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81.
J Steinbuch AC van Dijk FHBM Schreuder MTB Truijman J Hendrikse PJ Nederkoorn A van der Lugt E Hermeling APG Hoeks WH Mess 《Cardiovascular ultrasound》2017,15(1):9
Background
Mean or maximal intima-media thickness (IMT) is commonly used as surrogate endpoint in intervention studies. However, the effect of normalization by surrounding or median IMT or by diameter is unknown. In addition, it is unclear whether IMT inhomogeneity is a useful predictor beyond common wall parameters like maximal wall thickness, either absolute or normalized to IMT or lumen size. We investigated the interrelationship of common carotid artery (CCA) thickness parameters and their association with the ipsilateral internal carotid artery (ICA) stenosis degree.Methods
CCA thickness parameters were extracted by edge detection applied to ultrasound B-mode recordings of 240 patients. Degree of ICA stenosis was determined from CT angiography.Results
Normalization of maximal CCA wall thickness to median IMT leads to large variations. Higher CCA thickness parameter values are associated with a higher degree of ipsilateral ICA stenosis (p?<?0.001), though IMT inhomogeneity does not provide extra information. When the ratio of wall thickness and diameter instead of absolute maximal wall thickness is used as risk marker for having moderate ipsilateral ICA stenosis (>50%), 55 arteries (15%) are reclassified to another risk category.Conclusions
It is more reasonable to normalize maximal wall thickness to end-diastolic diameter rather than to IMT, affecting risk classification and suggesting modification of the Mannheim criteria.Trial registration
Clinical trials.gov NCT01208025.82.
Cecilia Wieder Clment Frainay Nathalie Poupin Pablo Rodríguez-Mier Florence Vinson Juliette Cooke Rachel PJ Lai Jacob G. Bundy Fabien Jourdan Timothy Ebbels 《PLoS computational biology》2021,17(9)
Over-representation analysis (ORA) is one of the commonest pathway analysis approaches used for the functional interpretation of metabolomics datasets. Despite the widespread use of ORA in metabolomics, the community lacks guidelines detailing its best-practice use. Many factors have a pronounced impact on the results, but to date their effects have received little systematic attention. Using five publicly available datasets, we demonstrated that changes in parameters such as the background set, differential metabolite selection methods, and pathway database used can result in profoundly different ORA results. The use of a non-assay-specific background set, for example, resulted in large numbers of false-positive pathways. Pathway database choice, evaluated using three of the most popular metabolic pathway databases (KEGG, Reactome, and BioCyc), led to vastly different results in both the number and function of significantly enriched pathways. Factors that are specific to metabolomics data, such as the reliability of compound identification and the chemical bias of different analytical platforms also impacted ORA results. Simulated metabolite misidentification rates as low as 4% resulted in both gain of false-positive pathways and loss of truly significant pathways across all datasets. Our results have several practical implications for ORA users, as well as those using alternative pathway analysis methods. We offer a set of recommendations for the use of ORA in metabolomics, alongside a set of minimal reporting guidelines, as a first step towards the standardisation of pathway analysis in metabolomics. 相似文献
83.
The effect of interfacial parameters on cup-bone relative micromotions. A finite element investigation. 总被引:6,自引:0,他引:6
Achieving stability is a prerequisite for allowing bone to grow into the porous surface of non-cemented acetabular cups. The purpose of this study is to estimate the effects of interfacial characteristics on relative cyclical micromotion between cup and bone during gait in the immediate postoperative phase. The technique used is finite element analysis. Six models with different interfacial characteristics are created in order to study the effects of fixation technique. These include representation of a 1 mm press-fit, 2 mm press-fits (with and without an initial polar gap) and exact-fit conditions (with and without additional screw fixation). Although direct validation of the model has not been performed, the calculated micromotions under a static load of 1112 N are compared with appropriate experimental data. Generally, the model tends to underestimate micromotion and this underestimate is significant in the case of relative surface-normal micromotion in polar regions for models with low- and no-interference. The most likely cause of this significant underestimate is a failure of the model to accurately represent penetration of rough contacting surfaces under compression. Other types of micromotion, although low, are within standard deviations reported by Kwong et al. (1994 Journal of Arthroplasty 9, 163-170). Quasi-static joint contact and muscle forces, representative of the stance phase of gait are then applied and maximum micromotions are found to occur consistently prior to toe off: this being the point of maximum force. With regard to the press-fit simulations, good cup-bone contact in the superior region of the interface is required for stability and the greatest micromotions occur in the models with the larger interference and larger polar gaps. In contrast to the press-fit models, muscle activity in exact-fit models influences the calculations. Specifically, the early activity of m.semimembranosus modelled causes opening of the peripheral seal. Taken together it is found that polar gaps reduce the stability of the model and lack of pre-compresssion in the periphery allows this region of the interface to be opened up. 相似文献
84.
