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PURPOSE: We aimed to develop a reliable identification algorithm combining diagnostic codes with several treatment factors for inpatients with acute ischemic stroke (AIS) to conduct pharmacoepidemiological studies using the administrative database MID-NET® in Japan. METHODS: We validated 11 identification algorithms based on 56 different diagnostic codes (International Classification of Diseases, Tenth Revision; ICD-10) using Diagnosis Procedure Combination (DPC) data combined with information on AIS therapeutic procedures added as "AND" condition or "OR" condition. The target population for this study was 366 randomly selected hospitalized patients with possible cases of AIS, defined as relevant ICD-10 codes and diagnostic imaging and prescription or surgical procedure, in three institutions between April 1, 2015 and March 31, 2017. We determined the positive predictive values (PPVs) of these identification algorithms based on comparisons with a gold standard consisting of chart reviews by experienced specialist physicians. Additionally, the sensitivities of them among 166 patients with the possible cases of AIS at a single institution were evaluated. RESULTS: The PPVs were 0.618 (95% confidence interval [CI]: 0.566-0.667) to 0.909 (95% CI: 0.708-0.989) and progressively increased with adding or limiting information on AIS therapeutic procedures as "AND" condition in the identification algorithms. The PPVs for identification algorithms based on diagnostic codes I63.x were >0.8. However, the sensitivities progressively decreased to a maximum of ~0.2 after adding information on AIS therapeutic procedures as "AND" condition. CONCLUSIONS: The identification algorithms based on the combination of appropriate ICD-10 diagnostic codes in DPC data and other AIS treatment factors may be useful to studies for AIS at a national level using MID-NET®.
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AVC Isquêmico , Algoritmos , Bases de Dados Factuais , Humanos , Classificação Internacional de Doenças , Valor Preditivo dos TestesRESUMO
BACKGROUND: An administrative database covering a whole population such as the national database in Japan may be used to estimate the nationwide prevalence of diseases including rheumatoid arthritis (RA) when a well-validated definition of the disease is available. In Japan, the record linkage between the administrative database and medical charts in hospitals is strictly prohibited. A "hospital-based" validation study is one of few possible validation studies where claims kept inside the study hospital are rearranged into the database structure. METHODS: We selected random samples of 19,734 patients from approximately 1.6 million patients who received medical care between February 2018 and January 2019 in one of the 64 hospitals of the Tokushukai Medical Group. We excluded patients whose observation period was less than 365 days and identified 334 patients who met the definition of "possible cases of RA" whose medical charts were then independently evaluated by two rheumatologists. In a sensitivity analysis, we assessed bias due to misclassifying some patients with RA who did not meet the definition of "possible cases of RA" as a patient with no RA. RESULTS: The kappa coefficient between the two rheumatologists was 0.80. The prevalence of RA in the study population was estimated to be 0.56%. We found that [condition code of RA] and ([any disease-modifying antirheumatic drug] or [oral corticosteroid with no systemic autoimmune diseases (other than RA) and no polymyalgia rheumatica]) had a relatively high sensitivity (approximately 73%) and a high positive predictive value (approximately 80%). In a sensitivity analysis, we found that when some patients with RA who did not meet the definition of "possible cases of RA" were misclassified as a patient with no RA, then this would lead to underestimation of the prevalence of the definition-positive patients and the adjusted prevalence. CONCLUSIONS: We recommend using the claims-based definition of RA (found in the current validation study) to estimate the prevalence of RA in Japan. We also suggest estimating the adjusted prevalence using the quantitative bias analysis method, since the prevalence of the disease in the "hospital-based" validation study is different from that in the administrative database. TRIAL REGISTRATION: The current study is not a clinical trial and hence not subject to trial registration.
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Antirreumáticos , Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Hospitais , Humanos , Japão/epidemiologia , ReumatologistasRESUMO
The inherent flexibility afforded by molecular design has accelerated the development of a wide variety of organic semiconductors over the past two decades. In particular, great advances have been made in the development of materials for organic light-emitting diodes (OLEDs), from early devices based on fluorescent molecules to those using phosphorescent molecules. In OLEDs, electrically injected charge carriers recombine to form singlet and triplet excitons in a 1:3 ratio; the use of phosphorescent metal-organic complexes exploits the normally non-radiative triplet excitons and so enhances the overall electroluminescence efficiency. Here we report a class of metal-free organic electroluminescent molecules in which the energy gap between the singlet and triplet excited states is minimized by design, thereby promoting highly efficient spin up-conversion from non-radiative triplet states to radiative singlet states while maintaining high radiative decay rates, of more than 10(6) decays per second. In other words, these molecules harness both singlet and triplet excitons for light emission through fluorescence decay channels, leading to an intrinsic fluorescence efficiency in excess of 90 per cent and a very high external electroluminescence efficiency, of more than 19 per cent, which is comparable to that achieved in high-efficiency phosphorescence-based OLEDs.
