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Herein, we present a new and simple electrochemical method to detect the intracellular electroactive substances by utilizing the electron tunnelling processes at the metal nanoparticles inside the cells. Intriguing discrete oxidation and reduction current spikes are obtained when testing the cells with loaded Au nanoparticles at the ultramicroelectrodes, which should come from reactive oxygen species (ROS) inside the single cell. The charges enclosed in the current spikes represent the ROS content inside the living cells, as confirmed by the fluorescence studies. As this simple electron tunnelling approach needs no nanoelectrodes or nanotip penetration processes, we believe it could have great potential applications in electrochemical analysis of single living cells.
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Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Espécies Reativas de Oxigênio , Elétrons , Eletrodos , Membrana CelularRESUMO
The in situ characterization of the heterostructure active sites during the hydrogen evolution reaction (HER) process and the direct elucidation of the corresponding catalytic structure-activity relationships are essential for understanding the catalytic mechanism and designing catalysts with optimized activity. Hence, exploring the underlying reasons behind the exceptional catalytic performance necessitates a detailed analysis. Herein, we employed scanning electrochemical microscopy (SECM) to in situ image the topography and local electrocatalytic activity of 1T/2H MoS2 heterostructures on mixed-phase molybdenum disulfide (MoS2) with 20 nm spatial resolution. Our measurements provide direct data about HER activity, enabling us to differentiate the superior catalytic performance of 1T/2H MoS2 heterostructures compared to other active sites on the MoS2 surface. Combining this spatially resolved electrochemical information with density functional theory calculations and numerical simulations enables us to reveal the existence of hydrogen spillover from the 1T MoS2 surface to 1T/2H MoS2 heterostructures. Furthermore, it has been verified that hydrogen spillover can significantly enhance the electrocatalytic activity of the heterostructures, in addition to its strong electronic interaction. This study not only contributes to the future investigation of electrochemical processes at nanoscale active sites on structurally complex electrocatalysts but also provides new design strategies for improving the catalytic activity of 2D electrocatalysts.
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Dual nanopipettes with two channels have been receiving great attention due to the convenient experimental setup and multiple measuring channels in sensing applications at nanoscale, while the involved dynamic and asymmetrical ion transport processes have not been fully elucidated. In this paper, both experimental and simulation methods are used to investigate the dynamic mass transport processes inside dual nanopipettes with two well-separated channels. The results present that the ion transport resistance through the two channels (R12) is always the add-up of the individual ones (R13 + R23) with respect to the bulk solutions, at various ionic strengths and scan rates. A constant zero-current potential is obtained when loading an asymmetrical electrolyte concentration in the two channels, and the zero-potential current displays a good linear relationship with the bulk concentration outside the pipet. Besides revealing the dynamic and asymmetrical concentration polarization in the dual nanopipettes, these results would also further promote the better usage of dual nanopipettes in electrochemical sensing and imaging applications.
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Electrochemical resistive-pulse (ERP) sensing with conductive carbon nanopipettes (CNPs) has recently been developed and employed for the detection of single liposomes and biological vesicles, and for the analysis of redox molecules contained in such vesicles. However, the origins of different shapes of current transients produced by the translocation of single vesicles through the CNP remain poorly understood. Herein, we report extensive finite-element simulations of both portions of an ERP transient, the current blockage by a vesicle approaching and passing through the pipet orifice and the faradaic current spike due to oxidation/reduction of redox species released from a vesicle on the carbon surface, for different values of parameters defining the geometry and dynamics of the vesicle/CNP system. The effects of the pipet geometry, surface charge, transport, vesicle trajectory, and collision location on the shape of current transients are investigated. The possibility of quantitative analysis of experimental ERP transients produced by translocations of liposomes and extracellular vesicles by fitting them to simulated curves is demonstrated. The developed theory can enable a more reliable interpretation of complicated ERP signals and characterization of the size and contents of single biological and artificial vesicles.
