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Paul Y Takahashi,1 Euijung Ryu,2 Suzette J Bielinski,3 Matthew Hathcock,2 Gregory D Jenkins,2 James R Cerhan,3 Janet E Olson3 1Division of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; 3Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USACorrespondence: Paul Y TakahashiDivision of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USATel +1-507-284-2511Fax +1-507-266-2297Email Takahashi.paul@mayo.eduBackground: The use of pharmacogenomics data is increasing in clinical practice. However, it is unknown if pharmacogenomics data can be used more broadly to predict outcomes like hospitalization or emergency department (ED) visit. We aim to determine the association between selected pharmacogenomics phenotypes and hospital utilization outcomes (hospitalization and ED visits).Methods: This cohort study utilized 10,078 patients from the Mayo Clinic Biobank in the RIGHT protocol with sequence and interpreted phenotypes for 10 selected pharmacogenes including CYP2D6, CYP2C9, CYP2C19, CYP3A5, HLA B 5701, HLA B 5702, HLA B 5801, TPMT, SLCO1B1, and DPYD. The primary outcome was hospitalization with ED visits as a secondary outcome. We used Cox proportional hazards model to test the association between each pharmacogenomics phenotype and the risk of the outcomes.Results: During the follow-up period (median [in years] = 7.3), 13% (n=1354) and 8% (n=813) of the subjects experienced hospitalization and ED visits, respectively. Compared to subjects who did not experience hospitalization, hospitalized patients were older (median age [in years]: 67 vs 65), poorer self-rated health (15% vs 4.7% for fair/poor), and higher disease burden (median number of chronic conditions: 7 vs 4) at baseline. There was no association of hospitalization with any of the pharmacogenomics phenotypes. The pharmacogenomics phenotypes were not associated with disease burden, a well-established risk factor for hospital utilization outcomes. Similar findings were observed for patients with ED visits during the follow-up period.Conclusion: We found no association of 10 well-established pharmacogenomics phenotypes with either hospitalization or ED visits in this relatively large biobank population and outside the context of specific drug use related to these genes. Traditional risk factors for hospitalization like age and self-rated health were much more likely to predict hospitalization and/or ED visits than this pharmacogenomics information.Keywords: pharmacogenomics, emergency department, hospitalization

Paul Y Takahashi,1 Gregory D Jenkins,2 Benjamin P Welkie,2 Shannon K McDonnell,2 Jared M Evans,2 James R Cerhan,2 Janet E Olson,2 Stephen N Thibodeau,3 Mine S Cicek,3 Euijung Ryu2 1Division of Primary Care Internal Medicine, 2Department of Health Sciences Research, 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Purpose: In aging adults, mitochondrial dysfunction may be an important contributor. We evaluated the association between mitochondrial DNA (mtDNA) copy number, which is a biomarker for mitochondrial function, and self-rated health status.Patients and methods: We conducted a cross-sectional study of patients enrolled within the Mayo Clinic Biobank. We utilized the questionnaire and sequence data from 944 patients. We examined the association between mtDNA copy number and self-rated health status with 3 collapsed categories for the latter variable (excellent/very good, good, and fair/poor). For analysis, we used proportional odds models after log-transforming mtDNA copy number, and we adjusted for age and sex. Results: We found the median age at enrollment was 61 years (25th–75th percentile: 51–71), and 64% reported excellent or very good health, 31% reported good health, and 6% reported fair/poor health. Overall, the median mtDNA copy number was 88.9 (25th–75th percentile: 77.6–101.1). Higher mtDNA copy number was found for subjects reporting better self-rated health status after adjusting for age, sex, and comorbidity burden (OR =2.3 [95% CI: 1.2–4.5] for having better self-rated health for a one-unit increase in log-transformed mtDNA copy number). Conclusion: We found that a higher mtDNA copy number is associated with better self-rated health status after adjustment for age, sex, and comorbidity burden. The current study implies that mtDNA copy number may serve as a biomarker for self-reported health. Further studies, potentially including cohort studies, may be required. Keywords: mitochondrial DNA copy number, self-rated health, personalized medicine

Paul Y Takahashi,1 Euijung Ryu,2 James R Cerhan,3 Suzette J Bielinski,3 Janet E Olson3 1Division of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; 3Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USACorrespondence: Paul Y TakahashiDivision of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USATel +1-507-284-2511Fax +1-507-266-2297Email Takahashi.paul@mayo.edu We appreciate the thoughts of Dr. Roman and his comments. We understand that the number of identified pharmacogenomic genes continues to increase with time, and the clinical utility also increases with time and expert opinion. We chose theseselected pharmacogenes because of their strong clinical practice recommendations and the data available at the time of the gene selection.1 Due largely to the efforts associated with other initiatives within the RIGHT study, our clinical practice set upspecific electronic medical record best practice alerts for these pharmacogenes, and it was believed that there was the potential for change in clinical care for patients with extreme phenotypes.2 We did not design the study to specifically look at allpharmacogenomic genes. View the original paper by Takahashi and colleagues This is in response to the Letter to the Editor

