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Jennifer K Lee,1– 3 Sean Tackett,4,5 Kimberly A Skarupski,2,4,6 Kathy Forbush,7 Barbara Fivush,2,3 Maria Oliva-Hemker,2,3 Rachel B Levine2,4 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine (JHU), Baltimore, MD, USA; 2Office of Faculty, JHU, Baltimore, MD, USA; 3Department of Pediatrics, JHU, Baltimore, MD, USA; 4Department of Medicine, JHU, Baltimore, MD, USA; 5Biostatistics, Epidemiology, and Data Management Core, JHU, Baltimore, MD, USA; 6Bloomberg School of Public Health, JHU, Baltimore, MD, USA; 7Human Resources, Office of Talent Management, JHU, Baltimore, MD, USACorrespondence: Jennifer K Lee, Email Jennifer.lee@jhmi.eduPurpose: The number of women in high-level leadership in academic medicine remains disproportionately low. Early career programs may help increase women’s representation in leadership. We evaluated the Early Career Women’s Leadership Program (ECWLP). We hypothesized that participants would rate themselves as having increased confidence in their leadership potential, improved leadership skills, and greater alignment between their goals for well-being and leading after the program. We also explored the participants’ aspirations and confidence around pursuing high-level leadership before and after the program.Methods: We surveyed women physicians and scientists before and after they participated in the 2023 ECWLP, consisting of 11 seminars over six months. We analyzed pre- and post-program data using Wilcoxon signed-rank tests. We analyzed answers to open-ended questions with a content analysis approach.Results: 47/51 (92%) participants responded, and 74% answered pre- and post-program questionnaires. Several metrics increased after the program, including women’s confidence in their ability to lead (p< 0.001), negotiate (p

Si Mong Yoon,1 Kwang Nam Jin,2 Hyo Jin Lee,3 Hyun Woo Lee,3 Tae Yun Park,3 Eun Young Heo,3 Deog Kyeom Kim,3 Jung-Kyu Lee3 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Radiology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaCorrespondence: Jung-Kyu Lee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20 Boramaero-5-Gil, Dongjak-Gu, Seoul, 07061, Republic of Korea, Tel +82-2-870-2235, Email jk1909@empas.comBackground: Preserved ratio impaired spirometry (PRISm) is a heterogeneous disease entity. Limited data are available regarding its prevalence, clinical course, or prognosis. We aimed to evaluate the longitudinal clinical course of patients with PRISm compared with chronic obstructive pulmonary disease (COPD).Methods: A retrospective study enrolled PRISm and COPD patients who underwent chest computed tomography and longitudinal pulmonary function tests between January 2013 and December 2020. We compared the incidence of acute exacerbations and lung function changes between PRISm and COPD patients.Results: Of the 623 patients, 40 and 583 had PRISm and COPD, respectively. Compared to COPD patients, PRISm patients were younger, more likely to be female and have a history of tuberculosis, and less likely to be smokers. They also had less severe comorbidities, lower forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO). The clinical course was not significantly different between the PRISm and COPD patients in terms of the risk of moderate-to-severe acute exacerbations or proportion of frequent exacerbators. During follow-up, PRISm patients had a significantly slower annual decline of forced expiratory volume in 1 second, FVC, and DLCO than COPD patients.Conclusion: PRISm patients had no significant difference in the risk of acute exacerbations, but a significantly slower decline of lung function during longitudinal follow-up, compared with COPD patients.Plain Language Summary: We evaluated the longitudinal clinical course of patients with preserved ratio impaired spirometry (PRISm) compared to patients with chronic obstructive pulmonary disease (COPD). PRISm and COPD patients showed no significant differences in the risk of moderate-to-severe acute exacerbations or frequent exacerbations, but the former group showed a significantly slower annual decline of lung function during longitudinal follow-up.Keywords: preserved ratio impaired spirometry, chronic obstructive pulmonary disease, exacerbation, lung function

Tanya M Laidlaw1,2 &ast;, Andrew Menzies-Gow3 &ast;, Scott Caveney,4 Joseph K Han,5 Nicole Martin,6,7 Elliot Israel,8 Jason K Lee,9,10 Jean-Pierre Llanos,11 Neil Martin,12,13 Ayman Megally,14 Bhavini Parikh,14 Sylvia Vong,15 Tobias Welte,16 Jonathan Corren17 1Jeff and Penny Vinik Center for Allergic Diseases Research, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3Royal Brompton and Harefield Hospitals, School of Immunology and Microbial Sciences, King’s College London, London, UK; 4Global Development, Inflammation, R&D, Amgen, Thousand Oaks, CA, USA; 5Department of Otolaryngology, Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, VA, USA; 6Biometrics, Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA; 7Cytel Inc, Waltham, MA, USA; 8Divisions of Pulmonary and Critical Care Medicine and Allergy and Clinical Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 9Evidence Based Medical Educator Inc., Toronto, ON, Canada; 10Toronto Allergy and Asthma Clinic, Toronto, ON, Canada; 11Global Medical Affairs, Amgen, Thousand Oaks, CA, USA; 12Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 13University of Leicester, Leicester, UK; 14Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 15Translational Science and Experimental Medicine, Early Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USA; 16Department of Respiratory Medicine and German Center for Lung Research, Hannover Medical School, Hannover, Germany; 17David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA&ast;These authors contributed equally to this workCorrespondence: Tanya M Laidlaw, Jeff and Penny Vinik Center for Allergic Diseases Research, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, 60 Fenwood Road, Boston, MA, 02115, USA, Email tlaidlaw@bwh.harvard.eduPurpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR.Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc).Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (– 12.57 points [– 19.40, – 5.73]) and 52 weeks (– 10.58 points [– 17.75, – 3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status.Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.Graphical Abstract: Plain Language Summary: Asthma is a long-term condition caused by ongoing inflammation of the lower airways. The main symptoms are difficulty breathing, coughing, wheezing and shortness of breath. Approximately 41% of patients with severe asthma also have chronic rhinosinusitis with nasal polyps, a condition that affects the upper airways and sinuses. Nasal polyps are painless soft growths inside your nose that can keep growing if not treated. Symptoms include nasal congestion with mucus, facial pain and a reduced sense of smell or taste. People with both severe asthma and nasal polyps often have severe symptoms.Thymic stromal lymphopoietin (TSLP) is a signaling molecule released by cells lining the airways in response to airborne triggers, such as smoke, pollen and viruses. TSLP activates several pathways that cause inflammation in the airways, leading to asthma symptoms. Tezepelumab is a biologic treatment that targets the very start of these inflammatory pathways by blocking TSLP.The 1-year-long clinical trial called “NAVIGATOR” reported that tezepelumab reduced asthma attacks and improved lung function and asthma symptom control compared with placebo in patients with severe asthma that was not controlled with their current medicines. This analysis of data from NAVIGATOR looked at patients with both severe asthma and nasal polyps, showing that tezepelumab treatment improved sino-nasal symptoms compared with placebo. Tezepelumab also reduced asthma attacks and improved asthma symptoms, regardless of a patient’s medical history of nasal polyps. The effects of tezepelumab in patients with severe nasal polyps are being investigated in another clinical trial called “WAYPOINT”.Keywords: chronic rhinosinusitis, nasal polyps, SNOT-22, thymic stromal lymphopoietin

Introduction: Fragility fractures, which occur after a low- trauma injury, increases with advancing age. Such fracture doubles the life-time risk of sustaining another fracture. This risk is highest in the immediate 18 months after the index fracture. However, most patients do not receive the appropriate risk assessment and intervention to reduce this risk. A coordinated model of care termed Fracture Liaison Service (FLS) has been reported to address this treatment gap. Materials and methods: This scoping review aims to explore the potential role and delivery of FLS services in Malaysia. Scientific and non-scientific sources relevant to FLS were identified from electronic bibliographic databases, specialist journals and relevant websites. Findings were categorised into themes and presented narratively. Results: FLS services remain concentrated in the Klang Valley. Even within FLS services, many do not have extensive coverage to risk assess all fracture patients. These services are multidisciplinary in nature where there are links between different departments, such as orthopaedics, osteoporosis expertise, bone densitometry, rehabilitation, falls services and primary care. FLS was able to increase the number of people undergoing fracture risk assessment and treatment. The importance of FLS was highlighted by local experts and stakeholders. Its implementation and delivery are supported by a number of national guidelines. Conclusion: FLS is central to our national efforts to reduce the impending fragility fracture crisis in the coming years. Continued effort is needed to increase coverage within FLS services and across the country. Training, awareness of the problem, research, and policy change will support this endeavour.

