Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

In-beam Mössbauer spectra of 57Mn implanted into lithium aluminum hydride.

In-beam Mössbauer spectra of 57Mn implanted into LiAlH4 were measured at different temperatures between 17 and 300 K. The Mössbauer spectrum measured at 17 K showed two sets of doublets, which were assigned to 57Fe atoms at substitutional sites at Al3+ and Li+ sites. The Debye temperatures θM for the 57Fe atoms at Al3+-substituted and Li+-substituted sites were estimated to be 194 K and 117 K, respectively. The assignments were confirmed by density functional theory calculations.

New methods for determination of the keyhole position in the lateral suboccipital approach to avoid transverse-sigmoid sinus injury: Proposition of the groove line as a new surgical landmark.

PURPOSE: The asterion is frequently used as an anatomical landmark to determine the location of a keyhole in the lateral suboccipital approach used in craniotomies. However, the asterion may not be ideal because of large individual differences among patients. We examined a simple and safe method for determining an optimal keyhole position (KP) using the digastric groove as a new landmark in the lateral suboccipital approach. METHODS: Thirty-three patients with trigeminal neuralgia who underwent surgery in our institute between April 2014 and December 2018 were included. The groove line (GL) was designed accurately, extending the digastric groove on the surface of the occipital bone, as the x-axis. The y-axis was depicted from the posterior edge of the digastric groove (the groove point: GP) vertical to the GL. The x-y coordinates represented the distances from GP on each axis. The x-y coordinates of median edge of the transverse-sigmoid sinus (TSJ point), asterion, and the intersection of the GL and transverse sinus (the transverse point: TP) were investigated, based on intraoperative findings and recorded videos. RESULTS: The x-y coordinated of the TSJ point were (23.9±3.9, 7.2±3.6). In all patients, the TSJ point was located superior to the GL. The x-y coordinates of the asterion were (27.3±6.0, 8.9±4.1), and in 28 of the 33 patients, their coordinates exceeded the TSJ points. The x-coordinate of the TP was 29.5±4.5, and was located behind the TSJ point on the GL in all patients. The shortest distance between the TSJ points and TP was approximately 3mm. According to these measurements, we decided that the optimal KP would be at 20mm from the GP, subjacent to the GL. CONCLUSIONS: Our methods of using the GL as a new surgical landmark for setting the optimal KP is simple, safe, and useful.

Prevalence and Correlates of Neurocognitive Disorders among HIV Patients on Antiretroviral Therapy at a Kenyan Hospital.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) represent a spectrum of cognitive abnormalities affecting attention, concentration, learning, memory, executive function, psychomotor speed, and/or dexterity. Our objectives in this analysis are to determine the prevalence of HAND and the covariates in a Kenyan population. METHODS: We conducted a cross-sectional study in a convenient sample of people living with HIV on antiretroviral therapy (ART) attending routine care visits at the Kenyatta National Hospital HIV clinic between July and August 2015. Baseline demographics were obtained using interviewer-administered questionnaires; clinical data were abstracted from patient records. Trained research clinicians determined the neurocognitive status by administration of the International HIV Dementia Scale (IHDS), the Montreal Cognitive Assessment (MOCA) scale, and the Lawton Instrumental Activities of Daily Living (IADL) scale. Cognitive impairment was defined as a score of ≤26 on the MOCA and ≤10 on the IHDS. Descriptive analysis and logistic regression to determine predictors of screening positive for HAND were done with the significance value set at <0.05. RESULTS: We enrolled 345 participants (202 men; 143 women). The mean age of the study population was 42 years (±standard deviation (SD) 9.5). Mean duration since HIV diagnosis and mean duration on ART were 6.3 (±SD 3.7) and 5.6 years (±SD 3.4), respectively. Median CD4 count at interview was 446 cells/mm3 (interquartile range (IQR) 278-596). Eighty-eight percent of participants screened positive for HAND, of whom 87% had asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorders (MND) grouped together while 1% had HIV-associated dementia (HAD). Patients on AZT/3TC/EFV were 3.7 times more likely to have HAND (OR = 3.7, p=0.03) compared to other HAART regimens. In the adjusted analysis, women were more likely to suffer any form of HAND than men (aOR = 2.17, 95% CI: 1.02, 4.71; p=0.045), whereas more years in school and a higher CD4 count (aOR = 0.58, 95% CI: 0.38, 0.88; p=0.012), (aOR = 0.998, 95% CI 0.997, 0.999; p=0.013) conferred a lowered risk. CONCLUSION: Asymptomatic and mild neurocognitive impairment is prevalent among people living with HIV on treatment. Clinical care for HIV-positive patients should involve regular screening for neurocognitive disorders while prioritizing women and those with low education and/or low CD4 counts.

