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Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. The objectives of this study were to establish whether serum periostin at birth, day of life (DOL) 28, and corrected 36 weeks' gestational age could be potential biomarkers for BPD.A total of 98 preterm Japanese infants born at 32 weeks and comparing 41 healthy controls born at term, were divided into BPD (n = 44) and non-BPD (n = 54) cohorts. Serum periostin levels were measured using an enzyme-linked immunosorbent assay.Among 98 preterm infants, the median serum periostin levels at birth were higher with BPD (338.0 ng/mL) than without (275.0 ng/mL, P 0.001). Multivariate analysis revealed that serum periostin levels at birth were significantly associated with BPD (P = 0.013). Serum periostin levels at birth with moderate/severe BPD (345.0 ng/mL) were significantly higher than those with non-BPD/mild BPD (283.0 ng/mL, P = 0.006).Serum periostin levels were significantly correlated with birth weight and gestational age, and serum periostin levels at birth in BPD infants were significantly higher than that in non-BPD infants.This study found higher serum periostin levels at birth in preterm infants subsequently diagnosed with bronchopulmonary dysplasia. It also emerged that serum periostin levels at birth significantly correlated with gestational age and birth weight. The mechanism by which serum periostin is upregulated in BPD infants needs further investigation.

Background: Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth. The soluble receptor for advanced glycosylated end-products (sRAGE) is impilicated in the development of various disease such as pulmonary diseases. The objectives of this study were to evaluate the perinatal factors associated with serum sRAGE levels at birth and to establish whether serum sRAGE levels at birth could be potential biomarkers for BPD. Methods: A total of 124 subjects included 84 preterm and 40 healthy infants were included in this study. Among 84 infants born at less than 32 weeks were categorized into BPD neonates (n=34) and non-BPD infants (n=50). The median serum sRAGE levels in cord blood were measured using an enzyme-linked immunosorbent assay. Results: There were significant positive correlations between gestational age, birth weight, and serum sRAGE levels at birth. Among preterm infants born at less than 32 weeks, serum sRAGE levels at birth were significantly lower in infants with BPD than without. However, serum RAGE levels were not associated with severity of BPD. Conclusions: Serum sRAGE levels at birth were significantly correlated with BW and GA. Furthermore, serum sRAGE levels at birth could serve as a biomarker for predicting BPD, but not its severity.

Bronchopulmonary dysplasia (BPD) is a common cause of pulmonary disease in preterm infants. The soluble receptor for advanced glycation end products (sRAGE) is implicated in the development of various pulmonary diseases. The objectives of the current study were to investigate perinatal factors associated with serum sRAGE levels at birth and to establish whether serum sRAGE could be a biomarker for BPD. This retrospective single-center study was conducted at Fukushima Medical University Hospital's Department of Pediatrics Neonatal Intensive Care Unit from April 2014 to September 2020. Mechanically ventilated or oxygenated neonates born at n = 34) or non-BPD (n = 50) neonates. The median gestational age (GA) and birthweight (BW) were significantly lower in BPD vs. non-BPD neonates (24.4 vs. 27.6 weeks, P < 0.001, 634 vs. 952 g, P < 0.001, respectively). Serum sRAGE at birth in all 124 preterm and term infants significantly correlated with BW (r = 0.417, P < 0.0001) and GA (r = 0.415, P < 0.0001). Among those born at P = 0.0005). Receiver operating characteristic analysis for sRAGE levels at birth in infants with and without BPD revealed that the area under the curve was 0.724 (95% confidence interval 0.714–0.834, P = 0.001). However, serum RAGE levels were not associated with severity of BPD. Serum sRAGE levels at birth were significantly correlated with BW and GA. Furthermore, serum sRAGE levels at birth could serve as a biomarker for predicting BPD, but not its severity.

Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth. Red blood cell distribution width (RDW), a measure of the variation of red blood cell size, could reflect oxidative stress and chronic inflammation in many diseases such as cardiovascular, pulmonary, and other diseases. The objectives of the present study were to evaluate perinatal factors affecting RDW and to validate whether RDW could be a potential biomarker for BPD. A total of 176 preterm infants born at P < 0.001) and DOL 28 (22.2% vs. 18.2%, P < 0.001) were significantly higher in BPD infants. Multivariate analysis revealed that RDW at DOL 28 was significantly higher in BPD infants (P = 0.001, odds ratio 1.63; 95% CI 1.22–2.19). Receiver operating characteristic analysis for RDW at DOL 28 in infants with and without BPD yielded an area under the curve of 0.87 (95% CI 0.78–0.91, P P < 0.001), moderate BPD (18.1% vs. 21.2%, P < 0.001), and severe BPD (18.1% vs. 24.0%, P < 0.001) were significantly higher than those with non-BPD, respectively. Furthermore, there are significant differences of RDW at DOL 28 among mild, moderate, and severe BPD. In summary, we conclude that RDW at DOL 28 could serve as a biomarker for predicting BPD and its severity. The mechanism by which RDW at DOL 28 is associated with the pathogenesis of BPD needs further elucidation.