Hyo Jin Lee,1 Kwang Nam Jin,2 Hyun Woo Lee,1 Jung-Kyu Lee,1 Tae Yeon Park,1 Eun Young Heo,1 Deog Kyeom Kim1,3 1Division of Respiratory and Critical Care, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, South Korea; 2Department of Radiology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, South Korea; 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South KoreaCorrespondence: Deog Kyeom Kim, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, South Korea, Tel +82-2-870-2130, Fax +82-2-831-0714, Email kimdkmd@snu.ac.krPurpose: Few studies have reported the association between the radiographic characteristics and the development of pneumonia in patients with chronic obstructive pulmonary disease (COPD) treated with inhaled corticosteroids (ICSs). Our study aimed to assess the effect of radiographic phenotypes on the risk of pneumonia in patients treated with ICSs.Patients and Methods: This study retrospectively analysed all patients with COPD treated with ICSs in a subset of the Korea Chronic Obstructive Pulmonary Disorders Subgroup Study registry between January 2017 and December 2019. The association between radiographic phenotypes including the presence and severity of emphysema, airway wall thickening, or bronchiectasis on chest computed tomography were determined visually/qualitatively and the risk of pneumonia was analyzed using the Cox regression model.Results: Among the 90 patients with COPD treated with ICSs, 41 experienced pneumonia more than once during the median follow-up of 29 (interquartile range, 8– 35) months. In univariate Cox regression analysis, older age, longer use of ICSs, use of fluticasone propionate or metered dose inhaler, and severe exacerbation events increased the risk of pneumonia. In multivariate analysis, the presence of emphysema (adjusted hazard ratio [aHR]=3.73, P=0.033), severity measured using the visual sum score (mild-to-moderate, aHR=8.58, P=0.016; severe, aHR=3.58, P=0.042), Goddard sum score (mild-to-moderate, aHR=3.31, P=0.058; severe, aHR=5.38, P=0.014), and the upper lobe distribution of emphysema (aHR=3.76, P=0.032) were associated with a higher risk of pneumonia. Subtypes of centrilobular and panlobular emphysema had a higher risk of pneumonia compared with paraseptal emphysema (aHR=3.98, P=0.033; HR=3.91, P=0.041 vs HR=2.74, P=0.304). The presence of bronchiectasis (aHR=2.41, P=0.02) and emphysema/bronchiectasis overlap phenotype (aHR=2.19, P=0.053) on chest CT was a risk factor for pneumonia in this population. However, severity of bronchiectasis and the presence or severity of bronchial wall thickening according to the visual sum score were not associated with the risk of pneumonia.Conclusion: Among patients with COPD treated with ICSs, radiographic phenotypes including the presence of emphysema, bronchiectasis or emphysema/bronchiectasis overlap phenotype, severity with emphysema, subtypes of centrilobular or panlobular emphysema, and upper lobe distribution of emphysema may help predict the risk of pneumonia.Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, pneumonia, chest computed tomography, CT

By 2050, it is predicted that six million hip fractures will occur each year of which the majority will happen in Asia. Malaysia is not spared from this predicted rise and its rate of increase will be one of the highest in this region. Much of this is driven by our unprecedented growth in the number of older people. Characteristics of individuals with hip fractures in Malaysia mirror what has been reported in other countries. They will be older multimorbid people who were already at risk of falls and fractures. Outcomes were poor with at least a quarter do not survive beyond 12 months and in those that do survive have limitation in their mobility and activities of daily living. Reviewing how these fractures are managed and incorporating new models of care, such as orthogeriatric care, could address these poor outcomes. Experts have warned of the devastating impact of hip fracture in Malaysia and that prompt action is urgently required. Despite that, there remains no national agenda to highlight the need to improve musculoskeletal health in the country

Ye-Jin Lee,1 SeungHo Choi,2 Sung-Youn Kwon,2 Yunhwan Lee,2 Jung Kyu Lee,3 Eun Young Heo,3 Hee Soon Chung,3,4 Deog Kyeom Kim3,4 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 2Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984 Korea; 3Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Boramae-Gil 41, Dongjak-gu, Seoul 156-707, Republic of KoreaTel +82-2-870-3207Fax +82-2-831-0714Email kimdkmd@gmail.comBackground: Identifying the genetic basis of airflow limitation is one of the most interesting issues for understanding chronic obstructive pulmonary disease (COPD) pathophysiology. Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association study (GWAS), especially in patients with moderate to severe COPD; genetic susceptibility for airflow limitation in the early COPD phase has not been widely studied.Objective: We investigated the genetic variants in early COPD.Methods: The present study analyzed Gene-environment interaction and phenotype (GENIE) cohort that included participants who received health screening examination. The association between single nucleotide polymorphism (SNP) and susceptibility to early COPD (FEV1 predicted ≥ 50% and FEV1/FVC < 0.7) was tested.Results: A total of 130 patients with early COPD and 3478 controls (1700 ever smokers and 1778 never smokers) were recruited. When compared with the total controls, certain SNPs (rs2818103, rs875033, rs9354627, rs34552148) on chromosome 6 were included at the top of our list (p= 5.6 × 10– 7 ∼ 9.6 × 10– 6) although they did not reach genome-wide significance. When compared with the never smoker controls, two SNPs (rs2857210, rs2621419) of the HLA-DQB2 gene class were persistently associated with susceptibility to early COPD.Conclusion: Certain SNPs located on chromosome 6 or the HLA-DQB2 gene were the top-scoring SNPs for the association with susceptibility to early COPD in the Korean GENIE cohort.Keywords: early chronic obstructive pulmonary disease, genome-wide association study, single nucleotide polymorphism, SNP, HLA-DQ gene

Jung-Ki Yoon,1 Jung-Kyu Lee,2 Chang-Hoon Lee,1 Yong Il Hwang,3 Hyunkuk Kim,4 Dongil Park,5 Ki-Eun Hwang,6 Sang-Heon Kim,7 Ki-Suck Jung,3 Kwang Ha Yoo,8 Seung Won Ra,9 Deog Kyeom Kim2,10 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Department of Internal Medicine, College of Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; 6Department of Internal Medicine, Wonkwang University, School of Medicine, Iksan, Republic of Korea; 7Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea; 9Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 10Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaTel +82-2-870-2228Fax +82-2-831-0714Email kimdkmd@snu.ac.krIntroduction: Blood eosinophils are a predictive marker for the use of inhaled corticosteroids (ICS). However, there is concern over whether a single measure of blood eosinophils is sufficient for outlining a treatment plan. Here, we evaluated the association between variability in blood eosinophils and the effects of ICS in stable COPD cohorts.Methods: COPD patients in the Korean COPD Subtype Study and the Seoul National University Airway Registry from 2011 to 2018 were analyzed. Based on blood eosinophils at baseline and at 1-year follow-up, the patients were classified into four groups with 250/μL as a cutoff value: consistently high (CH), consistently low (CL), variably increasing (VI), and variably decreasing (VD). We compared rates of acute exacerbations (AEs) according to ICS use in each group after calibration of severity using propensity score matching.Results: Of 2,221 COPD patients, 618 were analyzed and a total of 125 (20%), 355 (57%), 63 (10%), and 75 (12%) patients were classified into the CH, CL, VI, and VD groups, respectively. After calibration, we found that ICS users tended to have a lower AE rate in the CH group (RR 0.41, 95% CI 0.21– 0.74) and VI group (RR 0.45, 95% CI 0.22– 0.88), but not in the CL group (RR 1.42, 95% CI 1.08– 1.89) and VD group (RR 1.71, 95% CI 1.00– 2.96).Conclusion: More than one-fifth of patients had an inconsistent blood eosinophil level after the 1-year follow-up, and the AE-COPD rate according to ICS differed based on variability in eosinophils. Regular follow-up of blood eosinophils is required for COPD patients.Keywords: COPD, eosinophils, inhaled corticosteroids, acute exacerbations of COPD, COPD treatment