Gas filaments of the cosmic web located around active galaxies in a protocluster.

Cosmological simulations predict that the Universe contains a network of intergalactic gas filaments, within which galaxies form and evolve. However, the faintness of any emission from these filaments has limited tests of this prediction. We report the detection of rest-frame ultraviolet Lyman-α radiation from multiple filaments extending more than one megaparsec between galaxies within the SSA22 protocluster at a redshift of 3.1. Intense star formation and supermassive black-hole activity is occurring within the galaxies embedded in these structures, which are the likely sources of the elevated ionizing radiation powering the observed Lyman-α emission. Our observations map the gas in filamentary structures of the type thought to fuel the growth of galaxies and black holes in massive protoclusters.

A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

Nuclear Magnetic Field in Solids Detected with Negative-Muon Spin Rotation and Relaxation.

Using an intense negative muon (µ^{-}) source, we have studied the internal magnetic fields in a powder sample of magnesium hydride (MgH_{2}). By extracting the signal from the µ^{-} captured on Mg nuclei, we found that the negative muon spin rotation and relaxation (µ^{-}SR) spectra clearly showed a Kubo-Toyabe-type relaxation, which indicates a random magnetic field at the Mg site. The field distribution width obtained is very consistent with the predicted value at the Mg site estimated by dipole field calculations, supporting our claim to have observed the nuclear magnetic fields of hydrogens in MgH_{2}. As is the case with µ^{+}SR, µ^{-}SR promises to soon be an indispensable tool for materials analyses.

HRCT findings of collagen vascular disease-related interstitial pneumonia (CVD-IP): a comparative study among individual underlying diseases.

AIM: To identify characteristic high-resolution computed tomography (CT) findings for individual collagen vascular disease (CVD)-related interstitial pneumonias (IPs). MATERIALS AND METHODS: The HRCT findings of 187 patients with CVD, including 55 patients with rheumatoid arthritis (RA), 50 with systemic sclerosis (SSc), 46 with polymyositis/dermatomyositis (PM/DM), 15 with mixed connective tissue disease, 11 with primary Sjögren's syndrome, and 10 with systemic lupus erythematosus, were evaluated. Lung parenchymal abnormalities were compared among CVDs using χ2 test, Kruskal-Wallis test, and multiple logistic regression analysis. A CT-pathology correlation was performed in 23 patients. RESULTS: In RA-IP, honeycombing was identified as the significant indicator based on multiple logistic regression analyses. Traction bronchiectasis (81.8%) was further identified as the most frequent finding based on χ2 test. In SSc IP, lymph node enlargement and oesophageal dilatation were identified as the indicators based on multiple logistic regression analyses, and ground-glass opacity (GGO) was the most extensive based on Kruskal-Wallis test, which reflects the higher frequency of the pathological nonspecific interstitial pneumonia (NSIP) pattern present in the CT-pathology correlation. In PM/DM IP, airspace consolidation and the absence of honeycombing were identified as the indicators based on multiple logistic regression analyses, and predominance of consolidation over GGO (32.6%) and predominant subpleural distribution of GGO/consolidation (41.3%) were further identified as the most frequent findings based on χ2 test, which reflects the higher frequency of the pathological NSIP and/or the organising pneumonia patterns present in the CT-pathology correlation. CONCLUSION: Several characteristic high-resolution CT findings with utility for estimating underlying CVD were identified.

A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a ß-blocker-based strategy (ß-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the ß-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the ß-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes.

AIM: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.

New Pharmacogenomics Research Network: An Open Community Catalyzing Research and Translation in Precision Medicine.

The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.

Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis.

