The NIST silicon lattice comparator upgrade.

The NIST silicon lattice comparator has been in service, in various forms, since the 1970s. It is capable of measuring the difference in lattice spacing between specimens of high-quality float-zone silicon to Δd/d ≈ 6 × 10-9. It has recently undergone a thorough update of its control systems and mechanics. These upgrades result in the ability to collect data with improved stability, less settling time of the instrument, and less operator intervention.

Development of an Adaptive Computer-Aided Soft Sensor Diagnosis System for Assessment of Executive Functions.

The main objective of the present study is to highlight the role of technological (soft sensor) methodologies in the assessment of the neurocognitive dysfunctions specific to neurodevelopmental disorders (for example, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and specific learning disorder). In many cases neurocognitive dysfunctions can be detected in neurodevelopmental disorders, some of them having a well-defined syndrome-specific clinical pattern. A number of evidence-based neuropsychological batteries are available for identifying these domain-specific functions. Atypical patterns of cognitive functions such as executive functions are present in almost all developmental disorders. In this paper, we present a novel adaptation of the Tower of London Test, a widely used neuropsychological test for assessing executive functions (in particular planning and problem-solving). Our version, the Tower of London Adaptive Test, is based on computer adaptive test theory (CAT). Adaptive testing using novel algorithms and parameterized task banks allows the immediate evaluation of the participant's response which in turn determines the next task's difficulty level. In this manner, the subsequent item is adjusted to the participant's estimated capability. The adaptive procedure enhances the original test's diagnostic power and sensitivity. By measuring the targeted cognitive capacity and its limitations more precisely, it leads to more accurate diagnoses. In some developmental disorders (e.g., ADHD, ASD) it could be very useful in improving the diagnosis, planning the right interventions, and choosing the most suitable assistive digital technological service.

Measuring the α-particle charge radius with muonic helium-4 ions.

The energy levels of hydrogen-like atomic systems can be calculated with great precision. Starting from their quantum mechanical solution, they have been refined over the years to include the electron spin, the relativistic and quantum field effects, and tiny energy shifts related to the complex structure of the nucleus. These energy shifts caused by the nuclear structure are vastly magnified in hydrogen-like systems formed by a negative muon and a nucleus, so spectroscopy of these muonic ions can be used to investigate the nuclear structure with high precision. Here we present the measurement of two 2S-2P transitions in the muonic helium-4 ion that yields a precise determination of the root-mean-square charge radius of the α particle of 1.67824(83) femtometres. This determination from atomic spectroscopy is in excellent agreement with the value from electron scattering1, but a factor of 4.8 more precise, providing a benchmark for few-nucleon theories, lattice quantum chromodynamics and electron scattering. This agreement also constrains several beyond-standard-model theories proposed to explain the proton-radius puzzle2-5, in line with recent determinations of the proton charge radius6-9, and establishes spectroscopy of light muonic atoms and ions as a precise tool for studies of nuclear properties.

The NIST Vacuum Double-Crystal Spectrometer: A Tool for SI-Traceable Measurement of X-Ray Emission Spectra.

The NIST Vacuum Double-Crystal Spectrometer (VDCS) has been modernized and is now capable of recording reference-free wavelength-dispersive spectra in the 2 keV to 12 keV x-ray energy range. The VDCS employs crystals in which the lattice spacings are traceable to the definition of the meter through x-ray optical interferometry with a relative uncertainty ﹤10-8. VDCS wavelength determination relies upon precision angle difference measurements for which the encoders of the rotation stages have been calibrated using the circle closure method for accurate, absolute angle measurement. The new vacuum-compatible area detector allows quantification of the aberration functions contributing to the observed line shape and in situ alignment of the crystal optics. This latter procedure is augmented with the use of a thin lamella as the first crystal. With these new techniques, x-ray spectra are registered with the VDCS on an absolute energy scale with a relative uncertainty of 10-6.

Role of Adiponectin and Tumor Necrosis Factor-Alpha in the Pathogenesis and Evolution of Type 1 Diabetes Mellitus in Children and Adolescents.

