3D-imaging and quantitative assessment for size-related penetration of HfO2 nanoparticles in breast cancer tumor by synchrotron radiation microcomputed tomography.

The development of quantitative analytical methods to assess the heterogeneous distribution and penetration of nanodrugs in solid tumors is of great importance for anticancer nanomedicine. Herein, Expectation-Maximization (EM) iterate algorithm and threshold segmentation methods were used to visualize and quantify the spatial distribution patterns, penetration depth and diffusion features of two-sized hafnium oxide nanoparticles (s-HfO2 NPs in 2 nm and l-HfO2 NPs in 50 nm sizes) in mouse models of breast cancer using synchrotron radiation micro-computed tomography (SR-µCT) imaging technique. The three-dimensional (3D) SR-µCT images were reconstructed based on the EM iterate algorithm thus clearly displayed the size-related penetration and distribution within the tumors after intra-tumoral injection of HfO2 NPs and X-ray irradiation treatment. The obtained 3D animations clearly show that a considerable amount of s-HfO2 and l-HfO2 NPs diffused into tumor tissues at 2 h post-injection and displayed the obvious increase in the tumor penetration and distribution area within the tumors at day 7 after combination with low-dose X-ray irradiation treatment. A thresholding segmentation for 3D SR-µCT image was developed to assess the penetration depth and quantity of HfO2 NPs along the injection sites in tumors. The developed 3D-imaging techniques revealed that the s-HfO2 NPs presented more homogeneous distribution pattern, diffused more quickly and penetrated more deeply within tumor tissues than the l-HfO2 NPs did. Whereas, the low-dose X-ray irradiation treatment greatly enhanced the wide distribution and deep penetration of both s-HfO2 and l-HfO2 NPs. This developed method may provide quantitative distribution and penetration information for the X-ray sensitive high-Z metal nanodrugs in the cancer imaging and therapy.

Designing and validating a robust adaptive neuromodulation algorithm for closed-loop control of brain states.

Objective. Neuromodulation systems that use closed-loop brain stimulation to control brain states can provide new therapies for brain disorders. To date, closed-loop brain stimulation has largely used linear time-invariant controllers. However, nonlinear time-varying brain network dynamics and external disturbances can appear during real-time stimulation, collectively leading to real-time model uncertainty. Real-time model uncertainty can degrade the performance or even cause instability of time-invariant controllers. Three problems need to be resolved to enable accurate and stable control under model uncertainty. First, an adaptive controller is needed to track the model uncertainty. Second, the adaptive controller additionally needs to be robust to noise and disturbances. Third, theoretical analyses of stability and robustness are needed as prerequisites for stable operation of the controller in practical applications.Approach. We develop a robust adaptive neuromodulation algorithm that solves the above three problems. First, we develop a state-space brain network model that explicitly includes nonlinear terms of real-time model uncertainty and design an adaptive controller to track and cancel the model uncertainty. Second, to improve the robustness of the adaptive controller, we design two linear filters to increase steady-state control accuracy and reduce sensitivity to high-frequency noise and disturbances. Third, we conduct theoretical analyses to prove the stability of the neuromodulation algorithm and establish a trade-off between stability and robustness, which we further use to optimize the algorithm design. Finally, we validate the algorithm using comprehensive Monte Carlo simulations that span a broad range of model nonlinearity, uncertainty, and complexity.Main results. The robust adaptive neuromodulation algorithm accurately tracks various types of target brain state trajectories, enables stable and robust control, and significantly outperforms state-of-the-art neuromodulation algorithms.Significance. Our algorithm has implications for future designs of precise, stable, and robust closed-loop brain stimulation systems to treat brain disorders and facilitate brain functions.

A Robust and Adaptive Control Algorithm for Closed-Loop Brain Stimulation.

Developing closed-loop brain stimulation systems can benefit the treatment of neurological and neuropsychiatric disorders and facilitate brain functions. Current designs of closed-loop controllers have used time-invariant linear models of brain activity to devise non-adaptive controllers. However, unmodeled nonlinear dynamics can happen during real-time closed-loop control, leading to nonlinear uncertainty in the brain activity model. Current non-adaptive controllers cannot track the nonlinear model uncertainty and are not robust to noise, both of which can compromise their control performance. Here, within an ℒ1 adaptive control framework, we develop a new discrete-time robust and adaptive closed-loop control algorithm that addresses a general form of nonlinear model uncertainty. We conduct Monte Carlo simulations to validate the robust and adaptive control algorithm and show that it significantly outperforms existing closed-loop control algorithms. Our results can facilitate future designs of precise and safe closed-loop brain stimulation systems to treat neurological and neuropsychiatric disorders and modulate brain functions.

The Effect of COVID-19 on Herding Behavior in Eastern European Stock Markets.

