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To test the effectiveness of EGCG palmitate (EC16), a lipophilic derivative of (-)-epigallocatechin-3-gallate (EGCG, an anti-oxidant catechin component found in green tea), in reducing the neurological complications of persistent SARS CoV-2 infection particularly in the Human Olfactory Epithelium. The goal of this project was to evaluate the in vitro properties and antiviral activity of a prototype aqueous EC16 nanoformulation.

Hsu et al.used advanced methods from machine learning to analyze almost half a million genomes. They produced, for the first time, accurate genomic predictors for complex traits such as height, bone density, and educational attainment...We construct genomic predictors for heritable but extremely complex human quantitative traits (height, heel bone density, and educational attainment) using modern methods in high dimensional statistics (i.e., machine learning). The constructed predictors explain, respectively, ∼40, 20, and 9% of total variance for the three traits, in data not used for training. For example, predicted heights correlate ∼0.65 with actual height; actual heights of most individuals in validation samples are within a few centimeters of the prediction. The proportion of variance explained for height is comparable to the estimated common SNP heritability from genome-wide complex trait analysis (GCTA), and seems to be close to its asymptotic value (i.e., as sample size goes to infinity), suggesting that we have captured most of the heritability for SNPs. Thus, our results close the gap between prediction R-squared and common SNP heritability. The ∼20k activated SNPs in our height predictor reveal the genetic architecture of human height, at least for common variants. Our primary dataset is the UK Biobank cohort, comprised of almost 500k individual genotypes with multiple phenotypes. We also use other datasets and SNPs found in earlier genome-wide association studies (GWAS) for out-of-sample validation of our results.

Chip makers are actively working on the adoption of 0.33 numerical aperture (NA) EUV scanners for the 7-nm and 5-nm nodes (B. Turko, S. L. Carson, A. Lio, T. Liang, M. Phillips, et al., in ‘Proc. SPIE9776, Extreme Ultraviolet (EUV) Lithography VII’, vol. 977602 (2016) doi: 10.1117/12.2225014; A. Lio, in ‘Proc. SPIE9776, Extreme Ultraviolet (EUV) Lithography VII’, vol. 97760V (2016) doi: 10.1117/12.2225017). In the meantime, leading foundries and integrated device manufacturers are starting to investigate patterning options beyond the 5-nm node (O. Wood, S. Raghunathan, P. Mangat, V. Philipsen, V. Luong, et al., in ‘Proc. SPIE. 9422, Extreme Ultraviolet (EUV) Lithography VI’, vol. 94220I (2015) doi: 10.1117/12.2085022). To minimize the cost and process complexity of multiple patterning beyond the 5-nm node, EUV high-NA single-exposure patterning is a preferred method over EUV double patterning (O. Wood, S. Raghunathan, P. Mangat, V. Philipsen, V. Luong, et al., in ‘Proc. SPIE. 9422, Extreme Ultraviolet (EUV) Lithography VI’, vol. 94220I (2015) doi: 10.1117/12.2085022; J. van Schoot, K. van Ingen Schenau, G. Bottiglieri, K. Troost, J. Zimmerman, et al., ‘Proc. SPIE. 9776, Extreme Ultraviolet (EUV) Lithography VII’, vol. 97761I (2016) doi: 10.1117/12.2220150). The EUV high-NA scanner equipped with a projection lens of 0.55 NA is designed to support resolutions below 10 nm. The high-NA system is beneficial for enhancing resolution, minimizing mask proximity correction bias, improving normalized image log slope (NILS), and controlling CD uniformity (CDU). However, increasing NA from 0.33 to 0.55 reduces the depth of focus (DOF) significantly. Therefore, the source mask optimization (SMO) with sub-resolution assist features (SRAFs) are needed to increase DOF to meet the demanding full chip process control requirements (S. Hsu, R. Howell, J. Jia, H.-Y. Liu, K. Gronlund, et al., EUV ‘Proc. SPIE9048, Extreme Ultraviolet (EUV) Lithography VI’, (2015) doi: 10.1117/12.2086074). To ensure no assist feature printing, the assist feature sizes need to be scaled with λ/NA. The extremely small SRAF width (below 25 nm on the reticle) is difficult to fabricate across the full reticle. In this paper, we introduce an innovative ‘attenuated SRAF’ to improve SRAF manufacturability and still maintain the process window benefit. A new mask fabrication process is proposed to use existing mask-making capability to manufacture the attenuated SRAFs. The high-NA EUV system utilizes anamorphic reduction; 4× in the horizontal (slit) direction and 8× in the vertical (scanning) direction (J. van Schoot, K. van Ingen Schenau, G. Bottiglieri, K. Troost, J. Zimmerman, et al., ‘Proc. SPIE. 9776, Extreme Ultraviolet (EUV) Lithography VII’, vol. 97761I (2016) doi: 10.1117/12.2220150; B. Kneer, S. Migura, W. Kaiser, J. T. Neumann, J. van Schoot, in ‘Proc. SPIE9422, Extreme Ultraviolet (EUV) Lithography VI’, vol. 94221G (2015) doi: 10.1117/12.2175488). For an anamorphic system, the magnification has an angular dependency, and thus, familiar mask specifications such as mask error factor (MEF) need to be redefined. Similarly, mask-manufacturing rule check (MRC) needs to consider feature orientation.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