Sandipan Bhattacharjee,1 Jeannie K Lee,1 Nina Vadiei,1 Asad E Patanwala,2 Daniel C Malone,3 Shannon M Knapp,4 Wei-Hsuan Lo-Ciganic,5 William J Burke6 1Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA; 2Sydney Pharmacy School, University of Sydney, Sydney, Australia; 3Department of Pharmacotherapy, Skaggs College of Pharmacy, University of Utah, Salt Lake City, UT, USA; 4Statistics Consulting Laboratory, Bio5 Institute, The University of Arizona, Tucson, AZ, USA; 5Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA; 6Banner Alzheimer’s Institute, Phoenix, AZ, USACorrespondence: Sandipan BhattacharjeeDepartment of Pharmacy Practice and Science, The University of Arizona College of Pharmacy, Tucson, AZ, USATel +1 520 626-4124Fax +1 520-626-7355Email bhattacharjee@pharmacy.arizona.eduPurpose: Little is known about adherence to antidepressant treatment during acute and continuation phase of depression among older adults with dementia and newly diagnosed major depressive disorders (MDD). This study estimated the extent of and factors associated with adherence to acute and continuation phase antidepressant treatment among older adults with dementia and newly diagnosed MDD.Methods: We conducted a retrospective cohort study using the Medicare 5% sample claims data (2012– 2013) among older adults (age≥ 65 years) with dementia who were newly diagnosed with MDD. Intake period of our study was from 01-May-2012 through 30-April-2013. The dependent variables of this study were acute and continuation phase depression treatment adherence. Factors associated with acute and continuation phase antidepressant treatment adherence were identified using multiple logistic regression analyses.Results: The final study sample consisted of 6239 [adherent: N=4644 (74.44%)] and 5617 [adherent: N=3584 (63.81%)] older adults with dementia and MDD during the acute and continuation phase treatment, respectively. During the acute phase, only race/ethnicity was significantly associated with adherence to depression treatment, whereas race/ethnicity and baseline antipsychotic use were significantly associated with adherence to depression treatment during the continuation phase.Conclusion: Approximately, 74% and 64% older adults with dementia and MDD were adherent to acute and continuation phase antidepressant treatment in this nationally representative sample of Medicare beneficiaries, and we identified several modifiable and non-modifiable factors associated with adherence.Keywords: dementia, depression, antidepressants, adherence, acute phase depression, continuation phase depression

Jason K Lee,1 Suvina Amin,2 Michelle Erdmann,3 Atif Kukaswadia,4 Jelena Ivanovic,5 Aren Fischer,4 Alain Gendron6 1Clinical Immunology and Allergy, Internal Medicine, Evidence Based Medical Educator Inc. and Urticaria Canada, Toronto, ON, Canada; 2AstraZeneca, Gaithersburg, MD, USA; 3AstraZeneca, Mississauga, ON, Canada; 4IQVIA, Toronto, ON, Canada; 5IQVIA, Kanata, ON, Canada; 6AstraZeneca, Mississauga, Ontario, Canada and Department of Medicine, Université de Montréal, Montreal, QC, CanadaCorrespondence: Jason K LeeClinical Immunology and Allergy, Internal Medicine, Evidence Based Medical Educator Inc., Toronto, ON, CanadaTel +1 647-352-2554Email jason.k.lee@utoronto.caBackground: Omalizumab is a treatment option for pediatric and adult patients with moderate to severe allergic asthma poorly controlled with standard inhaled therapies. Clinical trials and observational studies have demonstrated the efficacy of omalizumab. There is limited real-world evidence on the characteristics and treatment patterns of Canadian asthma patients receiving omalizumab.Objective: We profiled Canadian omalizumab users to estimate time to omalizumab discontinuation and to assess changes in concurrent medication usage before, during, and after therapy.Methods: This was a retrospective, observational, cohort study that analyzed data from Canadian prescription claims databases. An algorithm was used to select naïve users of omalizumab with an inferred diagnosis of GINA 5-asthma who made a claim for omalizumab from February 1, 2007, to June 2, 2015. Demographic and baseline characteristics were assessed at index. Outcomes examined over the analysis period included (i) daily omalizumab dose per patient and per claim; (ii) omalizumab discontinuation (defined as ≥ 100-day gap in making omalizumab claims) and its potential predictors (ie, age, sex, province of residence, drug insurer; assessed by Cox Proportional Hazards Model); and (iii) for patients who discontinued omalizumab, changes in concurrent medication usage before, during, and 6 months after omalizumab usage.Results: The final study cohort consisted of 1160 patients (mean age: 45.8 ± 15.2 years; 64.7% female). During the first year of omalizumab therapy, 29.5% of patients discontinued treatment. The singular characteristic that predicted omalizumab discontinuation with statistical significance was age group (20‒34 years vs 12‒19 years; hazard ratio 1.75, 95% confidence interval 1.11– 2.76; P< 0.05). There were significant reductions in the use of some concurrent inhaled and oral asthma medications during and/or after omalizumab use (P< 0.05).Conclusion: Nearly one-third of patients who initiated omalizumab in Canada for refractory, moderate to severe allergic asthma discontinued treatment during the first year.Keywords: allergic asthma, omalizumab, real-world, observational study, claims database, Canadian asthma patients

Jung-Kyu Lee,1 Chin Kook Rhee,2 Kyungjoo Kim,2 Seung Won Ra,3 Jae Ha Lee,4 Ki-Suck Jung,5 Kwang Ha Yoo,6 Yoo-Il Kim,7 Deog Kyeom Kim1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 3Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 4Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 6Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 7Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, #395 Shindaebang-2-Dong, Dongjak-Gu, Seoul 156-707, Republic of KoreaTel +82-2-870-2228Fax +82-2-831-0714Email kimdkmd@snu.ac.krBackground: Methylxanthines and leukotriene receptor antagonists (LTRA) are not a first-line medical treatment for chronic obstructive pulmonary disease (COPD) but are frequently prescribed despite limited evidence. We aimed to elucidate the real prescribing status and clinical impacts of these agents in early COPD patients.Methods: Patients with mild-to-moderate COPD (FEV1>50%) were selected from the Korean National Health and Nutrition Examination Survey data between 2007 and 2012. Besides analyzing the prescription status of methylxanthines and LTRA and the contributing factors to the prescription, we evaluated the clinical impacts of these drugs on the exacerbation, hospitalization, and medical costs.Results: Of 2269 patients with mild-to-moderate COPD, 378 patients (16.7%) were under medical treatments, and the users of methylxanthines and/or LTRA were 279 patients (12.3%); however, only 139 patients (6.1%) were inhaler users. The contributing factors for the prescription of methylxanthines were a comorbidity of asthma or allergic disease, poor lung function, low quality of life, prescribing doctor from the specialty of internal medicine, and an institution type of private hospital. The prescription of LTRA was associated with the comorbidity of allergic disease. The methylxanthine and/or LTRA users had more hospital utilization but did not have significant differences in acute exacerbations and medical cost for hospital utilization, compared with the non-users.Conclusion: Methylxanthines and LTRA were used in a significant proportion of patients with mild-to-moderate COPD in real fields without favorable impacts on the exacerbations, hospitalizations, or medical costs. The use of more effective inhaled medications should be encouraged.Keywords: pulmonary disease, chronic obstructive, methylxanthine, leukotriene antagonists, drug prescriptions