BackgroundPeople with severe mental illness (SMI) have higher rates of a range of physical health conditions, yet little is known regarding the clustering of physical health conditions in this population. We aimed to investigate the prevalence and clustering of chronic physical health conditions in people with SMI, compared to people without SMI.Methods and findingsWe performed a cohort-nested accumulated prevalence study, using primary care data from the Clinical Practice Research Datalink (CPRD), which holds details of 39 million patients in the United Kingdom. We identified 68,783 adults with a primary care diagnosis of SMI (schizophrenia, bipolar disorder, or other psychoses) from 2000 to 2018, matched up to 1:4 to 274,684 patients without an SMI diagnosis, on age, sex, primary care practice, and year of registration at the practice. Patients had a median of 28.85 (IQR: 19.10 to 41.37) years of primary care observations. Patients with SMI had higher prevalence of smoking (27.65% versus 46.08%), obesity (24.91% versus 38.09%), alcohol misuse (3.66% versus 13.47%), and drug misuse (2.08% versus 12.84%) than comparators. We defined 24 physical health conditions derived from the Elixhauser and Charlson comorbidity indices and used logistic regression to investigate individual conditions and multimorbidity. We controlled for age, sex, region, and ethnicity and then additionally for health risk factors: smoking status, alcohol misuse, drug misuse, and body mass index (BMI). We defined multimorbidity clusters using multiple correspondence analysis (MCA) and K-means cluster analysis and described them based on the observed/expected ratio. Patients with SMI had higher odds of 19 of 24 conditions and a higher prevalence of multimorbidity (odds ratio (OR): 1.84; 95% confidence interval [CI]: 1.80 to 1.88, p < 0.001) compared to those without SMI, particularly in younger age groups (males aged 30 to 39: OR: 2.49; 95% CI: 2.27 to 2.73; p < 0.001; females aged 18 to 30: OR: 2.69; 95% CI: 2.36 to 3.07; p < 0.001). Adjusting for health risk factors reduced the OR of all conditions. We identified 7 multimorbidity clusters in those with SMI and 7 in those without SMI. A total of 4 clusters were common to those with and without SMI; while 1, heart disease, appeared as one cluster in those with SMI and 3 distinct clusters in comparators; and 2 small clusters were unique to the SMI cohort. Limitations to this study include missing data, which may have led to residual confounding, and an inability to investigate the temporal associations between SMI and physical health conditions.ConclusionsIn this study, we observed that physical health conditions cluster similarly in people with and without SMI, although patients with SMI had higher burden of multimorbidity, particularly in younger age groups. While interventions aimed at the general population may also be appropriate for those with SMI, there is a need for interventions aimed at better management of younger-age multimorbidity, and preventative measures focusing on diseases of younger age, and reduction of health risk factors.In an observational analysis of primary care data from the UK, Naomi Launders and colleagues study the prevalence and clustering of physical health conditions and multimorbidity in individuals with severe mental illnesses. 相似文献
85.