We report the utility of a rapid polarization-resolved hyperspectral stimulated Raman scattering (SRS) imaging technique developed for optical diagnosis and characterization of dental caries in the tooth. Hyperspectral SRS images (512 × 512 pixels) of the tooth covering both the fingerprint (800-1800 cm^−1) and high-wavenumber (2800-3600 cm^−1) regions can be acquired within 15 minutes, which is at least 10^3 faster in imaging speed than confocal Raman mapping. Hyperspectral SRS imaging uncovers the biochemical distributions and variations across the carious enamel in the tooth. SRS imaging shows that compared to the sound enamel, the mineral content in the body of lesion decreases by 55%; while increasing up to 110% in the surface zone, indicating the formation of a hyper-mineralized layer due to the remineralization process. Further polarized SRS imaging shows that the depolarization ratios of hydroxyapatite crystals (ν_1-PO_4 ^3- of SRS at 959 cm^−1) of the tooth in the sound enamel, translucent zone, body of lesion and the surface zone are 0.035 ± 0.01, 0.052 ± 0.02, 0.314 ± 0.1, 0.038 ± 0.02, respectively, providing a new diagnostic criterion for discriminating carious lesions from sound enamel in the teeth. This work demonstrates for the first time that the polarization-resolved hyperspectral SRS imaging technique can be used for quantitatively determining tooth mineralization levels and discriminating carious lesions from sound enamel in a rapid fashion, proving its promising potential of early detection and diagnosis of dental caries without labeling.

The goal of MD–PhD training programs is to produce physician–scientists with unique capacities to lead the future biomedical research workforce. The current dearth of physician–scientists with expertise outside conventional biomedical or clinical sciences raises the question of whether MD–PhD training programs should allow or even encourage scholars to pursue doctoral studies in disciplines that are deemed nontraditional, yet are intrinsically germane to major influences on health. This question is especially relevant because the central value and ultimate goal of the academic medicine community is to help attain the highest level of health and health equity for all people. Advances in medical science and practice, along with improvements in health care access and delivery, are steps toward health equity, but alone they will not come close to eliminating health inequalities. Addressing the complex health issues in our communities and society as a whole requires a biomedical research workforce with knowledge, practice, and research skills well beyond conventional biomedical or clinical sciences. To make real progress in advancing health equity, educational pathways must prepare physician–scientists to treat both micro and macro determinants of health. The authors argue that MD–PhD programs should allow and encourage their scholars to cross boundaries into less traditional disciplines such as epidemiology, statistics, anthropology, sociology, ethics, public policy, management, economics, education, social work, informatics, communications, and marketing. To fulfill current and coming health care needs, nontraditional MD–PhD students should be welcomed and supported as valuable members of our biomedical research workforce.

