Sensitivity and specificity of the ankle–brachial index to diagnose peripheral artery disease: a structured review

The ankle—brachial index (ABI) is a simple, inexpensive diagnostic test for peripheral artery disease (PAD). However, it has shown variable accuracy for identification of significant stenosis. The authors performed a structured review of the sensitivity and specificity of ABI ≤ 0.90 for the diagnosis of PAD. MEDLINE, EMBASE, Cochrane databases, Science Citation Index database, and Biological Abstracts database were searched for studies of the sensitivity and specificity of using ABI ≤ 0.90 for the diagnosis of PAD. Eight studies comprising 2043 patients (or limbs) met the inclusion criteria. The result indicated that, although strict inclusion criteria on studies were formulated, different reference standards were found in these studies, and methods of ABI determination and characteristics of populations varied greatly. A high level of specificity (83.3—99.0%) and accuracy (72.1—89.2%) was reported for an ABI ≤ 0.90 in detecting ≥ 50% stenosis, but there were different levels of sensitivity (15—79%). Sensitivity was low, especially in elderly individuals and patients with diabetes. In conclusion, the test of ABI ≤ 0.90 can be a simple and useful tool to identify PAD with serious stenosis, and may be substituted for other non-invasive tests in clinical practice

Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

Disk or Companion: Characterizing Excess Infrared Flux in Seven White Dwarf Systems with Near-Infrared Spectroscopy

Excess infrared flux from white dwarf stars is likely to arise from a dusty debris disk or a cool companion. In this work, we present near-infrared spectroscopic observations with Keck/MOSFIRE, Gemini/GNIRS, and Gemini/Flamingos-2 of seven white dwarfs with infrared excesses identified in previous studies. We confirmed the presence of dust disks around four white dwarfs (Gaia J0611-6931, Gaia J0006+2858, Gaia J2100+2122, and WD 0145+234) as well as two new white dwarf brown dwarf pairs (Gaia J0052+4505 and Gaia J0603+4518). In three of the dust disk systems, we detected for the first time near-infrared metal emissions (Mg I, Fe I, and Si I) from a gaseous component of the disk. We developed a new Markov Chain Monte Carlo framework to constrain the geometric properties of each dust disk. In three systems, the dust disk and the gas disk appear to coincide spatially. For the two brown dwarf white dwarf pairs, we identified broad molecular absorption features typically seen in L dwarfs. The origin of the infrared excess around Gaia J0723+6301 remains a mystery. Our study underlines how near-infrared spectroscopy can be used to determine sources of infrared excess around white dwarfs, which has now been detected in hundreds of systems photometrically.Comment: 23 pages, 10 figures, 5 tables, AJ, in pres

Isorhamnetin, A Flavonol Aglycone from Ginkgo biloba L., Induces Neuronal Differentiation of Cultured PC12 Cells: Potentiating the Effect of Nerve Growth Factor

Flavonoids, a group of compounds mainly derived from vegetables and herbal medicines, share a chemical resemblance to estrogen, and indeed some of which have been used as estrogen substitutes. In searching for possible functions of flavonoids, the neuroprotective effect in brain could lead to novel treatment, or prevention, for neurodegenerative diseases. Here, different subclasses of flavonoids were analyzed for its inductive role in neurite outgrowth of cultured PC12 cells. Amongst the tested flavonoids, a flavonol aglycone, isorhamnetin that was isolated mainly from the leaves of Ginkgo biloba L. showed robust induction in the expression of neurofilament, a protein marker for neurite outgrowth, of cultured PC12 cells. Although isorhamnetin by itself did not show significant inductive effect on neurite outgrowth of cultured PC12 cells, the application of isorhamnetin potentiated the nerve growth factor- (NGF-)induced neurite outgrowth. In parallel, the expression of neurofilaments was markedly increased in the cotreatment of NGF and isorhamnetin in the cultures. The identification of these neurite-promoting flavonoids could be very useful in finding potential drugs, or food supplements, for treating various neurodegenerative diseases, including Alzheimer's disease and depression

Protease-Independent Production of Poliovirus Virus-like Particles in Pichia pastoris: Implications for Efficient Vaccine Development and Insights into Capsid Assembly

The production of enterovirus virus-like particles (VLPs) that lack the viral genome have great potential as vaccines for a number of diseases, such as poliomyelitis and hand, foot, and mouth disease. These VLPs can mimic empty capsids, which are antigenically indistinguishable from mature virions, produced naturally during viral infection. Both in infection and in vitro, capsids and VLPs are generated by the cleavage of the P1 precursor protein by a viral protease. Here, using a stabilized poliovirus 1 (PV-1) P1 sequence as an exemplar, we show the production of PV-1 VLPs in Pichia pastoris in the absence of the potentially cytotoxic protease, 3CD, instead using the porcine teschovirus 2A (P2A) peptide sequence to terminate translation between individual capsid proteins. We compare this to protease-dependent production of PV-1 VLPs. Analysis of all permutations of the order of the capsid protein sequences revealed that only VP3 could be tagged with P2A and maintain native antigenicity. Transmission electron microscopy of these VLPs reveals the classic picornaviral icosahedral structure. Furthermore, these particles were thermostable above 37°C, demonstrating their potential as next generation vaccine candidates for PV. Finally, we believe the demonstration that native antigenic VLPs can be produced using protease-independent methods opens the possibility for future enteroviral vaccines to take advantage of recent vaccine technological advances, such as adenovirus-vectored vaccines and mRNA vaccines, circumventing the potential problems of cytotoxicity associated with 3CD, allowing for the production of immunogenic enterovirus VLPs in vivo. IMPORTANCE The widespread use of vaccines has dramatically reduced global incidence of poliovirus infections over a period of several decades and now the wild-type virus is only endemic in Pakistan and Afghanistan. However, current vaccines require the culture of large quantities of replication-competent virus for their manufacture, thus presenting a potential risk of reintroduction into the environment. It is now widely accepted that vaccination will need to be extended posteradication into the foreseeable future to prevent the potentially catastrophic reintroduction of poliovirus into an immunologically naive population. It is, therefore, imperative that novel vaccines are developed which are not dependent on the growth of live virus for their manufacture. We have expressed stabilized virus-like particles in yeast, from constructs that do not require coexpression of the protease. This is an important step in the development of environmentally safe and commercially viable vaccines against polio, which also provides some intriguing insights into the viral assembly process

