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LQXFA/B production series cryogenic assemblies are being built for the LHC upgrade by the HL-LHC Accelerator Upgrade Project (AUP). These contain a pair of MQXFA quadrupole magnets combined as a cold mass within a vacuum vessel, and are to be installed in the IR regions of the LHC. The LQXFA/B are being tested at 1.9 K to assess alignment and magnetic performance at Fermilab's horizontal test facility. The ∼10 m long assembly must meet stringent specifications for quadrupole strength and harmonic field integrals determination, magnetic axis location, and for variations in axis position and local field profiles. A multi-probe, PCB-based rotating coil and a Single Stretched Wire system are employed for these measurements. To accurately determine rotating coil location and angles within the cold mass, a laser tracker is utilized to record multiple targets at one end of the probe. This paper describes the measurements, probes/equipment, and techniques used to perform the necessary characterization of the cold mass.

IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

IntroductionSome models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.MethodsWe created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.ResultsCross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).DiscussionIndividualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Chiara Leoni,1 Germana Viscogliosi,1 Marco Tartaglia,2 Yoko Aoki,3 Giuseppe Zampino1,4 1Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy; 2Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy; 3Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan; 4Università Cattolica del Sacro Cuore, Rome, ItalyCorrespondence: Chiara Leoni, Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Largo Gemelli 8, Rome, IT-00168, Italy, Tel +39-063381344, Fax +39-063383211, Email chiara.leoni@policlinicogemelli.itAbstract: Costello syndrome (CS) is a rare neurodevelopmental disorder caused by germline mutations in HRAS. It belongs among the RASopathies, a group of syndromes characterized by alterations in components of the RAS/MAPK signaling pathway and sharing overlapping phenotypes. Its typical features include a distinctive facial appearance, growth delay, intellectual disability, ectodermal, cardiac, and musculoskeletal abnormalities, and cancer predisposition. Due to the several comorbidities having a strong impact on the quality of life, a multidisciplinary team is essential in the management of such a condition from infancy to adult age, to promptly address any detected issue and to develop appropriate personalized follow-up protocols and treatment strategies. With the present paper we aim to highlight the core and ancillary medical disciplines involved in managing the health challenges characterizing CS from pediatric to adult age, according to literature and to our large clinical experience.Keywords: multidisciplinary team, personalized medicine, HRAS, Costello syndrome, RASopathies

The high-luminosity Large Hadron Collider (HL-LHC) project aims at allowing to increase the collisions in the LHC by a factor of ten in the decade 2025-2035. One essential element is the superconducting magnet around the interaction region points, where the large aperture magnets will be installed to allow to further reduce the beam size in the interaction point. The core of this upgrade is the Nb3Sn triplet, made up of 150-mm aperture quadrupoles in the range of 7-8 m. The project is being shared between the European Organization for Nuclear Research and the US Accelerator Upgrade Program, based on the same design, and on the two strand technologies. The project is ending the short model phase, and entering the prototype construction. We will report on the main results of the short model program, including the quench performance and field quality. A second important element is the 11 T dipole that replaces a standard dipole making space for additional collimators. The magnet is also ending the model development and entering the prototype phase. A critical point in the design of this magnet is the large current density, allowing increase of the field from 8 to 11 T with the same coil cross section as in the LHC dipoles. This is also the first two-in-one Nb3Sn magnet developed so far. We will report the main results on the test and the critical aspects.

The development of Nb3Sn quadrupole magnets for the High-Luminosity LHC upgrade is a joint venture between the US LHC Accelerator Research Program (LARP)∗ and CERN with the goal of fabricating large aperture quadrupoles for the LHC interaction regions (IR). The inner triplet (low-β) NbTi quadrupoles in the IR will be replaced by the stronger Nb3Sn magnets boosting the LHC program of having 10-fold increase in integrated luminosity after the foreseen upgrades. Previously, LARP conducted successful tests of short and long models with up to 120 mm aperture. The first short 150 mm aperture quadrupole model MQXFS1 was assembled with coils fabricated by both CERN and LARP. The magnet demonstrated a strong performance at Fermilab's vertical magnet test facility reaching the LHC operating limits. This paper reports the latest results from MQXFS1 tests with changed prestress levels. The overall magnet performance, including quench training and memory, ramp rate, and temperature dependence, is also summarized.

