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1.  Healthy Colon, Healthy Life 
Background
Colorectal cancer (CRC) screening rates are increasing, but they are still low, particularly in ethnic minority groups. In many resource-poor settings, fecal occult blood test (FOBT) is the main screening option.
Intervention
Culturally tailored telephone counseling by community health advisors employed by a community-based organization, culturally tailored brochures, and customized FOBT kits.
Design
RCT. Participants were randomized to (1) basic intervention: culturally tailored brochure plus FOBT kit (n=765); (2) enhanced intervention: brochure, FOBT plus telephone counseling (n=768); or (3) usual care (n=256).
Setting/participants
Latino and Vietnamese primary care patients at a large public hospital.
Main outcome measures
Self-reported receipt of FOBT or any CRC screening at 1-year follow-up.
Results
1358 individuals (718 Latinos and 640 Vietnamese) completed the follow-up survey. Self-reported FOBT screening rates increased by 7.8 % in the control group, by 15.1 % in the brochure group, and by 25.1 % in the brochure/telephone counseling group (p<0.01 for differences between each intervention and usual care and for the difference between brochure/telephone counseling and brochure alone). For any CRC screening, rates increased by 4.1 % in the usual care group, by 11.9 % in the FOBT/brochure group, and by 21.4 % in the brochure/telephone counseling group (p<0.01 for differences between each intervention and usual care and for the difference between the basic and the enhanced intervention).
Conclusions
An intervention that included culturally tailored brochures and tailored telephone counseling increased CRC screening in Latinos and the Vietnamese. Brochure and telephone counseling together had the greatest impact. Future research should address replication and dissemination of this model for Latinos and Vietnamese in other communities, and adaptation of the model for other groups.
doi:10.1016/j.amepre.2010.02.020
PMCID: PMC4282133  PMID: 20547275
2.  Breast Cancer Screening Among Vietnamese Americans 
Background
Vietnamese-American women underutilize breast cancer screening.
Design
An RCT was conducted comparing the effect of lay health workers (LHWs) and media education (ME) to ME alone on breast cancer screening among these women.
Setting/participants
Conducted in California from 2004 to 2007, the study included 1100 Vietnamese-American women aged ≥40 years who were recruited through LHW social networks. Data were analyzed from 2007 to 2009.
Intervention
Both groups received targeted ME. The intervention group received two LHW educational sessions and two telephone calls.
Main outcome measures
Change in self-reported receipt of mammography ever, mammography within 2 years, clinical breast examination (CBE) ever, or CBE within 2 years.
Results
The LHW+ME group increased receipt of mammography ever and mammography in the past 2 years (84.1% to 91.6% and 64.7% to 82.1%, p<0.001) while the ME group did not. Both ME (73.1% to 79.0%, p<0.001) and LHW+ME (68.1% to 85.5%, p<0.001) groups increased receipt of CBE ever, but the LHW+ME group had a significantly greater increase. The results were similar for CBE within 2 years. In multivariate analyses, LHW+ME was significantly more effective than ME for all four outcomes, with ORs of 3.62 (95% CI=1.35, 9.76) for mammography ever; 3.14 (95% CI=1.98, 5.01) for mammography within 2 years; 2.94 (95% CI=1.63, 5.30) for CBE ever; and 3.04 (95% CI=2.11, 4.37) for CBE within 2 years.
Conclusions
Increased breast cancer screening by LHWs among Vietnamese-American women. Future research should focus on how LHWs work and whether LHW outreach can be disseminated to other ethnic groups.
doi:10.1016/j.amepre.2009.06.009
PMCID: PMC4282142  PMID: 19765502
3.  Hepatitis B Management in Vulnerable Populations: Gaps in Disease Monitoring and Opportunities for Improved Care 
Background
Hepatitis B (HBV) is prevalent in certain US populations and regular HBV disease monitoring is critical to reducing associated morbidity and mortality. Adherence to established HBV monitoring guidelines among primary care providers is unknown.
Aims
To evaluate HBV disease monitoring patterns and factors associated with adherence to HBV management guidelines in the primary care setting.
Methods
Primary providers within the San Francisco safety net healthcare system were surveyed for HBV management practices, knowledge, attitudes, and barriers to HBV care. Medical records from 1,727 HBV-infected patients were also reviewed retrospectively.
Results
Of 148 (45%) responding providers, 79% reported ALT and 44% reported HBV viral load testing every 6–12 months. Most providers were knowledgeable about HBV but 43% were unfamiliar with HBV management guidelines. Patient characteristics included: mean age 51 years; 54% male; 67% Asian. Within the past year, 75% had ALT; 24% viral load; 21% HBeAg tested, and 40% of at-risk patients had abdominal imaging for HCC. Provider familiarity with guidelines (OR 1.02, 95%CI 1.00–1.03), Asian patient race (OR 4.18, 95%CI 2.40–7.27), and patient age were associated with recommended HBV monitoring. Provider HBV knowledge and attitudes were positively associated, while provider age and perceived barriers were negatively associated with HCC surveillance.