Unlike past health crises that were more localized, the highly contagious coronavirus disease 2019 (COVID-19) crisis is impacting the world to an unprecedented extent. This is the first study examining how and whether the COVID-19 pandemic affects herding behavior in the Eastern European stock markets. Using samples from the stock markets of Russia, Poland, the Czech Republic, Hungary, Croatia, and Slovenia from January 1, 2010 to March 10, 2021, we demonstrate that the COVID-19 pandemic has increased herding behavior in all the sample stock markets. Our results show that the COVID-19 crisis reinforces the impact of global market returns on herding behavior in these specific stock markets. We find that COVID-19 strengthens the spillover effect of regional herding on herding behavior. Thus, financial authorities should monitor investors in the stock market to avoid the increase in herding behavior as well as the reinforcement of the global market returns and regional return dispersion on herding during the period of pandemic.

LDL-cholesterol change and goal attainment following statin intensity titration among Asians in primary care: a retrospective cohort study.

BACKGROUND: Clinical trials have demonstrated that either initiating or up-titrating a statin dose substantially reduce Low-Density Lipoprotein-Cholesterol (LDL-C) levels. However, statin adherence in actual practice tends to be suboptimal, leading to diminished effectiveness. This study aims to use real-world data to determine the effect on LDL-C levels and LDL-C goal attainment rates, when selected statins are titrated in Asian patients. METHODS: A retrospective cohort study over a 5-year period, from April 2014 to March 2019 was conducted on a cohort of multi-ethnic adult Asian patients with clinical diagnosis of Dyslipidaemia in a primary care clinic in Singapore. The statins were classified into low-intensity (LI), moderate-intensity (MI) and high-intensity (HI) groups according to the 2018 American College of Cardiology and American Heart Association (ACC/AHA) Blood Cholesterol Guidelines. Patients were grouped into "No statin", "Non-titrators" and "Titrators" cohorts based on prescribing patterns. For the "Titrators" cohort, the mean percentage change in LDL-C and absolute change in LDL-C goal attainment rates were computed for each permutation of statin intensity titration. RESULTS: Among the cohort of 11,499 patients, with a total of 266,762 visits, there were 1962 pairs of LDL-C values associated with a statin titration. Initiation of LI, MI and HI statin resulted in a lowering of LDL-C by 21.6% (95%CI = 18.9-24.3%), 28.9% (95%CI = 25.0-32.7%) and 25.2% (95%CI = 12.8-37.7%) respectively. These were comparatively lower than results from clinical trials (30 to 63%). The change of LDL-C levels due to up-titration, down-titration, and discontinuation were - 12.4% to - 28.9%, + 13.2% to + 24.6%, and + 18.1% to + 32.1% respectively. The improvement in LDL-C goal attainment ranged from 26.5% to 47.1% when statin intensity was up-titrated. CONCLUSION: In this study based on real-world data of Asian patients in primary care, it was shown that although statin titration substantially affected LDL-C levels and LDL-C goal attainment rates, the magnitude was lower than results reported from clinical trials. These results should be taken into consideration and provide further insight to clinicians when making statin adjustment recommendations in order to achieve LDL-C targets in clinical practice, particularly for Asian populations.

Real-world cost-effectiveness associated with infliximab maintenance therapy for moderate to severe Crohn's disease in China.

BACKGROUND: Infliximab was the first approved biologic treatment for moderate to severe Crohn's disease (MS-CD) in China. However, the cost-effectiveness of infliximab maintenance therapy (IMT) for MS-CD relative to conventional maintenance therapy remained unclarified. AIM: To assess the cost-effectiveness of IMT for MS-CD in Chinese patients from the perspective of Chinese public insurance payer. METHODS: A cohort of MS-CD patients managed in a Chinese tertiary care hospital was created to compare IMT with conventional maintenance therapy (CMT) for clinical outcomes and direct medical costs over a 1-year observation time using conventional regression analyses. A decision-analytic model with the generated evidence was constructed to assess the cost-effectiveness of IMT relative to CMT using reimbursed medical costs. RESULTS: Based on the included 389 patients, IMT was associated with significantly higher disease remission chance [odds ratio: 4.060, P = 0.003], lower risk of developing new complications (odds ratio: 0.527, P = 0.010), higher utility value for quality of life (coefficient 0.822, P = 0.008), and lower total hospital costs related to disease management (coefficient -0.378, P = 0.008) than CMT. Base-case cost-effectiveness analysis estimated that IMT could cost Chinese health insurance payers ¥55260 to gain one quality-adjusted life year (QALY). The cost-effectiveness of IMT was mainly driven by the estimate of quality of life, treatment efficacy of maintenance therapy, mortality risk associated with active disease, and unit price of infliximab. The probability that IMT was cost-effective at a willingness-to-pay threshold of three times gross domestic product [2018 Chinese gross domestic product per capita (GDPPC)] was 86.4%. CONCLUSION: IMT significantly improved real-world health outcomes and cost the Chinese public health insurance payers less than one GDPPC to gain one QALY in Chinese MS-CD patients.

