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Objective: To understand the epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023. Methods: The data of this study were collected from the ARI surveillance data from 16 provinces in China from 2009 to 2023, with a total of 28 278 ARI cases included in the study. The clinical specimens from ARI cases were screened for HRSV nucleic acid from 2009 to 2023, and differences in virus detection rates among cases of different age groups, regions, and months were analyzed. Results: A total of 28 278 ARI cases were enrolled from January 2009 to September 2023. The age of the cases ranged from<1 month to 112 years, and the age M ( Q 1 , Q 3 ) was 3 years (1 year, 9 years). Among them, 3 062 cases were positive for HRSV nucleic acid, with a total detection rate of 10.83%. From 2009 to 2019, the detection rate of HRSV was 9.33%, and the virus was mainly prevalent in winter and spring. During the Corona Virus Disease 2019 (COVID-19) pandemic, the detection rate of HRSV fluctuated between 6.32% and 18.67%. There was no traditional winter epidemic peak of HRSV from the end of 2022 to the beginning of 2023, and an anti-seasonal epidemic of HRSV occurred from April to May 2023. About 87.95% (2 693/3 062) of positive cases were children under 5 years old, and the difference in the detection rate of HRSV among different age groups was statistically significant ( P <0.001), showing a decreasing trend of HRSV detection rate with the increase of age ( P <0.001). Among them, the HRSV detection rate (25.69%) was highest in children under 6 months. Compared with 2009-2019, the ranking of HRSV detection rates in different age groups changed from high to low between 2020 and 2023, with the age M (Q 1 , Q 3 ) of HRSV positive cases increasing from 1 year (6 months, 3 years) to 2 years (11 months, 3 years). Conclusion: Through 15 years of continuous HRSV surveillance analysis, children under 5 years old, especially infants under 6 months old, are the main high-risk population for HRSV infection. During the COVID-19 pandemic, the prevalence and patterns of HRSV in China have changed.

Objective: To observe the clinical effect between orbital septum incision and classical incision of double eyelid plasty., Methods: We retrospectively analyzed 381 patients who underwent double eyelid blepharoplasty in the Department of Plastic and Laser Cosmetology of Hunan Provincial People's Hospital from January 2019 to December 2019. The patients were divided into two groups according to different surgical methods: group A (n = 146) received the classical method and group B (n = 235) received the orbital septum method. The incidence of early postoperative complications, scar depression from 6 months to 1 year after the operation, the condition of 'meat strip' (the accumulation of soft tissue in front of the tarsal plate after double eyelid surgery, including skin, muscle, and fascia fat, results in a hypertrophic appearance of the upper eyelid) below the double eyelid line, and the symmetry of double eyelids were analyzed and evaluated., Results: The total number of early postoperative complications in group A was seven cases (incidence rate: approximately 4.80%), and the total number of early postoperative complications in group B was two cases (incidence rate: approximately 0.85%), with a statistically significant difference (P < 0.05). The degree of scar depression in group B was significantly lighter than that in group A from 6 months to 1 year after the operation (P < 0.05). The score of 'meat strip' below the double eyelid line in group B was significantly lighter than that in group A (P < 0.05). The symmetry of double eyelids in group B was better than that in group A (P < 0.05) CONCLUSION: Compared to the classical double eyelid method, the orbital septum method has the advantages of reducing early postoperative complications, reducing the severity of the scar, slighting the 'meat strip,' and improving symmetry, which results in higher postoperative satisfaction LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 ., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: Long non-coding RNAs (lncRNAs) play vital roles in the development and progression of non-small-cell lung cancer (NSCLC); however, the role of most lncRNAs in NSCLC remains unknown. This study explored the clinical significance, biological function and underlying mechanism of lnc-GAN1 in NSCLC., Methods: With a custom lncRNA microarray we found that lnc-GAN1 is markedly downregulated in NSCLC tissues. Then lnc-GAN1 expression level was measured using qRT-PCR in NSCLC tissues and cell lines. Survival was assessed using the Kaplan-Meier method. The biological functions of lnc-GAN1 in lung cancer cells were evaluated in vitro and in vivo. RNA fluorescence in situ hybridization and subcellular localization assays revealed the subcellular distribution of lnc-GAN1 in cells. Bioinformatic analysis was adopted to predict miRNAs and signaling pathways regulated by lnc-GAN1. RNA immunoprecipitation and Dual-luciferase reporter assays were used to assess the interaction between lnc-GAN1 and miR-26a-5p in lung cancer cells., Results: lnc-GAN1 is downregulated in HCC tissues and associated with larger tumor size and poor overall survival and disease-free survival; its ectopic expression suppresses cell proliferation, colony formation, and cell cycle progression and induces apoptosis in NSCLC cells; it also inhibits tumor growth in the NSCLC xenograft model. We further proved that lnc-GAN1 is localized in cytoplasm and transcribed independently from its parental gene GAN. Mechanistically, lnc-GAN1 acts as a sponge for miR-26a-5p by two seed sequences, and the two non-coding RNAs have a negative relationship in NSCLC tissues; we further prove that PTEN is a direct target of miR-26a-5p and lnc-GAN1 inhibits cell cycle signaling pathway by activating PTEN, whose expression level correlated negatively with miR-26a-5p level but positively with lnc-GAN1 level in NSCLC samples., Conclusions: Lnc-GAN1 is downregulated and associated with poor survival of NSCLC patients, and mechanistically acts as a tumor suppressor via sponging and inhibiting miR-26a-5p to upregulate PTEN. This study provides a potential prognostic biomarker and treatment target for NSCLC.