Na Ri Park, Jun Hyung Moon, Jeong Kyu LeeDepartment of Ophthalmology, College of Medicine, Chung-Ang University Hospital, Dongjak-gu, Seoul, KoreaObjective: To compare exophthalmometry measured by Hertel exophthalmometer versus computed tomography (CT) scan.Methods: For this study, 133 patients with thyroid-associated orbitopathy (TAO) were analyzed retrospectively. Two experienced clinical observers independently measured proptosis using a Hertel exophthalmometer. The CT approaches used to measure proptosis included two previous methods and one new method. Method 1 used both lateral orbital rims–corneal surface in the axial plane, method 2 used lateral to medial orbital rims–corneal surface in the axial plane, and method 3 used superior to inferior orbital rims–corneal surface in the sagittal plane (new method). Patients were separated into two groups based on 2-mm differences in proptosis between eyes. Correlation analysis was performed to find the association between Hertel and CT values.Results: The Pearson’s coefficient (r) was 0.727 for Hertel exophthalmometry and CT method 1, 0.712 for Hertel and CT method 2, and 0.623 for Hertel and CT method 3. For patients with eye proptosis differences larger than 2 mm between eyes, Pearson’s coefficient (r) was 0.495 for Hertel exophthalmometry and CT method 1, 0.634 for Hertel and CT method 2, and 0.635 for Hertel and CT method 3.Conclusion: The three CT methods mentioned above had statistically significant relationships with Hertel exophthalmometry. Methods 2 and 3, which measured both eyes through different cut sections, had a significant relationship with Hertel values with eye proptosis differences larger than 2 mm. Thus, the new additive method may be effective for measuring proptosis in patients with differences greater than 2 mm between eyes.Keywords: orbital disease, exophthalmos, thyroid-associated orbitopathy

Shin-Woo Ha,1 Jin-Kyu Lee,2 George R Beck Jr1,3,4 1Division of Endocrinology, Department of Medicine, Emory University, Atlanta, GA, USA; 2Department of Chemistry, Seoul National University, Seoul, South Korea; 3The Atlanta Department of Veterans Affairs Medical Center, Decatur, 4The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA Abstract: To date, delivery of light-emitting diode (LED)-activated compounds to cells and tissue remains a challenge. Silica-based materials possess good biocompatibility and have advantages of control of size and shape. Fluorescent silica nanoparticles (NPs) have been synthesized and used for applications such as cell tracking and tumor identification. Here, we report the synthesis and optimization of fluorescent silica NPs, which incorporate a naphthalimide dye with triethoxysilanes that are excited by the blue LED wavelength (LEDex NPs). The NPs can be imaged in the 420–470 nm wavelength, demonstrate a high quantum yield, are stable in a range of pH, and are taken into the cells. Therefore, these NPs represent a novel imaging technology for biomedical applications. Keywords: naphthalimide, imaging, bone marrow stromal cell migration, reduced toxicity

Yong Suk Jo,1 Ju-Hee Park,2 Jung Kyu Lee,2 Eun Young Heo,2 Hee Soon Chung,2 Deog Kyeom Kim2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea Background and objective: There are limited data on pulmonary arterial hypertension (PAH) in patients with tuberculosis-destroyed lung (TDL), a sequela of pulmonary tuberculosis. We identified the risk factors for PAH and their effects on acute exacerbation and mortality in patients with TDL, as well as the clinical differences in patients with chronic obstructive pulmonary disease (COPD) and PAH.Methods: A retrospective cohort study was conducted from 2010 through 2015 in a municipal referral hospital in South Korea. PAH was defined when echocardiographic pulmonary arterial pressure (PAP) was >40 mmHg. The clinical features and course of TDL patients with or without PAH were evaluated and differences between patients with COPD and PAH were analyzed.Results: Among the 195 patients with TDL, echocardiographic data were available in 53 patients, and their mean PAP was 50.72±23.99 mmHg. The PAH group (n=37) had a smaller lung volume (forced vital capacity % predicted, 51.55% vs 72.37%, P

Ju-Hee Park, Jung-Kyu Lee, Eun Young Heo, Deog Kyeom Kim, Hee Soon Chung Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Purpose: A low body mass index has been associated with high mortalities in patients with chronic obstructive pulmonary disease (COPD), and studies reveal that obesity aggravates the clinical effects of COPD. We investigated the impact of obesity on patients newly identified with COPD.Patients and methods: This population-based, cross-sectional study, used data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted from 2010 to 2012. Through analyses of data from this survey, we compared concurrent comorbid diseases, symptoms, and lung functions between an obese and nonobese group of patients with COPD.Results: In total, 618 participants were diagnosed with COPD and the average forced expired volume in 1 s (FEV1) was 79.47%±0.69%. Of the total, 30.5% of the subjects were categorized into an obese group. Subjects in the obese group were likely to have metabolic syndrome (P

Junghyun Kim,1 Jung-Kyu Lee,2 Eun Young Heo,2 Hee Soon Chung,2 Deog Kyeom Kim2 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea Background: The hallmark of COPD is chronic airway inflammation, which may be mediated by renin–angiotensin system. The renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) have exhibited anti-inflammatory and immunomodulatory effects in patients with various diseases. We explored the effects of ACEi and ARBs on the risk of pneumonia in patients with COPD.Methods: A nested case–control study was performed on COPD patients recruited from January 2010 to August 2013 in two referral hospitals in Korea. A total of 130 COPD patients admitted with pneumonia were included, and 245 COPD patients without pneumonia were selected as controls from a total of 1,646 such patients. Controls were matched with test patients by age, sex, and severity of airflow limitation. The effects of ACEi/ARBs use on the odds ratio (OR) for the development of pneumonia were tested through conditional logistic regression.Results: Elderly patients (over 70 years of age) constituted ~30% of each group; most of the patients were male (85%). Of the COPD patients with pneumonia, 21.5% had taken ACEi/ARBs for a mean of 9.8 months (standard deviation ±3.5 months). The proportions of ACEi/ARBs users and the mean duration of such use did not differ when compared to those of the control patients (26.9%, P=0.25; 9.6±3.6 months, P=0.83). Univariate analyses indicated that the use of ACEi/ARBs was not associated with a decreased risk of pneumonia (OR =0.70, 95% confidence interval 0.41–1.23, P=0.21), whereas both a history of pulmonary tuberculosis (OR =1.85, 95% confidence interval 1.12–3.06, P=0.02) and exposure to systemic steroids (OR =2.33, 95% confidence interval 1.28–4.23, P=0.005) did show an association. After adjustment for a history of tuberculosis, comorbid chronic renal disease, and exposure to corticosteroids, ACEi/ARBs reduced the risk of pneumonia in COPD patients (OR =0.51, 95% confidence interval 0.27–0.98, P=0.04).Conclusion: This study revealed that the use of ACEi/ARBs was associated with reducing the risk of pneumonia in patients with COPD. Further prospective studies are necessary to confirm the protective effect of ACEi/ARBs and elucidate the underlying mechanisms in COPD patients. Keywords: angiotensin-converting enzyme inhibitors, angiotensin receptor antagonist, COPD, pneumonia

Ha Youn Lee,1,2 Ji Won Kim,2,3 Jung Kyu Lee,2,4 Eun Young Heo,2,4 Hee Soon Chung,2,4 Deog Keom Kim2,4 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Seoul National University College of Medicine, 3Division of Gastroenterology, 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Background: Helicobacter pylori infection is a major cause of gastric diseases. The clinical implications of H. pylori infection in various diseases outside the gastrointestinal system have also been reported, including in some respiratory disorders. In this study, we investigated the seroprevalence of H. pylori in patients with mild to moderate COPD in an Asian country with a high prevalence of H. pylori infection. Also, we aimed to elucidate the association between the seroprevalence of H. pylori and the decline of lung function in patients with COPD.Methods: Participants who underwent a medical checkup for H. pylori at a referral hospital in Korea were recruited for this study. All participants were tested for H. pylori infection using an immunoassay of the H. pylori-specific immunoglobulin G (IgG) concentration and a rapid urease test at the time of endoscopy with a gastric mucosal specimen. We assessed the decline in lung function using the spirometric data of those who underwent spirometry more than three times.Results: In total, 603 participants (201 patients with COPD and 402 controls) were analyzed. The seroprevalence of H. pylori IgG in the patients and controls was 45.8% and 52.2%, respectively (P=0.134). The H. pylori IgG level in patients with COPD was not significantly different from that of the controls (114.8 and 109.6 units/mL, respectively; P=0.549). In addition, there were no significant differences in the annual forced expiratory volume in 1 second or forced vital capacity between the participants with H. pylori seropositivity and seronegativity.Conclusion: This study showed no relationship between H. pylori infection and COPD in a country with a high burden of H. pylori infection. Furthermore, H. pylori infection did not affect the rate of lung function decline in this study population. Keywords: H. pylori, COPD, lung function decline