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Vesículas Extracelulares , Lipossomos , Humanos , Vesícula , Carbono , Condutividade ElétricaRESUMO
The in-depth study of single cells requires the dynamically molecular information in one particular nanometer-sized organelle in a living cell, which is difficult to achieve using current methods. Due to high efficiency of click chemistry, a new nanoelectrode-based pipette architecture with dibenzocyclooctyne at the tip is designed to realize fast conjugation with azide group-containing triphenylphosphine, which targets mitochondrial membranes. The covalent binding of one mitochondrion at the tip of the nanopipette allows a small region of the membrane to be isolated on the Pt surface inside the nanopipette. Therefore, the release of reactive oxygen species (ROS) from the mitochondrion is monitored, which is not interfered by the species present in the cytosol. The dynamic tracking of ROS release from one mitochondrion reveals the distinctive "ROS-induced ROS release" within the mitochondria. Further study of RSL3-induced ferroptosis using nanopipettes provides direct evidence for supporting the noninvolvement of glutathione peroxidase 4 in the mitochondria during RSL3-induced ROS generation, which has not previously been observed at the single-mitochondrion level. Eventually, this established strategy should overcome the existing challenge of the dynamic measurement of one special organelle in the complicated intracellular environment, which opens a new direction for electroanalysis in subcellular analysis.
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Mitocôndrias , Sobrevivência Celular , Mitocôndrias/química , Mitocôndrias/metabolismo , Química Click/instrumentação , Química Click/métodos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Revealing the electrocatalytic features of single redox enzyme is significant to both fundamental biological processes and practical catalysis and sensing applications. Herein, we directly reveal the electrocatalytic current from a single enzyme inside the carbon nanopipettes via electrochemical collision strategies, based on the increased activity at nanoscale confinement. Besides the staircase current steps from surface blockage, discrete H2O2 oxidation and reduction current transients catalyzed by a single enzyme are also displayed and analyzed. The carbon nanopipette would increase the catalytic activities of enzymes and lead to a detectable current response, thus opening a new way to investigate the fundamental enzymatic mechanisms at the single enzyme level.
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Carbono , Técnicas Eletroquímicas , Catálise , Peróxido de Hidrogênio , OxirreduçãoRESUMO
Herein, we report a sensitive scanning electrochemical microscopy (SECM) method based on the high transient current signals in carbon nanopipets (CNPs) under step potential waveforms. Taking advantage of the transient peak current, the approach curve can be conducted with very dilute (1 µM) or even no redox mediator and fitted by the scanning ion conductance microscopy (SICM) theory. In addition, a trace amount of electroactive species generated at the substrate can also be directly revealed from the transient current at the CNP tips. With the established feedback and generation/collection methods, we present the constant-height topography and electroactivity imaging of the substrates with only 1 µM K4Fe(CN)6. The developed new SECM method would allow the usage of CNPs to achieve both high sensitivity and spatial resolution with dilute or no redox mediator and thus find great potential applications in biological and electrocatalytic studies.
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Carbono , Microscopia , Microscopia/métodos , Microscopia Eletroquímica de Varredura , OxirreduçãoRESUMO
Conductive nanopipettes offer promising confined spaces to enable advanced electrochemical sensing applications in small spaces. Herein, a series of metal-decorated carbon nanopipettes (CNPs) were developed, in which Au, Ag, and Pt are modified at the inner walls of CNPs by a simple electrodeposition method. The fabricated tips show good sensing performances for a variety of important analytes, such as glucose, hydrogen peroxide, and chloride and hydrogen ions in biological and catalytic systems. This simple and effective approach can be further extended to prepare other functionalized nanopipette electrodes toward more versatile and powerful measurements in electrochemical sensing and imaging applications.
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Carbono , Nanopartículas Metálicas , Técnicas Eletroquímicas/métodos , Eletrodos , Peróxido de HidrogênioRESUMO
The analysis of biomolecules in a 3D cell model is crucial for the collection of spatial information close to the actual organ. In this work, a highly sensitive platinized open carbon nanocavity electrode is fabricated to investigate reactive oxygen species (ROS) in three regions (proliferating zone, quiescent zone, and necrotic core) of a 3D CT26 cell model. The presence of a nanocavity permits more frequent collisions of ROS on the Pt surface, accelerating electron transfer, and thus pushes the detection limit down to 1 nM. This improved detection sensitivity guarantees the spatial investigation of the ROS distribution in a 3D cell sphere, including a high concentration in the outer proliferating layer even without any external stimulus, a low concentration in the quiescent layer, and almost no ROS at the center. The observation of ROS in the cell sphere without the stimulus reveals the presence of oxygen stress in the 3D cancer cell model, which is obviously different from the previous observation in living cultured 2D cells. This discovery provides direct evidence about the discrepancy about the metabolism in 2D and 3D cells, which could also direct a new study in cell electroanalysis to achieve more actual molecular information in life study.
