formation process, including the activation related thermal budget should not relax the strain in the channel. In this paper we separately investigate the role of amorphization during implantation, different doping impurities and thermal budget on the junction and the transistor channel regions properties. Two approaches of dopant activation are discussed: low temperature solid phase epitaxial regrowth and high temperature conventional spike.
Tensile strained Si on SiGe Strain Relaxed Buffers (SRB) is an interesting candidate to increase both electron and hole mobility which results in improved device performance. Most of this work was/is based on thick (several μm), step-graded SRBs with or without Chemical Mechanical Polishing (CMP) planarisation. This approach bears several disadvantages such as issues with STI formation in the thick SiGe structure, and considerable self-heating effects due to the lower thermal conductivity of the SiGe material. Further, pMOS improvement requires SRBs with high Ge contents (> 30 %), which complicates device fabrication even more. To overcome these issues, we developed a new and cost efficient type of thin SRB (∼200 nm). The concept is based on the introduction of a thin carbon-containing layer during growth of a constant composition SiGe layer. The process relies on standard Chemical Vapor Deposition epitaxial technology without need for CMP. It is designed to allow both non-selective growth on blanket wafers and selective growth in the active area of structured wafers with Shallow Trench Isolation (STI). The selective epitaxial process for strained Si on thin SRBs proposed here, allows relatively simple and cost-effective fabrication of strained Si layers on existing STI structures without any process modification. Further, it offers a very flexible fabrication scheme to independently improve nMOS and pMOS devices. The SRB quality is comparable to the best reported in literature so far, with 70 % and 53 % mobility enhancements for long channel nMOSFETs on 22 % Ge SRBs grown on blanket and STI patterned wafers, respectively.
Initial studies (using Scanning Spreading Resistance Microscopy) on the lateral diffusion of B and As have shown an important influence of the thickness of oxy/nitride spacers. The latter phenomenon was tentatively ascribed to stress enhanced diffusion under the spacer region [1]. These studies have been complemented with Scanning Capacitance Microscopy (SCM) measurements, which confirm the SSRM-data. In fact both techniques shows a similar increase in lateral diffusion with increasing spacer thickness (∼ 0.2 nm/nm spacer thickness), whereby no effect is observed on the vertical diffusion. When using spacers with or without TEOS-liner, fairly similar enhancements could be seen. Micro-Raman and CBED stress measurements for these cases do however show a large reduction in stress when a TEOS-liner is used, suggesting that the correlation (at least to the final) stress is not really justified. A possible explanation could however be that the lateral diffusion occurs before the stress relaxation within the thermal treatment. In order to elucidate the diffusion mechanism (initial stress, interstitials, hydrogen incorporation, TED,..) we have expandedthe experimental matrix with a vacancy diffuser such as Sb and simulated the potential H-incorporation duringthe nitride deposition by a hydrogen anneal. Moreover we also have studied the impact of TED by splits with RTP-anneals before the nitride deposition.
State-of-the-art semiconductor devices require an accurate control of the complete twodimensional dopant distribution. The routine use of process simulators to predict the envisaged distributions and their resulting accuracy, is strongly linked to the physical models contained in these programs as well as their calibration. Whereas SIMS and SRP have been used extensively for the calibration of 1D-profiles, calibration of 2D-profiles has been very limited.
In this work, we report some results obtained with the 2D-profiling techniques SSRM (Scanning Spreading Resistance Microscopy) and SCM (Scanning Capacitance Microscopy ) for the study of two-dimensional effects on diffusion. In particular, we discuss the role of the nitride spacer on the lateral diffusion of arsenic and boron. Using series of transistors with different nitride spacers with or without TEOS-liners, a strong dependence between the lateral diffusion and the nitride spacer thickness can be observed using SSRM and SCM. The process flow eliminates the possible contribution of Transient enhanced diffusion (TED) as a dominant mechanism. At the same time an enhancement of the lateral stress underneath the spacers has been observed with CBED and Raman, suggesting a correlation between the lateral diffusion and the nitride spacers. The enhanced diffusion of As and B is strongly linked to the spacer size whereby the differences in enhancement suggest that the proximity of the dopants to the stress field field region is an important parameter.
When scaling down the MOS technology, the increasing local mechanical stress induced during the Ti- and Co/Ti silicidation can exceed the critical shear stress on the {111}<110> active glide system in the silicon substrate. This results in the heterogeneous nucleation of 60° dislocations in the silicon substrate underneath the silicide line. In the case of an undoped silicon substrate, these dislocations nucleate at the edge of the silicide lines and are parallel with the [110] oriented line edge. This paper will investigate the effects of As and BF2 junction implantation and implantation defects on the stress developed during the silicidation reaction and on the nucleation and growth of the stress induced 60° dislocations in the silicon.