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The development of efficient metal-free organic emitters with thermally activated delayed fluorescence (TADF) properties for deep-blue emission is still challenging. A new family of deep-blue TADF emitters based on a donor-acceptor architecture has been developed. The electronic interaction between donor and acceptor plays a key role in the TADF mechanism. Deep-blue OLEDs fabricated with these TADF emitters achieved high external quantum efficiencies over 19.2 % with CIE coordinates of (0.148, 0.098).
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Organic compounds that exhibit highly efficient, stable blue emission are required to realize inexpensive organic light-emitting diodes for future displays and lighting applications. Here, we define the design rules for increasing the electroluminescence efficiency of blue-emitting organic molecules that exhibit thermally activated delayed fluorescence. We show that a large delocalization of the highest occupied molecular orbital and lowest unoccupied molecular orbital in these charge-transfer compounds enhances the rate of radiative decay considerably by inducing a large oscillator strength even when there is a small overlap between the two wavefunctions. A compound based on our design principles exhibited a high rate of fluorescence decay and efficient up-conversion of triplet excitons into singlet excited states, leading to both photoluminescence and internal electroluminescence quantum yields of nearly 100%.
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Much effort has been devoted to developing highly efficient organic light-emitting diodes (OLEDs) that function through phosphorescence or thermally activated delayed fluorescence (TADF). However, efficient host materials for blue TADF and phosphorescent guest emitters are limited because of their requirement of high triplet energy levels. Herein, we report the rigid acceptor unit benzimidazobenzothiazole (BID-BT), which is suitable for use in bipolar hosts in blue OLEDs. The designed host materials, based on BID-BT, possess high triplet energy and bipolar carrier transport ability. Both blue TADF and phosphorescent OLEDs containing BID-BT-based derivatives exhibit external quantum efficiencies as high as 20 %, indicating that these hosts allow efficient triplet exciton confinement appropriate for blue TADF and phosphorescent guest emitters.
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AIMS: HMG-CoA reductase inhibitors are available for use in low density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records. METHODS: Patient backgrounds, laboratory tests and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C concentrations. The PPD analysis was performed using nonmem 7.2.0 with the first order conditional estimation method with interaction (FOCE-INTER). RESULTS: An indirect response Imax model, based on the 2863 LDL-C concentrations of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (Kin ) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg day(-1) ) led to superior clinical responses than those with high doses of rosuvastatin (5.0 mg day(-1) ) monotherapy, even in patients with higher baseline LDL-C concentrations prior to the treatment. CONCLUSIONS: A newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice.
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LDL-Colesterol/sangue , Registros Eletrônicos de Saúde , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Ezetimiba , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos BiológicosRESUMO
Make your OLED fluorescent: an aromatic molecule based on a spiro-acridine derivative was designed, and its photoluminescence and electroluminescence were characterized. By combining the donor and acceptor moieties a small energy gap between the lowest singlet and triplet states was achieved. This design leads to an organic light-emitting diode (OLED) that rivals phosphorescent devices regarding exciton generation efficiency.
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Dynamic light scattering (DLS) is a well-known technique for measuring the size of nanoparticles from the diffusion coefficient. We developed a new DLS technique with high sensitivity and used it as a detection tool in microchemical applications. We found a step-like downward change in the diffusion coefficient of nanoparticles just by starting a slight flow in the fluid channel. Because the diffusion coefficient is defined by the ratio of the force due to the chemical potential gradient to the frictional coefficient for the particle by a solvent, we propose that the frictional coefficient increased significantly. This result suggests that nanoscale friction under liquid motion differs from that under a steady state.
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A new type of dynamic light scattering method for the size measurement of nanoparticles was developed using a transmission grating. A sample cell was located behind the grating, and light was incident from the grating side. The scattered light by a solution with nanopariticles was mixed with diffracted light by the grating, and the mixed signal was detected; namely, the diffracted light was used as reference light for heterodyne detection. It was confirmed that the S/N ratio of the autocorrelation curve was 26-times improved by heterodyne detection. Furthermore, the S/N ratio was improved by setting the sample cell at the sample grating distance where the electromagnetic field is maximum due to the Talbot effect. Size measurements for several kinds of nanoparticles were demonstrated by this new method.