While many antibody therapeutics are formulated at low concentration (~10–20 mg/mL) for intravenous administration, high concentration (> 100 mg/mL) formulations may be required for subcutaneous delivery in certain clinical indications. For such high concentration formulations, product color is more apparent due to the higher molecular density across a given path-length. Color is therefore a product quality attribute that must be well-understood and controlled, to demonstrate process consistency and enable clinical trial blinding. Upon concentration of an IgG4 product at the 2000 L manufacturing scale, variability in product color, ranging from yellow to red, was observed. A small-scale experimental model was developed to assess the effect of processing conditions (medium composition and harvest conditions) on final bulk drug substance (BDS) color. The model was used to demonstrate that, for two distinct IgG4 products, red coloration occurred only in the presence of disulfide reduction-mediated antibody dissociation. The red color-causing component was identified as vitamin B12, in the hydroxocobalamin form, and the extent of red color was correlated with the cobalt (vitamin B12) concentration in the final pools. The intensity of redness in the final BDS was modulated by changing the concentration of vitamin B12in the cell culture media.

Friction is an essential part of human experience. We need traction to walk, stand, work, and drive. At the same time, we need energy to overcome the resistance to motion, hence, too much friction costs excess energy to perform work, introducing inefficiencies. In the 21stcentury, we are facing the dual challenges of energy shortage and global warming from burning fossil fuels. Therefore, the ability to control friction has become a top priority in our world today. Yet our understanding of the fundamental nature of friction is still lacking. Friction has always been a subject of curiosity. Intensive study of the origin of friction began in the 16th century, after the pioneering work by Leonardo da Vinci. Yet progress in understanding the nature of friction has been slow, hampered by the lack of instrument to measure friction precisely. Ingenious experiments performed by Amontons, Coulomb, and others have yielded important insights to build the foundation of our understanding. Beginning in the late 1800s and early 1900s, the advent of steam engines, locomotives, followed by the automobiles airplanes, and space exploration demands a clear understanding of friction and the ability to control it for the machinery to last. Significant progress on how to apply and control friction in engineering friction was made through trial and error. At the beginning of the 21stcentury, a new dimension of nanoscale friction came into the picture in conjunction with the arrival of nanotechnology. Our understanding of atomic and molecular friction has been expanding rapidly. However, integration of the new found knowledge of nanofriction into engineering practices has been elusive. Why? What is the scaling relationship between atomic friction and macro-friction? Is it possible to predict friction at the macro-level from nanoscale results? Why nanofriction values often do not agree with the macrofriction values given the same materials pair? Could it be there is a length scale dependent characteristic friction value? In engineering practice, progress since the 1980s has been slow. Most of the effort has been focused on lubrication research such as elastohydrodynamic theories and solid lubricants. Friction mechanisms and failures have received relative little attention while nanofriction received much of the attention. Today, energy efficiency and renewable energy generation demand our immediate attention while we seek reduction in carbon emission. The ability to control friction becomes an essential step in seeking sustainable technologies. Friction, after all, is an indicator of energy efficiency. If we can reduce the unnecessary parasitic energy losses and increase our current energy efficiency, it will give us time to develop alternative energy sources. This paper examines our current understanding of friction, filling some voids with experimental data, and attempts to integrate the various pieces to identify the gaps of our knowledge, hopefully to spark new avenues of investigations into this important area.

Acoustic radiation force impulse (ARFI) imaging has been shown to be capable of imaging local myocardial stiffness changes throughout the cardiac cycle. Expanding on these results, the authors present experiments using cardiac ARFI imaging to visualize and quantify the propagation of mechanical stiffness during ventricular systole. In vivo ARFI images of the left ventricular free wall of two exposed canine hearts were acquired. Images were formed while the heart was externally paced by one of two electrodes positioned on the epicardial surface and either side of the imaging plane. Two-line M-mode ARFI images were acquired at a sampling frequency of 120 Hz while the heart was paced from an external stimulating electrode. Two-dimensional ARFI images were also acquired, and an average propagation velocity across the lateral field of view was calculated. Directions and speeds of myocardial stiffness propagation were measured and compared with the propagations derived from the local electrocardiogram (ECG), strain, and tissue velocity measurements estimated during systole. In all ARFI images, the direction of myocardial stiffness propagation was seen to be away from the stimulating electrode and occurred with similar velocity magnitudes in either direction. When compared with the local epicardial ECG, the mechanical stiffness waves were observed to travel in the same direction as the propagating electrical wave and with similar propagation velocities. In a comparison between ARFI, strain, and tissue velocity imaging, the three methods also yielded similar propagation velocities.