Paul Y Takahashi,1 Euijung Ryu,2 Jyotishman Pathak,2 Gregory D Jenkins,2 Anthony Batzler,2 Matthew A Hathcock,2 John Logan Black,3 Janet E Olson,2 James R Cerhan,2 Suzette J Bielinski2 1Division of Primary Care Internal Medicine, Department of Medicine, 2Department of Health Sciences Research, 3Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Background: Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of clinically used drugs and other environmental exposures, but it is unclear whether the CYP2D6 phenotype is associated with adverse health outcomes. The aim was to determine the association of CYP2D6 phenotype with the risk of hospitalization or an emergency department (ED) visit among a group of primary care patients. Methods: In this study, 929 adult patients underwent CYP2D6 testing. The primary outcome was risk of hospitalization or an ED visit from January 2005 through September 2014. CYP2D6 genotypes were interpreted as 1 of 7 clinical phenotypes, from ultrarapid to poor metabolizer, and patients with the extensive metabolizer phenotype were used as the reference group. The hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for finding the association of CYP2D6 phenotypes with the risk of hospitalization or an ED visit by using Cox proportional hazard models and adjusting for age and sex. Results: The median age was 49 years (interquartile range, 46–52 years); 74% of patients had 3 or fewer chronic conditions, 285 had at least 1 hospitalization, and 496 had at least 1 ED visit. The risk of hospitalization was higher among patients who were ultrarapid metabolizers compared to extensive metabolizers (47% vs 30%; HR, 1.69; 95% CI, 1.11–2.57), as was the risk of an ED visit (62% vs 49%; HR, 1.50; 95% CI, 1.05–2.14). For poor metabolizers compared to extensive metabolizers, there was no difference in the risk of hospitalization (HR, 0.95; 95% CI, 0.58–1.56), but there was an increase in the risk of an ED visit (HR, 1.38; 95% CI, 0.96–1.98) (the difference was not statistically significant). Conclusion: We found an increased risk of hospitalization or an ED visit among ultrarapid compared to extensive CYP2D6 metabolizers. Further research identifying the mechanisms of the association and ultimate clinical utility is warranted. Keywords: cohort study, pharmacogenomics, emergency department, hospitalization

Paul Y Takahashi,1,2 Euijung Ryu,3 Janet E Olson,3 Erin M Winkler,4 Matthew A Hathcock,3 Ruchi Gupta,3 Jeff A Sloan,3 Jyotishman Pathak,3 Suzette J Bielinski,3 James R Cerhan3 1Division of Primary Care Internal Medicine, 2Department of Internal Medicine, 3Department of Health Sciences Research, 4Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Background: Hospital risk stratification models using electronic health records (EHRs) often use age and comorbid health burden. Our primary aim was to determine if quality of life or health behaviors captured in an EHR-linked biobank can predict future risk of hospitalization. Methods: Participants in the Mayo Clinic Biobank completed self-administered questionnaires at enrollment that included quality of life and health behaviors. Participants enrolled as of December 31, 2010 were followed for one year to ascertain hospitalization. Data on comorbidities and hospitalization were derived from the Mayo Clinic EHR. Hazard ratios (HR) and 95% confidence interval (CI) were used, adjusted for age and sex. We used gradient boosting machines models to integrate multiple factors. Different models were compared using C-statistic. Results: Of the 8,927 eligible Mayo Clinic Biobank participants, 834 (9.3%) were hospitalized. Self-perceived health status and alcohol use had the strongest associations with risk of hospitalization. Compared to participants with excellent self-perceived health, those reporting poor/fair health had higher risk of hospitalization (HR =3.66, 95% CI 2.74–4.88). Alcohol use was inversely associated with hospitalization (HR =0.57 95% CI 0.45–0.72). The gradient boosting machines model estimated self-perceived health as the most influential factor (relative influence =16%). The predictive ability of the model based on comorbidities was slightly higher than the one based on the self-perceived health (C-statistic =0.67 vs 0.65). Conclusion: This study demonstrates that self-perceived health may be an important piece of information to add to the EHR. It may be another method to determine hospitalization risk. Keywords: alcohol, aging, multiple chronic conditions, EHR, health behavior, hospitalization, quality of life