IntroductionWhite matter hyperintensities (WMHs) are areas of abnormal signal on magnetic resonance images (MRIs) that characterize various types of histopathological lesions. The load and location of WMHs are important clinical measures that may indicate the presence of small vessel disease in aging and Alzheimer's disease (AD) patients. Manually segmenting WMHs is time consuming and prone to inter-rater and intra-rater variabilities. Automated tools that can accurately and robustly detect these lesions can be used to measure the vascular burden in individuals with AD or the elderly population in general. Many WMH segmentation techniques use a classifier in combination with a set of intensity and location features to segment WMHs, however, the optimal choice of classifier is unknown.MethodsWe compare 10 different linear and nonlinear classification techniques to identify WMHs from MRI data. Each classifier is trained and optimized based on a set of features obtained from co-registered MR images containing spatial location and intensity information. We further assess the performance of the classifiers using different combinations of MRI contrast information. The performances of the different classifiers were compared on three heterogeneous multi-site datasets, including images acquired with different scanners and different scan-parameters. These included data from the ADC study from University of California Davis, the NACC database and the ADNI study. The classifiers (naïve Bayes, logistic regression, decision trees, random forests, support vector machines, k-nearest neighbors, bagging, and boosting) were evaluated using a variety of voxel-wise and volumetric similarity measures such as Dice Kappa similarity index (SI), Intra-Class Correlation (ICC), and sensitivity as well as computational burden and processing times. These investigations enable meaningful comparisons between the performances of different classifiers to determine the most suitable classifiers for segmentation of WMHs. In the spirit of open-source science, we also make available a fully automated tool for segmentation of WMHs with pre-trained classifiers for all these techniques.ResultsRandom Forests yielded the best performance among all classifiers with mean Dice Kappa (SI) of 0.66±0.17 and ICC=0.99 for the ADC dataset (using T1w, T2w, PD, and FLAIR scans), SI=0.72±0.10, ICC=0.93 for the NACC dataset (using T1w and FLAIR scans), SI=0.66±0.23, ICC=0.94 for ADNI1 dataset (using T1w, T2w, and PD scans) and SI=0.72±0.19, ICC=0.96 for ADNI2/GO dataset (using T1w and FLAIR scans). Not using the T2w/PD information did not change the performance of the Random Forest classifier (SI=0.66±0.17, ICC=0.99). However, not using FLAIR information in the ADC dataset significantly decreased the Dice Kappa, but the volumetric correlation did not drastically change (SI=0.47±0.21, ICC=0.95).ConclusionOur investigations showed that with appropriate features, most off-the-shelf classifiers are able to accurately detect WMHs in presence of FLAIR scan information, while Random Forests had the best performance across all datasets. However, we observed that the performances of most linear classifiers and some nonlinear classifiers drastically decline in absence of FLAIR information, with Random Forest still retaining the best performance.

The U.S. LHC Accelerator Research Program (LARP) and CERN combined their efforts in developing Nb3Sn magnets for the high-luminosity LHC upgrade. The ultimate goal of this collaboration is to fabricate large aperture Nb 3Sn quadrupoles for the LHC interaction regions. These magnets will replace the present 70-mm-Aperture NbTi quadrupole triplets for expected increase of the LHC peak luminosity up to 5 × 1034 cm-2s-1 or more. Over the past decade, LARP successfully fabricated and tested short and long models of 90 and 120-mm-Aperture Nb3Sn quadrupoles. Recently, the first short model of 150-mm-diameter quadrupole MQXFS was built with coils fabricated both by LARP and CERN. The magnet performance was tested at Fermilab's vertical magnet test facility. This paper reports the test results, including the quench training at 1.9 K, ramp rate and temperature dependence, as well as protection heater studies.

The U.S. LHC Accelerator Research Program (LARP) and CERN are developing high-gradient Nb3Sn magnets for the high luminosity LHC interaction regions. Magnetic measurements of the first 1.5-m long, 150-mm aperture model quadrupole, MQXFS1, were performed during magnet assembly at LBNL, as well as during cryogenic testing at Fermilab's Vertical Magnet Test Facility. This paper reports on the results of these magnetic characterization measurements, as well as on the performance of new probes developed for the tests.