Due to the continuous shrinking in half pitch and critical dimension (CD) in wafer processing, maintaining a reasonable process window such as depth of focus (DOF) & exposure latitude (EL) becomes very challenging. With the source mask optimization (SMO) methodology, the lithography process window can be improved and a smaller mask error enhancement factor (MEEF) can be achieved. In this paper, the Tachyon SMO work flow and methodology was evaluated. The optimum source was achieved through evaluation of the critical designs with Tachyon SMO software and the simulated performance was then verified on another test case. Criteria such as DOF, EL & MEEF were used to determine the optimum source achieved from the evaluation. Furthermore, the process variation band (PV-Band) and the number of hot spot (design weak points) were compared between the POR and the optimum source. The simulation result shows the DOF, MEEF & worst PV-Band were improved by 13%, 17% & 12%, respectively with the optimum SMO source. In order to verify the improvement from the optimum SMO at the silicon level, a new OPC model was recalibrated with wafer CD from the optimized source. The OPC recipe was also optimized and a reticle was retrofitted with the new OPC. By comparing the process window, hotspots and defects between the original vs. new reticle, the benefit of the optimized source was verified on silicon.

Source mask optimization (SMO) and double patterning technology (DPT) are considered key Resolution Enhancement Technique (RET) enablers for scaling 2x nodes and beyond design rules, using existing 193 nm ArF technology prior to EUV availability. SMO has been extensively shown to enlarge the process margin for critical layers in memory cells and test patterns; however the best SMO flow for a large random logic area up to full-chip application has been less explored. In this study, we investigated how the mask complexity in the source optimization impacts the final process window on a random logic layout after DPT, and proposed a new source optimization approach. Example used is a contact layer for 2x logic designs. The SMO source optimization is performed using the SRAM cells with different mask complexities. These optimized sources are then evaluated based on a large-area random logic layout after mask-only optimization. CD variation through process window is used as the metric for comparison. We found the best result is obtained when the source is optimized with the full flexibility of the source and mask with freeform SRAFs and minimal MRC constraints. The source optimized with this approach can reduce CD variation through process window in the random logic without increasing its mask complexity.

As lithography moves into lower k1imaging, traditional illumination "source" shapes may perform marginally in resolving complex layouts. Subsequently hot-spots or warm-spots can result, leading to yield loss in production. Typically, lithographers solve such problems by modifying the local layout instead of optimizing the DOE (diffractive optical element) illumination shape. FlexRayTMcan easily implement freeform source shapes and allows a high degree of freedom in source optimization. Therefore, it becomes practical to use pixelated freeform sources to resolve hot spots or warm spots. In this paper, we investigate the use of freeform source optimization (SO) on a critical dynamic random access memory (DRAM) layer with warm spots to verify the effectiveness of a SO only flow using Tachyon SMO. In order to improve the warm spots without changing baseline performance for other patterns, we optimized not only the warm spot patterns of concern but also the critical reference patterns. Since the optimization minimizes EPE (edge placement error) and maximizes imaging quality for all enclosed patterns, the final optimized source shape performs similar to the baseline source for the base patterns while improving the performance of the warm spot pattern areas. Although the SO source is similar in shape to the baseline source, the optimized source provides enhanced depth of focus (DoF) for all warm spot patterns without suffering degradation in the normalized image log-slope (NILS) performance. Evaluation of the optimized SO source shows no obvious negative impact on modeled CDs across an array of L/S pattern combinations which cover all the pitches appearing in the periphery. Finally, the optimized source is demonstrated using ASML's FlexRayTMfor on-wafer evaluation. According to the observations from on-wafer experiments, consistent results to simulation are verified. Overall DoF for the identified warm spot patterns is definitely improved and no obvious pattern shape changes are found, as well. From the positive demonstration in simulation and on-wafer verification, the vast flexibility of the freeform source enables the SO flow with more powerful capability to improve local hot spot or warm spot problems without negatively impacting the other patterns.

