[show abstract][hide abstract] ABSTRACT: Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risk, are highly heritable. Genome-wide association (GWA) studies for adiponectin level have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7,827 individuals, followed by two stages of replications in 4,298 and 5,954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P=3.0x10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P=1.2x10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P=6.8x10(-165)), ADIPOQ (P=1.8x10(-22)), PEPD (P=3.6x10(-12)), CMIP (P=2.1x10(-10)), ZNF664 (P=2.3x10(-7)) and GPR109A (P=7.4x10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial=0.020; Pconditional=7.0x10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P=3.3x10(-4)), HDL-C (P=4.9x10(-4)) and BMI-adjusted waist-hip ratio (P=9.8x10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity, and motivate further studies of underlying mechanisms.
Human Molecular Genetics 10/2013; · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
[show abstract][hide abstract] ABSTRACT: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
[show abstract][hide abstract] ABSTRACT: Transmission of rotavirus vaccine or vaccine-reassortant strains to unvaccinated contacts has been reported. Therefore, it is essential to evaluate and characterize the nature of vaccine-virus shedding among rotavirus vaccine recipients. Two groups of healthy infants who received a complete course of RotaTeq (RV5) or Rotarix (RV2) were enrolled (between March 2010 and June 2011) to compare fecal shedding for one month after each vaccine dose. Shedding was assessed using both enzyme immunoassay (EIA) and real-time reverse transcription-polymerase chain reaction (RT-PCR). Eighty-seven infants (34 girls and 53 boys) were enrolled in the study. After the first vaccine dose, the peak time of virus shedding occurred between day 4 and day 7, with positive detection rates of 80-90% by real-time RT-PCR and 20-30% by EIA. In both groups, vaccine shedding occurred as early as one day and as late as 25-28 days. Mixed effects logistic regression analysis of real-time RT-PCR data showed no significant differences between two groups when shedding rates were compared after the first vaccine dose (odds ratio [OR] 1.26; P=0.71) or after the second vaccine dose (odds ratio [OR] 1.26; P=0.99). However, infants receiving RV2 shed significantly higher viral loads than those receiving RV5 when compared after the first vaccine dose (P=0.001) and after the second dose (P=0.039). In terms of shedding rates detected by real-time RT-PCR, vaccine uptake of RV5 or RV2 among infants in Taiwan was comparable. Clinical significance of higher shedding viral loads in RV2 should be further observed.
[show abstract][hide abstract] ABSTRACT: In Taiwan, two rotavirus vaccines are available on the private market, but are not included in the National Immunization Program (NIP). To help assess whether to include rotavirus vaccines in the NIP, we examined the potential impact and cost-effectiveness of vaccination, from the health care system perspective alone.
We used a Microsoft Excel-based model to assess rotavirus vaccination impact on rotavirus disease burden and the cost-effectiveness of 2-dose and 3-dose vaccination programs among a birth cohort of Taiwanese children followed for 5 years. Principal model inputs included data on rotavirus disease burden and related healthcare costs, vaccination cost and coverage rates, and vaccine efficacy. Principal model outputs included the number of health-related events and costs averted and incremental cost per disability-adjusted life year averted.
A national rotavirus vaccination program, regardless of number of doses per course, would prevent 4 deaths, >10,500 hospitalizations, and >64,000 outpatient visits due to rotavirus infection among children <5 years annually, resulting in ∼80%, 90%, and 70% declines in these outcomes, respectively, and a ∼$7 million decline in annual medical costs. A national 2- or 3-dose vaccination program would be cost-saving up to $13.30/dose ($26.60/course) or $7.98/dose ($23.94/course), respectively; very cost-effective up to $24.08 per dose ($48.16/course) or $15.18/dose ($45.54/course), respectively; and cost-effective up to $45.65/dose ($91.30/course) or $29.59/dose ($88.77/course), respectively.
A national rotavirus vaccination program could substantially reduce rotavirus disease burden among Taiwanese children and be potentially cost-effective, depending on the vaccine price.
[show abstract][hide abstract] ABSTRACT: Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.