Conclusions
Comprehensive HBV disease monitoring including HCC screening with imaging were suboptimal. While familiarity with AASLD guidelines and patient factors were associated with HBV monitoring, only provider and practice factors were associated with HCC surveillance. These findings highlight the importance of targeted provider education to improve HBV care.
doi:10.1007/s10620-013-2870-z
PMCID: PMC3947196  PMID: 24052195
Hepatitis B; Hepatocellular carcinoma; Primary care; Provider education; Practice guidelines; Health disparities
4.  Three-dimensional treatment outcomes in Class II patients treated with the Herbst appliance: A pilot study 
Introduction
The aims of this study were to analyze 3-dimensional skeletal changes in subjects with Class II malocclusion treated with the Herbst appliance and to compare these changes with treated Class II controls using 3-dimensional superimposition techniques.
Methods
Seven consecutive Herbst patients and 7 Class II controls treated with Class II elastics who met the inclusion criteria had cone-beam computed tomographs taken before treatment, and either after Herbst removal or at posttreatment for the control subjects. Three-dimensional models were generated from the cone-beam computed tomography images, registered on the anterior cranial bases, and analyzed using color maps and point-to-point measurements.
Results
The Herbst patients demonstrated anterior translation of the glenoid fossae and condyles (right anterior fossa, 1.69 ± 0.62 mm; left anterior fossa, 1.43 ± 0.71 mm; right anterior condyle, 1.20 ± 0.41 mm; left anterior condyle, 1.29 ± 0.57 mm), whereas posterior displacement predominated in the controls (right anterior fossa, −1.51 ± 0.68 mm; left anterior fossa, −1.31 ± 0.61 mm; right anterior condyle, −1.20 ± 0.41 mm; left anterior condyle, −1.29 ± 0.57 mm; P <0.001). There was more anterior projection of B-point in the Herbst patients (2.62 ± 1.08 mm vs 1.49 ± 0.79 mm; P <0.05). Anterior displacement of A-point was more predominant in the controls when compared with the Herbst patients (1.20 ± 0.53 mm vs −1.22 ± 0.43 mm; P <0.001).
Conclusions
Class II patients treated with the Herbst appliance demonstrated anterior displacement of the condyles and glenoid fossae along with maxillary restraint when compared with the treated Class II controls; this might result in more anterior mandibular projection.
doi:10.1016/j.ajodo.2013.07.014
PMCID: PMC3999969  PMID: 24286905
5.  Using appropriate body mass index cut points for overweight and obesity among Asian Americans 
Preventive medicine  2014;65:1-6.
Objective
Asian Americans have low prevalence of overweight/obesity based on standard BMI cut points yet have higher rates of diabetes. We examined the prevalence of overweight/obesity, using lower BMI cut points recommended by the World Health Organization (WHO) for Asians, and diabetes in Asian American subgroups in California.
Method
Secondary analysis of the 2009 adult California Health Interview Survey (n = 45,946) of non-Hispanic Whites (NHW), African Americans, Hispanics and Asians (Vietnamese, Chinese, Korean, Filipino, South Asian and Japanese). WHO Asian BMI cut points (overweight = 23–27.5 kg/m2; obese ≥ 27.5 kg/m2) were used for Asian subgroups. Standard BMI cut points (overweight = 25–29.9 kg/m2; obese ≥ 30 kg/m2) were applied for other groups.
Results
Among Asian subgroups, overweight/obesity was highest among Filipinos (78.6%), which was higher than NHWs (p < 0.001) but similar to African Americans and Hispanics. Compared to NHW, diabetes prevalence was higher for Vietnamese, Koreans, Filipinos and South Asians with BMI = 23–24.9 kg/m2 and Koreans, Filipinos and Japanese with BMI = 27.5–29.9 kg/m2, the ranges WHO recommends as overweight or obese for Asians but not for other groups.
Conclusions
Filipinos should be a priority population for overweight/obesity screening. Filipinos, Vietnamese, Korean, South Asians and Japanese have higher diabetes prevalence at lower BMI cut points. WHO Asian BMI cut points may have clinical utility to identify at-risk Asian Americans.
doi:10.1016/j.ypmed.2014.04.010
PMCID: PMC4217157  PMID: 24736092
Obesity; Overweight; Type 2 diabetes mellitus; Asian Americans; Minority health
6.  Face symmetry assessment abilities: Clinical implications for diagnosing asymmetry 
Introduction
An accurate assessment of face symmetry is necessary for the development of a dentofacial diagnosis in orthodontics, and an understanding of individual differences in perception of face symmetry between patients and providers is needed to facilitate successful treatment.
Methods
Orthodontists, general dentists, and control participants completed a series of tasks to assess symmetry. Judgments were made on pairs of upright faces (similar to the longitudinal assessment of photographic patient records), inverted faces, and dot patterns. Participants completed questionnaires regarding clinical practice, education level, and self-confidence ratings for symmetry assessment abilities.
Results
Orthodontists showed expertise compared with controls (P <0.001), whereas dentists showed no advantage over controls. Orthodontists performed better than dentists, however, in only the most difficult face symmetry judgments (P = 0.006). For both orthodontists and dentists, accuracy increased significantly when assessing symmetry in upright vs inverted faces (t = 3.7, P = 0.001; t = 2.7, P = 0.02, respectively).
