The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

© ERS 2018. The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged < 7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3–6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible

Micro-fabrication of Carbon Structures by Pattern Miniaturization in Resorcinol-Formaldehyde Gel

A simple and novel method to fabricate and miniaturize surface and sub-surface micro-structures and micro-patterns in glassy carbon is proposed and demonstrated. An aqueous resorcinol-formaldehyde (RF) sol is employed for micro-molding of the master-pattern to be replicated, followed by controlled drying and pyrolysis of the gel to reproduce an isotropically shrunk replica in carbon. The miniaturized version of the master-pattern thus replicated in carbon is about one order of magnitude smaller than original master by repeating three times the above cycle of molding and drying. The micro-fabrication method proposed will greatly enhance the toolbox for a facile fabrication of a variety of Carbon-MEMS and C-microfluidic devices.Comment: 16 pages, 5 figure

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

Highly efficient separation of actinides from lanthanides by a phenanthroline-derived bis-triazine ligand

The synthesis, lanthanide complexation, and solvent ex- traction of actinide(III) and lanthanide(III) radiotracers from nitric acid solutions by a phenanthroline-derived quadridentate bis-triazine ligand are described. The ligand separates Am(III) and Cm(III) from the lanthanides with remarkably high efficiency, high selectivity, and fast extraction kinetics compared to its 2,2'-bipyridine counterpart. Structures of the 1:2 bis-complexes of the ligand with Eu(III) and Yb(III) were elucidated by X-ray crystallography and force field calculations, respec-tively. The Eu(III) bis-complex is the first 1:2 bis-complex of a quadridentate bis-triazine ligand to be characterized by crystallography. The faster rates of extraction were verified by kinetics measurements using the rotating membrane cell technique in several diluents. The improved kinetics of metal ion extraction are related to the higher surface activity of the ligand at the phase interface. The improvement in the ligand's properties on replacing the bipyridine unit with a phenanthroline unit far exceeds what was anticipated based on ligand design alone

Socioeconomic position Is associated with carotid intima-media thickness in mid-childhood: The longitudinal study of Australian children

Background: Lower socioeconomic position (SEP) predicts higher cardiovascular risk in adults. Few studies differentiate between neighborhood and family SEP or have repeated measures through childhood, which would inform understanding of potential mechanisms and the timing of interventions. We investigated whether neighborhood and family SEP, measured biennially from ages 0 to 1 year onward, was associated with carotid intima-media thickness (IMT) at ages 11 to 12 years.Methods and Results: Data were obtained from 1477 families participating in the Child Health CheckPoint study, nested within the Longitudinal Study of Australian Children. Disadvantaged family and neighborhood SEP was cross-sectionally associated with thicker maximum carotid IMT in separate univariable linear regression models. Associations with family SEP were not attenuated in multivariable analyses, and associations with neighborhood SEP were attenuated only in models adjusted for family SEP. The difference in maximum carotid IMT between the highest and lowest family SEP quartile measured at ages 10 to 11 years was 10.7 μm (95% CI, 3.4-18.0; P=0.004), adjusted for age, sex, pubertal status, passive smoking exposure, body mass index, blood pressure, and arterial lumen diameter. In longitudinal analyses, family SEP measured as early as age 2 to 3 years was associated with maximum carotid IMT at ages 11 to 12 years (difference between highest and lowest quartile: 8.5 μm; 95% CI, 1.3-15.8; P=0.02). No associations were observed between SEP and mean carotid IMT.Conclusions: We report a robust association between lower SEP in early childhood and carotid IMT in mid-childhood. Further investigation of mechanisms may inform pediatric cardiovascular risk assessment and prevention strategies

Socioeconomic Position Is Associated With Carotid Intima-Media Thickness in Mid-Childhood: The Longitudinal Study of Australian Children

Background Lower socioeconomic position (SEP) predicts higher cardiovascular risk in adults. Few studies differentiate between neighborhood and family SEP or have repeated measures through childhood, which would inform understanding of potential mechanisms and the timing of interventions. We investigated whether neighborhood and family SEP, measured biennially from ages 0 to 1 year onward, was associated with carotid intima–media thickness (IMT) at ages 11 to 12 years.Methods and Results Data were obtained from 1477 families participating in the Child Health CheckPoint study, nested within the Longitudinal Study of Australian Children. Disadvantaged family and neighborhood SEP was cross‐sectionally associated with thicker maximum carotid IMT in separate univariable linear regression models. Associations with family SEP were not attenuated in multivariable analyses, and associations with neighborhood SEP were attenuated only in models adjusted for family SEP. The difference in maximum carotid IMT between the highest and lowest family SEP quartile measured at ages 10 to 11 years was 10.7 μm (95% CI, 3.4–18.0; P=0.004), adjusted for age, sex, pubertal status, passive smoking exposure, body mass index, blood pressure, and arterial lumen diameter. In longitudinal analyses, family SEP measured as early as age 2 to 3 years was associated with maximum carotid IMT at ages 11 to 12 years (difference between highest and lowest quartile: 8.5 μm; 95% CI, 1.3–15.8; P=0.02). No associations were observed between SEP and mean carotid IMT.Conclusions We report a robust association between lower SEP in early childhood and carotid IMT in mid‐childhood. Further investigation of mechanisms may inform pediatric cardiovascular risk assessment and prevention strategies.</ul

Rates of Progression in Diabetic Retinopathy During Different Time Periods: A systematic review and meta-analysis

10.2337/dc09-0615Diabetes Care32122307-2313DICA

The High-Resolution Coronal Imager, Flight 2.1

The third flight of the High-Resolution Coronal Imager (Hi-C 2.1) occurred on May 29, 2018; the Sounding Rocket was launched from White Sands Missile Range in New Mexico. The instrument has been modified from its original configuration (Hi-C 1) to observe the solar corona in a passband that peaks near 172 Å, and uses a new, custom-built low-noise camera. The instrument targeted Active Region 12712, and captured 78 images at a cadence of 4.4 s (18:56:22 – 19:01:57 UT; 5 min and 35 s observing time). The image spatial resolution varies due to quasi-periodic motion blur from the rocket; sharp images contain resolved features of at least 0.47 arcsec. There are coordinated observations from multiple ground- and space-based telescopes providing an unprecedented opportunity to observe the mass and energy coupling between the chromosphere and the corona. Details of the instrument and the data set are presented in this paper