Jae Hoon Jeong,1 Jeong Kyu Lee,1,2 Dong Ik Lee,1 Yeoun Sook Chun,1 Bo Youn Cho2 1Department of Ophthalmology, College of Medicine, Chung-Ang University 2Thyroid Center, Chung-Ang University Hospital, Seoul, Korea Objective: To report the physiological monitoring of intraocular pressure (IOP) during the postoperative periods after orbital decompression surgery and ascertain the correlation between the clinical factors and IOP changes.Methods: The medical records of 113 orbits from 60 patients who underwent orbital decompression surgery were reviewed retrospectively. IOP measurement during the postoperative periods was classified based on the postoperative day: week 1 (1–7 days), month 1 (8–41 days), month 2 (42–70 days), month 3 (71–97 days), month 4 (98–126 days), and final (after 127 days). The mean postoperative follow-up was 286.5 days for orbits with at least 6 months of follow-up. Univariate and multivariate linear regression analyses were performed to assess the correlation between the IOP reduction percentage and clinical factors.Results: The mean IOP increased from 16.9 to 18.6 mmHg (10.1%) at postoperative week 1 and decreased to 14.4 mmHg (14.5%) after 2 months. Minimal little changes were observed postoperatively in the IOP after 2 months. Preoperative IOP had a significant positive effect on the reduction percentage both at postoperative week 1 (β=2.51, P=0.001) and after 2 months (β=1.07, P=0.029), and the spherical equivalent showed a positive correlation with the reduction level at postoperative week 1 (β=1.71, P=0.021).Conclusion: Surgical decompression caused a significant reduction in the IOP in thyroid-associated orbitopathy, and the amount of reduction was closely related to preoperative IOP; however, it may also cause a transient elevation in the IOP during the early postoperative phase in highly myopic eyes. Keywords: Graves’ ophthalmopathy, intraocular pressure, myopia, physiologic monitoring, postoperative periods, surgical decompression

Jason Kian Seng Lee, Elizabeth Poh Ying Wong, Su Ling HoNational Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore Background: The purpose of this study was to investigate the demographics of pseudoexfoliation syndrome (PXF) and pseudoexfoliative glaucoma (PXG) in a Singapore hospital eye outpatient clinic.Methods: A retrospective study of 93 consecutive patients (146 eyes) with PXF was undertaken by a single ophthalmologist over a period of 37 months (July 1, 2006, to July 31, 2009).Results: Ninety-three (2.8%) of 3,297 patients seen during the study period were diagnosed with PXF. Forty-three (46.2%) of the 93 PXF patients were male. Indians were 5.04 times more likely to develop PXF than Chinese (P

Jeannie K Lee,1 Samah Alshehri,1,2 Hussam I Kutbi,1,2 Jennifer R Martin1,3 1Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, AZ, USA; 2Department of Clinical Pharmacy, King Abdulaziz University College of Pharmacy, Jeddah, Saudi Arabia; 3Arizona Health Sciences Library, University of Arizona, Tucson, AZ, USA Abstract: As the world's population ages, global health care systems will face the burden of chronic diseases and polypharmacy use among older adults. The traditional tasks of medication dispensing and provision of basic education by pharmacists have evolved to active engagement in direct patient care and collaborative team-based care. The care of older patients is an especially fitting mission for pharmacists, since the key to geriatric care often lies with management of chronic diseases and polypharmacy use, and preventing harmful consequences of both. Because most chronic conditions are treated with medications, pharmacists, with their extensive training in pharmacotherapy and pharmacokinetics, are in a unique and critical position in the management of them. Pharmacists have the expertise to detect, resolve, and prevent medication errors and drug-related problems, such as overtreatment, undertreatment, adverse drug events, and nonadherence. Pharmacists are also competent in critically reviewing and applying clinical guidelines to the care of individual patients, and in some instances confront the lack of data (common in older adults) to provide the best possible patient-centered care. The current review aimed to depict the evidence of geriatric pharmacy care, demonstrate current impact of pharmacists’ interventions on older patients, survey the tools used by pharmacists to provide effective care, and explore their role in pharmacotherapy optimization in elders. The findings of the current review strongly support previous studies that showed positive impact of pharmacists’ interventions on older patients’ health-related outcomes. There is a clear role for pharmacists working directly or collaboratively to improve medication use and management in older populations. Therefore, in global health care systems, teams caring for elders should involve pharmacists to optimize pharmacotherapy. Keywords: pharmacist, elderly, older adult, pharmacotherapy, medication, polypharmacy

Jeong-A Lee,1,* Mi-Kyung Kim,1,* Hyoung-Mi Kim,2,* Jong Kwon Lee,3 Jayoung Jeong,4 Young-Rok Kim,5 Jae-Min Oh,2 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea; 3Hazard Substances Analysis Division, Gwangju Regional Food and Drug Administration, Ministry of Food and Drug Safety, Gwangju, Republic of Korea; 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea; 5Department of Food Science and Biotechnology, Kyung Hee University, Yongin, Republic of Korea *These authors contributed equally to this work Background: Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics.Methods: We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m2/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats.Results: N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca2+, although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein–particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size.Conclusion: We conclude that calcium carbonate nanoparticles can act more actively with biological matrices in vitro and ex vivo, but that in vivo, their biological interactions and biokinetics are not affected by particle size. Keywords: biological interaction, oral absorption, biokinetics, size effect, protein corona

Jae-Kwan Lee,1,4 Dong-Soon Choi,2,4 Insan Jang,2,4 Won-Youl Choi3,4 1Department of Periodontology, 2Department of Orthodontics, College of Dentistry, 3Department of Metal and Materials Engineering, 4Research Institute for Dental Engineering, Gangneung-Wonju National University, Gangneung, South Korea Abstract: TiO2 nanotube arrays on the surface of dental implants were fabricated by two-step anodic oxidation. Their effects on bone-implant contact were researched by a pilot in vivo study. The implants were classified into four groups. An implant group with TiO2 nanotube arrays and recombinant human bone morphogenetic protein-2 (rhBMP-2) was compared with various surface implants, including machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. The diameter of the TiO2 nanotube window and TiO2 nanotube were ~70 nm and ~110 nm, respectively. The rhBMP-2 was loaded into TiO2 nanotube arrays and elution was detected by an interferometric biosensing method. A change in optical thickness of ~75 nm was measured by flow cell testing for 9 days, indicating elution of rhBMP-2 from the TiO2 nanotube arrays. For the in vivo study, the four groups of implants were placed into the proximal tibia of New Zealand white rabbits. In the implant group with TiO2 nanotube arrays and rhBMP-2, the bone-to-implant contact ratio was 29.5% and the bone volume ratio was 77.3%. Bone remodeling was observed not only in the periosteum but also in the interface between the bone and implant threads. These values were higher than in the machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. Our results suggest that TiO2 nanotube arrays could potentially be used as a reservoir for rhBMP-2 to reinforce osseointegration on the surface of dental implants. Keywords: TiO2 nanotube arrays, drug reservoir, dental implant, bone morphogenetic protein

Jeong-A Lee,1 Mi-Kyung Kim,1 Hee-Jeong Paek,1 Yu-Ri Kim,2 Meyoung-Kon Kim,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Republic of Korea; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk–do, Republic of Korea Purpose: The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods: Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results: The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion: The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict potential toxicological effects of silica nanoparticles on target organs. Keywords: biological fate, size effect, target organ

