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PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity. ispartof: GENETICS IN MEDICINE vol:24 issue:9 pages:1967-1977 ispartof: location:United States status: published

Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 × 106 (n=3), 1 × 107 (n=3), 1 × 108 (n=3), or 1 × 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 × 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity. Citation Format: Adel Samson, Cristina Smolenschi, Philippe Cassier, Jai V. Patel, Chris Hammond, Marta Kurzawa, Sophie Sainte-Croix, Emma West, Alain Sadoun, Kaidre Bendjama. Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liver-dominant metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT190.

The aim of this study was to assess the feasibility of quantitative ultrasound imaging (QUI) in assessing the biceps brachii muscle and gastrocnemius muscle in adults with multiple sclerosis (MS).From May to October 2018, we prospectively performed B-mode ultrasound imaging and ultrasound strain elastography of the biceps brachii muscle and gastrocnemius muscle in 24 patients with MS and 10 age-matched healthy volunteers. ImageJ (https://imagej.nih.gov/ij) was used to assess the muscle pixel intensity in grayscale images. Using 2-dimensional speckle-tracking software, we estimated the muscle axial peak strain (maximum deformation) produced by manual compression with an ultrasound transducer and the muscle longitudinal peak strain (maximum displacement) produced by passive elbow and ankle movements. Muscle QUI parameters used in the study included the mean pixel intensity, axial peak strain ratio (SR = muscle strain/subcutaneous tissue strain), and longitudinal peak SR. Statistical analyses included 1-way analysis of variance and a post hoc test to examine the differences in QUI parameters among 3 groups (1, affected muscle in patients with MS; 2, unaffected muscle in patients with MS; and 3, healthy muscle in controls) and, in all paired groups, an unpaired t test to compare the muscle SR in patients with MS with a Modified Ashworth Scale (MAS) score of 1 or higher to those with an MAS score of 0.The mean age of the 24 patients with MS was 43 years, and all patients and volunteers were female. We observed a significant difference in QUI parameters among the affected muscle in MS, unaffected muscle in MS, and healthy muscle in all paired groups and in patients with MS between an MAS score of 1 or higher and an MAS score of 0 (all P .05). Interobserver and intraobserver variability in performing QUI was good (intraclass correlation coefficients0.75).Our results suggest that QUI is feasible to assess muscle echogenicity and mechanical behaviors in adult MS.

We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

A long handwritten letter by Professor W.H. Bragg, dated 16 December 1912 and addressed to the Vice-Chancellor of the University of Leeds (an extract of which is presented in this article), provides an authoritative record of the progress in X-ray crystallography from the beginning of the Bragg's father and son collaboration in August 1912–December 1914. The collaboration began at the village of Cloughton on the North Yorkshire coast but hitherto the house itself had not been identified. As a result of an historical investigation initiated by the writer and with the help of members of the Bragg and Barran families and the Cloughton Local History Group, it is now identified as ‘Whin Brow’, the summer home of Henry and Rosalie Barran, close friends of William and Gwendoline Bragg. A plaque at ‘Whin Brow’, commemorating the ‘new science of X-ray crystallography’, was unveiled by Mr Charles Bragg (great-grandson of William Bragg) on 5 July 2013.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

