Metrological traceability to common references supports the comparability of chemical measurement results produced by different analysts, at various times, and at separate places. Ideally, these ...references are realizations of base units of the International System of Units (SI). ISO/IEC 17025 (Clause 6.5) states that traceability of measurement results is a necessary attribute of analytical laboratory competence, and as such, has become compulsory in many industries, especially clinical diagnostics and healthcare. Historically, claims of traceability for organic chemical measurements have relied on calibration chains anchored on unique reference materials with linkage to the SI that is tenuous at best. A first-of-its-kind National Institute of Standards and Technology (NIST) reference material, ultrapure and extensively characterized PS1 Benzoic Acid Primary Standard for quantitative NMR (qNMR), serves as a definitive, primary reference (calibrant) that assuredly links the qNMR spectroscopy technique to SI units. As qNMR itself is a favorable method for accurate, direct characterization of chemical reference materials, PS1 is a standard for developing other traceable standards and is intended to establish traceability for the measurement of thousands of organic chemical species. NIST PS1 will play a critical role in directly promoting accuracy and worldwide comparability of measurement results produced by the chemical measurement community, supporting the soundness of clinical diagnostics, food safety and labeling, forensic investigation, drug development, biomedical research, and chemical manufacturing. Confidence in this link to the SI was established through (i) unambiguous identification of chemical structure; (ii) determinations of isotopic composition and molecular weight; (iii) evaluation of the respective molecular amount by multiple primary measurement procedures, including qNMR and coulometry; and (iv) rigorous evaluation of measurement uncertainty using state-of-the-art statistical methods and measurement models.
The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the ...positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.
We report the detection of continuous positional and polarization changes of the compact source SgrA* in high states (“flares”) of its variable near-infrared emission with the near-infrared ...GRAVITY-Very Large Telescope Interferometer (VLTI) beam-combining instrument. In three prominent bright flares, the position centroids exhibit clockwise looped motion on the sky, on scales of typically 150 μas over a few tens of minutes, corresponding to about 30% the speed of light. At the same time, the flares exhibit continuous rotation of the polarization angle, with about the same 45(±15) min period as that of the centroid motions. Modelling with relativistic ray tracing shows that these findings are all consistent with a near face-on, circular orbit of a compact polarized “hot spot” of infrared synchrotron emission at approximately six to ten times the gravitational radius of a black hole of 4 million solar masses. This corresponds to the region just outside the innermost, stable, prograde circular orbit (ISCO) of a Schwarzschild–Kerr black hole, or near the retrograde ISCO of a highly spun-up Kerr hole. The polarization signature is consistent with orbital motion in a strong poloidal magnetic field.
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated ...the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% or 1.8% of 217 families). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
Physical therapy following traumatic brain injury (TBI) can be negatively impacted by psychological symptoms, atypical symptom reporting, and response bias. We examined rates of Symptom Validity Test ...(SVT) failure in active duty military service members with a history of mild-moderate TBI and its impact on gait speed.
Intensive Outpatient Program at the National Intrepid Center of Excellence at Walter Reed National Military Medical Center.
Participants were 84 active duty service members with a history of mild-moderate TBI classified as SVT pass ( n = 49) or SVT fail ( n = 35).
Retrospective study.
Overground preferred and fast walking speed as well as Computer Assisted Rehabilitation Environment (CAREN) gait speed were recorded. Participants completed the Neurobehavioral Symptom Inventory and the Validity-10 was used to assign patients into the SVT pass and SVT fail groups. Gait speed metrics were compared across these groups and test operating characteristics were calculated.
Approximately 42% of the sample was classified into the SVT fail group. All 3 gait speed measures were significantly slower in the SVT fail group than in the SVT pass group ( P s < .001, d s = 0.60-0.80). Gait speed cutoffs for screeners or indicators of atypical reporting were identified.
The potential for response bias is a critical area for the clinician to consider when conducting physical therapy evaluations. Participants in the SVT fail group had slower walking speed on all 3 measures assessed. Several useful cutoffs were identified to serve as screeners or indicators of SVT failure, though these preliminary findings have limitations and need to be replicated.
To examine the relationship between service member/veteran (SM/V) traumatic brain injury (TBI) severity with caregiver health-related quality of life (HRQOL).
Military treatment facility.