Jee Young Kwon,1,* Hye Lim Kim,1,* Jong Yun Lee,2 Yo Han Ju,2 Ji Soo Kim,2 Seung Hun Kang,1 Yu-Ri Kim,3 Jong-Kwon Lee,4 Jayoung Jeong,4 Meyoung-Kon Kim,3 Eun Ho Maeng,2 Young Rok Seo1 1Department of Life Science, Institute of Environmental Medicine, Dongguk University, Seoul, 2Korea Testing and Research Institute, 3Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea *These authors contributed equally to this work and should be considered co-first authors Background: Silica dioxide (SiO2) has been used in various industrial products, including paints and coatings, plastics, synthetic rubbers, and adhesives. Several studies have investigated the genotoxic effects of SiO2; however, the results remain controversial due to variations in the evaluation methods applied in determining its physicochemical properties. Thus, well characterized chemicals and standardized methods are needed for better assessment of the genotoxicity of nanoparticles.Methods: The genotoxicity of SiO2 was evaluated using two types of well characterized SiO2, ie, 20 nm (-) charge (SiO2EN20(-)) and 100 nm (-) charge (SiO2EN100(-)). Four end point genotoxicity tests, ie, the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test, were conducted following the test guidelines of the Organization for Economic Cooperation and Development (OECD) with application of Good Laboratory Practice.Results: No statistically significant differences were found in the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test when tested for induction of genotoxicity in both two types of SiO2 nanoparticles.Conclusion: These results suggest that SiO2 nanoparticles, in particular SiO2EN20(-) and SiO2EN100(-), are not genotoxic in both in vitro and in vivo systems under OECD guidelines. Further, the results were generated in accordance with OECD test guidelines, and Good Laboratory Practice application; it can be accepted as reliable information regarding SiO2-induced genotoxicity. Keywords: genotoxicity test, Organization for Economic Cooperation and Development test guideline, Good Laboratory Practice, silica dioxide

Kyoung-Min Kim,1 Hye Min Kim,1 Won-Jae Lee,2 Chang-Woo Lee,3 Tae-il Kim,4 Jong-Kwon Lee,5 Jayoung Jeong,5 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, Republic of Korea; 2Department of Chemistry, Kyungpook National University, Taegu, Republic of Korea; 3Battelle-Korea Laboratory, International Center for Converging Technology, Korea University, Seoul, Republic of Korea; 4Department of Biosystems and Biomaterials Science and Engineering, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, Republic of Korea Abstract: An attempt was made to control the surface charge of colloidal silica nanoparticles with 20 nm and 100 nm diameters. Untreated silica nanoparticles were determined to be highly negatively charged and have stable hydrodynamic sizes in a wide pH range. To change the surface to a positively charged form, various coating agents, such as amine containing molecules, multivalent metal cation, or amino acids, were used to treat the colloidal silica nanoparticles. Molecules with chelating amine sites were determined to have high affinity with the silica surface to make agglomerations or gel-like networks. Amino acid coatings resulted in relatively stable silica colloids with a modified surface charge. Three amino acid moiety coatings (L-serine, L-histidine, and L-arginine) exhibited surface charge modifying efficacy of L-histidine > L-arginine > L-serine and hydrodynamic size preservation efficacy of L-serine > L-arginine > L-histidine. The time dependent change in L-arginine coated colloidal silica was investigated by measuring the pattern of the backscattered light in a Turbiscan™. The results indicated that both the 20 nm and 100 nm L-arginine coated silica samples were fairly stable in terms of colloidal homogeneity, showing only slight coalescence and sedimentation. Keywords: silica, nanoparticles, surface charge, colloidal stability, turbidity, amino acids

Yu-Ri Kim,1,* Sung Ha Park,2,* Jong-Kwon Lee,3 Jayoung Jeong,3 Ja Hei Kim,4 Eun-Ho Meang,5 Tae Hyun Yoon,6 Seok Tae Lim,7 Jae-Min Oh,8 Seong Soo A An,9 Meyoung-Kon Kim1 1Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea; 2Department of Biochemistry, University of Bath, Bath, UK; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Consumers Korea, Chongro-ku, 5General toxicology team, Korea Testing and Research Institute, 6Laboratory of Nanoscale Characterization and Environmental Chemistry, Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, 7Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju, Jellabuk-Do, 8Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 9Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea *Authors contributed equally to this work Abstract: Currently, products made with nanomaterials are used widely, especially in biology, biotechnologies, and medical areas. However, limited investigations on potential toxicities of nanomaterials are available. Hence, diverse and systemic toxicological data with new methods for nanomaterials are needed. In order to investigate the nanotoxicology of nanoparticles (NPs), the Research Team for Nano-Associated Safety Assessment (RT-NASA) was organized in three parts and launched. Each part focused on different contents of research directions: investigators in part I were responsible for the efficient management and international cooperation on nano-safety studies; investigators in part II performed the toxicity evaluations on target organs such as assessment of genotoxicity, immunotoxicity, or skin penetration; and investigators in part III evaluated the toxicokinetics of NPs with newly developed techniques for toxicokinetic analyses and methods for estimating nanotoxicity. The RT-NASA study was carried out in six steps: need assessment, physicochemical property, toxicity evaluation, toxicokinetics, peer review, and risk communication. During the need assessment step, consumer responses were analyzed based on sex, age, education level, and household income. Different sizes of zinc oxide and silica NPs were purchased and coated with citrate, L-serine, and L-arginine in order to modify surface charges (eight different NPs), and each of the NPs were characterized by various techniques, for example, zeta potentials, scanning electron microscopy, and transmission electron microscopy. Evaluation of the “no observed adverse effect level” and systemic toxicities of all NPs were performed by thorough evaluation steps and the toxicokinetics step, which included in vivo studies with zinc oxide and silica NPs. A peer review committee was organized to evaluate and verify the reliability of toxicity tests, and the risk communication step was also needed to convey the current findings to academia, industry, and consumers. Several limitations were encountered in the RT-NASA project, and they are discussed for consideration for improvements in future studies. Keywords: nanomaterials, nanotoxicity, toxicokinetics, physicochemical property, peer review

Hark-Soo Park,1 Sung-Sup Shin,1 Eun Ho Meang,1 Jeong-sup Hong,1 Jong-Il Park,1 Su-Hyon Kim,1 Sang-Bum Koh,1 Seung-Young Lee,1 Dong-Hyouk Jang,1 Jong-Yun Lee,1 Yle-Shik Sun,1 Jin Seok Kang,2 Yu-Ri Kim,3 Meyoung-Kon Kim,3 Jayoung Jeong,4 Jong-Kwon Lee,4 Woo-Chan Son,5 Jae-Hak Park6 1General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea; 2Department of Biomedical Laboratory Science, Namseoul University, Cheonan, Korea; 3Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Korea; 4National Institute of Food and Drug Safety Evaluation, Seoul, Korea; 5Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 6Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea Purpose: The widespread use of nanoparticles (NPs) in industrial and biomedical applications has prompted growing concern regarding their potential toxicity and impact on human health. This study therefore investigated the subchronic, systemic oral toxicity and no-observed-adverse-effect level (NOAEL) of 20 nm, negatively charged zinc oxide (ZnOSM20(-)) NPs in Sprague Dawley rats for 90 days.Methods: The high-dose NP level was set at 500 mg/kg of bodyweight, and the mid- and low-dose levels were set at 250 and 125 mg/kg, respectively. The rats were observed during a 14-day recovery period after the last NP administration for the persistence or reduction of any adverse effects. Toxicokinetic and distribution studies were also conducted to determine the systemic distribution of the NPs.Results: No rats died during the test period. However, ZnOSM20(-) NPs (500 mg/kg) induced changes in the levels of anemia-related factors, prompted acinar cell apoptosis and ductular hyperplasia, stimulated periductular lymphoid cell infiltration and excessive salivation, and increased the numbers of regenerative acinar cells in the pancreas. In addition, stomach lesions were seen at 125, 250, and 500 mg/kg, and retinal atrophy was observed at 250 and 500 mg/kg. The Zn concentration was dose-dependently increased in the liver, kidney, intestines, and plasma, but not in other organs investigated. Conclusion: A ZnOSM20(-) NP NOAEL could not be established from the current results, but the lowest-observed-adverse-effect level was 125 mg/kg. Furthermore, the NPs were associated with a number of undesirable systemic actions. Thus, their use in humans must be approached with caution. Keywords: negative charge, oral toxicity study, rat, ZnO