This study investigates a range of commercially available γ-Al2O3 powders by using a combination of integrated experimental techniques. These included general measurements of powder properties by using helium density, BET surface area, and scanning electron microscopy (SEM) analyses. In addition, dynamic light scattering and zeta potential measurements were used to investigate nanoparticle dispersions. Bulk crystal structures were analysed by using comparative X-ray and neutron powder diffraction (XRD and NPD) analyses. Conventional transmission electron microscopy (TEM) was used to determine particle morphology, particle size, composition, and structure. Aberration-corrected TEM was used to investigate the crystallinity of nanoparticles including the existence of any surface reconstruction on commonly observed facetted, cubeoctahedral γ-Al2O3 nanoparticles. From the observation of peak splittings in diffraction data, we favour a description of the γ-Al2O3 structure based on a distortion of the conventionally accepted face-centred cubic (Fd$\bar 3$m) structure into a tetragonal I41/amd structure. Distinct differences between TEM, XRD, and NPD data indicate the presence of some cation disorder within a rigid close-packed oxygen framework. The Rietveld refinement of the NPD data suggests a high level of microstrain of 1.2%. An improvement to the model is achieved by reducing the aluminium content in the unit cell, which is commensurate with the migration of aluminium ions to the surface and some degree of nonstoichiometry in the particle core. Aberration-corrected TEM imaging and exit wave reconstruction confirm previous evidence for the presence of enhanced surface contrast at {111} surface facets, which we associate with the presence of excess cation termination. In addition, these {111} facets are observed to be heavily stepped. These results may have important implications for the thermal stability of metal catalyst nanoparticles on these high-surface area supports; the migration of aluminium ions to the surface provides clear evidence of why these materials perform so well as catalyst supports. © 2013 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.

In October of 2008, an outbreak of trichinellosis occurred in northern California that sickened 30 of 38 attendees of an event at which meat from a black bear was served. Morphologic and molecular testing of muscle from the leftover portion of bear meat revealed that the bear was infected with Trichinella murrelli, a sylvatic species of Trichinella found in temperate North America. Clinical records revealed a high attack rate for this outbreak: 78% for persons consuming any bear meat and 100% for persons consuming raw or undercooked bear meat. To our knowledge, this report is the first published report of a human trichinellosis outbreak in the United States attributed to T. murrelli, and it is the second such outbreak reported worldwide.

Structure and distribution of animal territories are driven by a variety of environmental and demographic factors. A peninsular population of common loons (Gavia immer) nests on lakes in northwestern Montana, but does not occupy all apparently suitable breeding territories, suggesting unexplained limitations on population growth. To evaluate territorial dynamics of breeding loons in Montana, we created and tested occupancy models that evaluated the hypothesized effects of disturbance, habitat, and intraspecific relationships on territory occupancy by common loons in Montana from 2003 to 2007. Model-averaged results indicated that the abundance of feeding lakes within 10 km (i.e., forage quality) and the number of territorial pairs within 10 km (i.e., density of loons) were equally supported and related to probabilities of occupancy. We found substantial support that the population was in a state of equilibrium, with the numbers of occupied territories stable in time, but not space. We also found that density of territorial pairs was related to the likelihood that an existing territory would be abandoned, but did not influence the establishment of new territories, suggesting the presence of territorial pairs could be a stronger indicator of territory quality to loons than physical lake characteristics. Our index of human disturbance was not well-supported compared to other factors. Our results suggest management for stable or growing loon populations could be achieved using long-term monitoring and protection of occupied territorial lakes and nearby feeding lakes, because these factors most influenced the probability of occupancy of surrounding lakes. © 2011 The Wildlife Society.

In this study, fibre laser welds of alloy Ti-6%Al-2%Sn-4%Zr-6%Mo have been characterised. It has been found that although the microstructure of the welds is important in predicting properties, it is not enough to simply characterise the welds based on the microstructure, as crystallographic texturing is also important in determining mechanical properties. The texturing of the fibre laser welds is being characterized using EBSD mapping, with light microscopy to characterize the microstructure. This has been carried out for a weld that has been heat treated for 3 hours at 550 °C. At this temperature, relaxation of residual stress will occur, but changes to the microstructure will be minimal. It is planned that EBSD will now be carried out on the as received sample, and the results will be presented, along with a comparison with the heat treated weld.