Ja Yun Choi,1 Eui Jeong Ryu2 1College of Nursing, Chonnam National University, Chonnam Research Institute of Nursing Science, Gwangju, Republic of Korea; 2Department of Nursing, Dongshin University, Naju, Republic of KoreaCorrespondence: Eui Jeong Ryu, Department of Nursing, Dongshin University, 34-22, Dongshin-daegil, Naju, Jeolla Province, 58245, Republic of Korea, Tel +82-10-9193-9075, Fax +82-61-225-3307, Email yeswecan9075@naver.comBackground: The relevant factors and patterns of non-adherence to self-management among patients with chronic obstructive pulmonary disease (COPD) need to be elucidated to improve self-management.Purpose: This study was a survey to prioritize the relevance of factors associated with non-adherence to COPD self-management using the Delphi technique and analytic hierarchy process (AHP).Patients and Methods: A total of 15 expert panels were established to determine the priority of relevant factors in a three-round Delphi survey and an AHP. To develop the preliminary conceptual framework for non-adherence to COPD self-management, findings from a systematic literature review, a qualitative study using in-depth interviews with COPD patients, and the first round of the Delphi survey were integrated. Based on the preliminary framework, the content validity ratio (CVR) was analyzed to examine the consensus among expert panels in the second and third rounds of the Delphi survey, and the relative weight was determined by pairwise comparisons between alternative factors in the AHP.Results: In developing the preliminary conceptual framework, 8 factor categories and 53 factors were identified as relevant to non-adherence to COPD self-management. Of the 53 factors, 22 factors with a CVR of 0.49 or higher were identified in the Delphi survey. A total of 14 of the 53 factors were common to both the Delphi survey and AHP with high weights. The most notable factors were prolonged treatment, experience of treatment failure, and unknown effects of medication.Conclusion: Through consensus decision-making by experts, 14 factors were identified as relevant factors associated with non-adherence to COPD self-management. A hierarchical and systematic framework incorporating factors associated with non-adherence to COPD self-management was developed in this study. Further research is needed to develop intervention strategies based on factors associated with non-adherence to COPD self-management.Keywords: chronic obstructive pulmonary disease, self-management, non-adherence, Delphi technique, analytic hierarchy process

Euna Cho,1,2,* Eun Jin Ryu,2,3,* Fen Jiang,2,4 Ung Bae Jeon,3 Mong Cho,1,2 Cy Hyun Kim,1 Miyoung Kim,1 Nam Deuk Kim,5 Tae-Ho Hwang1,2 1Department of Pharmacology and Medical Research Center (MRC), Pusan National University School of Medicine, Yangsan, Korea; 2Department of Research and Development, Bionoxx Inc, Seongnam-si, Korea; 3Department of Radiology, Pusan National University Yangsan Hospital, Yangsan, Korea; 4School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou, China; 5Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, Korea *These authors contributed equally to this work Purpose: Oncolytic poxvirus has shown promise in treating various solid tumors, such as liver cancer, and administration of oncolytic poxvirus via the hepatic artery may provide more survival benefits than other routes of administration. However, there is a lack of safety information to guide the application of hepatic arterial infusion (HAI) of oncolytic poxvirus in human studies. To investigate the acute and chronic toxicity of HAI administration of oncolytic poxvirus in animals and provide safety information for future human studies. Methods: VVtk-, a vaccinia poxvirus with inactivated thymidine kinase gene, was administered via HAI to rabbits with normal liver function under angiography (1×108 or 1×109 pfu), and rats with N-nitrosomorpholine-induced precancerous liver cirrhosis under open surgery (1×108 pfu). Body weights and survival were monitored and blood samples were collected for hematological and biochemical tests. Distribution of A56 (a specific marker for poxvirus infection) in rabbit organs was evaluated using immunofluorescence assays. Results: HAI of high doses of VVtk- did not cause any acute or chronic changes in body weight, survival or in biochemical, hematological tests in the 2 animal models, and none of the changes showed dose dependency (in rabbit study), or were influenced by liver cirrhosis (in rat study). A56 was not detected in any of the major rabbit organs. Conclusion: HAI may provide a safe alternative route of oncolytic poxvirus administration for human studies. Keywords: oncolytic virus, transhepatic angiography, hepatocellular carcinoma, liver cirrhosis

Amal Kumar Ghimeray,1 Un Sun Jung,1,2 Ha Youn Lee,1 Young Hoon Kim,1 Eun Kyung Ryu,1 Moon Sik Chang11R&D Center, Natural Solution Co., Ltd, Gojan-dong, Namdong-gu, Incheon, Republic of Korea; 2Department of Horticultural Biotechnology, Kyung Hee University, Yongin, Republic of KoreaBackground: In phytotherapy, the therapeutic potential is based on the combined action of different herbal drugs. Our objective was to evaluate the antioxidant, anti-collagenase (in vitro), and anti-wrinkle (in vivo) effect of combined formulation containing Ginkgo biloba, Punica granatum, Ficus carica, and Morus alba fruits extract.Methods: Antioxidant evaluation was based on the scavenging activity of free radicals (1,1-diphenyl-2-picrylhydrazyl, H2O2, and O2-) and the anti-collagenase activity was based on the reduction of collagenase enzyme in vitro. In an in vivo study, 21 female subjects were examined in a placebo-controlled trail. Facial wrinkle, especially the crow's feet region of eyes, was treated with topical formulated 2% cream for 56 days and compared with the placebo.Results: In the in vitro study, the combination of fruits extract showed a higher antioxidant activity which was comparable with the positive standard (ascorbic acid, butylated hydroxyanisole, and Trolox). The data also showed a dose-dependent inhibition of collagenase. In the in vivo study, treatment with 2% formulated cream for 56 days significantly reduced the percentage of wrinkle depth, length, and area with 11.5, 10.07, and 29.55, respectively.Conclusion: The combined formulation of fruit extracts showed excellent antioxidative and anti-collagenase activity as well as a significant effect on anti-wrinkle activity on human skin.Keywords: antioxidant, anti-collagenase, anti-wrinkle, fruits, topical formulation