Type 1 diabetes mellitus (T1DM) is a complex condition caused by the destruction of pancreatic beta cells by autoimmune mechanisms. As a result, insulin deficiency and subsequent hyperglycemia occur. The aim of the present study is to investigate the role of adiponectin and tumor necrosis factor alpha (TNF-α) in the development of T1DM. The study is designed as an observational case-control study, involving 52 diabetic patients and 66 controls. Z scores for Body Mass Index (BMI), weight, height, and adiponectin and TNF-α serum levels were assessed in both groups. The T1DM group had significantly higher TNF-α levels and a significantly higher proportion of high-risk patients for inflammation based on TNF-α values as compared to the control group, while both groups had statistically similar adiponectin levels and a similar proportion of high/medium-risk patients based on adiponectin values. TNF-α plays a significant role in the pathogenesis and evolution of T1DM and it may represent an additional marker of disease progression, as well as a potential target of immunotherapeutic strategies. In the present study, no statistically significant differences were recorded in adiponectin levels neither in diabetic patients and controls, nor in high/medium severity risk diabetic patients.

The Role Of Adiponectin, TNF-α And Glutathione In The Pathogenesis And Evolution Of Type 1 Diabetes.

INTRODUCTION: Type 1 diabetes (T1DM) is a chronic autoimmune or idiopathic condition, featuring complex and unique interactions between proteins and enzyme systems. The purpose of the present study is to investigate the role of AdipoQ +276G>T, TNF-α-308G>A, GSTT1/GSTM1 polymorphic variants in the development of T1DM. MATERIALS AND METHODS: The study is designed as a cross-sectional study, involving 72 diabetic cases and 90 controls. Genotyping was carried out according to specific protocols for the above-mentioned polymorphic variants. RESULTS: The G allele of AdipoQ was associated with the development of type 1 diabetes (OR 0.577, CI95% 0.336-0.802, p=0.001), similar to the GG and GA genotypes (OR 0.405, CI95% 0.156-0.654, p=0.001 and OR 0.623, CI95% 0.401-0.855, p=0.004). The G allele of TNF-α was marginally associated with the development of type 1 diabetes (OR 0.789, CI95% 0.579-0.956, p=0.005). The presence of the T1 genotype was a strong predictor for type 1 diabetes (OR 3.4, CI95% 1.433-6.243, p<0.001). CONCLUSION: The results of our study suggest that G alleles of AdipoQ and TNFα act as a protective factor in T1DM, while the T1 allele for GST could be considered a risk factor for the development of Type 1 diabetes in our study group.

Bruising as the first sign of exocrine pancreatic insufficiency in infancy.

Exocrine pancreatic insufficiency is an important cause of chronic malnutrition, secondary to maldigestion-malabsorption, which can be caused in children especially by cystic fibrosis, but also by other much rarer diseases. The case of a 6 months and 3 weeks old male pediatric patient is reported, who was admitted to the clinic for head and forearms bruising. Laboratory findings identified vitamin K deficiency as the cause of the cutaneous hemorrhagic syndrome. Further investigations revealed association of steatorrhea (which is a marker of fat malabsorption), iron-deficiency anemia and hypovitaminosis D, which had been produced by nutritional deficiencies caused by malabsorption syndrome. From the numerous disorders that could be associated with pancreatic insufficiency in children, the following conditions had been excluded: cystic fibrosis (mucoviscidosis), cow's milk protein intolerance, gluten-sensitive enteropathy (coeliac disease), Shwachman-Diamond syndrome, abetalipoproteinemia, etc. Based upon decreased levels of stool pancreatic elastase in repeated measurements, together with low serum lipase, the final diagnosis of exocrine pancreatic insufficiency was established. Treatment of this case consisted mainly in pancreatic enzyme replacement therapy, but also oral iron supplementation and dietary supplements with fat-soluble vitamins (A, D, E, K). The outcome was favorable, characterized by normalization of intestinal passage, ascending growth curve and normalization of the majority of laboratory tests values that were modified between the time of patient admission to our clinic and initiation of specific therapy (serum level of vitamin K, vitamin D and lipase, coagulation profile, hemoglobin and red blood cell indexes), as well as higher value of fecal pancreatic elastase.

Prone Positioning on a Belly Board Decreases Rectal and Bowel Doses in Pelvic Intensity-Modulated Radiation Therapy (IMRT) for Prostate Cancer.