Background: Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. Periostin plays an important role in the development of various disease such as allergic and pulmonary diseases. The objectives of this study were to evaluate the perinatal factors affecting serum periostin levels at birth and to establish whether serum periostin at birth, day of life (DOL) 28 and corrected 36 week’s gestational age could be potential biomarkers for BPD.Methods: A total of 139 preterm (n=98) and healthy (n=41) infants were included in this study. Among of them, 98 infants born < 32 weeks were divided into BPD (n=44) and non-BPD infants (n=54). Serum periostin levels were measured using an enzyme-linked immunosorbent assay. Results: The median serum periostin levels at birth in preterm infants born < 32 weeks were significantly higher than those in healthy infants. Furthermore, there were significant inverse correlations between gestational age, birth weight, and serum periostin levels at birth among all 139 preterm and healthy infants. Among preterm infants born < 32 weeks, with BPD and without BPD infants, the median serum periostin levels at birth were higher with BPD than without (345.0 ng/mL vs 278.0 ng/mL, P=0.002). Multivariate analysis revealed that serum periostin levels at birth was significantly associated with BPD (P=0.032). Receiver operating characteristic analysis for serum periostin levels at birth in infants with and without BPD revealed that the area under the curve were 0.725 (95% CI 0.627- 0.822, P=0.0001). Serum periostin levels at birth with moderate/severe BPD were significantly higher than those with non-BPD/mild BPD (338.5 ng/mL vs 283.5 ng/mL, P=0.0032).Conclusions: Serum periostin levels at birth were significantly correlated with BW and GA. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD.

Although self-aligned double and quadruple patterning (SADP, SAQP) have promising processes for sub-20 nm node advanced technologies and beyond, not all layouts are compatible with them. In advanced technologies, feasible wafer image should be generated effectively by utilizing SADP and SAQP where a wafer image is determined by a selected mandrel pattern. However, predicting a mandrel pattern is not easy since it is different from the wafer image (or target pattern). In this paper, we propose new routing methods for spacer-is-dielectric (SID)-type SADP, SID-type SAQP, and spacer-is-metal (SIM)-type SADP to generate a feasible layout satisfying the connection requirements. Routing algorithms comprising simple connecting and cutting rules are performed on a new grid structure where two (SID-type SADP) or three colors (SID-type SAQP and SIM-type SADP) are assigned alternately to grid-nodes. Then a mandrel pattern is selected without complex coloring or decomposition methods. Also, we try to reduce hotspots (potentially defective regions) by the proposed dummy pattern flipping for SID-type SADP. In experiments, feasible layouts meeting the connection requirements are generated and the effectiveness of the proposed framework is confirmed.

Self-Aligned Quadruple Patterning (SAQP) is one of the most leading techniques in 14 nm node and beyond. However, the construction of feasible layout configurations must follow stricter constraints than in LELELE triple patterning process. Some SAQP layout decomposition methods were recently proposed. However, due to strict constraints required for feasible SAQP layout, the decomposition strategy considering an arbitrary layout does not seem realistic. In this paper, we propose a new routing method for feasible SAQP layout requiring no decomposition. Our method performs detailed routing by correct-by-construction approach and offers compliant layout configuration without any pitch conflict.

In this paper, we propose a new flexible routing method for Self-Aligned Double Patterning (SADP). SADP is one of the most promising candidates for patterning sub-20 nm node advanced technology but wafer images must satisfy tighter constraints than litho-etch-litho-etch process. Previous SADP routing methods require strict constraints induced from the relation between mandrel and trim patterns, so design freedom is unexpectedly lost. Also these methods assume to form narrow patterns by trimming process without consideration of resolution limit of optical lithography. The proposed method realizes flexible SADP routing with dynamic coloring requiring no decomposition to extract mandrel patterns and no worries about coloring conflicts. The proposed method uses realizable trimming process only for insulation of patterns. The effectiveness of the proposed method is confirmed in the experimental comparisons.

Although Self-Aligned Double and Quadruple Patterning (SADP, SAQP) have become the most promising processes for sub-20 nm and sub-14 nm node advanced technologies, not all wafer images are realized by them. In advanced technologies, feasible wafer images should be generated effectively by utilizing SADP and SAQP where a wafer image is uniquely determined by a selected mandrel pattern. However, predicting the wafer image of a mandrel pattern is not easy. In this paper, we propose a routing method of generating a feasible wafer image satisfying the connection requirements. Routing algorithms comprising simple connecting and cutting rules are performed on a new grid structure where two (SADP) or three colors (SAQP) are assigned alternately to grid-nodes. Then a mandrel pattern is selected without complex coloring or decomposition methods. Also, hotspot reduction by dummy pattern flipping is proposed. In experiments, feasible wafer images meeting the connection requirements are generated and the effectiveness of the proposed framework is confirmed.