Transcriptome analysis reveals manifold mechanisms of cyst development in ADPKD

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes progressive loss of renal function in adults as a consequence of the accumulation of cysts. ADPKD is the most common genetic cause of end-stage renal disease. Mutations in polycystin-1 occur in 87% of cases of ADPKD and mutations in polycystin-2 are found in 12% of ADPKD patients. The complexity of ADPKD has hampered efforts to identify the mechanisms underlying its pathogenesis. No current FDA (Federal Drug Administration)-approved therapies ameliorate ADPKD progression. RESULTS: We used the de Almeida laboratory's sensitive new transcriptogram method for whole-genome gene expression data analysis to analyze microarray data from cell lines developed from cell isolates of normal kidney and of both non-cystic nephrons and cysts from the kidney of a patient with ADPKD. We compared results obtained using standard Ingenuity Volcano plot analysis, Gene Set Enrichment Analysis (GSEA) and transcriptogram analysis. Transcriptogram analysis confirmed the findings of Ingenuity, GSEA, and published analysis of ADPKD kidney data and also identified multiple new expression changes in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways related to cell growth, cell death, genetic information processing, nucleotide metabolism, signal transduction, immune response, response to stimulus, cellular processes, ion homeostasis and transport and cofactors, vitamins, amino acids, energy, carbohydrates, drugs, lipids, and glycans. Transcriptogram analysis also provides significance metrics which allow us to prioritize further study of these pathways. CONCLUSIONS: Transcriptogram analysis identifies novel pathways altered in ADPKD, providing new avenues to identify both ADPKD's mechanisms of pathogenesis and pharmaceutical targets to ameliorate the progression of the disease

Isospin dependence of collective flow in heavy-ion collisions at intermediate energies

Within the framework of an isospin-dependent Boltzmann-Uehling-Uhlenbeck (BUU) model using initial proton and neutron densities calculated from the nonlinear relativistic mean-field (RMF) theory, we compare the strength of transverse collective flow in reactions $^{48}Ca+^{58}Fe$ and $^{48}Cr+^{58}Ni$, which have the same mass number but different neutron/proton ratios. The neutron-rich system ($^{48}Ca+^{58}Fe$) is found to show significantly stronger negative deflection and consequently has a higher balance energy, especially in peripheral collisions. NOTE ADDED IN PROOF: The new phenomenon predicted in this work has just been confirmed by an experiment done by G.D. Westfall et al. using the NSCL/MSU radioactive beam facility and a spartan soccer. A paper by R. Pak et al. is submitted to PRL to report the experimental result.Comment: Latex file, 9 pages, 4 figures availabe upon request; Phys. Rev. Lett. (June 3, 1996) in pres

The effect of artificial selection on phenotypic plasticity in maize

Remarkable productivity has been achieved in crop species through artificial selection and adaptation to modern agronomic practices. Whether intensive selection has changed the ability of improved cultivars to maintain high productivity across variable environments is unknown. Understanding the genetic control of phenotypic plasticity and genotype by environment (G × E) interaction will enhance crop performance predictions across diverse environments. Here we use data generated from the Genomes to Fields (G2F) Maize G × E project to assess the effect of selection on G × E variation and characterize polymorphisms associated with plasticity. Genomic regions putatively selected during modern temperate maize breeding explain less variability for yield G × E than unselected regions, indicating that improvement by breeding may have reduced G × E of modern temperate cultivars. Trends in genomic position of variants associated with stability reveal fewer genic associations and enrichment of variants 0–5000 base pairs upstream of genes, hypothetically due to control of plasticity by short-range regulatory elements

Can it be harmful for parents to talk to their child about their weight? A meta-analysis

Many parents express concern that raising the issue of weight risks harming their child's physical self-perceptions and wellbeing. Such concerns can deter families from engaging with weight management services. This systematic review aimed to investigate the evidence behind these concerns by analysing the association between parent-child weight-talk and child wellbeing. A systematic search of eight databases identified four intervention studies and 38 associative studies. Meta-analysis was only possible for the associative studies; to facilitate more meaningful comparisons, weight-talk was categorized into four communication types and effect size estimates for the association between these and wellbeing indicators were calculated through a random effects model. Encouraging children to lose weight and criticizing weight were associated with poorer physical self-perceptions and greater dieting and dysfunctional eating (effect sizes: 0.20 to 0.47). Conversely, parental encouragement of healthy lifestyles without explicit reference to weight was associated with better wellbeing, but this was only measured in two studies. Of the four intervention studies, only one isolated the effects of parents' communication on wellbeing outcomes, reporting a positive effect. There was no effect of age on the strength of associations, but dysfunctional eating was more strongly associated with parent communication for girls than boys. The findings indicate that some forms of parent-child weight-talk are associated with poor wellbeing, but suggest that this is not inevitable. Encouraging healthy behaviours without reference to weight-control, and positive parental involvement in acknowledging and addressing weight-concern may avoid such outcomes. More longitudinal research is needed to analyse the direction of these effects