Conclusions
Orthodontists showed expertise in assessing face symmetry compared with both laypersons and general dentists, and they were more accurate when judging upright than inverted faces. When using accurate longitudinal photographic records to assess changing face symmetry, orthodontists are likely to be incorrect in less than 15% of cases, suggesting that assistance from some additional technology is infrequently needed for diagnosis.
doi:10.1016/j.ajodo.2013.06.020
PMCID: PMC4017242  PMID: 24182582
7.  Three-dimensional analysis of maxillary changes associated with facemask and rapid maxillary expansion compared with bone anchored maxillary protraction 
Introduction
Our objectives in this study were to evaluate in 3 dimensions the growth and treatment effects on the midface and the maxillary dentition produced by facemask therapy in association with rapid maxillary expansion (RME/FM) compared with bone-anchored maxillary protraction (BAMP).
Methods
Forty-six patients with Class III malocclusion were treated with either RME/FM (n = 21) or BAMP (n = 25). Three-dimensional models generated from cone-beam computed tomographic scans, taken before and after approximately 1 year of treatment, were registered on the anterior cranial base and measured using color-coded maps and semitransparent overlays.
Results
The skeletal changes in the maxilla and the right and left zygomas were on average 2.6 mm in the RME/FM group and 3.7 mm in the BAMP group; these were different statistically. Seven RME/FM patients and 4 BAMP patients had a predominantly vertical displacement of the maxilla. The dental changes at the maxillary incisors were on average 3.2 mm in the RME/FM group and 4.3 mm in the BAMP group. Ten RME/FM patients had greater dental compensations than skeletal changes.
Conclusions
This 3-dimensional study shows that orthopedic changes can be obtained with both RME/FM and BAMP treatments, with protraction of the maxilla and the zygomas. Approximately half of the RME/FM patients had greater dental than skeletal changes, and a third of the RME/FM compared with 17% of the BAMP patients had a predominantly vertical maxillary displacement.
doi:10.1016/j.ajodo.2013.07.011
PMCID: PMC3972125  PMID: 24182587
8.  Influenza and Pneumococcal Vaccination Rates among Vietnamese, Asian, and Non-Hispanic White Americans 
Background
Vaccination data for Asian Americans are comparable to those for whites, possibly because they are reported in aggregate rather than for subgroups. We compared influenza and pneumococcal vaccination rates among eligible Asian Americans and white Americans, and for Vietnamese Americans as a subgroup, and assessed factors associated with these vaccinations.
Methods
Cross-sectional study of data collected from three ethnic groups over 4 years by telephone survey. Data were weighted for selection probability and population estimates and analyzed by multivariate logistic regression.
Results
Vietnamese Americans had a higher rate of influenza vaccination (61%) than Asian Americans (45%) and white Americans (52%), and lower rate of pneumococcal vaccination (41%) than Asian Americans (56%), both lower than white Americans (67%).
Conclusion
When analyzed as a subgroup, Vietnamese Americans had a higher influenza vaccination rate, but a lower pneumococcal vaccination rate, compared to Asian Americans and white Americans, which may indicate that health behaviors and outcomes can differ widely among Asian subgroups. Analyses of preventive care measures in Asian Americans should focus on subgroups to ensure accuracy and quality of assessments.
doi:10.1007/s10903-008-9195-6
PMCID: PMC4075262  PMID: 18839311
Vietnamese Americans; Adult immunizations; Racial/Ethnic disparities
9.  Increasing Hepatitis B Screening for Hmong adults: Results from a randomized controlled community-based study 
Background
Hepatitis B-linked liver cancer disproportionately affects Hmong Americans. With an incidence rate of 18.9/100,000, Hmong Americans experience liver cancer at a rate that is 6–7 times greater than that of non-Hispanic Whites. Serological testing for the hepatitis B virus (HBV) is a principal means to prevent liver cancer deaths through earlier identification of those at risk.
Methods
Academic researchers and Hmong leaders collaborated in the design, conduct, and evaluation of a 5-year randomized controlled trial testing a lay health worker (LHW) intervention to promote HBV testing among 260 Hmong adults through in-home education and patient navigation.
Results
Intervention group participants were more likely to report receiving serological testing for HBV (24% vs. 10%, p=0.0056) and showed a greater mean increase in knowledge score (1.3 vs. 0.3 points, p=0.0003) than control group participants. Multivariable modeling indicated that self-reported test receipt was associated with intervention group assignment (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.3–9.2), improvement in knowledge score (OR 1.3 per point, 95% CI 1.02–1.7), female gender (OR 5.3, 95% CI 1.7–16.6), and having seen a doctor in the past year at baseline (OR 4.8, 95% CI 1.3–17.6). The most often cited reason for testing was a doctor’s recommendation.
Conclusions
LHWs were effective in bringing about HBV screening. Doctor visits and adherence to doctors’ recommendations were pivotal. Participation of health care providers is essential to increase HBV testing.
Impact
LHWs can significantly increase HBV screening rates for Hmong, but their doctors’ recommendation is highly influential and should be pursued.
doi:10.1158/1055-9965.EPI-12-1399
PMCID: PMC3650126  PMID: 23613027
Hepatitis B; Hmong; Randomized controlled trial; community-based; liver cancer
10.  Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver 
BMC Bioinformatics  2014;15:83.