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Carbono , Oxigênio , Eletrodos , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Análise EspacialRESUMO
Exploring the electrochemical collision features at nanoelectrodes is highly desirable for revealing new physical insights and further expanding its applications at smaller spaces. Herein, we study the collision processes of single silver nanoparticles (AgNPs) inside carbon nanopipettes (CNPs). Results show that AgNPs undergo multiple collision and oxidation processes prior to fully oxidation after entering into the CNPs. Different from the disk electrodes, the produced Ag+ cannot immediately diffuse away from the cavity and will be reduced once switching to reductive potentials. More intriguingly, we observe discrete cathodic spikes from the Ag+ reduction, which are presumably due to the negatively charged carbon surface confined in the CNPs. The elucidated collision features in a CNP would enable its better usage for single entity measurements at confined spaces.
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Nanopartículas Metálicas , Nanopartículas , Carbono , Eletrodos , Oxirredução , PrataRESUMO
BACKGROUND: Accelerated translation of real-world interventions for hypertension management is critical to improving cardiovascular outcomes and reducing disparities. OBJECTIVE: To determine whether a positive deviance approach would improve blood pressure (BP) control across diverse health systems. DESIGN: Quality improvement study using 1-year cross sections of electronic health record data over 5 years (2013-2017). PARTICIPANTS: Adults ≥ 18 with hypertension with two visits in 2 years with at least one primary care visit in the last year (N = 114,950 at baseline) to a primary care practice in Better Health Partnership, a regional health improvement collaborative. INTERVENTIONS: Identification of a "positive deviant" and dissemination of this system's best practices for control of hypertension (i.e., accurate/repeat BP measurement; timely follow-up; outreach; standard treatment algorithm; and communication curriculum) using 3 different intensities (low: Learning Collaborative events describing the best practices; moderate: Learning Collaborative events plus consultation when requested; and high: Learning Collaborative events plus practice coaching). MAIN MEASURES: We used a weighted linear model to estimate the pre- to post-intervention average change in BP control (< 140/90 mmHg) for 35 continuously participating clinics. KEY RESULTS: BP control post-intervention improved by 7.6% [95% confidence interval (CI) 6.0-9.1], from 67% in 2013 to 74% in 2017. Subgroups with the greatest absolute improvement in BP control included Medicaid (12.0%, CI 10.5-13.5), Hispanic (10.5%, 95% CI 8.4-12.5), and African American (9.0%, 95% CI 7.7-10.4). Implementation intensity was associated with improvement in BP control (high: 14.9%, 95% CI 0.2-19.5; moderate: 5.2%, 95% CI 0.8-9.5; low: 0.2%, 95% CI-3.9 to 4.3). CONCLUSIONS: Employing a positive deviance approach can accelerate translation of real-world best practices into care across diverse health systems in the context of a regional health improvement collaborative (RHIC). Using this approach within RHICs nationwide could translate to meaningful improvements in cardiovascular morbidity and mortality.
