Performance metrics of an optical spectral imaging system for intra-operative assessment of breast tumor margins.

As many as 20-70% of patients undergoing breast conserving surgery require repeat surgeries due to a close or positive surgical margin diagnosed post-operatively [1]. Currently there are no widely accepted tools for intra-operative margin assessment which is a significant unmet clinical need. Our group has developed a first-generation optical visible spectral imaging platform to image the molecular composition of breast tumor margins and has tested it clinically in 48 patients in a previously published study [2]. The goal of this paper is to report on the performance metrics of the system and compare it to clinical criteria for intra-operative tumor margin assessment. The system was found to have an average signal to noise ratio (SNR) >100 and <15% error in the extraction of optical properties indicating that there is sufficient SNR to leverage the differences in optical properties between negative and close/positive margins. The probe had a sensing depth of 0.5-2.2 mm over the wavelength range of 450-600 nm which is consistent with the pathologic criterion for clear margins of 0-2 mm. There was <1% cross-talk between adjacent channels of the multi-channel probe which shows that multiple sites can be measured simultaneously with negligible cross-talk between adjacent sites. Lastly, the system and measurement procedure were found to be reproducible when evaluated with repeated measures, with a low coefficient of variation (<0.11). The only aspect of the system not optimized for intra-operative use was the imaging time. The manuscript includes a discussion of how the speed of the system can be improved to work within the time constraints of an intra-operative setting.

Effect of peak inert-mode temperature on elemental carbon measured using thermal-optical analysis

Thermal-optical analysis is a conventional method for classifying carbonaceous aerosols as organic carbon (OC) and elemental carbon (EC). This article examines the effects of three different temperature protocols on the measured EC. For analyses of parallel punches from the same ambient sample, the protocol with the highest peak helium-mode temperature (870°C) gives the smallest amount of EC, while the protocol with the lowest peak helium-mode temperature (550°C) gives the largest amount of EC. These differences are observed when either sample transmission or reflectance is used to define the OC/EC split. An important issue is the effect of the peak helium-mode temperature on the relative rate at which different types of carbon with different optical properties evolve from the filter. Analyses of solvent-extracted samples are used to demonstrate that high temperatures (870°C) lead to premature EC evolution in the helium-mode. For samples collected in Pittsburgh, this causes the measured EC to be biased low because the attenuation coefficient of pyrolyzed carbon is consistently higher than that of EC. While this problem can be avoided by lowering the peak helium-mode temperature, analyses of wood smoke dominated ambient samples and levoglucosan-spiked filters indicate that too low helium-mode peak temperatures (550°C) allow non-light absorbing carbon to slip into the oxidizing mode of the analysis. If this carbon evolves after the OC/EC split, it biases the EC measurements high. Given the complexity of ambient aerosols, there is unlikely to be a single peak helium-mode temperature at which both of these biases can be avoided. Copyright © American Association for Aerosol Research.

One hundred years of forgetting: A quantitative description of retention

A sample of 210 published data sets were assembled that (a) plotted amount remembered versus time, (b) had 5 or more points, and (c) were smooth enough to fit at least 1 of the functions tested with a correlation coefficient of .90 or greater. Each was fit to 105 different 2-parameter functions. The best fits were to the logarithmic function, the power function, the exponential in the square root of time, and the hyperbola in the square root of time. It is difficult to distinguish among these 4 functions with the available data, but the same set of 4 functions fit most data sets, with autobiographical memory being the exception. Theoretical motivations for the best fitting functions are offered. The methodological problems of evaluating functions and the advantages of searching existing data for regularities before formulating theories are considered.

CD4 enumeration technologies: a systematic review of test performance for determining eligibility for antiretroviral therapy.

BACKGROUND: Measurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration. METHODS AND FINDINGS: Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained. CONCLUSIONS: A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.

Sensitive and precise quantification of insulin-like mRNA expression in Caenorhabditis elegans.

Insulin-like signaling regulates developmental arrest, stress resistance and lifespan in the nematode Caenorhabditis elegans. However, the genome encodes 40 insulin-like peptides, and the regulation and function of individual peptides is largely uncharacterized. We used the nCounter platform to measure mRNA expression of all 40 insulin-like peptides as well as the insulin-like receptor daf-2, its transcriptional effector daf-16, and the daf-16 target gene sod-3. We validated the platform using 53 RNA samples previously characterized by high density oligonucleotide microarray analysis. For this set of genes and the standard nCounter protocol, sensitivity and precision were comparable between the two platforms. We optimized conditions of the nCounter assay by varying the mass of total RNA used for hybridization, thereby increasing sensitivity up to 50-fold and reducing the median coefficient of variation as much as 4-fold. We used deletion mutants to demonstrate specificity of the assay, and we used optimized conditions to assay insulin-like gene expression throughout the C. elegans life cycle. We detected expression for nearly all insulin-like genes and find that they are expressed in a variety of distinct patterns suggesting complexity of regulation and specificity of function. We identified insulin-like genes that are specifically expressed during developmental arrest, larval development, adulthood and embryogenesis. These results demonstrate that the nCounter platform provides a powerful approach to analyzing insulin-like gene expression dynamics, and they suggest hypotheses about the function of individual insulin-like genes.

