Exploring naturally occurring clinical subgroups of post-traumatic headache.

OBJECTIVE: To explore naturally occurring clinical subgroups of post-traumatic headache. BACKGROUND: Persistent post-traumatic headache (PTH) is defined as a headache developing within 7 days of an injury that lasts for greater than 3 months. However, there is no evidence available from the International Classification of Headache Disorders (ICHD) based classification between persistent and acute PTH based on clinical phenotypes. METHODS: We conducted a retrospective study using the Stanford Research Repository Cohort Discovery Tool. We reviewed 500 electronic patient charts between January 2015 to September 2019 using inclusion criteria of adults older than 18 years with a diagnosis of PTH. The following variables were extracted from each patient's chart: diagnosis of PTH as dependent variable, and predictor variables as age, sex, history of migraine, loss of consciousness during head injury, pre-existing psychological history, duration of PTH and new PTH-associated comorbidities (e.g. new onset vertigo, post-traumatic stress disorder). Logistic regression was employed to identify clinical phenotypes predicting persistent PTH. All predictor variables were tested in one block to determine their predictive capacity while controlling for other predictors in the model. Two-step cluster analysis was conducted to identify naturally occurring PTH subgroups. RESULTS: A total of 300 patients were included (150 acute, 150 persistent PTH) with a median age of 47 years (IQR 31, 59) and female: male ratio of 2.7:1. Two hundred patients were excluded due to misdiagnoses. Pre-existing psychological history (standardized beta 0.16), history of migraine (0.20), new PTH-associated comorbidities (0.23) and medication overuse (0.37) statistically significantly predicted the presence of persistent PTH (p <  0.0001). Clustering analysis revealed PTH subgrouping comparable to ICHD-based classification: 140 patients in Cluster 1 (76% persistent PTH) and 160 patients in Cluster 2 (83% acute PTH). Four distinct clusters were found within persistent PTH. CONCLUSION: Pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse predicted the occurrence of persistent PTH as well as two naturally occurring PTH clusters correlating to acute and persistent PTH. Management emphasis should focus on these phenotypes.

High-dose corticosteroids for acute cytomegalovirus-associated transverse myelitis in the immunocompetent patient: a case report and systematic review.

We present an immunocompetent patient with transverse myelitis (TM) during acute cytomegalovirus (CMV) infection, as evidenced by a reactive serum CMV IgM and CMV viremia. The patient had an excellent outcome after receiving only high-dose methylprednisolone. Given concerns that practitioners may have around the use of immunosuppressive therapy for this potentially infectious myelopathy, we systematically reviewed the literature to assess outcomes after administration of high-dose corticosteroids to this population. Despite severe disease at clinical nadir with inability to ambulate, immunocompetent patients with acute CMV-associated TM who received high-dose corticosteroids had good clinical outcomes 1 month to 1 year after presentation.

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

PURPOSE: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. METHODS: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. RESULTS: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. CONCLUSION: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

database.bio: a web application for interpreting human variations.

UNLABELLED: Rapid advances of next-generation sequencing technology have led to the integration of genetic information with clinical care. Genetic basis of diseases and response to drugs provide new ways of disease diagnosis and safer drug usage. This integration reveals the urgent need for effective and accurate tools to analyze genetic variants. Due to the number and diversity of sources for annotation, automating variant analysis is a challenging task. Here, we present database.bio, a web application that combines variant annotation, prioritization and visualization so as to support insight into the individual genetic characteristics. It enhances annotation speed by preprocessing data on a supercomputer, and reduces database space via a unified database representation with compressed fields. AVAILABILITY AND IMPLEMENTATION: Freely available at https://database.bio.

Regioselectivity control of graphene functionalization by ripples.

Ripples naturally occur in graphene sheets. First-principles calculations reveal that, by altering the pyramidalization angles of the carbon atoms, these ripples can be used to direct the chemical reactivity of graphene towards hydrogenation. A fraction of the carbon atoms of a rippled graphene, located around the crests and troughs, show significantly increased reactivity. The remaining carbon atoms have comparable reactivity to those in a flat graphene. To illustrate the increased reactivity, we show that hydrogenation becomes exothermic when the characteristic ratio between the amplitude and wavelength reaches ~0.55. This finding offers a practical chemical venue for regioselectivity control of graphene functionalization. While the rippling does not directly affect the band gap of the graphene, the rippling-induced hydrogenation does.

Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation.