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Hipertensão , Adulto , Pressão Sanguínea , Determinação da Pressão Arterial , Humanos , Hipertensão/diagnóstico , Hipertensão/terapia , Atenção Primária à Saúde , Melhoria de QualidadeRESUMO
INTRODUCTION: Various methods have been used to interpret the reports of pediatric polypharmacy across the literature. This is the first scoping review that explores outcome measures in pediatric polypharmacy research. OBJECTIVES: The aim of our study was to describe outcome measures assessed in pediatric polypharmacy research. METHODS: A search of electronic databases was conducted in July 2017, including Ovid Medline, PubMed, Elsevier Embase, Wiley Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO CINAHL, Ovid PsyclNFO, Web of Science Core Collection, ProQuest Dissertations and Thesis A&I. Data were extracted about study characteristics and outcome measures, and also synthesized by harms or benefits mentioned. RESULTS: The search strategy initially identified 8169 titles and screened 4398 using the inclusion criteria after de-duplicating. After the primary screening, a total of 363 studies were extracted for the data analysis. Polypharmacy (prevalence) was identified as an outcome in 31.4% of the studies, prognosis-related outcomes in 25.6%, and adverse drug reactions in 16.5%. A total of 265 articles (73.0%) mentioned harms, including adverse drug reactions (26.4%), side effects (24.2%), and drug-drug interactions (20.9%). A total of 83 studies (22.9%) mentioned any benefit, 48.2% of which identified combination for efficacy, 24.1% combination for treatment of complex diseases, and 19.3% combination for treatment augmentation. Thirty-eight studies reported adverse drug reaction as an outcome, where polypharmacy was a predictor, with various designs. CONCLUSIONS: Most studies of pediatric polypharmacy evaluate prevalence, prognosis, or adverse drug reaction-related out-comes, and underscore harms related to polypharmacy. Clinicians should carefully weigh benefits and harms when introducing medications to treatment regimens.
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BACKGROUND: Polypharmacy can be either beneficial or harmful to children. We conducted a scoping review to examine the concept of pediatric polypharmacy: its definition, prevalence, extent and gaps in research. In this manuscript, we report our transdisciplinary scoping review methodology. METHODS: After establishing a transdisciplinary team, we iteratively developed standard operating procedures for the study's search strategy, inclusion/exclusion criteria, screening, and data extraction. We searched eight bibliographic databases, screened abstracts and full text articles, and extracted data from included studies using standardized forms. We held regular team meetings and performed ongoing internal validity measurements to maintain consistent and quality outputs. RESULTS: With the aid of EPPI Reviewer collaborative software, our transdisciplinary team of nine members performed dual reviews of 363 included studies after dual screening of 4398 abstracts and 1082 full text articles. We achieved overall agreement of 85% and a kappa coefficient of 0.71 (95% CI 0.68-0.74) while screening full text articles. The screening and review processes required about seven hours per extracted study. The two pharmacists, an epidemiologist, a neurologist, and a librarian on the review team provided internal consultation in these key disciplines. A stakeholder group of 10 members with expertise in evidence synthesis, research implementation, pediatrics, mental health, epilepsy, pharmacoepidemiology, and pharmaceutical outcomes were periodically consulted to further characterize pediatric polypharmacy. CONCLUSIONS: A transdisciplinary approach to scoping reviews, including internal and external consultation, should be considered when addressing complex cross-disciplinary questions.
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Comportamento Cooperativo , Equipe de Assistência ao Paciente/estatística & dados numéricos , Pediatria/métodos , Polimedicação , Criança , Bases de Dados Bibliográficas/estatística & dados numéricos , Atenção à Saúde/métodos , Atenção à Saúde/estatística & dados numéricos , Atenção à Saúde/tendências , Humanos , Comunicação Interdisciplinar , Equipe de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/tendências , Literatura de Revisão como AssuntoRESUMO
The rupture of atherosclerotic plaques remains one of the leading causes of morbidity and mortality worldwide. The plaques have certain pathological characteristics including a fibrous cap, inflammation, and extensive lipid deposition in a lipid core. Various invasive and noninvasive imaging techniques can interrogate structural aspects of atheroma; however, the composition of the lipid core in coronary atherosclerosis and plaques cannot be accurately detected. Fiber-optic Raman spectroscopy has the capability of in vivo rapid and accurate biomarker detection as an emerging omics technology. Previous studies demonstrated that an intravascular Raman spectroscopic technique may assess and manage the therapeutic and medication strategies intraoperatively. The Raman spectral information identified plaque depositions consisting of lipids, triglycerides, and cholesterol esters as the major components by comparing normal region and early plaque formation region with histology. By focusing on the composition of plaques, we could identify the subgroups of plaques accurately and rapidly by Raman spectroscopy. Collectively, this fiber-optic Raman spectroscopy opens up new opportunities for coronary atherosclerosis and plaque detection, which would assist optimal surgical strategy and instant postoperative decision-making. In this paper, we will review the advancement of label-free fiber-optic Raman probe spectroscopy and its applications of coronary atherosclerosis and atherosclerotic plaque detection.