Effects of chronic mild traumatic brain injury on white matter integrity in iraq and afghanistan war veterans

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. © 2012 Wiley Periodicals, Inc.

Material properties, geometry and their effect on the fatigue life of two flip-chip models

This paper describes how modeling technology has been used in providing fatigue life time data of two flip-chip models. Full-scale three-dimensional modeling of flip-chips under cyclic thermal loading has been combined with solder joint stand-off height prediction to analyze the stress and strain conditions in the two models. The Coffin-Manson empirical relationship is employed to predict the fatigue life times of the solder interconnects. In order to help designers in selecting the underfill material and the printed circuit board, the Young's modulus and the coefficient of thermal expansion of the underfill, as well as the thickness of the printed circuit boards are treated as variable parameters. Fatigue life times are therefore calculated over a range of these material and geometry parameters. In this paper we will also describe how the use of micro-via technology may affect fatigue life

Reliability analysis of flip chip designs via computer simulation

A flip chip component is a silicon chip mounted to a substrate with the active area facing the substrate. This paper presents the results of an investigation into the relationship between a number of important material properties and geometric parameters on the thermal-mechanical fatigue reliability of a standard flip chip design and a flip chip design with the use of microvias. Computer modeling has been used to analyze the mechanical conditions of flip chips under cyclic thermal loading where the Coffin-Manson empirical relationship has been used to predict the life time of the solder interconnects. The material properties and geometry parameters that have been investigated are the Young's modulus, the coefficient of thermal expansion (CTE) of the underfill, the out-of-plane CTE (CTEz) of the substrate, the thickness of the substrate, and the standoff height. When these parameters vary, the predicted life-times are calculated and some of the features of the results are explained. By comparing the predicted lifetimes of the two designs and the strain conditions under thermal loading, the local CTE mismatch has been found to be one of most important factors in defining the reliability of flip chips with microvias.

Modelling the Performance of Flexible Substrates for Lead-Free Applications

In this paper, the performance of flexible substrates for lead-free applications was studied using finite element method (FEM). Firstly, the thermal induced stress in the flex substrate during the lead free solder reflow process was predicted. The shear stress at the interface between the copper track and flex was plotted. This shear stress increases with the thickness of the copper track. Secondly, an ACF flip chip was taken as a typical lead-free application of the flex substrate. The reflow effect on the reliability of ACF interconnections was analyzed. Higher stress was identified along the interface between the conductive particle and the metallization, and the interfacial stress increases with the reflow peak temperature and the coefficient of thermal expansion (CTE) of the adhesive. The moisture effect on the reliability of ACF joints were studied using a macro-micro modeling technique, the predominantly tensile stress found at the interface between the conductive particle and metallization could reduce the contact area and even cause the electrical failure. Modeling results are consistent with the findings in the experimental work

Moisture Effects on the Reliability of Anisotropic Conductive Films

Anisotropic conductive film (ACF) which consists of an adhesive epoxy matrix and randomly distributed conductive particles are widely used as the connection material for electronic devices with high I/O counts. However, for the semiconductor industry the reliability of the ACF is still a major concern due to a lack of experimental reliability data. This paper reports an investigation into the moisture effects on the reliability of ACF interconnections in the flip-chip-on-flex (FCOF) applications. A macro-micro 3D finite element modeling technique was used in order to make the multi-length-scale modeling of the ACF flip chip possible. The purposes of this modeling work was to understand the role that moisture plays in the failure of ACF flip chips, and to look into the influence of physical properties and geometric characteristics, such as the coefficient of the moisture expansion (CME), Young's modulus of the adhesive matrix and the bump height on the reliability of the ACF interconnections in a humid environment. Simulation results suggest that moisture-induced swelling of the adhesive matrix is the major cause of the ACF joint opening. Modeling results are consistent with the findings in the experimental work.