A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.
We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1.
These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.
[show abstract][hide abstract] ABSTRACT: Our understanding of whether the use of acetaminophen and/or antibiotics in early life can cause allergic diseases in later childhood remains inconclusive. The objective of this study was to investigate the temporal relationship between exposure to acetaminophen and/or antibiotics in early life and the development of allergic diseases in later childhood, using two independent birth cohorts derived from the National Health Insurance Research Database (NHIRD) in Taiwan.
The authors conducted a prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, separately, from the NHIRD. Exposure status of acetaminophen and/or antibiotics and potential confounding factors were included in the analyses. Cox proportional hazards models were applied to determine the temporal relationship between acetaminophen and/or antibiotic exposure and the development of allergic diseases.
We observed a positive relationship between acetaminophen and/or antibiotic exposure during the 1st year of life and the subsequent development of the three examined allergic diseases (atopic dermatitis, asthma and allergic rhinitis) in the 1998 birth cohort, but the observed relationship of drug exposure in the 2003 cohort, especially for atopic dermatitis and asthma, was lower than for those in the 1998 cohort and was not statistically significant.
Our findings provide suggestive evidence that the temporal effect of exposure to acetaminophen and/or antibiotics influences the development of common allergic diseases in later childhood. Further functional studies and/or animal studies are needed to better understand the underlying regulatory mechanisms driving this important clinical and public health issue.
International Journal of Epidemiology 08/2013; 42(4):1087-1099. · 6.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
[show abstract][hide abstract] ABSTRACT: PurposeIn response to the inconsistent cutoff points for the diagnosis of low muscle mass in elderly, the study endeavored to establish a preferred norm for sarcopenia screening by comparing three muscle indices with physical functional assessment.Methods
One thousand healthy adults aged 20–40 were recruited for body composition assessment using bioelectric impedance analysis (BIA, Tanita BC-418, Japan) with segmental measures during annual health examination. Additionally, 308 elderly ambulatory outpatients recruited for comprehensive geriatric assessment were assessed for muscle strength, physical performance, and body composition using the same BIA device.ResultsWith the definition of low muscle mass set at 2 standard deviations below the mean value of appendicular skeletal muscle index (ASMI, appendicular skeletal muscle mass/height2) in the young reference groups, the cutoff points for men and women were 6.76 and 5.28 kg/m2, respectively. The ratios of low muscle mass in the elderly subjects read 8.5% for men and 13.5% for women. The cutoff points of the other two muscle indices – total skeletal muscle index (total skeletal muscle mass/height2, TSMI), and skeletal muscle index (ASM/total body weight, SMI) – were also calculated and the ratios of low muscle mass appeared to be 25.6% and 69.8%, respectively. Compared to their compartments, the elderly with low muscle mass defined by ASMI were older and demonstrated a higher proportion of physical frailty, lower body mass index, lower muscle strength, and poorer physical performance.Conclusions
Compared with TSMI and SMI, ASMI might serve as a preferred index for the diagnosis of low muscle mass.
European geriatric medicine 06/2013; 4(3):145–149. · 0.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung cancer (NSCLC), we performed a consistency meta-analysis study utilizing genome-wide association approaches for overall survival in 327 never smoker NSCLC patients from the MD Anderson Cancer Center and 293 cases from the Mayo Clinic. We then performed a two-pronged validation of the top 25 variants that included additional validation in 1,256 NSCLC patients from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a p-value of 10-6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 (HR:1.44, 95%CI:1.01-2.06) and rs10766739 (HR:1.23, 95%CI:1.00-1.51). These loci resulted in a reduction in median survival time of at least 8 and 5 months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biological mechanism for a subset of these observed associations.
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
[show abstract][hide abstract] ABSTRACT: Physical performance is a major determinant of health in older adults, and is related to lifestyle factors. Dietary fiber has multiple health benefits. It remains unclear whether fiber intake is independently linked to superior physical performance. We aimed to assess the association between dietary fiber and physical performance in older adults.