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(6R)-l-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for monoamine and nitric oxide (NO) production. Sepiapterin reductase (SPR) catalyzes the final step in BH4 biosynthesis. We analyzed the cardiovascular function of adult Spr gene-disrupted (Spr-/-) mice for the first time. After weaning, Spr-/- mice suffered from hypertension with fluctuation and bradycardia, while the monoamine contents in these mice were less than 10% of those in the wild-type mice as a result of BH4 depletion. Heart rate variability analysis indicated the sympathetic dominant state in Spr-/- mice. The endothelium-dependent vascular relaxation in response to acetylcholine was significantly impaired in Spr-/- mice after sexual maturation (above 4 months old). Protein amounts of α1 adrenergic receptor and eNOS in the aorta were not altered. Spr-/- mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of Spr-/- mice would be caused by an imbalance of sympathetic and parasympathetic input and impaired nitric oxide production in endothelial cells. We suggest an important role of BH4 and SPR in age-related hypertension and a possible relationship with the cardiovascular instabilities in autonomic diseases, including Parkinson's disease and spinal cord injury.
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Oxirredutases do Álcool/genética , Pressão Sanguínea/genética , Bradicardia/genética , Frequência Cardíaca/genética , Hipertensão/genética , Fatores Etários , Oxirredutases do Álcool/metabolismo , Animais , Aorta/metabolismo , Glicemia/metabolismo , Bradicardia/metabolismo , Comportamento Alimentar/fisiologia , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores Adrenérgicos alfa 1/metabolismoRESUMO
The design of organic compounds with nearly no gap between the first excited singlet (S1) and triplet (T1) states has been demonstrated to result in an efficient spin-flip transition from the T1 to S1 state, that is, reverse intersystem crossing (RISC), and facilitate light emission as thermally activated delayed fluorescence (TADF). However, many TADF molecules have shown that a relatively appreciable energy difference between the S1 and T1 states (~0.2 eV) could also result in a high RISC rate. We revealed from a comprehensive study of optical properties of TADF molecules that the formation of delocalized states is the key to efficient RISC and identified a chemical template for these materials. In addition, simple structural confinement further enhances RISC by suppressing structural relaxation in the triplet states. Our findings aid in designing advanced organic molecules with a high rate of RISC and, thus, achieving the maximum theoretical electroluminescence efficiency in organic light-emitting diodes.
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AIM: To develop a population pharmacodynamic (PPD) model describing the time course for the hemoglobin A1c (HbA1c)-lowering effects of adding treatment of DPP-4 inhibitors and to assess the efficacy of combination therapy in type 2 diabetes mellitus patients based on electronic medical records. METHODS: Information on patients was collected retrospectively from electronic medical records. Of the 4 DPP-4 inhibitors used, we focused on sitagliptin as it had the best time-response relationships. A physiological indirect response model was developed to describe changes in HbA1c levels. RESULTS: An indirect response model, based on the 1300 HbA1c levels of 160 patients, described the time course for the HbA1c-lowering effects of adding sitagliptin. The combination with pioglitazone decreased the HbA1c synthesis rate by 7.74% relative to without pioglitazone. Bayesian forecasting based on the final PDD model using the first two HbA1c observations, before and within 30days after the addition of sitagliptin, gave a precise prediction of HbA1c-lowering effects individually. CONCLUSIONS: Our PPD model quantitatively described the beneficial effects of combination therapy with pioglitazone and sitagliptin. The proposal methodology is also expected to be applicable to other medicines based on electronic medical records in clinical practice.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hipoglicemiantes/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Metal complexes emitting thermally activated delayed fluorescence based on intra-ligand charge transfer and enhanced by metallization were synthesized. Organic light-emitting diodes using a thermally stable zinc complex processed by vacuum vapor deposition achieved an external quantum efficiency of nearly 20%.
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We analyzed and compared the frequency components of the heart rate variability in human neonate, rat, white chicken, turtle, and frog during the developments. Frequency analysis with autocorrelation-FFT method was applied to the heart rate and respiration waves to calculate the respiration induced frequency component in the power spectra. The comparative analysis of the cardiopulmonary reflex in human and rat neonates resulted in a similar developmental progress. In case of human immature neonate, respiration induced frequency component in the heart rate variability was negligible at day-old 0, and significantly increased at postnatal 1 month. The rat neonates also showed no or negligible respiration induced components until days 8 and it became significant approximately postnatal 1 month. The white chicken also indicated negligible respiration induced component before and a few days after hatching, and became significant after 38 days-old (17 days post hatching). However the frog and the turtle indicated no clear response in entire periods of the development even in adult. The results strongly suggested that gravity may be a possible essential factor of the appearance of the post natal development of the cardiopulmonary reflex.