FlexRay programmable illumination and LithoTuner software is combined in several use cases. The first use case is source mask optimization (SMO) in which the process window is maximized for a static random access memory (SRAM) design. In a 55 nm half-pitch contact hole array ($k_{1} = 0.38$, $\mathrm{NA}= 1.35$, $\lambda = 193$ nm), the process window (PW) with FlexRay programmable illumination is twice as large as the PW with cQuad illumination defined through completely refractive illumination. The second use case is optical proximity error (OPE) minimization in which the large PW from SMO is realized on every scanner in the fab. The OPE error is reduced by 17% with LithoTuner and FlexRay. The third use case is matching two ArF scanners, a 1950i with FlexRay to a 1700i with diffractive optical element (DOE) illumination. With LithoTuner and FlexRay, the root means squared (rms) critical dimension (CD) error is reduced by 29% in this third use case. The last use case, intrafield dose optimization with DoseMapper is combined with FlexRay programmable source optimization to reduce the CD error on a wafer from a mean-to-target critical dimension (CD) error in the mask manufacturing process. This combination was optimized with LithoTuner to reduce the root mean square (rms) wafer CD error by 30%.

A cost-efficient technique for full-chip source and mask optimization is proposed in this paper. This technique has two components: SMO source optimization for full-chip and flexible mask optimization (FMO). During the technology development stage of source optimization, a novel pattern-selection technique was used to identify critical clips from a full-set of design clips; SMO was then used to optimize the source based on those selected critical-clips. This pattern-selection technique enables reasonable SMO runtime to optimize the source that covers the full range of patterns. During the process development stage and product tapeout stage, FMO is employed. The FMO framework allows the use of different OPC computational techniques on different chip areas that have different sensitivities to process variations. Advanced OPC methods are applied only where they are needed, therefore achieving optimum process performance with the least tapeout and mask cost.

Shear wave elasticity imaging (SWEI) was employed to track acoustic radiation force impulse (ARFI)-induced shear waves in the mid-myocardium of the left ventricular free wall (LVFW) of a beating canine heart. Shear waves were generated and tracked with a linear ultrasound transducer that was placed directly on the exposed epicardium. Acquisition was ECG-gated and coincided with the mid-diastolic portion of the cardiac cycle. Axial displacement profiles consistent with shear wave propagation were clearly evident in all SWEI acquisitions (i.e., those including an ARFI excitation); displacement data from control cases (i.e., sequences lacking an ARFI excitation) offered no evidence of shear wave propagation and yielded a peak absolute mean displacement below 0.31 μm after motion filtering. Shear wave velocity estimates ranged from 0.82 to 2.65 m/s and were stable across multiple heartbeats for the same interrogation region, with coefficients of variation less than 19% for all matched acquisitions. Variations in velocity estimates suggest a spatial dependence of shear wave velocity through the mid-myocardium of the LVFW, with velocity estimates changing, in limited cases, through depth and lateral position.

Acoustic radiation force impulse (ARFI) imaging has been demonstrated to be capable of visualizing changes in local myocardial stiffness through a normal cardiac cycle. As a beating heart involves rapidly-moving tissue with cyclically-varying myocardial stiffness, it is desirable to form images with high frame rates and minimize susceptibility to motion artifacts.Three novel ARFI imaging methods, pre-excitation displacement estimation, parallel-transmit excitation and parallel-transmit tracking, were implemented. Along with parallel-receive, ECG-gating and multiplexed imaging, these new techniques were used to form high-quality, high-resolution epicardial ARFI images. Three-line M-mode, extended ECG-gated three-line M-mode and ECG-gated two-dimensional ARFI imaging sequences were developed to address specific challenges related to cardiac imaging. In vivoepicardial ARFI images of an ovineheart were formed using these sequences and the quality and utility of the resultant ARFI-induced displacement curves were evaluated. The ARFI-induced displacement curves demonstrate the potential for ARFI imaging to provide new and unique information into myocardial stiffness with high temporal and spatial resolution.