The U.S. LHC Accelerator Research Program (LARP) has been developing Nb3Sn quadrupoles of increasing performance for the high-luminosity upgrade of the large hadron collider. The 120-mm aperture high-field quadrupole (HQ) models are the last step in the RD phase supporting the development of the new IR Quadrupoles (MQXF). Three series of HQ coils were fabricated and assembled in a shell-based support structure, progressively optimizing the design and fabrication process. The final set of coils consistently applied the optimized design solutions and was assembled in the HQ03a model. This paper reports a summary of the HQ03a test results, including training, mechanical performance, field quality, and quench studies.

The Fermilab Mu2e experiment has been developed to search for evidence of charged lepton flavor violation through the direct conversion of muons into electrons. The transport solenoid is an s-shaped magnet that guides the muons from the source to the stopping target. It consists of 52 superconducting coils arranged in 27 coil modules. A full-size prototype coil module, with all the features of a typical module of the full assembly, was successfully manufactured by a collaboration between INFN-Genoa and Fermilab. The prototype contains two coils that can be powered independently. To validate the design, the magnet went through an extensive test campaign. Warm tests included magnetic measurements with a vibrating stretched wire and electrical and dimensional checks. The cold performance was evaluated by a series of power tests and temperature dependence and minimum quench energy studies.

Two patients with metabolic disorders presented with clinical and radiologic features suggestive of sporadic Creutzfeldt-Jakob disease (sCJD). Case 1 was a 50-year-old man with rapid decline in cognitive, behavioral, and motor function following new-onset seizures. MRI was read as consistent with CJD, and he was referred for a treatment trial, but it was determined that he recently experienced rapid correction of hyponatremia resulting in extrapontine myelinolysis. Case 2 was a 66-year-old woman with poorly controlled diabetes mellitus who was found unconscious after a suspected insulin overdose. Examination showed altered mental status and neuroimaging was remarkable for cortical/striatal hyperintensities suggestive of sCJD. On autopsy, she had hypoglycemic/hypoxic nerve cell loss. Although characteristic MRI findings have high sensitivity and specificity for sCJD, potentially reversible metabolic disorders sometimes present rapidly and can resemble sCJD both clinically and radiologically. These cases highlight the importance of establishing a broad differential diagnosis when evaluating a patient with suspected sCJD.

Large-aperture, high-field, Nb3Sn quadrupoles are being developed by the U.S. LHC accelerator research program (LARP) for the High luminosity upgrade of the Large Hadron Collider (HiLumi-LHC). The first 1 m long, 120 mm aperture prototype, HQ01, was assembled with various sets of coils and tested at LBNL and CERN. Based on these results, several design modifications have been introduced to improve the performance for HQ02, the latest model. From the field quality perspective, the most relevant improvements are a cored cable for reduction of eddy current effects, and more uniform coil components and fabrication processes. This paper reports on the magnetic measurements of HQ02 during recent testing at the Vertical Magnet Test Facility at Fermilab. Results of baseline measurements performed with a new multilayer circuit board probe are compared with the earlier magnet. An analysis of probe and measurement system performance is also presented.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = ‐0.125 ± 0.054, 95% bootstrap confidence interval [CI] [‐0.2309, ‐0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease.Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury.PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration.PVS's effect on executive function was mediated by GFAP and white matter disease. [ABSTRACT FROM AUTHOR]

Large-aperture, high-field, Nb3Sn quadrupoles are being developed by the U.S. LHC accelerator research program (LARP) for the High luminosity upgrade of the Large Hadron Collider (HiLumi-LHC). The first 1 m long, 120 mm aperture prototype, HQ01, was assembled with various sets of coils and tested at LBNL and CERN. Based on these results, several design modifications have been introduced to improve the performance for HQ02, the latest model. From the field quality perspective, the most relevant improvements are a cored cable for reduction of eddy current effects, and more uniform coil components and fabrication processes. This paper reports on the magnetic measurements of HQ02 during recent testing at the Vertical Magnet Test Facility at Fermilab. Results of baseline measurements performed with a new multilayer circuit board probe are compared with the earlier magnet. An analysis of probe and measurement system performance is also presented.