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The catecholamines, mainly dopamine (DA), are present in the cellular cytosol with low abundance, while, play key roles in various neurodegenerative disorders. Here, platinized nanocavity carbon electrodes are employed to analyze cytosolic catecholamines in a single living PC12 cell, which is not easily quantified using the classic electrodes. The confined structure and excellent conductivity in the platinized nanocavity accelerate the electron transfer of the DA, resulting in a low detection limit down to 50 nM. The sensitivity of DA detection is improved to be 10.73 pA mM-1 nm-1 in the response range of 50 nM-100 µM, which guarantees quantitative analysis of cytosolic catecholamines with low abundance. Eventually, the platinized nanocavity electrode is employed to detect cytosolic catecholamines in a single PC12 cell without an obvious interruption of cellular catecholamine level. The cytosolic catecholamines in a single PC12 cell is measured in situ to be 0.1 µM, which is achieved for the first time at the single cell level using the electrochemical method. The results demonstrate that the nanocavity electrode with a high sensitivity could offer a promising means to dynamically track catecholamines in a single cell.
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Catecolaminas , Dopamina , Catecolaminas/análise , Citosol/química , Dopamina/análise , Eletrodos , Carbono , Técnicas EletroquímicasRESUMO
Introduction: Depressive and manic states contribute significantly to the global social burden, but objective detection tools are still lacking. This study investigates the feasibility of utilizing voice as a biomarker to detect these mood states. Methods:From real-world emotional journal voice recordings, 22 features were retrieved in this study, 21 of which showed significant differences among mood states. Additionally, we applied leave-one-subject-out strategy to train and validate four classification models: Chinese-speech-pretrain-GRU, Gate Recurrent Unit (GRU), Bi-directional Long Short-Term Memory (BiLSTM), and Linear Discriminant Analysis (LDA). Results: Our results indicated that the Chinese-speech-pretrain-GRU model performed the best, achieving sensitivities of 77.5% and 54.8% and specificities of 86.1% and 90.3% for detecting depressive and manic states, respectively, with an overall accuracy of 80.2%. Discussion: These findings show that machine learning can reliably differentiate between depressive and manic mood states via voice analysis, allowing for a more objective and precise approach to mood disorder assessment.
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Hepatitis B virus (HBV) infection results in liver cirrhosis and hepatocellular carcinoma (HCC). HBx/nuclear factor (NF)-κB pathway plays a role in HBV replication. However, whether NF-κB-interacting long noncoding RNA (NKILA), a suppressor of NF-κB activation, regulates HBV replication remains largely unknown. In this study, gain-and-loss experiments showed that NKILA inhibited HBV replication by inhibiting NF-κB activity. In turn, HBV infection down-regulated NKILA expression. In addition, expression levels of NKILA were lower in the peripheral blood-derived monocytes (PBMCs) of HBV-positive patients than in healthy individuals, which were correlated with HBV viral loads. And a negative correlation between NKILA expression level and HBV viral loads was observed in blood serum from HBV-positive patients. Lower levels of endogenous NKILA were also observed in HepG2 cells expressing a 1.3-fold HBV genome, HBV-infected HepG2-NTCP cells, stable HBV-producing HepG2.2.15 and HepAD38 âcells, compared to those HBV-negative cells. Furthermore, HBx was required for NKILA-mediated inhibition on HBV replication. NKILA decreased HBx-induced NF-κB activation by interrupting the interaction between HBx and p65, whereas NKILA mutants lack of essential domains for NF-ĸB inhibition, lost the ability to inhibit HBV replication. Together, our data demonstrate that NKILA may serve as a suppressor of HBV replication via NF-ĸB signalling.