Tuberculosis (TB) occurs as a result of complex interactions between the host immune system and pathogen virulence factors. Human leukocyte antigen (HLA) class II molecules play an important role in the host immune system. However, no study has assessed the association between HLA class II genes and susceptibility to TB caused by specific strains. This study investigated the possible association of HLA class II genes with TB caused by modern and ancient Mycobacterium tuberculosis (MTB). The study included 682 patients with TB and 836 control subjects who were typed for HLA-DRB1 and HLA-DQB1 alleles. MTB strains were classified using a large sequence polymorphism typing method. Association analysis was performed using common HLA alleles and haplotypes in different MTB strains. HLA association analysis of patients infected with modern MTB strains showed significant association for HLA-DRB1*09:01 (odds ratio [OR] = 1.82; P-value = 9.88 × 10-4 ) and HLA-DQB1*03:03 alleles (OR = 1.76; P-value = 1.31 × 10-3 ) with susceptibility to TB. Haplotype analysis confirmed that these alleles were in strong linkage disequilibrium and did not exert an interactive effect. Thus, the results of this study showed an association between HLA class II genes and susceptibility to TB caused by modern MTB strains, suggesting the importance of strain-specific analysis to determine susceptibility genes associated with TB.

Gender differences of muscle and crural fascia origins in relation to the occurrence of medial tibial stress syndrome.

Although women reportedly have a higher prevalence of medial tibial stress syndrome (MTSS) than men, the possible role of gender-based anatomical differences has not been investigated. The aim of the present study was to investigate the presence of gender-based differences in the range of muscle attachments along the entire medial tibia, the proportion of muscle attachment at the middle and distal thirds of the medial margin of the tibia, the structure of the crural fascia, and chiasm position. The specimens were 100 legs of 55 Japanese cadavers. Statistical analysis was carried out using a chi-square test to compare anatomical features between the sexes. The flexor digitorum longus (FDL) had a higher proportion of attachment to the middle and distal thirds of the medial margin of the tibia than the soleus (SOL; P < 0.001). The proportion of the SOL attachment to the middle and distal thirds of the medial margin of the tibia was 33.3% in men and 72.5% in women (P < 0.001). The soleal aponeurosis was not observed in any specimen. In all specimens the FDL formed the top layer of both chiasms. These results suggest that the higher prevalence of MTSS reported among women may be the result of gender-based anatomical differences.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Influence of Nonenzymatic Glycation in Dentinal Collagen on Dental Caries.

Advanced glycation end-products (AGEs) are generated via nonenzymatic glycation of dentinal collagen, resulting in accumulation of AGEs in dentin tissue. Since accumulated AGEs cause crosslinking between amino acid polypeptides in the collagen molecule and modify mechanical properties of dentinal collagen, the authors assumed that there would be a significant interaction between the generation of AGEs and progression of caries in dentin. To confirm such an interaction, spectroscopic imaging analyses (i.e., nanosecond fluorescence lifetime imaging and second harmonic generation light imaging) were performed in addition to biochemical and electron microscopic analyses in the present study. Seven carious human teeth were fixed in paraformaldehyde and cut longitudinally into 1-mm sections using a low-speed diamond saw for the following analyses. In transmission electron microscopy (TEM) analysis, nondecalcified specimens were embedded in epoxy resin and sliced into thin sections for observation. For the immunohistochemical analysis, the specimens were paraffin embedded after decalcification for 2 wk and sectioned with a microtome. Resultant sections were stained with anti-AGE and anticollagen antibodies. The demineralized specimens were used for spectroscopic analyses without additional treatment. For Western blotting analysis, specimens were separated into carious and sound dentin. Each specimen was homogenized with a bead crusher and an ultrasonic homogenizer and then treated with hydrochloric acid. In carious dentin, the collagen fibers showed an amorphous structure in the TEM image, and the AGEs were localized in the areas of bacterial invasion in the immunostaining image. The total amount of AGEs in carious dentin was higher than in sound dentin in Western blotting. The ultrastructure of type I collagen and total amount of AGEs varied markedly in the dentinal caries region. The fluorescence lifetime was shorter in the carious area than that in the sound areas, indicating an increase of AGEs in the carious area. The increase of AGEs could influence the progression of dentinal caries.

A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin.

One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

Genomewide Association Studies in Pharmacogenomics: Meeting Report of the NIH Pharmacogenomics Research Network-RIKEN (PGRN-RIKEN) Collaboration.

Genomewide association studies (GWAS) have resulted in the identification of many heritable genetic factors that underlie risk for human disease or variation in physiologic traits. In contrast, there are fewer GWAS of drug response phenotypes, despite extensive unexplained interindividual variability. To address this urgent need, the NIH Pharmacogenomics Research Network (PGRN) and the Center for Integrative Medical Sciences (IMS) at RIKEN support a collaboration, PGRN-RIKEN, with the goal of accelerating GWAS of drug response phenotypes.