Determination of the avidity of immunoglobulin G (IgG) directed against a specific marker has become an established diagnostic tool for identifying or excluding acute infections with pathogens. A novel assay format termed AVIcomp (avidity competition based on mass action) circumventing the conventional chaotropic format has been developed for determination of the avidity of marker-specific IgG in patient specimens. Its applications for cytomegalovirus (CMV) and Toxoplasma gondiiare presented. Specific high-avidity IgG from the patient specimen is selectively blocked using a soluble antigen in a sample pretreatment reagent, and the amount of remaining specific low-avidity IgG is determined relative to that in an untreated control. The comparison of the conventional chaotropic format, represented by the Radim CMV IgG Avidity assay, and the newly developed AVIcomp method, as exemplified by the Architect CMV IgG Avidity assay, on blood drawn within 4 months after seroconversion revealed a sensitivity of 100% (97.3% by an alternative calculation) for the AVIcomp format versus 87.5% (75.7% by an alternative calculation) for the chaotropic avidity assay. The specificity on 312 CMV IgG reactive and CMV IgM nonreactive specimens from pregnant women was 100% for the AVIcomp assay and 99.7% for the conventional avidity assay. The Architect Toxo IgG Avidity assay showed an agreement of 97.2% with the bioMe´rieux Vidas Toxo IgG Avidity Assay employing chaotropic reagents. These performance data suggest that the AVIcomp format shows superior sensitivity and equivalent specificity for the determination of IgG avidity to assays based on the chaotropic method and that the AVIcomp format may also be applicable to other disease states.

Intracardiac echocardiography (ICE) has demonstrated utility in providing high-resolution cardiac ultrasound images for guidance of numerous catheter-based interventions, including radiofrequency ablations (RFA). However, the training of interventionalists and refinement of procedures involving intracardiac catheters is costly and time consuming due to necessary clinical and animal studies. As a result, research and development of ICE for other purposes is gradual and deliberate. Intracardiac acoustic radiation force impulse (ARFI) imaging has been demonstrated to be a suitable modality to monitor the progress of RFA procedures; however, a clinical protocol has been slow to develop due to the expense and demands of clinical experiments. We report on the development and use of an ex vivoheart model to evaluate ICE and intracardiac ARFI imaging.The ability of this model to provide clinically-relevant intracardiac imaging angles was investigated by inserting an intracardiac probe into the heart and imaging it from various positions and orientations. ARFI images of all four chambers also were formed. RFAs were also performed to create stiffer lesions within the right and left ventricles. Upon completion of the ablation, ARFI imaging was used to visualize the lesion and compared with images taken from pathology. The results show the ovine heart model to be a suitable apparatus for recreating several clinically-relevant intracardiac viewing angles of the heart. Also, the results indicate the potential of the heart model to be a valuable tool in the future development and refinement of a clinical protocol for intracardiac ARFI imaging based guidance and assessment of cardiac radiofrequency ablations.

Racial and ethnic variations in the incidence of IgA nephropathy (IgAN) could imply both genetic and environmental influences that exist in a complex and poorly understood interplay to modify the expression of the IgAN clinical phenotype. Progress in identifying genetic factors that influence either susceptibility to IgAN or its progression has been slow. Recent progress using family based approaches (genome-wide scan for linkage and family based genetic association studies) to study the genetic basis for susceptibility to familial and sporadic IgAN strongly point to clinical and genetic heterogeneity in the entity we presently call IgAN. The inconsistent findings reported from case-control genetic association studies may be explained by new understanding of the haplotype block structure of the human genome. Rapid improvements in available and developing technologies in the postgenomic era are needed and are expected to accelerate progress in understanding genetic factors underlying IgAN.