The presence of normal tissues in the irradiated volume limits dose escalation during pelvic radiotherapy (RT) for prostate cancer. Supine and prone positions on a belly board were compared by analyzing the exposure of organs at risk (OARs) using intensity modulated RT (IMRT). The prospective trial included 55 high risk, localized or locally advanced prostate cancer patients, receiving definitive image-guided RT. Computed tomography scanning for irradiation planning was carried out in both positions. Gross tumor volume, clinical and planning target volumes (PTV) and OARs were delineated, defining subprostatic and periprostatic rectal subsegments. At the height of the largest antero-posterior (AP) diameter of the prostate, rectal diameters and distance from the posterior prostate wall were measured. IMRT plans were generated. Normal tissue exposure and structure volumes were compared between supine and prone plans using paired t-test. In the volumes of the prostate, PTV, colon and small bowel, no significant differences were found. In prone position, all rectal volumes, diameters, and rectum-prostate distance were significantly higher, the irradiated colon and small bowel volume was lower in dose ranges of 20-40 Gy, and the exposure to all rectal segments was more favorable in 40-75 Gy dose ranges. No significant difference was found in the exposure of other OARs. Prone positioning on a belly board is an appropriate positioning method aiming rectum and bowel protection during pelvic IMRT of prostate cancer. The relative reduction in rectal exposure might be a consequence of the slight departure between the prostate and rectal wall.

The Molybdenum K-shell X-ray Emission Spectrum.

We present newly measured spectra of the X-ray emission of a molybdenum metal anode subject to electron bombardment, using a very high dispersion silicon double-crystal spectrometer. The measurement includes the dipole-allowed KL, KM, and KN emission lines, based on an energy scale traceable to the Système International (SI) definition of the meter with a systematic uncertainty below ΔE/E = 10-6. The data are presented as parametrized multi-Lorentzian fits to the results, and as supplementary data with the complete spectrum of each line group, corrected for instrumental effects. The MoKL 3 (Kα 1) line energy was in complete statistical agreement with published measurements, and it showed no asymmetry. Other lines showed varying discrepancies with the literature which lie outside the bounds of probable experimental errors.

Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices.

Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify variants. Laboratories differed widely on: (1) technologies used for large rearrangement detection; (2) criteria for minimum read depths; (3) non-coding regions sequenced; (4) variant classification criteria and approaches; (5) testing volume ranging from 2 to 2.5 × 105 tests annually; and (6) deposition of variants into public databases. These data may be useful for national and international agencies to set recommendations for quality standards for BRCA1/BRCA2 clinical testing. These standards could also be applied to testing of other disease genes.

Erratum: Author Correction: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk.

[This corrects the article DOI: 10.1038/s41523-017-0024-8.].

High-precision measurement of the X-ray Cu Kα spectrum.

The structure of the X-ray emission lines of the Cu Kα complex has been remeasured on a newly commissioned instrument, in a manner directly traceable to the Système Internationale definition of the meter. In this measurement, the region from 8000 eV to 8100 eV has been covered with a highly precise angular scale, and well-defined system efficiency, providing accurate wavelengths and relative intensities. This measurement updates the standard multi-Lorentzian-fit parameters from Härtwig, Hölzer, et al., and is in modest disagreement with their results for the wavelength of the Kα1 line when compared via quadratic fitting of the peak top; the intensity ratio of Kα1 to Kα2 agrees within the combined error bounds. However, the position of the fitted top of Kα1 is very sensitive to the fit parameters, so it is not believed to be a robust value to quote without further qualification. We also provide accurate intensity and wavelength information for the so-called Kα3,4 "satellite" complex. Supplementary data is provided which gives the entire shape of the spectrum in this region, allowing it to be used directly in cases where simplified, multi-Lorentzian fits to it are not sufficiently accurate.

Erratum: Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk.

Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA1/2-negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European-Caucasian multi-institutional cohort. Case-control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high-risk (odds ratio > 5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case-control analysis demonstrated associations with familial breast cancer for ATM, PALB2, and TP53 mutations (odds ratio > 3.0, p < 10-4), BARD1 mutations (odds ratio = 3.2, p = 0.012), and CHEK2 truncating mutations (odds ratio = 1.6, p = 0.041). Our results demonstrate that approximately 4.7% of BRCA1/2 negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified PALB2 and TP53 as high-risk, ATM and BARD1 as moderate risk, and CHEK2 truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case-control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes.

