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Large, distributed collections of miniaturized, wireless electronic devices1,2 may form the basis of future systems for environmental monitoring3, population surveillance4, disease management5 and other applications that demand coverage over expansive spatial scales. Aerial schemes to distribute the components for such networks are required, and—inspired by wind-dispersed seeds6—we examined passive structures designed for controlled, unpowered flight across natural environments or city settings. Techniques in mechanically guided assembly of three-dimensional (3D) mesostructures7–9 provide access to miniature, 3D fliers optimized for such purposes, in processes that align with the most sophisticated production techniques for electronic, optoelectronic, microfluidic and microelectromechanical technologies. Here we demonstrate a range of 3D macro-, meso- and microscale fliers produced in this manner, including those that incorporate active electronic and colorimetric payloads. Analytical, computational and experimental studies of the aerodynamics of high-performance structures of this type establish a set of fundamental considerations in bio-inspired design, with a focus on 3D fliers that exhibit controlled rotational kinematics and low terminal velocities. An approach that represents these complex 3D structures as discrete numbers of blades captures the essential physics in simple, analytical scaling forms, validated by computational and experimental results. Battery-free, wireless devices and colorimetric sensors for environmental measurements provide simple examples of a wide spectrum of applications of these unusual concepts. With a design inspired by wind-dispersed seeds, a series of three-dimensional passive fliers at the macro-, meso- and microscale are realized that can bear active electronic payloads.

We fabricated a functional pentacene/CH3NH3PbI3−xClx perovskite interface where optical gating and field assisted charge retention occur. Using a pentacene/perovskite field effect transistor (FET) test platform, we investigated the interfacial charge transfer associated with optical gating through threshold voltage measurements under illumination. Importantly, bistable electrical conduction in pentacene/perovskite FET devices was achieved as a result of field-induced charge retention at the interface and the origin is discussed to be associated with interfacial charging at the pentacene/perovskite interface. Interfacial contact modification associated with ion migration and other possible effects in the perovskite layer plays a crucial role in forming a functional interface involving organic semiconducting materials.

Objectives The established Beers Criteria consider side effects and safety concerns when prescribing drugs to the elderly. As the criteria suggest that attention should be paid toward prescriptions rather than prescription prohibition lists, these Beers Criteria medications (BCMs) are used appropriately under unavoidable circumstances. Methods Patients aged ≥ 65 years and with an experience of being prescribed inappropriate medications at Konyang University Hospital, South Korea, were selected. We analyzed data from the Korea Adverse Event Reporting System (KAERS) and the Food and Drug Administration Adverse Event Reporting System (FAERS) of the United States to identify medication-induced adverse drug events (ADEs). The actual incidence was predicted by multiplying the incidence and number of BCMs prescribed to the patients. The proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated using KAERS and FAERS data. Results We predicted that the incidence of ADEs would be higher for metoclopramide, chlorpheniramine, and amitriptyline in patients using medications for more than 1 day and metoclopramide, chlorpheniramine, and ketoprofen in patients using medications only for 1 day. Among the ADEs reported to KAERS and FAERS, significant ROR and PRR values were noted for clonazepam (drowsiness), nortriptyline (sleepiness), and zolpidem (amnesia, somnambulism, agitation, dependence, nightmare, and dysgeusia). Conclusion This study highlighted the actual status of BCM prescriptions in clinical institutions and predicted the incidence of ADEs. We concluded that greater care must be taken while prescribing BCMs to the elderly and indicators, such as PRR and ROR should be monitored regularly.

Background Bisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer. Methods This study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods. Results The stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-β signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes. Conclusion This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.

Objective To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. Methods Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing, and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established postmortem. Results Using VirScan, enrichment of dengue viral antibodies was detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but postmortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months antemortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency, and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. Interpretation Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting, and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system causing a panencephalitis and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Furthermore, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiology. ANN NEUROL 2019;86:695-703.