Background: Previous findings have indicated that the tumor, nodes, and metastases (TNM) staging system is not sufficient to accurately predict survival outcomes in patients with non-small lung carcinoma (NSCLC). Thus, this study aims to identify a long non-coding RNA (lncRNA) signature for predicting survival in patients with NSCLC and to provide additional prognostic information to TNM staging system., Methods: Patients with NSCLC were recruited from a hospital and divided into a discovery cohort (n = 194) and validation cohort (n = 172), and detected using a custom lncRNA microarray. Another 73 NSCLC cases obtained from a different hospital (an independent validation cohort) were examined with qRT-PCR. Differentially expressed lncRNAs were determined with the Significance Analysis of Microarrays program, from which lncRNAs associated with survival were identified using Cox regression in the discovery cohort. These prognostic lncRNAs were employed to construct a prognostic signature with a risk-score method. Then, the utility of the prognostic signature was confirmed using the validation cohort and the independent cohort., Results: In the discovery cohort, we identified 305 lncRNAs that were differentially expressed between the NSCLC tissues and matched, adjacent normal lung tissues, of which 15 are associated with survival; a 4-lncRNA prognostic signature was identified from the 15 survival lncRNAs, which was significantly correlated with survivals of NSCLC patients. This signature was further validated in the validation cohort and independent validation cohort. Moreover, multivariate Cox analysis demonstrates that the 4-lncRNA signature is an independent survival predictor. Then we established a new risk-score model by combining 4-lncRNA signature and TNM staging stage. The receiver operating characteristics (ROC) curve indicates that the prognostic value of the combined model is significantly higher than that of the TNM stage alone, in all the cohorts., Conclusions: In this study, we identified a 4-lncRNA signature that may be a powerful prognosis biomarker and can provide additional survival information to the TNM staging system.