This was a cross-sectional study conducted with community-dwelling adults aged 55 years and older (n=2680) from the ongoing Healthy Aging Longitudinal Study (HALST) in Taiwan 2008-2010. Daily dietary fiber intake was assessed using a validated food frequency questionnaire. Physical performance was determined objectively by measuring gait speed, 6-minute walk distance, timed "up and go" (TUG), summary performance score, hand grip strength.
Adjusting for all potential confounders, participants with higher fiber intake had significantly faster gait speed, longer 6-minute walk distance, faster TUG, higher summary performance score, and higher hand grip strength (all P <.05). Comparing with the highest quartile of fiber intake, the lowest quartile of fiber intake was significantly associated with the lowest sex-specific quartile of gait speed (adjusted OR, 2.18 in men [95% CI, 1.33-3.55] and 3.65 in women [95% CI, 2.20-6.05]), 6-minute walk distance (OR, 2.40 in men [95% CI, 1.38-4.17] and 4.32 in women [95% CI, 2.37-7.89]), TUG (OR, 2.42 in men [95% CI, 1.43-4.12] and 3.27 in women [95% CI, 1.94-5.52]), summary performance score (OR, 2.12 in men [95% CI, 1.19-3.78] and 5.47 in women [95% CI, 3.20-9.35]), and hand grip strength (OR, 2.64 in men [95% CI, 1.61-4.32] and 4.43 in women [95% CI, 2.62-7.50]).
Dietary fiber intake was independently associated with better physical performance.
PLoS ONE 01/2013; 8(11):e80209. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: As is generally assumed, clusters in protein-protein interaction (PPI) networks perform specific, crucial functions in biological systems. Various network community detection methods have been developed to exploit PPI networks in order to identify protein complexes and functional modules. Due to the potential role of various regulatory modes in biological networks, a single method may just apply a single graph property and neglects communities highlighted by other network properties. This work presents a novel integration method to capture protein modules/ protein complexes by multiple network features detected by different algorithms. The integration method is further implemented in a web-based platform with a highly effective interactive network analyser. Conventionally adopted methods with different perspectives on network community detection (e.g., CPM, FastGreedy, HUNTER, MCL, LE, SpinGlass, and WalkTrap) are also executed simultaneously. Analytical results indicate that the proposed method performs better than the conventional ones. The proposed approach can capture the transcription and RNA splicing machineries from the yeast protein network. Meanwhile, proteins that are highly associated with each other, yet not described in both machineries are also identified. In sum, a protein that is closely connected to components of a known module or a complex in the network view implies the functional association among them. Importantly, our method can detect these unique network features, thus facilitating efforts to discover unknown components of functional modules/ protein complexes.
[show abstract][hide abstract] ABSTRACT: Hormone replacement therapy (HRT) and EGFR single nucleotide polymorphisms (SNPs) have been reported as risk factors for lung cancer in never smokers. We investigate the interaction of EGFR SNPs and HRT for lung adenocarcinoma risk in never-smoking women. This study included 532 never-smoking female lung adenocarcinoma patients and 532 controls, with EGFR SNPs retrieved from a genome-wide association study. The associations of EGFR SNPs with the lung adenocarcinoma risk were estimated by multivariate-adjusted logistic regression. The Haploview program was used to select tagged EGFR SNPs interacted with HRT and construct haplotype blocks. The Benjamini and Hochberg method was used to reduce the multiple testing effects. Among 84 EGFR SNPs retrieved, 11 tagging EGFR SNPs showed an interaction with HRT and lung adenocarcinoma risk, which were mostly located near the tyrosine kinase domain. Eight of the tagged SNPs were in two haplotype blocks. The interactions between HRT and numbers of protective EGFR SNP genotypes are significant in both blocks (p for interaction = 0.0004 and 0.0032, respectively). A trend of decrease in lung adenocarcinoma risk was found in subjects with HRT harboring an increasing number of protective EGFR SNP genotypes in both blocks (p = 0.0032 and 0.0046, respectively). In conclusion, HRT use may modify the association of EGFR SNPs with lung adenocarcinoma risk. The EGFR SNPs have a cumulative effect on decreasing lung adenocarcinoma risk in never-smoking women with HRT use.