Objective. We propose 2 Medical Dictionary for Regulatory Activities–enabled pharmacovigilance algorithms, MetaLAB and MetaNurse, powered by a per-year meta-analysis technique and improved subject sampling strategy. Matrials and methods. This study developed 2 novel algorithms, MetaLAB for laboratory abnormalities and MetaNurse for standard nursing statements, as significantly improved versions of our previous electronic health record (EHR)–based pharmacovigilance method, called CLEAR. Adverse drug reaction (ADR) signals from 117 laboratory abnormalities and 1357 standard nursing statements for all precautionary drugs (n = 101) were comprehensively detected and validated against SIDER (Side Effect Resource) by MetaLAB and MetaNurse against 11 817 and 76 457 drug-ADR pairs, respectively. Results. We demonstrate that MetaLAB (area under the curve, AUC = 0.61 ± 0.18) outperformed CLEAR (AUC = 0.55 ± 0.06) when we applied the same 470 drug-event pairs as the gold standard, as in our previous research. Receiver operating characteristic curves for 101 precautionary terms in the Medical Dictionary for Regulatory Activities Preferred Terms were obtained for MetaLAB and MetaNurse (0.69 ± 0.11; 0.62 ± 0.07), which complemented each other in terms of ADR signal coverage. Novel ADR signals discovered by MetaLAB and MetaNurse were successfully validated against spontaneous reports in the US Food and Drug Administration Adverse Event Reporting System database. Discussion. The present study demonstrates the symbiosis of laboratory test results and nursing statements for ADR signal detection in terms of their system organ class coverage and performance profiles. Conclusion. Systematic discovery and evaluation of the wide spectrum of ADR signals using standard-based observational electronic health record data across many institutions will affect drug development and use, as well as postmarketing surveillance and regulation.

Preemptive and multi-variant genotyping is suggested to improve the safety of patient drug therapy. The number of South Koreans who would benefit from this approach is unknown. We aimed to quantify the number of patients who may experience serious adverse drug events (ADEs) due to high-risk pharmacogenetic variants and who may benefit from preemptive genotyping. The health claims dataset of the Korean Health Insurance Review and Assessment service for 3 % of the South Korean population for year 2011 was used to calculate the number of patients exposed to 84 drugs covered by National Health Insurance with pharmacogenomic biomarkers. The product of ADE risk-conferring genotype prevalence, ADE prevalence rates, and genotype effect sizes in South Koreans or East Asians derived from published literature and the 1000 Genomes Project, and the drug exposure data were solved to estimate the number of South Koreans in whom preemptive genotyping may prevent serious ADEs. Among 1,341,077 patients in the dataset with prescriptions, 47.4 % were prescribed a drug whose response was affected by genetic variants and 31.9 % were prescribed at least one drug with serious ADEs modulated by these variants. Without genetic testing, the number of South Korean patients predicted to experience serious ADEs due to their higher ADE risk genotypes was estimated at 729. Extrapolating this to the total South Korean population indicated that approximately 24,300 patients in 2011 might have benefitted from preemptive genotyping. This study quantified the number of South Korean patients predicted to have serious ADEs and demonstrated the need for preemptive genotyping to assist safer drug therapy in South Korea.

Integration of controlled vocabulary-based electronic health record (EHR) observational data is essential for real-time large-scale pharmacovigilance studies. To provide a semantically enriched adverse drug reaction (ADR) dictionary for post-market drug safety research and enable multicenter EHR-based extensive ADR signal detection and evaluation, we developed a comprehensive controlled vocabulary-based ADR signal dictionary (CVAD) for pharmacovigilance. A CVAD consists of (1) administrative disease classifications of the International Classification of Diseases (ICD) codes mapped to the Medical Dictionary for Regulatory Activities Preferred Terms (MedDRA® PTs); (2) two teaching hospitals’ codes for laboratory test results mapped to the Logical Observation Identifiers Names and Codes (LOINC) terms and MedDRA® PTs; and (3) clinical narratives and ADRs encoded by standard nursing statements (encoded by the International Classification for Nursing Practice [ICNP]) mapped to the World Health Organization–Adverse Reaction Terminology (WHO-ART) terms and MedDRA® PTs. Of the standard 4514 MedDRA® PTs from Side Effect Resources (SIDER) 4.1, 1130 (25.03%), 942 (20.86%), and 83 (1.83%) terms were systematically mapped to clinical narratives, laboratory test results, and disease classifications, respectively. For the evaluation, we loaded multi-source EHR data. We first performed a clinical expert review of the CVAD clinical relevance and a three-drug ADR case analyses consisting of linezolid-induced thrombocytopenia, warfarin-induced bleeding tendency, and vancomycin-induced acute kidney injury. CVAD had a high coverage of ADRs and integrated standard controlled vocabularies to the EHR data sources, and researchers can take advantage of these features for EHR observational data-based extensive pharmacovigilance studies to improve sensitivity and specificity.