Objective: To identify the role of interferon (IFN)-γ during respiratory syncytial virus (RSV) re-infection in mice. Method: Female wild type C57BL/6 mice and IFN-γ knockout mice (IFN-γ(-/-) mice) at the age of 6 to 8 weeks were randomly divided into two groups: control group and RSV group, according to random number table.Each group was further divided into primary infection group and re-infection group.There were 8 groups.Mice were sacrificed on days 5, 7, 14 to collect samples.There were 5-8 mice in each group at each time point.And experiment was repeated twice. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, left lung tissues were stained with HE and histopathological scoring (HPS) was performed.The concentrations of IFN-γ, IL-5, IL-13 were determined with ELISA. T test or single factor analysis of variance was used to compare between groups. Result: (1) Mice infected or reinfected with RSV showed pale hair, weight loss, decreased activity and anorexia.(2) IFN-γ levels significantly increased on days 5 and 7 following RSV primary infection and reinfection as compared to control groups in wild type mice ((192±44) vs .(36±8) and (531±161) vs .(23±4) pg/ml on day 5, (100±23) vs .(36±8) and (862±186) vs .(23±4) pg/ml on day 7, t =2.654, 2.513, 2.654, 3.968, all P <0.05). (3) Compared to the RSV-reinfected IFN-γ(-/-) mice, RSV-reinfected wild type mice had less body weight loss ((13.6±2.6)% vs .(22.7±2.9)% on day 5, (18.0±3.1)% vs .(26.5±1.8)% on day 7, t =2.314, 2.308, both P <0.05), lower lung tissue histopathological score ((1.50±0.09) vs .(2.07±0.11) on day 5, (1.53±0.11) vs .(2.08±0.09) on day 7, (1.10±0.06) vs .(1.59±0.08) on day 14, t =3.916, 3.890, 4.837, all P <0.01), less BALF inflammatory cells count ((11.6±2.0) vs .(44.2±10.6)×10(5)/ml on day 5, (18.2±3.9) vs .(38.3±2.2)×10(5)/ml on day 7, t =2.818, 4.786, both P <0.05), and lower levels of IL-5 and IL-13 ((24±3) vs .(148±23), (23±4) vs .(169±26) pg/ml on day 5, (30±8) vs .(233±44), (20±5) vs .(182±19) pg/ml on day 7, (91±6) vs .(129±19), (62±8) vs .(132±5) pg/ml on day 14, t =5.252, 5.445, 4.517, 7.326, 3.816, 7.577, all P <0.01). Conclusion: IFN-γ can alleviate airway inflammation following RSV reinfection in mice.

This study sought to develop an effective and reliable nomogram for predictions of recurrence for postoperative adjuvant transarterial chemoembolization (PA-TACE) in patients with hepatitis B virus-related (HBV) hepatocellular carcinoma (HCC).The nomogram was established based on data obtained from a retrospective study on 235 consecutive patients with HBV HCC who received PA-TACE as an initial therapy from 2006 to 2010 in our center. Eighty-four patients who were collected at another institution between 01/2008 and 12/2010 served as an external validation set. Recurrence-free survival (RFS) was collected. The nomogram for tumor recurrence was developed based on the data obtained before the PA-TACE procedure. Predictive accuracy and discriminative ability of the nomogram were assessed by concordance index (C-index), calibration curves, and validation set.The 1, 2, 3-year RFS rates were 55.5%, 27.0%, and 14.1%, respectively, in the patients from the derivation set and 60.7%, 33.2%, and 23.8% in those from the validation set. Four risk factors (HBV-DNA level, vascular invasion, change of Child-Pugh score, and tumor diameter) in the multivariate analysis were significantly associated with RFS. The statistical nomogram incorporated these 4 factors achieved good calibration and discriminatory abilities with the c-index of 0.74 (95% CI 0.66-0.82). The findings were supported by the independent external validation set (c-index, 0.70; 95% CI 0.58-0.83). The area under the receiver operating characteristic curve in our model was greater than those of conventional staging systems in the validation patients (corresponding c-indices, 0.56-0.64).The novel nomogram may achieve an optimal prediction for recurrence outcome in HBV-related HCC with PA-TACE.

Hepatocellular carcinoma (HCC) is a common cancer with very poor survival due to lack of reliable biomarker for early diagnosis. In this study, we investigated microRNA (miRNA) profile of whole blood with a custom microarray containing probes for 1849 miRNA species in a total 213 successive subjects who were divided into a discovery set and a validation set. An 88-miRNA signature was established to diagnose health controls (HC), chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC with 100% accuracy in the discovery set using Fisher discriminant analysis. This diagnostic signature was confirmed in the validation set with accuracy rates of 100%, 95.2%, 93.7% and 98.4% for HC, CHB, LC and HCC patients, respectively. Compared with AFP, the only available non-invasive and routinely used biomarker for diagnosis of HCC, the 88-miRNA signature has much higher accuracy (99.5% vs 76.5%), sensitivity (100% vs 63.8%), and specificity (99.2% vs 84.2%). More importantly, the signature detects small HCCs (<3cm) with 100% (17/17) accuracy while AFP has only 64.7% (11/17). In conclusion, we have identified a powerful and sensitive blood 88-miRNA signature for diagnosing early HCC and other chronic liver diseases (CHB and LC) with a high accuracy.