Background
The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional level remains unknown. To explore this aspect, we analyzed hepatic transcriptional dynamics in Sprague-Dawley rats over a period of 24 hours to assess the genome-wide responses.
Results
Using an unsupervised consensus clustering method, we identified four major gene expression clusters, corresponding to central carbon and nitrogen metabolism, membrane integrity, immune function, and DNA repair, all of which have dynamics which suggest regulation in a circadian manner. With the assumption that transcription factors (TFs) that are differentially expressed and contain CLOCK:BMAL1 binding sites on their proximal promoters are likely to be clock-controlled TFs, we were able to use promoter analysis to putatively identify additional clock-controlled TFs besides PARF and RORA families. These TFs are both functionally and temporally related to the clusters they regulate. Furthermore, we also identified significant sets of clock TFs that are potentially transcriptional regulators of gene clusters.
Conclusions
All together, we were able to propose a regulatory structure for circadian regulation which represents alternative paths for circadian control of different functions within the liver. Our prediction has been affirmed by functional and temporal analyses which are able to extend for similar studies.
doi:10.1186/1471-2105-15-83
PMCID: PMC3987685  PMID: 24666587
Circadian rhythm; Microarray analysis; Gene expression; Consensus clustering; Promoter analysis; Transcription factor; Circadian regulation
11.  Tissue-Specific Gene Expression and Regulation in Liver and Muscle Following Chronic Corticosteroid Administration 
Although corticosteroids (CSs) affect gene expression in multiple tissues, the array of genes that are regulated by these catabolic steroids is diverse, highly tissue specific, and depends on their functions in the tissue. Liver has many important functions in performing and regulating diverse metabolic processes. Muscle, in addition to its mechanical role, is critical in maintaining systemic energy homeostasis and accounts for about 80% of insulin-directed glucose disposal. Consequently, a better understanding of CS pharmacogenomic effects in these tissues would provide valuable information regarding the tissue-specificity of transcriptional dynamics, and would provide insights into the underlying molecular mechanisms of action for both beneficial and detrimental effects.
We performed an integrated analysis of transcriptional data from liver and muscle in response to methylprednisolone (MPL) infusion, which included clustering and functional annotation of clustered gene groups, promoter extraction and putative transcription factor (TF) identification, and finally, regulatory closeness (RC) identification.
This analysis allowed the identification of critical transcriptional responses and CS-responsive functions in liver and muscle during chronic MPL administration, the prediction of putative transcriptional regulators relevant to transcriptional responses of CS-affected genes which are also potential secondary bio-signals altering expression levels of target-genes, and the exploration of the tissue-specificity and biological significance of gene expression patterns, CS-responsive functions, and transcriptional regulation.
The analysis provided an integrated description of the genomic and functional effects of chronic MPL infusion in liver and muscle.
doi:10.4137/GRSB.S13134
PMCID: PMC3956809  PMID: 24653645
liver; muscle; glucocorticoids; corticosteroids; gene expression; gene regulation; promoter analysis
12.  Population-environment drivers of H5N1 avian influenza molecular change in Vietnam 
Health & place  2012;18(5):1122-1131.
This study identifies population and environment drivers of genetic change in H5N1 avian influenza viruses (AIV) in Vietnam using a landscape genetics approach. While prior work has examined how combinations of local-level environmental variables influence H5N1 occurrence, this research expands the analysis to the complex genetic characteristics of H5N1 viruses. A dataset of 125 highly pathogenic H5N1 AIV isolated in Vietnam from 2003–2007 is used to explore which population and environment variables are correlated with increased genetic change among viruses. Results from non-parametric multidimensional scaling and regression analyses indicate that variables relating to both the environmental and social ecology of humans and birds in Vietnam interact to affect the genetic character of viruses. These findings suggest that it is a combination of suitable environments for species mixing, the presence of high numbers of potential hosts, and in particular the temporal characteristics of viral occurrence, that drive genetic change among H5N1 AIV in Vietnam.
doi:10.1016/j.healthplace.2012.04.009
PMCID: PMC3904498  PMID: 22652510
landscape genetics; H5N1 avian influenza; Vietnam; disease ecology
13.  Understanding and Use of Nicotine Replacement Therapy and Nonpharmacologic Smoking Cessation Strategies Among Chinese and Vietnamese Smokers and Their Families 
Introduction
Population-based studies have reported high rates of smoking prevalence among Chinese and Vietnamese American men. Although nicotine replacement therapy (NRT) is effective, recommended, and accessible without prescription, these populations underuse NRT for smoking cessation. The aim of this study was to assess understanding and use of NRT and nonpharmacologic treatments among Chinese and Vietnamese American male smokers and their families.
Methods
In-depth qualitative interviews were conducted with 13 smoker–family pairs, followed by individual interviews with each participant. A total of 39 interviews were conducted in Vietnamese or Chinese, recorded, translated, and transcribed into English for analysis.
Results
Four themes were identified: use and understanding of NRT, nonpharmacologic strategies, familial and religious approaches, and willpower. Both smokers and their family members believed strongly in willpower and a sense of personal responsibility as the primary drivers for stopping smoking. Lack of these 2 qualities keeps many Chinese and Vietnamese men from using NRT to quit smoking. Those who do use NRT often use it incorrectly, following their own preferences rather than product instructions.