The relationship between the number of withdrawn/restricted drugs and socioeconomic, health, and welfare indicators were investigated in a comprehensive review of drug regulation information in the United Nations (UN) countries. A total of of 362 drugs were withdrawn and 248 were restricted during 1950-2010, corresponding to rates of 12.02 ± 13.07 and 5.77 ± 8.69 (mean ± SD), respectively, among 94 UN countries. A socioeconomic, health, and welfare analysis was performed for 33 OECD countries for which data were available regarding withdrawn/restricted drugs. The gross domestic product (GDP) per capita, GDP per hour worked, health expenditure per GDP, and elderly population rate were positively correlated with the numbers of withdrawn and restricted drugs (P < 0.05), while the out-of-pocket health expenditure payment rate was negatively correlated. The number of restricted drugs was also correlated with the rate of drug-related deaths (P < 0.05). The World Bank data cross-validated the findings of 33 OECD countries. The lists of withdrawn/restricted drugs showed markedly poor international agreement between them (Fleiss's kappa = -0.114). Twenty-seven drugs that had been withdrawn internationally by manufacturers are still available in some countries. The wide variation in the numbers of drug withdrawals and restrictions among countries indicates the need to improve drug surveillance systems and regulatory communication networks.

Jimin Lee,1 Yoojin Noh,1 Sooyoung Shin,1 Hong-Seok Lim,2 Rae Woong Park,3 Soo Kyung Bae,4 Euichaul Oh,4 Grace Juyun Kim,5 Ju Han Kim,5 Sukhyang Lee1 1Division of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea; 2Department of Cardiology, School of Medicine, Ajou University, Suwon, South Korea; 3Department of Biomedical Informatics, School of Medicine, Ajou University, Suwon, South Korea; 4Division of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea; 5Division of Biomedical Informatics, College of Medicine, Seoul National University, Seoul, South Korea Abstract: Statin therapy is beneficial in reducing cardiovascular events and mortalities in patients with atherosclerotic cardiovascular diseases. Yet, there have been concerns of increased risk of diabetes with statin use. This study was aimed to evaluate the association between statins and new onset diabetes mellitus (NODM) in patients with ischemic heart disease (IHD) utilizing the Korean Health Insurance Review and Assessment Service claims database. Among adultpatients with preexisting IHD, new statin users and matched nonstatin users were identified on a 1:1 ratio using proportionate stratified random sampling by sex and age. They were subsequently propensity score matched further with age and comorbidities to reduce the selection bias. Overall incidence rates, cumulative rates and hazard ratios (HRs) between statin use and occurrence of NODM were estimated. The subgroup analyses were performed according to sex, age groups, and the individual agents and intensities of statins. A total of 156,360 patients (94,370 in the statin users and 61,990 in the nonstatin users) were included in the analysis. The incidence rates of NODM were 7.8% and 4.8% in the statin users and nonstatin users, respectively. The risk of NODM was higher among statin users (crude HR 2.01, 95% confidence interval [CI] 1.93–2.10; adjusted HR 1.84, 95% CI 1.63–2.09). Pravastatin had the lowest risk (adjusted HR 1.54, 95% CI 1.32–1.81) while those who were exposed to more than one statin were at the highest risk of NODM (adjusted HR 2.17, 95% CI 1.93–2.37). It has been concluded that all statins are associated with the risk of NODM in patients with IHD, and it is believed that our study would contribute to a better understanding of statin and NODM association by analyzing statin use in the real-world setting. Periodic screening and monitoring for diabetes are warranted during prolonged statin therapy in patients with IHD. Keywords: Atorvastatin, Fluvastatin, Lovastatin, Rosuvastatin, Pitavastatin, Pravastatin, Simvastatin, Ischemic heart disease, IHD, new onset diabetes mellitus, NODM