This study sought to develop a reliable and easy-to-use scoring model to guide the decision to perform postsurgical adjuvant transarterial chemoembolization (PA-TACE) in patients with hepatitis B-related hepatocellular carcinoma (HCC).The study included 235 consecutive patients with hepatitis B-related HCC undergoing PA-TACE at our medical center. Patients were assigned to 2 sets according to the PA-TACE date: initial (2005-2007; n = 130) and internal validation (2008-2009; n = 105) sets. With the aid of a Cox regression model, we developed a risk-scoring model from the independent predictive factors of our initial set designed as a guide for PA-TACE, and the performance of the model was validated with an internal set. External validation was also performed with an independent dataset (n = 84) to assess the discriminatory power of the scoring model.In the multivariate analysis, 4 risk factors (an increase in Child-Pugh score of at least 1 point, hepatitis B virus deoxyribonucleic acid [HBV-DNA] level >10 IU/mL, tumor diameter ≥5 cm, and the presence of vascular invasion) were significantly associated with prognosis. These factors were incorporated into a novel clinicopathological scoring model (assessment for PA-TACE [APT] risk-scoring model) ranging from 0 to 8 that was correlated with prognosis. Different survival outcomes were identified in three groups (0-2 points, 3-6 points, and 7-8 points). The risk-scoring model was further confirmed with 2 independent sets.The novel APT risk-scoring model, merging 4 prognostic factors, may achieve an optimal postsurgical prediction of PA-TACE in HBV-related HCC. The risk for an individual patient with an APT score of ≥7.0 prior to the PA-TACE, who may not profit from further PA-TACE, can be determined, and this may lead to a more appropriate choice of treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Objective: This study sought to establish an effective and reliable prognostic nomogram to guide the decision for post-surgical adjuvant transarterial chemoembolization (PA-TACE) in patients with hepatitis B virus-related (HBV) hepatocellular carcinoma (HCC)., Results: The 1, 3, 5-year overall survival rates were, respectively, 87.7%, 52.1% and 28.3% in the patients from the derivation set and 91.7%, 57.1% and 34.1% in those from the validation set. Five risk factors (HBV-DNA level, platelet count, vascular invasion, change of Child-Pugh score, and tumor diameter) in the multivariate analysis were significantly associated with prognosis. The statistical nomogram incorporated these five factors achieved good calibration and discriminatory abilities with c-index of 0.75 (95% CI 0.67 to 0.83). The findings were supported by the independent external validation set (c-index, 0.69; 95% CI 0.56 to 0.83). Patients who had a nomogram score of less than 180 was considered to have higher survival benefit from PA-TACE., Methods: The nomogram was established based on data obtained from a retrospective study on 235 consecutive patients with HBV HCC who received PA-TACE as an initial therapy from 2006 to 2010 in our center. 84 patients who were collected at another institution between 01/2008 and 12/2010 served as an external validation set. The prognostic nomogram was developed based on the data obtained before the PA-TACE procedure. Predictive accuracy and discriminative ability of the nomogram were assessed by concordance index (C-index), calibration curves, and validation set., Conclusions: The novel nomogram may achieve an optimal prognostic prediction for PA-TACE in HBV-related HCC., Competing Interests: The authors report no declarations of interest.

Objective: To observe the levels of pulmonary surfactant proteins A and D (SP-A, SP-D) in bronchoalveolar lavage fluid (BALF) of children with pneumonia, and to explore their relationships with clinical characteristics., Methods: Thirty-five children with pneumonia were enrolled in this study. Differential cell counts were obtained by Countstar counting board. The levels of SP-A and SP-D in BALF were detected using ELISA., Results: In children with pneumonia, SP-D levels were significantly higher than SP-A levels (P<0.001). SP-D levels were negatively correlated with the neutrophil percentage in BALF (r(s)=-0.5255, P<0.01). SP-D levels in BALF in children with increased blood C-reactive protein levels (>8 mg/L) were significantly lower than in those with a normal level of C-reactive protein (P<0.05). Compared with those in children without wheezing, SP-D levels in children with wheezing were significantly lower (P<0.01). There was no correlation between SP-A levels and clinical characteristics., Conclusions: SP-D levels in BALF are significantly higher than SP-A levels, and have a certain correlation with clinical characteristics in children with pneumonia. As a protective factor, SP-D plays a more important role than SP-A in regulating the immune and inflammatory responses.