Highly efficient induction of protective immunity by a vaccinia virus vector defective in late gene expression 总被引:3,自引:0,他引:3 下载免费PDF全文
Holzer GW Remp G Antoine G Pfleiderer M Enzersberger OM Emsenhuber W Hämmerle T Gruber F Urban C Falkner FG Dorner F 《Journal of virology》1999,73(6):4536-4542
Vaccinia viruses defective in the essential gene coding for the enzyme uracil DNA glycosylase (UDG) do not undergo DNA replication and do not express late genes in wild-type cells. A UDG-deficient vaccinia virus vector carrying the tick-borne encephalitis (TBE) virus prM/E gene, termed vD4-prME, was constructed, and its potential as a vaccine vector was evaluated. High-level expression of the prM/E antigens could be demonstrated in infected complementing cells, and moderate levels were found under noncomplementing conditions. The vD4-prME vector was used to vaccinate mice; animals receiving single vaccination doses as low as 10(4) PFU were fully protected against challenge with high doses of virulent TBE virus. Single vaccination doses of 10(3) PFU were sufficient to induce significant neutralizing antibody titers. With the corresponding replicating virus, doses at least 10-fold higher were needed to achieve protection. The data indicate that late gene expression of the vaccine vector is not required for successful vaccination; early vaccinia virus gene expression induces a potent protective immune response. The new vaccinia virus-based defective vectors are therefore promising live vaccines for prophylaxis and cancer immunotherapy. 相似文献
86.
87.
Chemical synthesis and biological characterization of phosphorothioate analogs of 2', 5'-3'-deoxyadenylate trimer. 总被引:1,自引:1,他引:0 下载免费PDF全文
In continued studies to elucidate the requirements for binding to and activation of the 2',5'-oligoadenylate (2-5A) dependent endoribonuclease (RNase L), four 2-5A trimer analogs were examined to evaluate the effect of chirality of phosphorothioate substitution on biological activity. The chemical syntheses and purification of the four isomers of P-thio-3'-deoxyadenylyl-(2'-5')-P-thio-3'- deoxyadenylyl-(2'-5')-3'-deoxyadenosine, by the phosphoramidite approach, is described. The isolated intermediates were characterized by elemental and spectral analyses. The fully deblocked compounds were characterized by 1H and 31P NMR and HPLC analyses. The 2',5'-(3'dA)3 cores with either Rp or Sp chirality in the 2',5'-internucleotide linkages will bind to but will not activate RNase L. This is in contrast to 2',5'-A3 core analogs with either RpRp or SpRp phosphorothioate substitution in the 2',5'-internucleotide linkages which can bind to and activate RNase L. There are also marked differences in the ability of the 2',5'-A3 analogs to activate RNase L following introduction of the 5'-monophosphate. For example, the 5'monophosphates of 2',5'-(3'dA)3-RpRp and 2',5'-(3'dA)3-SpRp can bind to and activate RNase L, whereas the 5'-monophosphates of 2',5'-(3'dA)3-RpSp and 2',5'-(3'dA)3-SpSp can bind to but can not activate RNase L. 相似文献
88.
Improved analyses of human mtDNA sequences support a recent African origin for Homo sapiens 总被引:3,自引:1,他引:2
New quantitative methods are applied to the 135 human mitochondrial
sequences from the Vigilant et al. data set. General problems in analyzing
large numbers of short sequences are discussed, and an improved strategy is
suggested. A key feature is to focus not on individual trees but on the
general "landscape" of trees. Over 1,000 searches were made from random
starting trees with only one tree (a local optimum) being retained each
time, thereby ensuring optima were found independently. A new tree
comparison metric was developed that is unaffected by rearrangements of
trees around many very short internal edges. Use of this metric showed that
downweighting hypervariable sites revealed more evolutionary structure than
studies that weighted all sites equally. Our results are consistent with
convergence toward a global optimum. Crucial features are that the best
optima show very strong regional differentiation, a common group of 49
African sequences is found in all the best optima, and the best optima
contain the 16 !Kung sequences in a separate group of San people. The other
86 sequences form a heterogeneous mixture of Africans, Europeans,
Australopapuans, and Asians. Thus all major human lineages occur in Africa,
but only a subset occurs in the rest of the world. The existence of these
African-only groups strongly contradicts multiregional theories for the
origin of Homo sapiens that require widespread migration and interbreeding
over the entire range of H. erectus. Only when the multiregional model is
rejected is it appropriate to consider the root, based on a single locus,
to be the center of origin of a population (otherwise different loci could
give alternative geographic positions for the root). For this data, several
methods locate the root within the group of 49 African sequences and are
thus consistent with the recent African origin of H. sapiens. We
demonstrate that the time of the last common ancestor cannot be the time of
major expansion in human numbers, and our results are thus also consistent
with recent models that differentiate between the last common ancestor,
expansion out of Africa, and the major expansion in human populations. Such
a two-phase model is consistent with a wide range of molecular and
archeological evidence.