Background: It is very important to prescribe appropriate drugs and adjust medication and dosage for optimal disease management not only to maximize patient outcomes, but also to minimize adverse events. So, the accuracy of drug information and consistency among different resources would have a significant effect on drug therapy. Objectives: We aimed to evaluate the concordance among five drug information sources regarding the recommendations for dosage adjustment in renal impairment. Methods: The five drug information resources were selected the Korean National Formulary Drug (KNF), the British national formula 2013 (BNF 65), Daily Med in USA, Lexicomp-online, and Drug Prescribing in Renal Failure (DPRF, 5th ed.). After having classified the degrees of renal function and defined the terms used for the dosing methods, we analyzed the concordance in dosing recommendations in renal deficiency among the information sources by calculating Fleiss Kappa. Results: In the dosing adjustments of patients with renal insufficiency, there were some cases of contraindicated drugs that were not matched in each reference. Statistical analysis of the concordance of four references, except DPRF, and evaluation of 168 of the drugs that were mentioned in all four sources showed the Fleiss Kappa coefficientto be 0.243. This indicatesfair agreement among the data. Conclusion: Fair agreement was observed among 4 sources. This may be owing to discrepancies in the frequency of updating drug information sources. We suggest that the quantitative standard be used to classify renal function and to maintain consistency in definition of renal impairment.

Background The Beers Criteria released by the American Geriatrics Society includes a list of drugs to avoid in the geriatric population and is frequently used as a safety resource in geriatric pharmacotherapy. Objective To evaluate the exposure of South Korean geriatrics to potentially inappropriate medications according to the Beers Criteria and the risk of adverse events from these medications. Methods This study included medications recommended to be avoided in patients 65 years or older regardless of concomitant drug therapy or disease. The exposure of South Korean geriatrics to each of the study medications were examined using health claims data of 2011. The number of South Korean geriatrics at risk of experiencing adverse drug events from the study medications were estimated by multiplying the number of patients exposed to the medication in 2011 and the incident rate of the event obtained from literature sources. Results This study examined 166,822 geriatrics for Beers Criteria medication exposure and adverse drug event risk. The most prevalent Beers Criteria medication prescribed in South Korean geriatrics >1 day was chlorpheniramine (53.9%) and the adverse drug event with the highest number of this geriatric population at risk of was amitriptyline related dry mouth (4.9%). The proportion of South Korean geriatrics on chronic Beers Criteria medications >1 day at risk of adverse drug events from these medications was significantly higher than in US geriatrics (0.005 vs. 0.001, 2-way ANOVA post hoc pairwise t-test P