Species that live in ecosystems with extremely different seasonal conditions must balance the constraints of each season to survive. Alpine species that do not migrate seasonally are especially adept at balancing the constraints created by short growing seasons and long, harsh winters. We investigated the habitat characteristics of hoary marmots in western Montana to provide a better understanding about habitat selection at the southern extent of this species’ distribution. Hoary marmots are an alpine obligate of special concern in western Montana; given that climate change is impacting alpine ecosystems at a rapid rate, this species may be especially vulnerable at the southern edge of their range. We conducted occupancy surveys in three study areas along a latitudinal gradient in 2014 and 2015 to assess the importance of specific habitat characteristics to their presence on the landscape. Slope, aspect, and presence of shrubs were all important habitat characteristics. Marmots preferred shallow slopes and southern aspects, similar to findings from other studies on hoary marmots and other marmot species. Our results provide evidence that marmots may strike a balance between the environmental conditions they require during summer and winter. Shallow slopes typically accumulate deeper snow in winter that provide the best insulating snowpack. However, a preference for southern aspects allows for more snow-free areas in spring, providing a slightly longer growing season than northern aspects. Hoary marmots may be selecting areas with shrubs because shrubs can accumulate deeper snow and the additional insulation can increase subnivian temperatures. Other studies suggest that marmot survival is influenced by snowpack, indicating that marmot distribution may be more closely tied to winter conditions rather than summer conditions. This highlights the difficulty of working on marmots and other alpine obligates, as most studies occur only during the short growing season. Given the current and projected increases in temperature and reduction in snowpack in Montana, areas that provide the winter conditions hoary marmots require may become more limited. Effectively conserving, monitoring, and managing alpine obligates under an uncertain climate future will require a closer look at how winter conditions drive habitat selection and distributions on the landscape.

Superplastic forming of conventional titanium alloy sheet is limited commercially by the relatively long cycle times imposed by the high temperatures and slow strain rates required. In order to minimise cycle times material with a fine grain size is required to allow either, an increase in the forming rate or a reduction in the deformation temperature. This study details the manufacture of Ti-6Al-4V-0.5B powder with a nanocrystalline grain size, which was produced by mechanical milling. The material was consolidated by hot isostatic pressing at a range of temperatures during which ∼2.5 vol.-%TiB was formed by an in situ reaction between the titanium and boron. The TiB particles limited the growth of the grain size in the titanium from the nanocrystalline structure in the powder to sizes in the range 600 nm-4 μm after consolidation. The consolidated material was hot tensile tested at a range of temperatures and strain rates. A superplastic elongation of 310% was achieved when testing at 900°C at a strain rate of 6 × 10 s -1 compared with 220% for conventional Ti-6Al-4V sheet. However, extensive cavitation, induced by the presence of argon, occurred during high temperature deformation and limited the superplastic extensions achieved.

The sources of contrast in metals and alloys, which are exploited in photoemission electron microscopy, and the problems of image interpretation which may arise, are summarised and discussed in relation to the design of the Balzers KE3 Metioscope. The preparation procedures for the different types of specimen which may be used are briefly described. The relative advantages and disadvantages of photoemission electron microscopy in comparison with other “in situ” high-temperature dynamical microscopical techniques are discussed in relation to the field of metallurgical research, and some examples of recent results obtained with the Balzers KE3 Metioscope are given which illustrate the potential of the technique.