Conclusion
Our findings indicate the importance of culturally appropriate patient education about NRT. It may be necessary to teach smokers and their families at an individual level about NRT as a complementary approach that can strengthen their resolve to quit smoking. At a community level, public health education on the indication and appropriate use of evidence-based smoking cessation resources, such as NRT, would be an important component of effective tobacco control.
doi:10.5888/pcd11.130299
PMCID: PMC3938957  PMID: 24556252
14.  Developing Theoretically Based and Culturally Appropriate Interventions to Promote Hepatitis B Testing in 4 Asian American Populations, 2006–2011 
Introduction
Hepatitis B infection is 5 to 12 times more common among Asian Americans than in the general US population and is the leading cause of liver disease and liver cancer among Asians. The purpose of this article is to describe the step-by-step approach that we followed in community-based participatory research projects in 4 Asian American groups, conducted from 2006 through 2011 in California and Washington state to develop theoretically based and culturally appropriate interventions to promote hepatitis B testing. We provide examples to illustrate how intervention messages addressing identical theoretical constructs of the Health Behavior Framework were modified to be culturally appropriate for each community.
Methods
Intervention approaches included mass media in the Vietnamese community, small-group educational sessions at churches in the Korean community, and home visits by lay health workers in the Hmong and Cambodian communities.
Results
Use of the Health Behavior Framework allowed a systematic approach to intervention development across populations, resulting in 4 different culturally appropriate interventions that addressed the same set of theoretical constructs.
Conclusions
The development of theory-based health promotion interventions for different populations will advance our understanding of which constructs are critical to modify specific health behaviors.
doi:10.5888/pcd11.130245
PMCID: PMC4008952  PMID: 24784908
15.  Engaging Traditional Medicine Providers in Colorectal Cancer Screening Education in a Chinese American Community: A Pilot Study 
Introduction
Although colorectal cancer (CRC) screening is effective in preventing colon cancer, it remains underused by Asian Americans. Because Chinese Americans often use traditional Chinese medicine (TCM), we conducted a pilot study to explore the feasibility and acceptability of having TCM providers deliver education about CRC screening.
Methods
Four TCM providers (2 herbalists and 2 acupuncturists) were trained to deliver small-group educational sessions to promote CRC screening. Each provider recruited 15 participants aged 50 to 75. Participants completed a baseline survey on CRC-related knowledge, attitudes, and behaviors and then attended one 2-hour educational session delivered by the providers in Cantonese or Mandarin. Three months later, participants completed a postintervention survey.
Results
Sixty participants were recruited from the San Francisco Chinatown neighborhood. The average age was 62.4 years. Most participants had limited English proficiency (96.7%), annual household income less than $20,000 per year (60%), and low educational attainment (65.1% < high school education). At postintervention (n = 57), significant increases were found in having heard of CRC (from 52.6% to 79.0%, P < .001) and colon polyps (from 64.9% to 84.2%, P < .001). Knowledge regarding screening frequency recommendations also increased significantly. The rate of ever having received any CRC screening test increased from 71.9% to 82.5% (P <.001). The rate of up-to-date screening increased from 70.2% to 79.0% (P = .04).
Conclusion
The findings suggest that TCM providers can be trained to deliver culturally and linguistically appropriate outreach on CRC screening within their community. Participants reached by TCM providers increased CRC knowledge and self-reported CRC screening.
doi:10.5888/pcd11.140341
PMCID: PMC4264464  PMID: 25496557
16.  Antiviral Susceptibility of Highly Pathogenic Avian Influenza A(H5N1) Viruses Isolated from Poultry, Vietnam, 2009–2011 
Emerging Infectious Diseases  2013;19(12):1963-1971.
We assessed drug susceptibilities of 125 avian influenza A(H5N1) viruses isolated from poultry in Vietnam during 2009–2011. Of 25 clade 1.1 viruses, all possessed a marker of resistance to M2 blockers amantadine and rimantadine; 24 were inhibited by neuraminidase inhibitors. One clade 1.1 virus contained the R430W neuraminidase gene and reduced inhibition by oseltamivir, zanamivir, and laninamivir 12-, 73-, and 29-fold, respectively. Three of 30 clade 2.3.4 viruses contained a I223T mutation and showed 7-fold reduced inhibition by oseltamivir. One of 70 clade 2.3.2.1 viruses had the H275Y marker of oseltamivir resistance and exhibited highly reduced inhibition by oseltamivir and peramivir; antiviral agents DAS181 and favipiravir inhibited H275Y mutant virus replication in MDCK-SIAT1 cells. Replicative fitness of the H275Y mutant virus was comparable to that of wildtype virus. These findings highlight the role of drug susceptibility monitoring of H5N1 subtype viruses circulating among birds to inform antiviral stockpiling decisions for pandemic preparedness.
doi:10.3201/eid1912.130705
PMCID: PMC3840871  PMID: 24274711
Influenza; viruses; H5N1; Oseltamivir; H275Y; antiviral; zoonoses
17.  GENETIC VARIATION OF HIGHLY PATHOGENIC H5N1 AVIAN INFLUENZA VIRUSES IN VIETNAM SHOWS BOTH SPECIES-SPECIFIC AND SPATIOTEMPORAL ASSOCIATIONS 
Avian diseases  2011;55(4):659-666.