Caregivers ...( N = 316) of SM/Vs following a TBI divided into 2 groups based on SM/V TBI severity: (1) caregivers of SM/Vs following an uncomplicated mild TBI (UnMTBI Caregiver group, n = 246), and (2) caregivers of SM//Vs following a complicated mild, moderate, severe, or penetrating TBI (STBI Caregiver group, n = 70). The STBI Caregiver group was further divided into 2 subgroups: Parent ( n = 21) versus Intimate Partner ( n = 49). The UnMTBI Caregiver group consisted of intimate partners.
Prospective cohort.
Caregivers completed 15 HRQOL measures.
Using analysis of variance and chi-square analysis, the UnMTBI Caregiver group reported worse scores on 12 HRQOL measures and more clinically elevated scores for 6 of 15 comparisons than the STBI Caregiver group. The UnMTBI Caregiver group also reported worse scores on 10 HRQOL measures than intimate partners in the STBI Caregiver group and 5 measures than parents in the STBI Caregiver group. Parents reported worse scores on 3 measures than intimate partners in the STBI Caregiver group. The UnMTBI Caregiver group reported more clinically elevated scores for 7 of 15 comparisons than intimate partners in the STBI Caregiver group.
Intimate partner caregivers of an SM/V following a remote uncomplicated MTBI reported worse HRQOL than intimate partners and parent caregivers of an SM/V following a more severe TBI, mostly likely due to SM/V physical and mental health comorbidities. Interventions that focus on the SM/V's TBI and other comorbidities, the caregiver's behavioral health problems, and the relationship and family factors that interact with each other will likely have the most success in improving individual and family outcomes for military families.
Introduction
To date, there has been little effort to develop standards for metabolome-based gut microbiome measurements despite the significant efforts toward standard development for DNA-based ...microbiome measurements.
Objectives
The National Institute of Standards and Technology (NIST), The BioCollective (TBC), and the North America Branch of the International Life Sciences Institute (ILSI North America) are collaborating to extend NIST’s efforts to develop a Human Whole Stool Reference Material for the purpose of method harmonization and eventual quality control.
Methods
The reference material will be rationally designed for adequate quality assurance and quality control (QA/QC) for underlying measurements in the study of the impact of diet and nutrition on functional aspects of the host gut microbiome and relationships of those functions to health. To identify which metabolites deserve priority in their value assignment, NIST, TBC, and ILSI North America jointly conducted a workshop on September 12, 2019 at the NIST campus in Gaithersburg, Maryland. The objective of the workshop was to identify metabolites for which evidence indicates relevance to health and disease and to decide on the appropriate course of action to develop a fit-for-purpose reference material.
Results
This document represents the consensus opinions of workshop participants and co-authors of this manuscript, and provides additional supporting information. In addition to developing general criteria for metabolite selection and a preliminary list of proposed metabolites, this paper describes some of the strengths and limitations of this initiative given the current state of microbiome research.
Conclusions
Given the rapidly evolving nature of gut microbiome science and the current state of knowledge, an RM (as opposed to a CRM) measured for multiple metabolites is appropriate at this stage. As the science evolves, the RM can evolve to match the needs of the research community. Ultimately, the stool RM may exist in sequential versions. Beneficial to this evolution will be a clear line of communication between NIST and the stakeholder community to ensure alignment with current scientific understanding and community needs.
For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur ...commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.
Recent research has examined potential influences to performance validity testing beyond intentional feigning. The current study sought to examine the hypothesized relationships of two psychological ...constructs (self-efficacy and health locus of control) with performance validity testing (PVT).
Retrospective review of 158 mild traumatic brain injury (mTBI) cases referred to an Army outpatient clinic for neuropsychological evaluation. The mTBI cases were classified according to passing or failing the Medical Symptom Validity Test (MSVT) or Non-Verbal Medical Symptom Validity Test (NV-MSVT). Group comparisons were performed utilizing one-way ANOVA to evaluate the differences between the PVT-Pass and PVT-Fail groups on self-efficacy (MMPI-2-RF Inefficacy scale) and locus of control (Multi-Dimensional Health Locus of Control).
There was no relationship between self-efficacy or health locus of control and passing/failing PVTs.
Further research is warranted to explore potential influences on PVT performance, which we conceptualize as analogous to experimental nuisance variables that may be amenable to intervention.
Objective
Pathogenic variants in SCN3A, encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the ...spectrum of clinical, genetic, and neuroimaging features of SCN3A‐related neurodevelopmental disorder.
Methods
Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293T cells).
Results
Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.
Interpretation
Our study defines SCN3A‐related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348–362
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