Objective: To investigate the pathogenic mechanisms of airway inflammation and recurrent wheezing induced by recurrent respiratory virus infection after respiratory syncytial virus (RSV) infection., Methods: Sixty-four female BALB/c mice (aged 6-8 weeks) were randomly divided into four groups: control, RSV, Poly(I:C), and RSV+Poly(I:C) (n=16 each). The bronchoalveolar lavage fluid (BALF) was collected on the 3rd day after Poly(I:C) administration, and the total cell number and differential counts in BALF were determined. Hematoxylin-eosin staining was used to observe pulmonary pathological changes. The airway responsiveness was detected. ELISA was used to measure the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-13 (IL-13), matrix metallopeptidase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in BALF., Results: Compared with the other three groups, the RSV+Poly(I:C) group had significant increases in the total number of inflammatory infiltrating cells in the airway, airway responsiveness, and MMP-9 level in BALF (P<0.05). The RSV+Poly(I:C) group showed more severe pulmonary tissue injuries compared with the control and RSV groups (P<0.01). Compared with the RSV group, the RSV+Poly(I:C) group showed significant reductions in the levels of IL-4 and TIMP-1 in BALF (P<0.01)., Conclusions: Viral re-infection in the late stage of RSV infection may cause an imbalance of MMP-9/TIMP-1 expression and thus contribute to aggravated airway inflammation.

MicroRNAs are important in cancer development and progression. In the present study, the clinical significance and function of microRNA-711 (miR-711) expression in breast cancer were investigated. The expression level of miR-711 was analyzed in breast cancer tissue samples using reverse transcription-quantitative polymerase chain reaction. Cell proliferation, colony formation, apoptosis and Transwell assays were performed in breast cancer cell lines transfected with miR-711 mimics or inhibitors, or control sequence. miR-711 was found to be upregulated in 30 formalin-fixed paraffin-embedded breast cancer tissue samples compared with paired non-cancerous breast tissues (P<0.05). Furthermore, a higher miR-711 expression was demonstrated to be associated with poor overall and disease-free survival times in 161 breast cancer patients, and miR-711 was identified as an independent prognostic factor using multivariate Cox regression analysis. In vitro , overexpression of miR-711 resulted in a significant increase in proliferation, colony formation, migration and invasion of breast cancer cells. By contrast, downregulating miR-711 inhibited cell proliferation, colony formation, migration and invasion and enhanced the rate of apoptosis of breast cancer cells. To the best of our knowledge, the present study is the first to demonstrate that miR-711 is an independent prognostic factor and serves an important oncogenic function in breast cancer, suggesting that miR-711 is a potential biomarker of prognosis and a molecular therapeutic target in breast cancer.

In general, microRNAs, a class of small (~21 nucleotide) non-coding RNAs, negatively regulate the expression of their target genes. Dysregulation of miRNAs is a common feature in human cancers, but this phenomenon has not been studied extensively in hepatocellular carcinoma (HCC). miR‑148a, a member of the miR-148/152 family, has been found to be downregulated in several tumor types and has been suggested to be a tumor suppressor gene; however, its function in HCC remains unclear. Herein, we describe the epigenetic regulation of miR-148a and its impact on HCC cells. We found that, due to the hypermethylation of its CpG island, miR-148a undergoes methylation-mediated silencing in HCC cell lines. Additionally, DNMT1, the DNA methyltransferase that maintains methylation patterns, is aberrantly upregulated in HCC cell lines, and its overexpression is responsible for hypermethylation of the miR-148a promoter. Intriguingly, the expression of DNMT1, which is a target of miR-148a, is inversely correlated with the expression of miR-148a in HCC cells. These results lead us to propose the existence of a negative feedback regulatory loop between miR-148a and DNMT1 in HCC. Importantly, we demonstrate that the overexpression of miR-148a significantly inhibits HCC cell proliferation and cell cycle progression. Our results suggest the existence of a novel miR-148a-DNMT1 regulatory circuit and indicate that miR-148a acts as a tumor suppressor during hepatocellular carcinogenesis. These results may provide a promising alterative strategy for the therapeutic treatment of HCC.