Summary
Domestic poultry act as a reservoir for persistent H5N1 endemicity in Vietnam, and the circulation of poultry flocks across farms and to market is thought to drive the spatial movement and evolution of avian influenza viruses. Using a dataset of complete or nearly full genomic sequences from highly pathogenic H5N1 avian influenza viruses collected in domestic poultry in Vietnam from 2003 to 2007, we explore potential differences in genetic characteristics according to species of isolation and the spatio-temporal characteristics of the viruses. Clustering algorithms and analysis of variance indicate that H5N1 viruses in Vietnam show differences in the amount of genetic change that chicken viruses experience as compared to duck viruses, with duck viruses showing higher rates of molecular evolution on all eight of influenza's gene segments. There also exist distinct patterns of genetic differentiation according to the year in which they were isolated. These findings suggest that genetic evolution of avian influenza viruses is continuous through time but could also be mediated by the species in which the viruses occur, information which has implications for prevention efforts.
PMCID: PMC3841065  PMID: 22312987
H5N1 avian influenza; genetic differentiation; poultry; ecology; cluster analysis; analysis of variance
18.  Highly Pathogenic H5N1 Avian Influenza Viruses Exhibit Few Barriers to Gene Flow in Vietnam 
EcoHealth  2012;9(1):60-69.
Locating areas where genetic change is inhibited can illuminate underlying processes that drive evolution of pathogens. The persistence of highly pathogenic H5N1 avian influenza in Vietnam since 2003, and the continuous molecular evolution of Vietnamese avian influenza viruses, indicates that local environmental factors are supportive not only of incidence but also of viral adaptation. This article explores whether gene flow is constant across Vietnam, or whether there exist boundary areas where gene flow exhibits discontinuity. Using a dataset of 125 highly pathogenic H5N1 avian influenza viruses, principal components analysis and wombling analysis are used to indicate the location, magnitude, and statistical significance of genetic boundaries. Results show that a small number of geographically minor boundaries to gene flow in highly pathogenic H5N1 avian influenza viruses exist in Vietnam, but that overall there is little division in genetic exchange. This suggests that differences in genetic characteristics of viruses from one region to another are not the result of barriers to H5N1 viral exchange in Vietnam, and that H5N1 avian influenza is able to spread relatively unimpeded across the country.
doi:10.1007/s10393-012-0749-7
PMCID: PMC3771539  PMID: 22350419
H5N1 avian influenza; gene flow; wombling; Vietnam
19.  Three-dimensional assessment of maxillary changes associated with bone anchored maxillary protraction 
Introduction
Bone-anchored maxillary protraction has been shown to be an effective treatment modality for the correction of Class III malocclusions. The purpose of this study was to evaluate 3-dimensional changes in the maxilla, the surrounding hard and soft tissues, and the circummaxillary sutures after bone-anchored maxillary protraction treatment.
Methods
Twenty-five consecutive skeletal Class III patients between the ages of 9 and 13 years (mean, 11.10 ± 1.1 years) were treated with Class III intermaxillary elastics and bilateral miniplates (2 in the infrazygomatic crests of the maxilla and 2 in the anterior mandible). Cone-beam computed tomographs were taken before initial loading and 1 year out. Three-dimensional models were generated from the tomographs, registered on the anterior cranial base, superimposed, and analyzed by using color maps.
Results
The maxilla showed a mean forward displacement of 3.7 mm, and the zygomas and the maxillary incisors came forward 3.7 and 4.3 mm, respectively.
Conclusions
This treatment approach produced significant orthopedic changes in the maxilla and the zygomas in growing Class III patients.
doi:10.1016/j.ajodo.2011.04.025
PMCID: PMC3734342  PMID: 22133943
20.  Dynamics of hepatic gene expression profile in a rat cecal ligation and puncture model 
The Journal of Surgical Research  2011;176(2):583-600.
Background
Sepsis remains a major clinical challenge in intensive care units. The difficulty in developing new and more effective treatments for sepsis exemplifies our incomplete understanding of the underlying pathophysiology of it. One of the more widely used rodent models for studying polymicrobial sepsis is cecal ligation and puncture (CLP). While a number of CLP studies investigated the ensuing systemic inflammatory response, they usually focus on a single time point post CLP and therefore fail to describe the dynamics of the response. Furthermore, previous studies mostly use surgery without infection (herein referred to as Sham CLP, SCLP) as a control for the CLP model, however SCLP represents an aseptic injurious event that also stimulates a systemic inflammatory response. Thus, there is a need to better understand the dynamics and expression patterns of both injury- and sepsis- induced gene expression alterations to identify potential regulatory targets. In this direction, we characterized the response of the liver within the first 24 h in a rat model of SCLP and CLP using a time series of microarray gene expression data.