The U.S. LHC Accelerator Research Program has been developing Nb3Sn quadrupole magnets of progressively increasing performance and complexity for the High-Luminosity LHC project. The magnets are wound with Rutherford cables following the wind-and-react process. The resulting inter-strand coupling can generate strong field distortions during current ramp. The latest series of 120 mm aperture magnets (HQ) are designed and built for high field quality, offering an opportunity for detailed studies of these effects. Magnetic measurements of first-generation HQ magnets showed strong ramp-rate dependence. A stainless-steel core was introduced for the second generation of magnet coils to control the inter-strand coupling currents and the resulting dynamic multipoles. We report the observed dynamic effects and compare with calculations taking into account the coil geometry and cross-contact resistance in the Rutherford cable. In particular, the dependence of field quality on width and position of the stainless steel core is discussed. © 2002-2013 IEEE.

The U.S. LHC Accelerator Research Program has been developing Nb3Sn quadrupole magnets of progressively increasing performance and complexity for the High-Luminosity LHC project. The magnets are wound with Rutherford cables following the wind-and-react process. The resulting inter-strand coupling can generate strong field distortions during current ramp. The latest series of 120 mm aperture magnets (HQ) are designed and built for high field quality, offering an opportunity for detailed studies of these effects. Magnetic measurements of first-generation HQ magnets showed strong ramp-rate dependence. A stainless-steel core was introduced for the second generation of magnet coils to control the inter-strand coupling currents and the resulting dynamic multipoles. We report the observed dynamic effects and compare with calculations taking into account the coil geometry and cross-contact resistance in the Rutherford cable. In particular, the dependence of field quality on width and position of the stainless steel core is discussed. © 2002-2013 IEEE.

With the first test of LQS03, the long quadrupole (LQ) R&D by LARP (the US LHC Accelerator Research Program, a collaboration of BNL, FNAL, LBNL, and SLAC) is approaching conclusion. LQS03 is the third 3.7-m-long quadrupole, with 90 mm aperture, using a full new set of Nb3Sn coils. The LQS03 coils were made using 108/127 RRP strand (with 108 Nb3Sn subelements) produced by Oxford Superconducting Technology, whereas both previous models used 54/61 RRP strand (with 54 larger Nb3Sn subelements). In this paper, LQS03 test results are presented and discussed. The test results are also compared with the performances of the previous models. Observations are made for the future use of Nb3Sn in accelerator magnets. © 2002-2011 IEEE.

With the first test of LQS03, the long quadrupole (LQ) R&D by LARP (the US LHC Accelerator Research Program, a collaboration of BNL, FNAL, LBNL, and SLAC) is approaching conclusion. LQS03 is the third 3.7-m-long quadrupole, with 90 mm aperture, using a full new set of Nb3Sn coils. The LQS03 coils were made using 108/127 RRP strand (with 108 Nb3Sn subelements) produced by Oxford Superconducting Technology, whereas both previous models used 54/61 RRP strand (with 54 larger Nb3Sn subelements). In this paper, LQS03 test results are presented and discussed. The test results are also compared with the performances of the previous models. Observations are made for the future use of Nb3Sn in accelerator magnets. © 2002-2011 IEEE.

After the successful test of the first long Nb 3Sn quadrupole (LQS01) the US LHC Accelerator Research Program (LARP, a collaboration of BNL, FNAL, LBNL and SLAC) is assessing training memory, reproducibility, and other accelerator quality features of long Nb 3Sn quadrupole magnets. LQS01b (a reassembly of LQS01 with more uniform and higher pre-stress) was subjected to a full thermal cycle and reached the previous plateau of 222 T/m at 4.5 K in two quenches. A new set of four coils, made of the same type of conductor used in LQS01 (RRP 54/61 by Oxford Superconducting Technology), was assembled in the LQS01 structure and tested at 4.5 K and lower temperatures. The new magnet (LQS02) reached the target gradient (200 T/m) only at 2.6 K and lower temperatures, at intermediate ramp rates. The preliminary test analysis, here reported, showed a higher instability in the limiting coil than in the other coils of LQS01 and LQS02. © 2011 IEEE.