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Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/patologia , Vírus da Hepatite B/genética , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Proteínas Virais Reguladoras e AcessóriasRESUMO
1.2 Previous studies have confirmed that air and light pollution can cause damage to a number of systems throughout the body, including the ocular surface and retina. However, the exact effect of air pollution and light pollution on tear film function is not clear. This study explored the different operation room environmental exposures on tear film function before and after operation. Sixty medical staff in the operating room were selected and divided into 4 groups according to different surgical methods to evaluate the tear film function before and after operation: Da Vinci surgery group (DVSS), Laparoscopic surgery group (LS), Traditional surgery group (TS), and Ophthalmic microsurgery group (OM). The results showed that the levels of light and air pollution were elevated in operating rooms during the operation and the changes of tear film function in the other three groups were statistically significant except for DVSS group. In TS group, particulate matter (pm) 1 (R = 0.61, p < 0.01), pm2.5 (R = 0.63, p < 0.01), and pm10 (R = 0.67, p < 0.01) were positively correlated with eye redness index, and first and average noninvasive tear film break-up times were positively correlated with illuminance (R = 0.54, p < 0.05; R = 0.97, p < 0.01). In OM group, there was a positive correlation between the operation time and the first (R = 0.69, p < 0.01) and average (R = 0.89, p < 0.01) noninvasive tear film break-up times. Our research found that exposure to different operating room environment will lead to damage of tear film function, but also provide a theoretical basis for the improvement of surgical environment.
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Conductive nanopipettes have been recognized as powerful multifunctional platforms for electrochemical sensing applications in confined spaces. However, the electron-transfer processes of many biological analytes (i.e., enzymes or proteins) are slow and coupled with chemical reactions, which have not been well elucidated in conductive nanopipettes. In this Letter, both experimental and simulation methods are used to study electron-transfer processes coupled to chemical reactions (EC mechanism) in carbon nanopipettes (CNPs). It is demonstrated that the electroactive species can serve as redox mediator to help oxidize and reduce the nonelectroactive analytes of interest in the solution and produce noticeable catalytic current signals. Besides, glutathione was directly measured by using ferrocenemethanol as the redox mediator in the CNPs. The elucidated EC processes in CNPs would offer a new opportunity to measure nonelectroactive analytes in biological fields.
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Background: Insomnia is a common disease, and the application of various types of sleeping pills for cognitive impairment is controversial, especially as different doses can lead to different effects. Therefore, it is necessary to evaluate the cognitive impairment caused by different sleeping pills to provide a theoretical basis for guiding clinicians in the selection of medication regimens. Objective: To evaluate whether various different doses (low, medium and high) of anti-insomnia drugs, such as the dual-orexin receptor antagonist (DORA), zopiclone, eszopiclone and zolpidem, induce cognitive impairment. Methods: The PubMed, Embase, Scopus, Cochrane Library, and Google Scholar databases were searched from inception to September 20th, 2022 for keywords in randomized controlled trials (RCTs) to evaluate the therapeutic effects of DORA, eszopiclone, zopiclone and zolpidem on sleep and cognitive function. The primary outcomes were indicators related to cognitive characteristics, including scores on the Digit Symbol Substitution Test (DSST) and daytime alertness. The secondary outcomes were the indicators associated with sleep and adverse events. Continuous variables were expressed as the standard mean difference (SMD). Data were obtained through GetData 2.26 and analyzed by Stata v.15.0. Results: A total of 8702 subjects were included in 29 studies. Eszopiclonehigh significantly increased the daytime alertness score (SMD = 3.00, 95 % CI: 1.86 to 4.13) compared with the placebo, and eszopiclonehigh significantly increased the daytime alertness score (SMD = 4.21, 95 % CI: 1.65 to 6.77; SMD = 3.95, 95 % CI: 1.38 to 6.51; SMD = 3.26, 95 % CI: 0.38 to 6.15; and SMD = 3.23, 95 % CI: 0.34 to 6.11) compared with zolpidemlow, zolpidemhigh, DORAlow, and eszopiclonemid, respectively. Compared with the placebo, zopiclone, zolpidemmid, and eszopiclonehigh, DORA significantly increased the TST (SMD = 2.39, 95 % CI: 1.11 to 3.67; SMD = 6.00, 95 % CI: 2.73 to 9.27; SMD = 1.89, 95 % CI: 0.90 to 2.88; and SMD = 1.70, 95 % CI: 0.42 to 2.99, respectively). Conclusion: We recommend DORA as the best intervention for insomnia because it was highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem had a more pronounced effect on sleep maintenance, this drug is better for short-term use. Eszopiclone and zopiclone improved sleep, but their cognitive effects have yet to be verified.