The analysis of the mechanical behaviour of flip-chip interconections is an essential aspect of the reliability of the devices using this technique. When manufacturing them and during their operation, the interconective systems are submitted to thermal and mechanically induced stresses. By cyclic micromechanical testing and from analysis by micro Raman of singularities, we studied the mechanical response and the failure of samples, consisting of a substrate, the interconections and a chip.
Two sort of low melting point alloys were investigated, with different metallurgies for the pads, holding the interconections.
The primary objective of this work is to carry out a combined experimental and numerical investigation of the mechanical stress induced during the Ti-silicidation of narrow lines spaced by a Poly Buffered Local field oxide. Therefore micro-Raman spectroscopy (μRS) measurements of local mechanical stress are combined with simulations by Finite Element Modeling (FEM). Numerical determination of the local stress in the Si-substrate by means of FEM becomes more and more important when scaling down the device dimensions because the spatial resolution of μRS is limited at about 1μm and because the stress in the Si-substrate underneath silicided lines can not be detected using pRS unless the silicide is very thin. The Finite Element analysis was done using SYSTUS and involves a two dimensional plane strain thermo-elastic formulation. A good agreement was obtained between the FEM simulations and the μRS data for line widths above 1Bm making the extrapolation of the FEM to line widths smaller than I1m an attractive alternative for μRS.
The local mechanical stress induced in a silicon substrate by silicide lines (CoSi2, CoSi, C49 and C54 TiSi2) with different thicknesses, widths and spacings is studied using micro-Raman spectroscopy. The results show that the stress becomes larger with increasing line thickness and decreasing line spacing. For the different silicides, the stress increases according to: CoSi < CoSi2 < C49 TiSi2 < C54 TiSi2. By fitting a simple stress model to the Raman data, quantitative values for the stress components can be determined. The dependence of the TiSi2 phase on thickness and line width is studied for the same samples. These studies show that micro-Raman spectroscopy can provide local information (μm resolution) on the TiSi2 phase.
Micro-Raman spectroscopy, XRD, and analytical modelling are used to study stresses in and surrounding tungsten lines of different widths and spacing. The stress in the lines and in the adjacent substrate is calculated using a concentrated- and a distributed edge force model. Both models are adapted such that the substrate-stress components can also be calculated for an array of lines. The results from XRD and micro-Raman spectroscopy and the results from the distributed edge force model are in agreement. The combination of data from the two experimental techniques is shown to give some important feed-back to the theoretical models.
The application of CoSi2 in ever shrinking Si CMOS source-drain technologies demands a better knowledge of the states of stress caused by the formation of cobalt-silicides in Si. In this study the variation in local mechanical stress in the silicon substrate near arrays of polycrystalline cobalt-silicide lines was investigated by micro-Raman spectroscopy. The lines were formed by annealing Co sputtered in windows in lithographically patterned, thermal oxide coated Si wafers. The CoSi2 lines varied in width from ˜0.25 to 5.0μ, in number from 2 to 7, and in thickness from ˜ 10 to 230nm. The spacing between lines was 1 and 3 times the line width.
Trends in the Si stress between CoSi2 lines are described as a function of line width and line thickness. From the stress measured in the Si, information is obtained about the stress in the CoSi2 lines. In addition, the Si stress due to lines of primarily CoSi phase (monosilicide) is compared with the Si stress due to polycrystalline-CoSi2 (disilicide) lines.
Cross section TEM and SEM micrographs of the CoSix line morphologies are used to aid the description of the resulting stress profiles. Some theoretical modeling of the stress in the Si due to the CoSix lines is presented for comparison with the micro-Raman spectroscopy results.
Sil-xGex, undoped strained layers with a pure Si-capping layer were grown epitaxially by UHV CVD on Si (100) substrates. The samples were subjected to thermal treatments corresponding to typical deviceprocessing. Effects connected with thermally induced relaxations were studied by Raman scattering, XRD, photoluminescence (PL) and defect etching. The thickness of the layers was determined from X-ray reflectance measurement. Strain values for the as-grown and relaxed samples were extracted from Raman scattering, XRD measurements and defect etching and correlated. Sil-xGex-layer related peaks were observed in PL spectra of several samples. An explanation why those peaks are not observed in all the samples is suggested.