Background/Objectives Addition of cilostazol or sarpogrelate to the standard dual antiplatelet therapy of aspirin and clopidogrel has been implemented in patients that underwent percutaneous coronary intervention (PCI) with stents in Korea. This study aimed to evaluate the efficacy and safety of triple antiplatelet therapies. Methods This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service from January 1, 2009 to December 31, 2014. The study cohort population consisted of patients with ischemic heart diseases and a history of PCI. They were treated with antiplatelet therapy of aspirin, clopidogrel (AC); aspirin, clopidogrel, cilostazol (ACCi); or aspirin, clopidogrel, sarpogrelate (ACSa) during the index period from January 1, 2010 to December 31, 2011. During the follow-up period up to December 31, 2014, the major adverse cardiac or cerebral events (MACCE) including death, myocardial infarction, target lesion revascularization, and ischemic stroke were assessed. Bleeding complications were also evaluated as adverse drug events. Results Out of 93,876 patients with PCI during the index period, 69,491 patients started dual (AC) or triple therapy (ACSa or ACCi). The clinical outcomes of comparing ACSa and ACCi therapy showed beneficial effects in the ACSa group in the prevention of subsequent cardiac or cerebral events. After Propensity score-matching between ACSa and ACCi groups, there were significant differences in MI and revascularization, with corresponding HR of 0.38 (95% CI, 0.20–0.73) and 0.66 (95% CI, 0.53–0.82) in ACSa vs. ACCi at 12 months, respectively. At the 24-month follow-up, the triple therapy groups (ACS or ACC) had a higher incidence of MACCE compared to the dual therapy (AC) group; ACSa vs. AC HR of 1.69 (95% CI, 1.62–1.77); ACC vs. AC HR of 1.22 (95% CI, 1.06–1.41). There was no significant difference in severe or life-threatening bleeding risk among three groups; ACSa vs. AC, HR of 0.68 (95% CI, 0.37–1.24), ACCi vs. AC, HR of 0.91 (95% CI, 0.77–1.09). Conclusion Sarpogrelate-containing triple antiplatelet therapy demonstrated comparable rates of MACCE prevention to the conventional dual antiplatelet therapy after PCI without significantly increasing bleeding risk during the two-year follow-up period.

Background Duplicate prescribing is known to occur across health systems and is one of the most frequent drug related problems. Therapeutic duplication (TD) increases the risk of adverse drug reactions without additional therapeutic benefits. Objectives This study aimed to develop TD criteria concerning four drug categories which are acid-related disorder drugs, antimicrobials, antihypertensives, and lipid modifying drugs and to estimate the prevalence of therapeutic duplicate prescribing at the ambulatory care settings in Korea. Methods TD criteria were developed using the WHO anatomical therapeutic chemical classification and modified with an expert consensus panel using the Delphi method. The prevalence of TD including ingredient duplication (ID) of four drug categories was examined using National Health Insurance claim database including 15 million patients during one month in 2009 (December). TD was defined as prescribing medications within the same category in the developed TD criteria list. Results The numbers of patients who received acid-related disorder drugs, antimicrobials, antihypertensives, and lipid-modifying drugs in the study period were 10,049,292, 7,584,131, 4,349,945, and 1,425,292 respectively. In the field of acid-related disorder drugs prescribed, there were 0.3 % IDs and 2.5 % TDs within a prescription issued by one prescriber. There were 8.4 % IDs and 14.5 % TDs between prescriptions issued at different ambulatory visits. In the field of antimicrobial medicines, there were 0.1 % IDs and 2.6 % TDs within a prescription, while there were 5.0 % IDs and 7.6 % TDs between different prescriptions. Amongst the antihypertensives prescribed, there were 0.4 % IDs and 1.9 % TDs within a prescription, while there were 9.9 % IDs and 11.5 % TDs between prescriptions. Lastly, looking at lipid-modifying drugs prescribed, there were 0.3 % IDs and 0.5 % TDs within one prescription, while there were 8.9 % IDs and 9.4 % TDs between prescriptions. Conclusion The prevalence of duplicate prescribing was substantial in the ambulatory care setting which is to be improved using the TD criteria developed from this study in the national drug utilization review system in Korea.

This paper proposes user authentication methods and encryption techniques that support reliable u-City user authentication services, based on biometric technology, (the use of face, vein, fingerprint, and iris recognition). Even in an advanced wire/wireless network environment, there remain the possibilities that personal confidential information may be exposed. Therefore, this paper proposes a method that prevents damage and effectively copes with security vulnerabilities, using an encryption method that applies to characteristics information twice, in addition to an authentication method based on biometric technology. The proposed user authentication technique randomly selects several biometric information items at the time of authentication, and applies more than two items of biometric information. In addition, the proposed encryption technique uses double encryption, utilizing the user's biometric characteristics information. This paper aims to guarantee an efficient and reliable user authentication service in a u-City environment, based on this methodology.