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Frequência Cardíaca/fisiologia , Fisiologia Comparada , Respiração , Animais , Embrião de Galinha , Galinhas , Biologia do Desenvolvimento , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Larva , Rana catesbeiana , Ratos , Ratos Wistar , TartarugasRESUMO
We examined the developmental change by which autonomic neural activity associated respiration modulates spontaneous firing rate of sinus (SA) node and atrioventricular (AV) conduction in premature infants born with low birth weight (LBWI). The purpose of this study was to clarify whether variation of PR is correlated with that of PP or those are independent in LBWI with immature autonomic nervous system. We investigated, therefore, whether there are spontaneous functional differences in the innervation of SA and AV nodes. Further, we evaluated the maturation of autonomic nervous system progressing in the period, on the day of birth (Day 0) to approximately one month after the birth (Month 1). This study was performed in thirteen LBWI during deep sleep. EEG, EOG, ECG, respiratory waves were digitized on line, spontaneous firing cycle of SA node (PP), and AV nodal conduction time (PR) that were recorded on Day 0 and Month 1. Then, the data were analyzed as follows: 1) correlations among the means and standard deviations (SD) of PP, PR and RR, 2) variance evaluation of PP and PR intervals by Lorenz plot analysis method, 3) correlation analysis among PP, PR and RR intervals by linear regression method and 4) frequency analysis for PP and PR intervals by high-speed Fourier transform method (FFT) and determination of frequency density. The PP interval decreased as growing in the period. Contrary PR interval increased. In LBWI, the automatic nervous activities including parasympathetic nerve activity for spontaneous firing cycle of SA node and ventricular excitation cycle on Month 1 were higher than Day 0. It was assumed that the vagal nerve activity for the AV conduction was enhanced. However, there was no significant change in linear regression slope for the spontaneous firing cycle of SA node and the AV conduction time. Postnatal LF/HF changes for PP and PR obtained by frequency analysis, were opposite. Therefore, it was suggested that the maturity of autonomic nervous system progresses in the period, Day 0 to approximately Month 1, but the variations in PP and PR are independent each other.
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Nó Atrioventricular/fisiologia , Sistema Nervoso Autônomo/fisiologia , Fenômenos Fisiológicos Respiratórios , Nó Sinoatrial/fisiologia , Eletrocardiografia , Eletroencefalografia , Eletroculografia , Frequência Cardíaca/fisiologia , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Nervo Vago/fisiologiaRESUMO
Highly efficient exciplex systems incorporating a heptazine derivative () as an electron acceptor and 1,3-di(9H-carbazol-9-yl)benzene () as an electron donor are developed. An organic light-emitting diode containing 8 wt% : as an emitting layer exhibits a maximum external quantum efficiency of 11.3%.
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Objectives. Doxapram hydrochloride is a respiratory stimulant that has an inhibitory effect on myocardial IK1 potassium channels and is thought to increase membrane instability and excitability in myocardial cells. We examined the arrhythmogenic effects of doxapram hydrochloride in a rat model of halothane adrenaline-induced arrhythmia. Methods. Thirteen female Wistar rats (12-14 weeks old) were used in the study. Animals were anesthetized with inhalation of halothane to permit observation of the effects of doxapram hydrochloride on halothane adrenaline-induced arrhythmia. Time-dependent changes in ECG repolarization characteristics (QT, QTc, JTp, JT, and Tp-e intervals) were studied. Results. Doxapram hydrochloride itself did not induce arrhythmia but did induce bidirectional ventricular tachycardia after addition of adrenaline. Conclusion. Drug-induced impairment of intracellular Ca(2+) regulation caused BVT in the absence of genetic abnormalities in proteins in the sarcoplasmic reticulum.
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An orange-red organic light-emitting diode containing a heptazine derivative exhibits high performance with a maximum external quantum efficiency of 17.5 ± 1.3% and a peak luminance of 17000 ± 1600 cd m⻲ without any light out-coupling enhancement. The high electroluminescence performance can be ascribed to the presence of an efficient up-conversion channel from the lowest triplet state to the lowest singlet state.