Methods
Rats were randomly divided into three groups, sham, SCLP and CLP. Rats in SCLP group are subjected to laparotomy, cecal ligation and puncture while those in CLP group are subjected to the similar procedures without cecal ligation and puncture. Animals were saline resuscitated and sacrificed at defined time points (0, 2, 4, 8, 16, and 24 h). Liver tissues were explanted and analyzed for their gene expression profiles using microarray technology. Unoperated animals (Sham) serve as negative controls. After identifying differentially expressed probesets between sham and SCLP or CLP conditions over time, the concatenated data sets corresponding to these differentially expressed probesets in sham and SCLP or CLP groups were combined and analyzed using a “consensus clustering” approach. Promoters of genes that share common characteristics were extracted, and compared with gene batteries comprised of co expressed genes in order to identify putatative transcription factors which could be responsible for the co regulation of those genes.
Results
The SCLP/CLP genes whose expression patterns significantly changed compared to sham over time were identified, clustered, and finally analyzed for pathway enrichment. Our results indicate that both CLP and SCLP triggered the activation of a pro-inflammatory response, enhanced synthesis of acute-phase proteins, increased metabolism and tissue damage markers. Genes triggered by CLP which can be directly linked to bacteria removal functions were absent in SCLP injury. In addition, genes relevant to oxidative stress induced damage were unique to CLP injury, which may be due to the increased severity of CLP injury vs. SCLP injury. Pathway enrichment identified pathways with similar functionality but different dynamics in the two injury models, indicating that the functions controlled by those pathways are under the influence of different transcription factors and regulatory mechanisms. Putatively identified transcription factors, notably including CREB, NF-KB and STAT, were obtained through analysis of the promoter regions in the SCLP/CLP genes. Our results show that while transcription factors such as NF-KB, HOMF, and GATA were common in both injuries for the IL-6 signaling pathway, there were many other transcription factors associated with that pathway which were unique to CLP, including FKHD, HESF and IRFF. There were 17 transcription factors that were identified as important in at least 2 pathways in the CLP injury, but only 7 transcription factors with that property in the SCLP injury. This also supports the hypothesis of unique regulatory modules that govern the pathways present in both the CLP and SCLP response.
Conclusions
By using microarrays to assess multiple genes in a high throughput manner, we demonstrate that an inflammatory response involving different dynamics and different genes is triggered by SCLP and CLP. From our analysis of the CLP data, the key characteristics of sepsis are a pro inflammatory response which drives hypermetabolism, immune cell activation, and damage from oxidative stress. This contrasts with SCLP, which triggers a modified inflammatory response leading to no immune cell activation, decreased detoxification potential, and hyper metabolism. Many of the identified transcription factors that drive the CLP-induced response are not found in the SCLP group, suggesting that SCLP and CLP induce different types of inflammatory responses via different regulatory pathways.
doi:10.1016/j.jss.2011.11.1031
PMCID: PMC3368040  PMID: 22381171
sepsis; trauma; gene expression; transcription factor; microarray; inflammation; liver
21.  Hepatocellular Carcinoma Screening Practices and Impact on Survival among Hepatitis B-Infected Asian Americans 
Journal of Viral Hepatitis  2012;19(8):594-600.
Asians Americans have a high burden of hepatitis B (HBV) associated hepatocellular carcinoma (HCC). HCC screening practices in this population are unknown. We aimed to investigate predictors and patterns of HCC screening and its impact on survival in HBV-infected Asian Americans. Clinical data were obtained from a retrospective cohort of 1870 HBsAg-positive Asians in San Francisco’s safety net clinics. In 824 patients at-risk for HCC, screening (≥1 imaging and/or AFP per year) decreased from 67% to 47% to 24% from the first to second to tenth year after HBV diagnosis, respectively. AFP, imaging, and imaging plus AFP were used in 37%, 14%, and 49% during the first year after diagnosis, and imaging plus AFP increased to 64% by the tenth year. Among 1431 patients followed in 2007, age 40-64 years, female gender, cirrhosis, hepatologist evaluation, HBV diagnosis after 2003, and testing for HBeAg were associated with HCC screening. Of the 51 patients with HCC, more cirrhotics received screening and were diagnosed with early stage disease. Median survival following HCC diagnosis was higher in screened patients (1624 vs.111 days, p=0.02). MELD score at HCC diagnosis (HR 1.2, 95%CI: 1.1-1.3) and receipt of curative therapy (HR 0.3, 95%CI: 0.08-0.94) were associated with survival. Screening rates in at-risk Asian Americans, particularly among non-cirrhotics, were suboptimal and decreased over time. Among patients with HCC, receipt of prior screening improved survival, and this survival benefit was related to better liver function at HCC diagnosis and receipt of curative therapy.
doi:10.1111/j.1365-2893.2011.01577.x
PMCID: PMC3390753  PMID: 22762144
liver cancer; hepatitis B; safety net healthcare system; cirrhosis; mortality
22.  A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff 
Fly  2012;6(2):80-92.
We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted.
Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w1118; iso-2; iso-3 strain and the reference y1; cn1 bw1 sp1 strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in the 5′UTR. We found, as expected, that the SNP frequency is proportional to the recombination frequency (i.e., highest in the middle of chromosome arms). We also found that start-gain or stop-lost SNPs in Drosophila melanogaster often result in additions of N-terminal or C-terminal amino acids that are conserved in other Drosophila species. It appears that the 5′ and 3′ UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus.