Inflammatory cells, macrophages induced by lipopolysaccharide (LPS) stimulation, lead to the production of inflammatory cytokines, which are crucial to host defense. MicroRNAs are short noncoding RNAs that regulate key biological processes via suppression of gene expression at posttranscriptional levels. Recently, miR-146a has been shown to be involved in the regulation of immune and inflammatory responses. However, the role of miR-146a in LPS-induced RAW264.7 macrophage cells remains unclear. In this study, we found that the expression of miR-146a was upregulated in RAW264.7 macrophage cells in response to LPS stimulation in a dose- and time-dependent manner by one-step real-time quantitative PCR. In addition, miR-146a mimics decreased, while miR-146a inhibitor increased, the expression of inflammatory cytokine interleukin-6, but did not affect tumor necrosis factor-α expression in LPS-stimulated RAW264.7 macrophage cells. Bioinformatics analyses predict that Notch1 is a potential target of miR-146a. Moreover, miR-146a overexpression in LPS-treated RAW264.7 macrophage cells did significantly decrease Notch1 mRNA and protein levels. These results suggested that miR-146a may function as a novel feedback negative regulator to LPS-induced production of inflammatory cytokines, at least in part, via inhibiting the expression of Notch1.

MicroRNAs (miRNAs) are a class of ~22-nucleotides noncoding RNAs that regulate gene expression by specifically binding with 3'-untranslated region (3'-UTR) of target gene mRNAs to posttranscriptionally effect mRNA stability and translation,and play essential roles in a variety of biological processes, including cell development, proliferation, differentiation, and apoptosis. Liver fibrosis is the occurrence of liver cell necrosis and inflammatory stimulation, and is characterized by excessive accumulation of extracellular matrices(ECMs). In the fibrotic liver, hepatic stellate cells (HSCs), which are regulated by multiple signal transduction pathways, undergo myofibroblastic transdifferentiation and are generally regarded as the major ECM producer responsible for liver fibrosis. A growing body of evidence suggests that divergent miRNAs participate in liver fibrotic process and activation of HSC. Moreover, members of many signal transduction pathways are important targets for miRNAs. In this review, we make a summary on current understanding of the roles of miRNAs in the development of liver fibrosis, HSC functions and their potential as novel drug targets., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Activation of hepatic stellate cells (HSC) plays a pivotal role in the development of hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor responsible for the activation of HSC. MicroRNAs (miRNAs) have recently been shown to regulate cell proliferation, differentiation, and apoptosis. The involvement of miRNAs and their roles in TGF-β1-induced HSC activation remains largely unknown. Our study found that the expression of miR-146a was downregulated in HSC in response to TGF-β1 stimulation in dose-dependent manner by one-step real-time quantitative PCR. Moreover, we sought to examine whether miR-146a became dysregulated in CCl(4)-induced hepatic fibrosis in rats. Our study revealed that miR-146a was downregulated in liver fibrotic tissues. In addition, The HSC transfected with miR-146a mimics exhibited attendated TGF-β1-induced α-smooth muscle actin (α-SMA) expression compared with the control. Furthermore, overexpression of miR-146a suppressed TGF-β-induced HSC proliferation, and increased HSC apoptosis. Bioinformatics analyses predict that SMAD4 is the potential target of miR-146a. MiR-146a overexpression in TGF-β1-treated HSC did not decrease target mRNA levels, but significantly reduced target protein expression. These results suggested that miR-146a may function as a novel regulator to modulate HSC activation during TGF-β1 induction by targeting SMAD4., (Copyright © 2012 Elsevier Inc. All rights reserved.)