相似文献
89.
A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages 总被引:17,自引:13,他引:4
Lockhart PJ; Steel MA; Barbrook AC; Huson DH; Charleston MA; Howe CJ 《Molecular biology and evolution》1998,15(9):1183-1188
The aims of the work were (1) to develop statistical tests to identify
whether substitution takes place under a covariotide model in sequences
used for phylogenetic inference and (2) to determine the influence of
covariotide substitution on phylogenetic trees inferred for photosynthetic
and other organisms. (Covariotide and covarion models are ones in which
sites that are variable in some parts of the underlying tree are invariable
in others and vice versa.) Two tests were developed. The first was a
contingency test, and the second was an inequality test comparing the
expected number of variable sites in two groups with the observed number.
Application of these tests to 16S rDNA and tufA sequences from a range of
nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and
eukaryotes suggests the occurrence of a covariotide mechanism. The degree
of support for partitioning of taxa in reconstructed trees involving these
organisms was determined in the presence or absence of sites showing
particular substitution patterns. This analysis showed that the support for
splits between (1) photosynthetic eukaryotes and prokaryotes and (2)
photosynthetic and nonphotosynthetic organisms could be accounted for by
patterns arising from covariotide substitution. We show that the additional
problem of compositional bias in sequence data needs to be considered in
the context of patterns of covariotide/covarion substitution. We argue that
while covariotide or covarion substitution may give rise to
phylogenetically informative patterns in sequence data, this may not always
be so.
相似文献
90.
Y Devash A Gera D H Willis M Reichman W Pfleiderer R Charubala I Sela R J Suhadolnik 《The Journal of biological chemistry》1984,259(6):3482-3486
The effect of the 5'-dephosphorylated 2',5'-adenylate trimer and its 2',5'-trimer core analogs on the inhibition of tobacco mosaic virus (TMV) replication was determined in tobacco leaf discs, protoplasts, and whole tobacco plants, using infectivity tests and enzyme-linked immunosorbent assays. A structure-activity-metabolic stability-toxicity analysis of the 2',5'-adenylate trimer core molecule in TMV-infected Nicotiana glutinosa was determined. Modification at either the 6-amino position of the adenylate residues (i.e. inosinate trimer core) or at the 2' terminus (i.e. A-A-ara-A or A-A-Tu) inhibited replication of TMV. Modification of the 3'-hydroxyl group of the adenylate residues to 3-deoxyribose (i.e. the 2',5'-cordycepin trimer core) inhibited TMV replication better than the 2',5'-adenylate trimer core molecule. With enzyme-linked immunosorbent assays, there was complete inhibition of TMV replication by 200 nM 2',5'-adenylate trimer core for 60 h and by 200 nM 2',5'-cordycepin trimer core for 96 h. The amount of 2',5'-oligonucleotides associated with the leaves was determined using 2',5'-[3H]cordycepin trimer core; 1 X 10(-12) mol/cm2 of plant leaves inhibited TMV replication by 99%. No 2',5'-phosphodiesterase activity was detected in TMV-infected and noninfected leaf extracts. Therefore, the 2',5'-trimer cores were potent inhibitors of TMV replication at nanomolar concentrations, i.e. at 1000-fold lower concentration than that required in mammalian systems. 相似文献