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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

Summary: Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19‐year‐old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene‐targeted panel of next‐generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ‐glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ‐glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K‐dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate‐to‐severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE‐like phenotypes. What is already known about this topic?Pseudoxanthoma elasticum (PXE) is caused in most cases by mutations in the ABCC6 gene.Combined PXE and cutis laxa (CL)‐like clinical findings have been encountered with vitamin K‐dependent coagulation factor deficiency frequently caused by GGCX mutations.GGCX encodes a γ‐glutamyl carboxylase necessary for activation of vitamin K‐dependent coagulation factors in the liver. What does this study add?This study reports a unique case with an overlapping PXE/CL‐like clinical phenotype with no evidence of a coagulation disorder.The patient carries compound heterozygous mutations in GGCX, adding to the mutation spectrum of GGCX‐associated phenotypes. [ABSTRACT FROM AUTHOR]

Presents a novel semiconductor quantum well (QW) structure consisting of alternating (In,Ga)As and Ga(P,As,Sb0 layers grown pseudomorphically on a GaAs substrate by all-solid-source molecular beam epitaxy. Determination of the band gap of the QW by the thickness and composition of both types of layers; Explanation for the strong room-temperature photoluminescence.

Along with the development of modern technology, the variety of higher-level activities of daily living has steadily expanded. However, no reports have examined the capacities for the higher-level activities in stroke survivors. Moreover, the relationship between these capacities and executive functions has not been reported. This preliminary study longitudinally measured changes in the capacities for high-level activities of modern daily living in community-dwelling stroke survivors. In addition, we examined whether changes in these capacities were correlated with executive functions. The results showed no significant reduction in the capacities for high-level activities of modern daily living at 1 year after stroke. Significant improvements were observed in one aspect of executive functions: planning. The changes in the capacities for higher-level activities of modern daily living were significantly correlated with executive function. The results suggest that, in stroke survivors, (a) it is likely feasible to maintain the capacities for higher-level activities of modern daily living, and (b) these capacities are related to executive functions.

Hypertension is the most common comorbidity among cancer survivors, although there is no model for predicting hypertension in this population. Therefore, we developed a model for predicting hypertension using data from 6,480 Korean cancer survivors who were ≥20 years old. The odds ratios (ORs) for hypertension were calculated using stepwise logistic regression analyses, and a nomogram was generated to predict hypertension. Hypertension was independently associated with an age of ≥65 years (OR: 3.058), male gender (OR: 1.195), obesity (OR: 1.998), prehypertension (OR: 2.06), dyslipidaemia (OR: 2.011) and diabetes mellitus (OR: 2.297). Each variable in the nomogram was assigned a specific number of points, and the total score (range: 0–400) was used to obtain a value for predicting hypertension. The estimated prevalence of hypertension increased when the total nomogram score exceeded the sixth decile (total points: 128; p for trend <.001). Therefore, among Korean cancer survivors, hypertension was significantly associated with an age of >65 years, male gender, obesity, and having various comorbidities (e.g., prehypertension, dyslipidaemia and diabetes mellitus). Furthermore, our nomogram could predict the incidence of hypertension, and the sixth decile of the total nomogram score predicted an increased risk of hypertension. [ABSTRACT FROM AUTHOR]