Hark-Soo Park,1 Seon-Ju Kim,1 Taek-Jin Lee,1 Geon-Yong Kim,1 EunHo Meang,1 Jeong-Sup Hong,1 Su-Hyon Kim,1 Sang-Bum Koh,1 Seung-Guk Hong,1 Yle-Shik Sun,1 Jin Seok Kang,2 Yu-Ri Kim,3 Meyoung-Kon Kim,3 Jayoung Jeong,4 Jong-Kwon Lee,4 Woo-Chan Son,5 Jae-Hak Park61General Toxicology Team, Korea Testing and Research Institute, Seoul, 2Department of Biomedical Laboratory Science, Namseoul University, Cheonan, 3Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, 4National Institute of Food and Drug Safety Evaluation, Seoul, 5Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 6Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, KoreaPurpose: The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnOSM,20(+)) nanoparticles in Sprague Dawley rats for 90 days.Methods: For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnOSM,20(+) NPs.Results: No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group.Conclusion: There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.Keywords: positive charge, oral-toxicity study, no-observed-adverse-effect level, ZnO

Kyoung-Min Kim,1 Mun-Hyoung Choi,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Yu-Ri Kim,4 Meyoung-Kon Kim,4 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 2Department of Chemistry, Kyungpook National University, Taegu, 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea Abstract: In this study, four types of standardized ZnO nanoparticles were prepared for assessment of their potential biological risk. Powder-phased ZnO nanoparticles with different particle sizes (20 nm and 100 nm) were coated with citrate or L-serine to induce a negative or positive surface charge, respectively. The four types of coated ZnO nanoparticles were subjected to physicochemical evaluation according to the guidelines published by the Organisation for Economic Cooperation and Development. All four samples had a well crystallized Wurtzite phase, with particle sizes of ~30 nm and ~70 nm after coating with organic molecules. The coating agents were determined to have attached to the ZnO surfaces through either electrostatic interaction or partial coordination bonding. Electrokinetic measurements showed that the surface charges of the ZnO nanoparticles were successfully modified to be negative (about −40 mV) or positive (about +25 mV). Although all the four types of ZnO nanoparticles showed some agglomeration when suspended in water according to dynamic light scattering analysis, they had clearly distinguishable particle size and surface charge parameters and well defined physicochemical properties. Keywords: ZnO nanoparticles, surface coating, surface charge, particle size, physicochemical properties

Jin-Ku Lee,1,2,* Kyeung Min Joo,3 Jeongwu Lee,4 Yeup Yoon,5,* Do-Hyun Nam2,5 1Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea; 2Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 5Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea *These authors contributed equally to this work Abstract: Glioblastoma multiforme (GBM) is the most common human primary brain malignancy and has a dismal prognosis. Aggressive treatments using maximal surgical resection, radiotherapy, and temozolomide result in median survival of only 14.6 months in patients with GBM. Numerous clinical approaches using small molecule inhibitors have shown disappointing results because of the genetic heterogeneity of GBM. The epithelial to mesenchymal transition (EMT) is a crucial biological process occurring in the early development stages of many species. However, cancer cells often obtain the ability to invade and metastasize through the EMT, which triggers the scattering of cells. The hepatocyte growth factor (HGF)/MET signaling pathway is indicative of the EMT during both embryogenesis and the invasive growth of tumors, because HGF potently induces mesenchymal transition in epithelial-driven cells. Activation of MET signaling or co-overexpression of HGF and MET frequently represents aggressive growth and poor prognosis of various cancers, including GBM. Thus, efforts to treat cancers by inhibiting MET signaling using neutralizing antibodies or small molecule inhibitors have progressed during the last decade. In this review, we discuss HGF/MET signaling in the development of diseases, including cancers, as well as updates on MET inhibition therapy. Keywords: glioblastoma multiforme, epithelial to mesenchymal transition, MET signaling

John J Kim,1,2 Nathan Buchbinder,1,† Simon Ammanuel,1,4,5,† Robert Kim,1,† Erika Moore,1 Neil O'Donnell,1 Jennifer K Lee,3 Ewa Kulikowicz,3 Soumyadipta Acharya,1 Robert H Allen,1,9 Ryan W Lee,6,7 Michael V Johnston4–81Department of Biomedical Engineering, Whiting School of Engineering, The Johns Hopkins University, 2The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins University School of Medicine, 3Department of Anesthesia and Critical Care Medicine, Johns Hopkins University, 4Kennedy Krieger Institute, 5Hugo W Moser Research Institute, 6Department of Neurology, 7Department of Pediatrics, 8Department of Physical Medicine and Rehabilitation Johns Hopkins University School of Medicine, Baltimore, MD; 9Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA†These authors contributed equally to this workAbstract: Despite recent advances in neonatal care and monitoring, asphyxia globally accounts for 23% of the 4 million annual deaths of newborns, and leads to hypoxic-ischemic encephalopathy (HIE). Occurring in five of 1000 live-born infants globally and even more in developing countries, HIE is a serious problem that causes death in 25%–50% of affected neonates and neurological disability to at least 25% of survivors. In order to prevent the damage caused by HIE, our invention provides an effective whole-body cooling of the neonates by utilizing evaporation and an endothermic reaction. Our device is composed of basic electronics, clay pots, sand, and urea-based instant cold pack powder. A larger clay pot, lined with nearly 5 cm of sand, contains a smaller pot, where the neonate will be placed for therapeutic treatment. When the sand is mixed with instant cold pack urea powder and wetted with water, the device can extract heat from inside to outside and maintain the inner pot at 17°C for more than 24 hours with monitoring by LED lights and thermistors. Using a piglet model, we confirmed that our device fits the specific parameters of therapeutic hypothermia, lowering the body temperature to 33.5°C with a 1°C margin of error. After the therapeutic hypothermia treatment, warming is regulated by adjusting the amount of water added and the location of baby inside the device. Our invention uniquely limits the amount of electricity required to power and operate the device compared with current expensive and high-tech devices available in the United States. Our device costs a maximum of 40 dollars and is simple enough to be used in neonatal intensive care units in developing countries.Keywords: therapeutic hypothermia, evaporative cooling, hypoxic ischemic encephalopathy, birth asphyxia, neuroprotection

Chang-Moon Lee,1–4,* Hwan-Jeong Jeong,1–4,* Kuk-No Yun,1–3 Dong Wook Kim,1–4 Myung-Hee Sohn,1–4 Jong Kwon Lee,5 Jayoung Jeong,5 Seok Tae Lim1–4 *These authors contributed equally to this work.1Department of Nuclear Medicine; 2Cyclotron Research Center; 3Research Institute of Clinical Medicine; 4Institute for Medical Sciences, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Osong-Eup, Chungchungbuk-Do, Republic of KoreaBackground: Understanding how nanomaterials are distributed in the body after exposure is important for assessing whether they are safe. In this study, we investigated the behavior and accumulation of nanoscaled and submicron-scaled zinc oxide (ZnO) particles in the body using optical imaging following oral exposure.Methods: To trace these nanoparticles in the body, ZnO nanoparticles were conjugated with a monoreactive hydroxysuccinimide ester of Cy5.5 (Cy5.5-NHS), and the conjugation-stabilizing effect of Cy5.5 on the nanoparticles was evaluated in simulated gastric fluid (pH 1.2) for 7 hours. To compare the distribution of Cy5.5-NHS and Cy5.5-conjugated ZnO nanoparticles, Cy5.5-NHS 0.5 mg/kg and Cy5.5-conjugated ZnO nanoparticles 250 mg/kg were administered orally to healthy rats. We collected blood from the rats at predesignated time points for 7 hours after administration, and optical imaging studies were performed at 1, 2, 3, 5, and 7 hours after dosing. To investigate the extent of nanoparticle accumulation in the organs and tissues, the mice were sacrificed at 23 hours after administration, and the organs were removed and imaged.Results: Cy5.5-conjugated ZnO nanoparticles were stable in simulated gastric fluid for 7 hours. The signal intensity of Cy5.5-NHS in blood was highest 3 hours after oral administration, and Cy5.5-conjugated ZnO nanoparticles showed the highest signal intensity in blood 5–7 hours after administration. In vivo optical images indicated that Cy5.5-NHS showed optical signals in the lung, liver, and gastrointestinal tract after oral administration, whereas Cy5.5-conjugated ZnO nanoparticles were seen only in the gastrointestinal tract. Seven hours following administration, biodistribution studies demonstrated that Cy5.5-NHS accumulated in the lung and liver, and Cy5.5-conjugated ZnO nanoparticles resulted in a strong signal in the kidney and liver. Different-sized ZnO nanoparticles showed dissimilar patterns of biodistribution in ex vivo optical images.Conclusion: ZnO nanoparticles are absorbed into the tissues following oral exposure and their behavior can be monitored and evaluated using optical imaging.Keywords: zinc oxide nanoparticles, biodistribution, optical imaging, oral administration