BACKGROUND: The association between protein S deficiency (PSD) and ischemic stroke is controversial and warrants further investigation. METHODS: We conducted a genotype and MRI correlation study in a Chinese family in which hereditary PSD cosegregated with premature ischemic strokes. Six out of 11 family members inherited PSD type III in an autosomal dominant manner. RESULTS: Among all PSD members, a novel missense mutation 1063C→T in exon 10 of protein S alpha (PROS1) was identified, which encoded a substitution of arginine to cysteine at position 355 (R355C) in the first globular domain of laminin A of protein S. Wild-type PROS1 sequences were retained in non-PSD members. MRI detected deep white matter infarctions predominantly distributed in the borderzone regions. The infarct topography was homogeneous in all adult mutant carriers. By contrast, cerebral infarction was absent in nonmutant carriers. Extensive investigation in the family did not reveal any confounding stroke risk. Haplotype analysis with high-density single nucleotide polymorphism markers revealed a 6.1-Mb minimally rearranged region (rs12494685 to rs1598240) in 3q11.2, lod = 3.0. Among the 7 annotated genes in this region, PROS1 is known to be associated with thrombotic disorders. MRI screening in an additional 10 PSD families without R355C showed no cerebral infarction. CONCLUSIONS: PROS1 R355C mutation cosegregated with PSD type III and premature white matter infarctions in the index family. The findings substantiate an association between PSD and stroke. Study of the mechanism underlying this association may improve our understanding of premature cryptogenic white matter infarction.

Morphology and texture evolution of nanostructured CaF2 films on amorphous substrates under oblique incidence flux.

The morphology and biaxial texture of vacuum evaporated CaF(2) films on amorphous substrates as a function of vapour incident angle, substrate temperature and film thickness were investigated by scanning electron microscopy, x-ray pole figure and reflection high energy electron diffraction surface pole figure analyses. Results show that an anomalous [220] out-of-plane texture was preferred in CaF(2) films deposited on Si substrates at < 200 °C with normal vapour incidence. With an increase of the vapour incident angle, the out-of-plane orientation changed from [220] to [111] at a substrate temperature of 100 °C. In films deposited with normal vapour incidence, the out-of-plane orientation changed from [220] at 100 °C to [111] at 400 °C. In films deposited with an oblique vapour incidence at 100 °C, the texture changed from random at small thickness (5 nm) to biaxial at larger thickness (20 nm or more). Using first principles density functional theory calculation, it was shown that [220] texture formation is a consequence of energetically favourable adsorption of CaF(2) molecules onto the CaF(2)(110) facet.

Experimental investigation on regulated and unregulated emissions of a diesel/methanol compound combustion engine with and without diesel oxidation catalyst.

The use of methanol in combination with diesel fuel is an effective measure to reduce particulate matter (PM) and nitrogen oxides (NOx) emissions from in-use diesel vehicles. In this study, a diesel/methanol compound combustion (DMCC) scheme was proposed and a 4-cylinder naturally-aspirated direct-injection diesel engine modified to operate on the proposed combustion scheme. The effect of DMCC and diesel oxidation catalyst (DOC) on the regulated emissions of total hydrocarbons (THC), carbon monoxide (CO), NOx and PM was investigated based on the Japanese 13 Mode test cycle. Certain unregulated emissions, including methane, ethyne, ethene, 1,3-butadiene, BTX (benzene, toluene, xylene), unburned methanol and formaldehyde were also evaluated based on the same test cycle. In addition, the soluble organic fraction (SOF) in the particulate and the particulate number concentration and size distribution were investigated at certain selected modes of operation. The results show that the DMCC scheme can effectively reduce NOx, particulate mass and number concentrations, ethyne, ethene and 1,3-butadiene emissions but significantly increase the emissions of THC, CO, NO(2), BTX, unburned methanol, formaldehyde, and the proportion of SOF in the particles. After the DOC, the emission of THC, CO, NO(2), as well as the unregulated gaseous emissions, can be significantly reduced when the exhaust gas temperature is sufficiently high while the particulate mass concentration is further reduced due to oxidation of the SOF.

Efficient first-principles simulation of noncontact atomic force microscopy for structural analysis.