[show abstract][hide abstract] ABSTRACT: To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Few randomized controlled trials (RCTs) report interventions targeting improvement of frailty status as an outcome. METHODS: This RCT enrolled 117 older adults (65-79 years of age) in Toufen, Taiwan who scored 3-6 on The Chinese Canadian Study of Health and Aging Clinical Frailty Scale Telephone Version and then score >=1 on the Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF). With a two by two factorial design, subjects were randomly assigned to interventions (Exercise and nutrition, EN, n = 55 or problem solving therapy, PST, n = 57) or controls (non-EN, n = 62 or non-PST, n = 60). Educational booklets were provided to all. EN group subjects received nutrition consultation and a thrice-weekly exercise-training program while PST group subjects received 6 sessions in 3 month. Subjects were followed at 3, 6, and 12 months. Primary outcome was improvement of the CHS_PCF by at least one category (from pre-frail to robust, or from frail to pre-frail or robust) from baseline assessments. One hundred and one completed final assessments. Intention-to-treat analysis with the generalized estimating equation model was applied with adjustment for time and treatment-by-time interactions. RESULTS: Mean age was 71.4 +/- 3.7 years, with 59% females. Baseline characteristic were generally comparable between groups. EN group subjects had a higher improvement rate on the primary outcome than non-EN group subjects (45% vs 27%, adjusted p = 0.008) at 3 months, but not 6 or 12 months. They also had more increase of serum 25(OH) vitamin D level (4.9 +/- 7.7 vs 1.2 +/- 5.4, p = 0.006) and lower percentage of osteopenia (74% vs 89% p = 0.042) at 12 months. PST group subjects had better improvement (2.7 +/- 6.1 vs 0.2 +/- 6.7, p = 0.035, 6-month) and less deterioration (-3.5 +/- 9.7 vs -7.1 +/- 8.7, p = 0.036, 12-month) of dominant leg extension power than non-PST subjects. Some secondary outcomes were also improved in control groups (non-EN or non-PST). No adverse effects were reported. CONCLUSIONS: The three-month EN intervention resulted in short-term (3-month) frailty status improvement and long-term effect on bone mineral density and serum vitamin D (12-month) among Taiwanese community-dwelling elders. The effect of PST was less pronounce.Trial registrationClinicalTrials.gov: EC0970301.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Nontyphoid Salmonella spp. have been among the most common pathogens of acute gastroenteritis in children in Taiwan. However, the principal sources of transmission remain poorly defined. METHODS: A matched case-control study was conducted from January 2009 to October 2010. Cases were children aged 2 to 60 months who were hospitalized at three medical centers in Taiwan because of diarrhea and found to have culture-proven nontyphoidal Salmonella infection. Controls were healthy children or children with acute diseases other than gastroenteritis and matched to cases by age, gender, study site, and enrollment date. RESULTS: A total of 396 cases and 930 matched controls were included for analysis. Multivariate analysis using conditional logistic regression identified contact with household members having diarrhea (matched odds ratio [mOR], 17.9; 95% confidence interval [CI], 8.82-36.34; P < .0001), consumption of instant powdered milk (mOR, 2.04; 95% CI, 1.05-3.94; P = .0344), visits to health-care facilities (mOR, 1.66; 95% CI, 1.12-2.48; P = .0126), and consumption of purchased groundwater (mOR, 1.50; 95% CI, 1.06-2.11; P = .0214) within 1 week preceding enrollment as independent factors associated with increased risk of salmonellosis. Hand-washing before meals (P = .0311), breastfeeding (P = .0370), consumption of chicken (P = .0019), and consumption of food prepared by caregivers (P = .0011) were protective against Salmonella infection. CONCLUSIONS: The principal transmission routes of Salmonella infection in Taiwanese children are person-to-person, waterborne, and environmental contacts. The possibility of powdered milk and groundwater contamination of Salmonella cannot be excluded and requires further investigation.
The Pediatric Infectious Disease Journal 08/2012; · 3.57 Impact Factor