Although lithography conditions, such as NA, illumination condition, resolution enhancement technique (RET), and material stack on wafer, have been determined to obtain hotspot-free wafer images, hotspots are still often found on wafers. This is because the lithography conditions are optimized with a limited variety of patterns. For 40 nm technology node and beyond, it becomes a critical issue causing not only the delay of process development but also the opportunity loss of the business. One of the easiest ways to avoid unpredictable hotspots is to verify an enormous variety of patterns in advance. This, however, is time consuming and cost inefficient. This paper proposes a new method to create a group of patterns to cover pattern variations in a chip layout based on Higher-Order Local Autocorrelation (HLAC), which consists of two phases. The first one is the "analyzing phase" and the second is the "generating phase". In the analyzing phase, geometrical features are extracted from actual layouts using the HLAC technique. Those extracted features are statistically analyzed and define the "feature space". In the generating phase, a group of patterns representing actual layout features are generated by correlating the feature space and the process margin. By verifying the proposed generated patterns, the lithography conditions can be optimized efficiently and the number of hotspots dramatically reduced.

Below 40nm design node, systematic variation due to lithography must be taken into consideration during the early stage of design. So far, litho-aware design using lithography simulation models has been widely applied to assure that designs are printed on silicon without any error. However, the lithography simulation approach is very time consuming, and under time-to-market pressure, repetitive redesign by this approach may result in the missing of the market window. This paper proposes a fast hotspot detection support method by flexible and intelligent vision system image pattern recognition based on Higher-Order Local Autocorrelation. Our method learns the geometrical properties of the given design data without any defects as normal patterns, and automatically detects the design patterns with hotspots from the test data as abnormal patterns. The Higher-Order Local Autocorrelation method can extract features from the graphic image of design pattern, and computational cost of the extraction is constant regardless of the number of design pattern polygons. This approach can reduce turnaround time (TAT) dramatically only on 1CPU, compared with the conventional simulation-based approach, and by distributed processing, this has proven to deliver linear scalability with each additional CPU.

Systematic design for manufacturability ( DfM ) scheme including triple gates for hot spot elimination under the low-k 1 lithography condition is proposed and efficient approaches to the hot spot elimination at each development stage in the DfM scheme are discussed in view of the actual situation under the concurrent development of design rule ( DR ), layout, process, optical proximity correction ( OPC ) and resolution enhancement technique ( RET ) technologies. Integrated-type lithography simulation system with OPC tool is much available for the fast processing at the initial stage and promising to be complementarily used for the verification of chip-level layout with conventional-type one at the final development stage. Low order of the lithography empirical model originating moderate prediction accuracy for all kinds of patterns is hopeful to be used at the initial development stage because it is difficult to obtain a lot of reliable experimental data for making the accurate empirical lithography model due to frequent improvement of the process, OPC and RET technologies. At the final development stage, sufficient and reliable experimental data for device pattern variations allow us to implement the higher order of the empirical model. The DfM scheme with efficient approaches in view of the actual situation under the concurrent development is found to be promising for the robust pattern formation under the low-k 1 lithography condition.

Design and optical proximity correction (OPC) flow with hybrid OPC and manufacturability check (MC) tool was found to be effective for making robust pattern formation without any hot spots within feasible lead time under the low-k1 lithography condition. MC at design stage is essential for cleaning up hot spots in three ways; the refinement of design rule, the guideline for repairing hot spots for designers and the refinement of OPC deck. Hybrid OPC and MC tools with library- and model-based modules are available for reducing lead time by taking advantage of library system. Due to the design and OPC flow with the library-based OPC and MC tool, total lead time can be reduced to 55% of that in the case of conventional flow with MC. Assuming that a refined mask is ordered due to issue of hot spots without MC, the total lead time in the new flow can be reduced to 11% of that in the case of conventional technology.

Advanced hybrid optical proximity correction (OPC) system with OPC segment library and a model-based correction module has been found to be much promising for reducing the mask data processing time. Recycling the OPC segment library made of previous products for next derivative products with common design rule could reduce the OPC process time down to 11% at the sixth Application Specific Integrated Circuit product for the conventional hybrid OPC scheme. Then, under the circumstances that the block-level layout verification tool with the hybrid OPC tool and the lithography simulator is utilized by designers for avoiding the lithographic dangers in the early stage of design, the most effective library can be generated in this layout verification flow and used for the correction of the completed layout. Due to this scheme, the OPC process time could be decreased to 11-16% for 256-Mbit Dynamic Random Access Memory gate and metal layer.