Effects of solder reflow on the reliability of flip-chip on flex interconnections using anisotropic conductive adhesives

This work describes the work of an investigation of the effects of solder reflow process on the reliability of anisotropic conductive film (ACF) interconnection for flip-chip on flex (FCOF) applications. Experiments as well as computer modeling methods have been used. The results show that the contact resistance of ACF interconnections increases after the reflow and the magnitude of the increase is strongly correlated to the peak reflow temperature. In fact, nearly 40 percent of the joints are open when the peak reflow temperature is 260°C, while there is no opening when the peak temperature is 210°C. It is believed that the coefficient of thermal expansion (CTE) mismatch between the polymer particle and the adhesive matrix is the main cause of this contact degradation. To understand this phenomenon better, a three-dimensional (3-D) finite element (FE) model of an ACF joint has been analyzed in order to predict the stress distribution in the conductive particles, adhesive matrix and metal pads during the reflow process. The stress level at the interface between the particle and its surrounding materials is significant and it is the highest at the interface between the particle and the adhesive matrix.

Computer simulation of aluminium wirebonds with globtop in power electronics modules

In this paper, computer modelling techniques are used to analyse the effects of globtops on the reliability of aluminium wirebonds in power electronics modules under cyclic thermal-mechanical loading conditions. The sensitivity of the wirehond reliability to the changes of the geometric and the material property parameters of wirebond globtop are evaluated and the optimal combination of the Young's modulus and the coefficient of thermal expansion have been predicted.

Modeling the diffusion of solid copper into liquid solder alloys

During the soldering process, the copper atoms diffuse into liquid solders. The diffusion process determines integrity and the reworking possibility of a solder joint. In order to capture the diffusion scenarios of solid copper into liquid Sn–Pb and Sn–Cu solders, a computer modeling has been performed for 10 s. An analytical model has also been proposed for calculating the diffusion coefficient of copper into liquid solders. It is found that the diffusion coefficient for Sn–Pb solder is 2.74 × 10− 10 m2/s and for Sn–Cu solder is 6.44 × 10−9 m2/s. The modeling results reveal that the diffusion coefficient is one of the major factors that govern the rate at which solid Cu dissolve in the molten solder. The predicted dissolved amounts of copper into solders have been validated with the help of scanning electron microscopic analysis.

Rheological characterisation of solder pastes and isotropic conductive adhesives used for flip-chip assembly

Solder pastes and isotropic conductive adhesives (ICAs) are widely used as a principal bonding medium in the electronic industry. This study investigates the rheological behaviour of the pastes (solder paste and isotropic conductive adhesives) used for flip-chip assembly. Oscillatory stress sweep test are performed to evaluate solid characteristic and cohesiveness of the lead-free solder pastes and isotropic conductive adhesive paste materials. The results show that the G' (storage modulus) is higher than G '' (loss modulus) for the pastes material indicating a solid like behaviour. It result shows that the linear visco-elastic region for the pastes lies in a very small stress range, below 10 Pa. in addition, the stress at which the value of storage modulus is equal to that of loss modulus can be used as an indicator of the paste cohesiveness. The measured cross-over stress at G'=G '' shows that the solder paste has higher stress at G'=G '' compared to conductive adhesives. Creep-recovery test method is used to study the slump behaviour in the paste materials. The conductive adhesive paste shows a good recovery when compared to the solder pastes. (C) 2008 Elsevier B.V. All rights reserved.

ATR-FTIR spectroscopy and spectroscopic imaging of solvent and permeant diffusion across model membranes

The uptake and diffusion of solvents across polymer membranes is important in controlled drug delivery, effects on drug uptake into, for example, infusion bags and containers, as well as transport across protective clothing. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy has been used to monitor the effects of different solvents on the diffusion of a model compound, 4-cyanophenol (CNP) across silicone membrane and on the equilibrium concentration of CNP obtained in the membrane following diffusion. ATR-FTIR spectroscopic imaging of membrane diffusion was used to gain an understanding of when the boundary conditions applied to Fick's second law, used to model the diffusion of permeants across the silicone membrane do not hold. The imaging experiments indicated that when the solvent was not taken up appreciably into the membrane, the presence of discrete solvent pools between the ATR crystal and the silicone membrane can affect the diffusion profile of the permeant. This effect is more significant if the permeant has a high solubility in the solvent. In contrast, solvents that are taken up into the membrane to a greater extent, or those where the solubility of the permeant in the vehicle is relatively low, were found to show a good fit to the diffusion model. As such these systems allow the ATR-FTIR spectroscopic approach to give mechanistic insight into how the particular solvents enhance permeation. The solubility of CNP in the solvent and the uptake of the solvent into the membrane were found to be important influences on the equilibrium concentration of the permeant obtained in the membrane following diffusion. In general, solvents which were taken up to a significant extent into the membrane and which caused the membrane to swell increased the diffusion coefficient of the permeant in the membrane though other factors such as solvent viscosity may also be important.