We propose an efficient scheme to simulate noncontact atomic force microscopy images by using first-principles self-consistent potential from the sample as input without explicit modeling of the atomic force microscopy tip. Our method is applied to various types of semiconductor surfaces including Si(111)-(7x7), TiO2(110)-(1x1), Ag/Si(111)-(sqrt[3]xsqrt[3])R30 degrees, and Ge/Si(105)-(1x2) surfaces. We obtain good agreement with experimental results and previous theoretical studies, and our method can aid in identifying different structural models for surface reconstruction.

Emission reduction from diesel engine using fumigation methanol and diesel oxidation catalyst.

This study is aimed to investigate the combined application of fumigation methanol and a diesel oxidation catalyst for reducing emissions of an in-use diesel engine. Experiments were performed on a 4-cylinder naturally-aspirated direct-injection diesel engine operating at a constant speed of 1800 rev/min for five engine loads. The experimental results show that at low engine loads, the brake thermal efficiency decreases with increase in fumigation methanol; but at high loads, it slightly increases with increase in fumigation methanol. The fumigation method results in a significant increase in hydrocarbon (HC), carbon monoxide (CO), and nitrogen dioxide (NO(2)) emissions, but decrease in nitrogen oxides (NO(x)), smoke opacity and the particulate mass concentration. For the submicron particles, the total number of particles decreases. In all cases, there is little change in geometrical mean diameter of the particles. After catalytic conversion, the HC, CO, NO(2), particulate mass and particulate number concentrations were significantly reduced at medium to high engine loads; while the geometrical mean diameter of the particles becomes larger. Thus, the combined use of fumigation methanol and diesel oxidation catalyst leads to a reduction of HC, CO, NO(x), particulate mass and particulate number concentrations at medium to high engine loads.

Algorithms for the electronic and vibrational properties of nanocrystals.

Solving the electronic structure problem for nanoscale systems remains a computationally challenging problem. The numerous degrees of freedom, both electronic and nuclear, make the problem impossible to solve without some effective approximations. Here we illustrate some advances in algorithm developments to solve the Kohn-Sham eigenvalue problem, i.e. we solve the electronic structure problem within density functional theory using pseudopotentials expressed in real space. Our algorithms are based on a nonlinear Chebyshev filtered subspace iteration method, which avoids computing explicit eigenvectors except at the first self-consistent-field iteration. Our method may be viewed as an approach to solve the original nonlinear Kohn-Sham equation by a nonlinear subspace iteration technique, without emphasizing the intermediate linearized Kohn-Sham eigenvalue problems. Replacing the standard iterative diagonalization at each self-consistent-field iteration by a Chebyshev subspace filtering step results in a significant speed-up, often an order of magnitude or more, over methods based on standard diagonalization. We illustrate this method by predicting the electronic and vibrational states for silicon nanocrystals.

Real space method for the electronic structure of one-dimensional periodic systems.

We present a real space pseudopotential method for calculating the electronic structure of one-dimensional periodic systems such as nanowires. As an application of this method, we examine H-passivated Si nanowires. The band structure and heat of formation of the Si nanowires are presented and compared to plane wave methods. Our method is able to offer the same accuracy as the traditional plane wave methods but offers a number of computational advantages such as faster convergence for heteropolar nanowires.

Size limits on doping phosphorus into silicon nanocrystals.

We studied the electronic properties of phosphorus-doped silicon nanocrystals using the real-space first-principles pseudopotential method. We simulated nanocrystals with a diameter of up to 6 nm and made a direct comparison with experimental measurement for the first time for these systems. Our calculated size dependence of hyperfine splitting was in excellent agreement with experimental data. We also found a critical nanocrystal size below which we predicted that the dopant will be ejected to the surface.

Experimental investigation on the performance, gaseous and particulate emissions of a methanol fumigated diesel engine.

Experiments were conducted on a 4-cylinder direct-injection diesel engine with fumigation methanol injected into the air intake of each cylinder. The fumigation methanol was injected to top up 10%, 20% and 30% of the power output under different engine operating conditions. The effects of fumigation methanol on engine performance, gaseous emissions and particulate emission were investigated. The experimental results show that there is a decrease in the brake thermal efficiency when fumigation methanol is applied, except at the highest load of 0.67 MPa. At low loads, the brake thermal efficiency decreases with increase in fumigation methanol; but at high loads, it increases with increase in fumigation methanol. The fumigation method results in a significant increase in hydrocarbon (HC), carbon monoxide (CO), and nitrogen dioxide (NO(2)) emissions. The concentration of nitrogen oxides (NOx) is significantly reduced except at close to full load condition. There is also a reduction in the smoke opacity and the particulate matter (PM) mass concentration. For the submicron particles, the total number of particles decreases at low and medium loads but increases at high loads. In all cases, there is a shift of the particles towards smaller geometrical mean diameter, especially at high loads. The increase in nano-sized particles and the increase in NO(2) emission could have serious impact on human health.