Miri Baek,1,* Hae-Eun Chung,1,* Jin Yu,1,* Jung-A Lee,1 Tae-Hyun Kim,2 Jae-Min Oh,2 Won-Jae Lee,3 Seung-Min Paek,3 Jong Kwon Lee,4 Jayoung Jeong, 4 Jin-Ho Choy,5 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women's University, Seoul, 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Gangwondo; 3Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, Taegu, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 5Center for Intelligent Nano-Bio Materials, Department of Bioinspired Science and Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea*These authors contributed equally to this workBackground: This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats.Methods: Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed.Results: The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues.Conclusion: ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs.Keywords: ZnO nanoparticles, pharmacokinetics, tissue distribution, excretion, fate

Kwon JY, Kim HL, Lee JY, et al. Int J Nanomedicine. 2014;9(Suppl 2):173–181.The title of the paper “Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests” should read “Undetectable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests”.Read the original article

The purpose of this study was to determine suture-holding properties of tissue-engineered neocartilage relative to native articular cartilage. To this end, suture pull-out strength was quantified for native articular cartilage and for neocartilages possessing various mechanical properties. Suture-holding properties were examined in vitro and in vivo. Neocartilage from bovine chondrocytes was engineered using two sets of exogenous stimuli, resulting in neotissue of different biochemical compositions. Compressive and tensile properties and glycosaminoglycan, collagen, and pyridinoline cross-link contents were assayed (study 1). Suture pull-out strength was compared between neocartilage constructs, and bovine and leporine native cartilage. Uniaxial pull-out test until failure was performed after passing 6-0 Vicryl through each tissue (study 2). Subsequently, neocartilage was implanted into a rabbit model to examine short-term suture-holding ability in vivo (study 3). Neocartilage glycosaminoglycan and collagen content per wet weight reached 4.55 ± 1.62% and 4.21 ± 0.77%, respectively. Tensile properties for neocartilage constructs reached 2.6 ± 0.77% MPa for Young's modulus and 1.39 ± 0.63 MPa for ultimate tensile strength. Neocartilage reached ~ 33% of suture pull-out strength of native articular cartilage. Neocartilage cross-link content reached 50% of native values, and suture pull-out strength correlated positively with cross-link content (R² = 0.74). Neocartilage sutured into rabbit osteochondral defects was successfully maintained for 3 weeks. This study shows that pyridinoline cross-links in neocartilage may be vital in controlling suture pull-out strength. Neocartilage produced in vitro with one-third of native tissue pull-out strength appears sufficient for construct suturing and retention in vivo.

Osteoarthritis, a degenerative disease of the load-bearing joints, greatly reduces quality of life for millions of Americans and places a tremendous cost on the American healthcare system. Due to limitations of current treatments, tissue engineering of articular cartilage may provide a promising therapeutic option to treat cartilage defects. However, cartilage tissue engineering has yet to recapitulate the functional properties of native tissue. During normal joint loading, cartilage tissue experiences variations in osmolarity and subsequent changes in ionic concentrations. Motivated by these known variations in the cellular microenvironment, this study sought to improve the mechanical properties of neocartilage constructs via the application of hyperosmolarity and transient receptor potential vanilloid 4 (TRPV4) channel activator 4α-phorbol 12,13-didecanoate (4αPDD). It was shown that 4αPDD elicited significant increases in compressive properties. Importantly, when combined, 4αPDD positively interacted with hyperosmolarity to modulate its effects on tensile stiffness and collagen content. Thus, this study supports 4αPDD-activated channel TRPV4 as a purported mechanosensor and osmosensor that can facilitate the cell and tissue level responses to improve the mechanical properties of engineered cartilage. To our knowledge, this study is the first to systematically evaluate the roles of hyperosmolarity and 4αPDD on the functional (i.e., mechanical and biochemical) properties of self-assembled neotissue. Future work may combine 4αPDD-induced channel activation with other chemical and mechanical stimuli to create robust neocartilages suitable for treatment of articular cartilage defects.

L-selectin, a lectin-like receptor, mediates rolling of lymphocytes on high endothelial venules (HEVs) in secondary lymphoid organs by interacting with HEV ligands. These ligands consist of a complex of sialomucins, candidates for which are glycosylation- dependent cell adhesion molecule 1 (GlyCAM-1), CD34, and podocalyxin. The ligands must be sialylated, fucosylated, and sulfated for optimal recognition by L-selectin. Our previous structural characterization of GlyCAM-1 has demonstrated two sulfation modifications, Gal-6-sulfate and GlcNAc-6-sulfate in the context of sialyl Lewis x. We now report the cloning of a Gal-6-sulfotransferase and a GlcNAc-6-sulfotransferase, which can modify GlyCAM-1 and CD34. The Gal-6-sulfotransferase shows a wide tissue distribution. In contrast, the GlcNAc-6-sulfotransferase is highly restricted to HEVs, as revealed by Northern analysis and in situ hybridization. Expression of either enzyme in Chinese hamster ovary cells, along with CD34 and fucosyltransferase VII, results in ligand activity, as detected by binding of an L-selectin/IgM chimera. When coexpressed, the two sulfotransferases synergize to produce strongly enhanced chimera binding.

Inward rectifying K channels are essential for maintaining resting membrane potential and regulating excitability in many cell types. Previous studies have attributed the rectification properties of strong inward rectifiers such as Kir2.1 to voltage-dependent binding of intracellular polyamines or Mg to the pore (direct open channel block), thereby preventing outward passage of K ions. We have studied interactions between polyamines and the polyamine toxins philanthotoxin and argiotoxin on inward rectification in Kir2.1. We present evidence that high affinity polyamine block is not consistent with direct open channel block, but instead involves polyamines binding to another region of the channel (intrinsic gate) to form a blocking complex that occludes the pore. This interaction defines a novel mechanism of ion channel closure.

Rationale and objectivesThe authors examined the prognostic value of magnetic resonance (MR) imaging in stress injuries of bone.Materials and methodsClinical follow-up data were collected in 35 patients who underwent MR imaging because of suspected stress fractures. MR findings were correlated with total duration of symptoms, the time to return to sports activity, and findings at follow-up radiography.ResultsThe MR imaging finding of a "fracture" or "fatigue" line or a cortical signal intensity abnormality was predictive of a longer symptomatic period, whereas muscle edema was predictive of a shorter symptomatic period. A published grading system could be used in only 24 patients; the MR imaging grade of injury did not show correlation with clinical outcome.ConclusionThe MR imaging finding of either a medullary line or a cortical abnormality appears to indicate a more severe stress injury of bone. A previously published MR imaging grading system for stress injuries of the tibia was not prognostic in this more heterogeneous patient group.