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia.

Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.

The Lattice Spacing Variability of Intrinsic Float-Zone Silicon.

Precision lattice spacing comparison measurements at the National Institute of Standards and Technology (NIST) provide traceability of X-ray wavelength and powder diffraction standards to the international system of units (SI). Here, we both summarize and document key measurements from the last two decades on six lots of intrinsic float-zone silicon, including unpublished results and recent internal-consistency checks. The comparison measurements link the unknown lattice spacing of a test crystal to a standard crystal for which the lattice spacing has been accurately determined by X-ray/optical interferometry in units traceable to the definition of the meter. The crystal that serves as the standard in all the comparisons is WASO 04, for which the lattice spacing is known with a relative uncertainty of 5 × 10-9. Individual lattice spacing comparison results have typical uncertainties of 1 ×10-8; taking material variability into account, measurements yield relative uncertainties for the test materials of a few tens of nanometers. It is observed that in the case of nearly perfect modern intrinsic float-zone silicon, the variability of the lattice spacing is sufficiently small that for most diffraction applications, a recommended reference value may be used.

Antipsychotics influence Toll-like receptor (TLR) expression and its relationship with cognitive functions in schizophrenia.

Increasing evidence suggests that altered immune functions are related to the pathophysiology of schizophrenia. Relatively little information is available on Toll-like receptors (TLRs), which are implicated in the recognition of molecular patterns associated with pathogens and internal cellular damage signals. By using immunophenotyping and flow cytometry, we investigated TLRs in CD14+ monocytes, CD4+CD25+Foxp3+ regulatory T cells (Treg), and CD3+CD4+CD25+ activated T cells (Tact) in 35 drug-naïve patients with schizophrenia before and after an 8-week period of antipsychotic treatment with risperidone or olanzapine. As compared with 30 healthy control individuals, drug-naïve patients with schizophrenia exhibited an increased percentage of TLR4+ and TLR5+ monocytes and TLR5+ Treg/Tact cells. At the end of the treatment period, we observed normalized TLR4+ monocytes and an up-regulation of TLR2+ monocytes and Treg/Tact cells. Mean fluorescent intensity values, indicating receptor density, were consistent with these findings. In the drug-naïve state, but not after treatment, higher percentages of TLR4+ and TLR5+ monocytes were correlated with more severe cognitive deficits. Positive, negative, and general clinical symptoms were not associated with TLRs. There were no significant differences between patients receiving olanzapine and risperidone. These results indicate that abnormal expression of TLRs can be detected in the earliest stage of schizophrenia, which is modulated by antipsychotics. Immunological alterations in unmedicated schizophrenia patients may be linked to cognitive deficits.

Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.

Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole-exome sequencing in 404 individuals in 253 families and classified 1,640 variants. Potentially clinically actionable (likely pathogenic [LP] or pathogenic [P]) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant with locus-specific databases and Clinvar. LP or P mutations were identified in 12 of 25 breast cancer susceptibility genes in 26 families without identified BRCA1/2 mutations (11%). Evaluation of 84 additional genes associated with autosomal-dominant cancer susceptibility identified LP or P mutations in only two additional families (0.8%). However, individuals from 10 of 253 families (3.9%) had incidental LP or P mutations in 32 non-cancer-associated genes, and 9% of individuals were monoallelic carriers of a rare LP or P mutation in 39 genes associated with autosomal-recessive cancer susceptibility. Furthermore, 95% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant-classification guidelines. Additionally, evaluation of extended panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.

Collaborative science in the next-generation sequencing era: a viewpoint on how to combine exome sequencing data across sites to identify novel disease susceptibility genes.

The purpose of this article is to inform readers about technical challenges that we encountered when assembling exome sequencing data from the 'Simplifying Complex Exomes' (SIMPLEXO) consortium-whose mandate is the discovery of novel genes predisposing to breast and ovarian cancers. Our motivation is to share these obstacles-and our solutions to them-as a means of communicating important technical details that should be discussed early in projects involving massively parallel sequencing.