Quantum size effect on the diffusion barriers and growth morphology of Pb/Si(111).

An intriguing growth morphology of Pb islands on a Si(111) surface is observed in our STM experiments: the growth of a Pb layer on Pb islands with unstable heights starts from the periphery and moves towards the center, while the nucleation of the next layer on stable Pb islands starts away from the periphery. Using first-principles total energy calculations, we have studied the diffusion barriers of Pb adatoms on a freestanding Pb(111) film as a function of film thickness. The diffusion barriers are found to be very low (<60 meV), and a bi-layer oscillation due to the quantum size effect (QSE) is observed, with a lower barrier on the odd-layered, relatively unstable Pb films. The diffusion barrier difference between the odd- and even-layered film is as large as 40 meV. The observed unusual growth can be attributed to this big difference in the diffusion barriers due to QSE.

[Experimental study on ultrafine particle characteristics exhausted from various fuelled vehicles].

The fine particle size distribution characteristics obtained from a diesel taxi, a diesel light bus, a gasoline private car and a liquefied petroleum gas (LPG) fuelled taxi were carried out on a chassis dynamometer system. The measurements were performed at different driving modes, i.e. , with low and high idling and from 10 kmxh(-1) to 70 kmxh(-1), 4 cruise operations using the instrument SMPS for collecting particles of 0.015-0.7microm diameter in range. It was found that different fuelled vehicles and different driving modes characterize considerable differences in size number and mass concentration distributions. Diesel vehicles contribute much more nuclei and accumulation mode particles of 30 - 150 nm, while LPG and gasoline fuelled vehicles exhaust much more nuclei mode particles of 15-30 nm. Overall, diesel-fuelled vehicles exhaust much more particles number and mass than gasoline and LPG fuelled vehicles; In the present study, diesel vehicles exhaust the ranges of total SMPS particle number, mass concentration with (0.3-3.6) x 10(8) number x cm(-3), 0.03 - 0.6 microg cm(- 3) respectively, and gasoline and LPG fuelled vehicles exhaust 2.3 x 10(4) - 1.2 x 10(7) number x cm(-3), 8 x 10(-5)-0.1 microgxcm(-3); 8.2 x 10(3)8.8 x 10(6) number x cm(-3), 1.7 x 10(-5) -0.09 microg x cm(-3), respectively; For all types of vehicles, the particle number and mass concentrations are small at low-idle and low-speed-driving modes, and are large at high-idle and high-speed-driving modes. They generally increase with the vehicle speed increasing from 10 to 70 kmx h(-1).

BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs.

BACKGROUND: Malignant melanoma arising from different body compartments may be associated with differing aetiological factors and clinical behaviour, and may manifest diverse molecular genetic profiles. Although many studies have focused on cutaneous melanoma, little is known of mucosal and other types of melanoma. In particular, malignant melanoma of soft parts is different from other melanomas in many respects, yet manifests a common melanocytic differentiation. Mutation of BRAF is now known to be common in cutaneous melanomas, and raises possible new therapeutic options of anti-RAF treatment for these patients. Few data are available for non-cutaneous melanomas. AIMS: To study the incidence of BRAF and NRAS mutations in melanomas arising in diverse internal organs. METHODS: Fifty one melanomas from various internal organs were investigated for BRAF and NRAS mutation by direct DNA sequencing. RESULTS: BRAF and NRAS mutations were found in two and five mucosal melanomas arising from the aerodigestive and female genital tracts (n = 36). Their occurrence is mutually exclusive, giving a combined mutation incidence rate of 19.4% in mucosal melanomas. Both BRAF and NRAS mutations were absent in malignant melanoma of soft parts (n = 7). BRAF mutation was also absent in uveal melanoma (n = 6), but was seen in two of five cutaneous melanomas. The incidence of BRAF or combined BRAF/NRAS mutations in all non-cutaneous groups was significantly lower than published rates for cutaneous melanomas. CONCLUSION: Each melanoma subtype may have a unique oncogenetic pathway of tumour development, and only a small fraction of non-cutaneous melanomas may benefit from anti-RAF treatment.