As genome sequencing is becoming inexpensive and routine, SnpEff enables rapid analyses of whole-genome sequencing data to be performed by an individual laboratory.
doi:10.4161/fly.19695
PMCID: PMC3679285  PMID: 22728672
Drosophila melanogaster; Personal Genomes; next generation DNA sequencing; whole-genome SNP analysis
23.  An Agent-Based Model of Cellular Dynamics and Circadian Variability in Human Endotoxemia 
PLoS ONE  2013;8(1):e55550.
As cellular variability and circadian rhythmicity play critical roles in immune and inflammatory responses, we present in this study an agent-based model of human endotoxemia to examine the interplay between circadian controls, cellular variability and stochastic dynamics of inflammatory cytokines. The model is qualitatively validated by its ability to reproduce circadian dynamics of inflammatory mediators and critical inflammatory responses after endotoxin administration in vivo. Novel computational concepts are proposed to characterize the cellular variability and synchronization of inflammatory cytokines in a population of heterogeneous leukocytes. Our results suggest that there is a decrease in cell-to-cell variability of inflammatory cytokines while their synchronization is increased after endotoxin challenge. Model parameters that are responsible for IκB production stimulated by NFκB activation and for the production of anti-inflammatory cytokines have large impacts on system behaviors. Additionally, examining time-dependent systemic responses revealed that the system is least vulnerable to endotoxin in the early morning and most vulnerable around midnight. Although much remains to be explored, proposed computational concepts and the model we have pioneered will provide important insights for future investigations and extensions, especially for single-cell studies to discover how cellular variability contributes to clinical implications.
doi:10.1371/journal.pone.0055550
PMCID: PMC3559552  PMID: 23383223
24.  Three-dimensional assessment of mandibular and glenoid fossa changes after bone-anchored Class III intermaxillary traction 
Introduction
Conventional treatment for young Class III patients involves extraoral devices designed to either protract the maxilla or restrain mandibular growth. The use of skeletal anchorage offers a promising alternative to obtain orthopedic results with fewer dental compensations. Our aim was to evaluate 3-dimensional changes in the mandibles and the glenoid fossae of Class III patients treated with bone-anchored maxillary protraction.
Methods
Twenty-five consecutive skeletal Class III patients between the ages of 9 and 13 years (mean age, 11.10 ± 1.1 year) were treated with Class III intermaxillary elastics and bilateral miniplates (2 in the infrazygomatic crests of the maxilla and 2 in the anterior mandible). The patients had cone-beam computed tomography images taken before initial loading and at the end of active treatment. Three-dimensional models were generated from these images, registered on the anterior cranial base, and analyzed by using color maps.
Results
Posterior displacement of the mandible at the end of treatment was observed in all subjects (posterior ramus: mean, 2.74 ± 1.36 mm; condyles: mean, 2.07 ± 1.16 mm; chin: mean, −0.13 ± 2.89 mm). Remodeling of the glenoid fossa at the anterior eminence (mean, 1.38 ± 1.03 mm) and bone resorption at the posterior wall (mean, −1.34 ± 0.6 mm) were observed in most patients.
Conclusions
This new treatment approach offers a promising alternative to restrain mandibular growth for Class III patients with a component of mandibular prognathism or to compensate for maxillary deficiency in patients with hypoplasia of the midface. Future studies with long-term follow-up and comparisons with facemask and chincup therapies are needed to better understand the treatment effects.
doi:10.1016/j.ajodo.2012.01.017
PMCID: PMC3553657  PMID: 22748987
25.  Comparison of the Cytokine and Chemokine Dynamics of the Early Inflammatory Response in Models of Burn Injury and Infection 
Cytokine  2011;55(3):362-371.
The inflammatory response, and its subsequent resolution, are the result of a very complex cascade of events originating at the site of injury or infection. When the response is severe and persistent, Systemic Inflammatory Response Syndrome can set in, which is associated with a severely debilitating systemic hypercatabolic state. This complex behavior, mediated by cytokines and chemokines, needs to be further explored to better understand its systems properties and potentially identify multiple targets that could be addressed simultaneously. In this context, short term responses of serum cytokines and chemokines were analyzed in two types of insults: rats receiving a “sterile” cutaneous dorsal burn on 20% of the total body surface area (TBSA); rats receiving a cecum ligation and puncture treatment (CLP) to induce infection. Considering the temporal variability observed in the baseline corresponding to the control group, the concept of area under the curve (AUC) was explored to assess the dynamic responses of cytokines and chemokines. MCP-1, GROK/KC, IL-12, IL-18 and IL-10 were observed in both burn and CLP groups. While IL-10 concentration was only increased in the burn group, Eotaxin was only elevated in CLP group. It was also observed that Leptin and IP-1 concentrations were decreased in both CLP and sham-CLP groups. The link between the circulating protein mediators and putative transcription factors regulating the cytokine/chemokine gene expression was explored by searching the promoter regions of cytokine/chemokine genes in order to characterize and differentiate the inflammatory responses based on the dynamic data. Integrating multiple sources together with the bioinformatics tools identified mediators sensitive to type and extent of injury, and provided putative regulatory mechanisms. This is essential to gain a better understanding for the important regulatory points that can be used to modulate the inflammatory state at molecular level.
doi:10.1016/j.cyto.2011.05.010
PMCID: PMC3148335  PMID: 21652218
Cytokines; Chemokines; Burn injury; Cecum ligation and puncture

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