Objectives.—To determine the relationship between levels of ouabain-like compounds (OLC) in the cerebrospinal fluid (CSF) and the occurence of idiopathic intracranial hypertension (IIH). Background.—OLC are naturally occurring inhibitors of the sodium-potassium ATPase that are found in the CSF of mammals. Since the production of CSF is dependent upon sodium-potassium ATPase activity, and since there is evidence that the increased intracranial pressure found in the condition of IIH may be the result of increased CSF production, we hypothesized that the level of endogenous OLC would be reduced in the CSF of patients with IIH. Methods.—CSF samples were obtained from n = 7 patients with IIH and n = 31 patients with neurological disorders other than IIH (“control” patients) who had lumbar puncture as part of their routine evaluation or treatment. The concentration of OLC in the CSF samples was measured using an established ELISA. Results.—Patients with IIH exhibited a concentration of OLC in the CSF of 0.11 ± 0.03 ng/mL. In comparison, the concentration of OLC in CSF samples from non-IIH control patients was 0.12 ± 0.01 ng/mL. These values were not statistically different when compared with a t-test (P= 0.31). However, the concentration of OLC did negatively correlate to the opening pressure on lumbar puncture, but only in the IIH group (r=−0.80, P= .03). Furthermore, IIH patients who were newly diagnosed or who were unsuccessfully treated (n = 5 of 7 IIH patients) exhibited OLC concentrations of 0.06 ± 0.1 ng/mL, which is nearly lower than that of the control group (P= .06). Conclusions.—The average concentration of OLC in IIH patients (treated and untreated) is unlikely to be distinguishable from that in non-IIH control patients with other neurological conditions. However, the concentration of OLC may be inversely related to the intracranial pressure in patients with IIH, and it may prove to be lower in the subgroup of untreated and unsuccessfully treated IIH patients.

Introduction Limited evidence suggests that focal neurological injury (e.g., acute flaccid paralysis) caused by infection with the West Nile virus (WNV) is more common in older patients. We re-evaluate this association in a series of patients who were infected with the WNV during the 2002 epidemic. Methods We performed a retrospective chart review of 34 patients who were hospitalized for treatment of serologically confirmed WNV infection. Measurements included the patient's demographic characteristics, baseline medical diagnoses, the occurrence of symptoms and exam findings, the results of various diagnostic tests, and the patient's clinical outcome. Results Patients infected with the WNV who developed focal neurological injury were found to be comparable to patients who did not develop focal neurological injury both in terms of patient age and the number of medical conditions the patient had prior to infection. This is in contrast to WNV-infected patients who developed an encephalitis-like clinical course, or who died or were institutionalized after their hospitalization; such patients tended to be older and–in cases with a poor outcome–have more medical conditions prior to WNV infection. Conclusions In our patient group, focal neurological injury caused by WNV infection was not related to advanced patient age or to the number of medical conditions the patient had prior to infection. Our findings bring into question commonly held views about the development of focal neurological injury caused by WNV infection, and they raise concerns about the management of future WNV epidemics and the testing and use of potential antiviral treatments against this infection.

The superplastic forming (SPF) of titanium alloys is an established technology. A reduction in grain size from that of the typical sheet materials would lead to enhanced SPF properties and hence a reduction in production cycle times. This study describes the microstructural development and superplastic behaviour of fine-grained Ti-6%Al-4%V alloys. Ball-milling Ti-6%Al-4%V powder produces a nanocrystalline material; however on consolidation by hot isostatic pressing rapid grain growth occurs. Addition of boron powder during milling leads to boride precipitates in the matrix of the consolidated alloy. The precipitates are dispersed inhomogeneously, resulting in localized grain refinement. Superplastic testing revealed cavitation formation but in comparison to conventional sheet material, large elongations were achieved at relatively high strain rates.

The reduction in grain size of a metal can lead to significant improvement in mechanical properties. Mechanical alloying (MA) with a second phase is a possible route to producing fine-grained, particulate reinforced material. This study describes the microstructural development of Ti-6%Al-4%V milled with increasing concentrations of boron. Mechanical milling of Ti-6%Al-4%V powder produces a nanocrystalline material. MA of Ti-6%Al-4%V with boron results in the alloying of the two to form either a boride or an amorphous phase when the local concentration of boron is ∼ 50 at.%. During milling, the boron tends to remain near to its original particle form and in these boron-rich regions TiB is formed. Beyond these regions small amounts of boron (a few at.%) mix with the titanium matrix and reduce further the grain size of the titanium. An increase in the global concentration of boron increases the volume fraction of boride produced.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. © 2011 Macmillan Publishers Limited. All rights reserved.