Cost-Effectiveness of Reimbursing Infliximab for Moderate to Severe Crohn's Disease in China.

OBJECTIVES: To assess the cost-effectiveness of reimbursing infliximab for moderate-to-severe Crohn's disease (MS-CD) in China from the perspective of public insurance payers. METHODS: A decision-analytic model with a lifetime time horizon was constructed to simulate the disease progression and direct medical costs in Chinese MS-CD patients under two scenarios: reimbursing infliximab vs. not reimbursing infliximab. A cross-sectional study and literature review were conducted to estimate model variables. The constructed decision-analytic model ran the base case, one-way sensitivity, and probabilistic sensitivity analyses (PSA) to assess the cost-effectiveness of reimbursing infliximab using reimbursed medical costs. RESULTS: Base case analysis discounting health benefits and costs estimated that reimbursing infliximab could increase overall survival by 0.604 years, increase total quality-adjusted life years (QALY) by 0.697 QALY, reduce absolute lifetime surgery risk by 13.1%, and increase reimbursed costs by ¥29,409. The incremental cost-effectiveness ratio per gained additional QALY (ICER) based on discounted health benefits and reimbursed medical costs (3% per year) was ¥42,198. The one-way sensitivity analyses identified that the cost-effectiveness of reimbursing infliximab for MS-CD was mainly driven by the treatment efficacies of maintenance therapy, quality of life, and unit price of infliximab. PSA estimated that reimbursing infliximab was associated with a 63.8% chance to be cost-effective under the willingness-to-pay of the 2018 Chinese gross domestic product per capita (GDPPC). CONCLUSION: Reimbursing infliximab for MS-CD in Chinese patients was highly attractive, costing Chinese public insurance payers less than the 2018 Chinese GDPPC to gain 1 QALY.

Toxicological assessment of multi-walled carbon nanotubes combined with nonylphenol in male mice.

Carbon nanotubes have attracted increasing attention attributable to their widespread application. To evaluate the joint toxicity of multi-walled carbon nanotubes (MWCNTs) and nonylphenol (NP), we investigated the toxicological effects of NP, pristine MWCNTs, and MWCNTs combined with NP in male mice. After exposing male mice by gavage for 5 days, intracellular superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, as well as malondialdehyde (MDA) and glutathione (GSH) levels in tissues were determined to evaluate in vivo oxidative stress. In addition, genotoxicity was assessed by examining DNA damage in mouse liver and sperm via the comet assay, and transmission electron microscopy (TEM) was used for direct visual observations of mitochondrial damage in the liver. Results from the oxidative damage and DNA damage experiments indicate that after adsorbing NP, MWCNTs at a high dose induce oxidative lesions in the liver and cause DNA damage in mouse sperm; these data offer new insights regarding the toxicological assessment of MWCNTs.

Assessment of aflatoxin B1 myocardial toxicity in rats: mitochondrial damage and cellular apoptosis in cardiomyocytes induced by aflatoxin B1.

Objective The number of deaths from heart disease is increasing worldwide. Aflatoxin B1 (AFB1), a toxin produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is frequently detected in improperly processed/stored human food products. While AFB1 hepatotoxicity and carcinogenic properties have been well addressed, its myocardial toxicity is poorly documented. This study aimed to investigate myocardial toxic activity of AFB1. Methods Ten rats were fed with AFB1 at a dose that did not result in acute toxic reactions for 30 days and 10 vehicle-fed rats served as controls. Transmission electron microscopy was used to assess mitochondrial damage in cardiomyocytes. The terminal deoxynucleotidyl transferase-mediated UTP nick-end labelling assay was performed to detect apoptosis of cardiomyocytes. Western blotting was performed to measure apoptotic proteins (i.e., active caspase-3, Bax, and Bcl-2) in heart tissue. Results AFB1 treatment resulted in mitochondrial membrane disruption and disorganization of cristae, which are indicators of mitochondrial damage. Myocardial cell apoptosis was significantly higher after AFB1 treatment (22.07% ± 3.29%) compared with controls (6.27% ± 2.78%, P < 0.05). AFB1 treatment enhanced expression of active caspase-3, Bax, and Bcl-2 in cardiac tissue. Conclusion Various adverse effects are exerted by AFB1 on the heart, indicating AFB1 myocardial toxicity.

[Comprehensive assessment on control measures of Ambrosia artemisiifolia L].

Three control measures of Ambrosia artemisiifolia, including biological control, chemical control, and CK without any treatment, were evaluated by analytic hierarchy process (AHP). Corresponding contributions of the three control measures to comprehensive profit (CP) and comprehensive cost (CC) were calculated and ranked, which were regarded as the assessment criteria of the control measures. The results showed that among the three control measures, biological control had the highest CP and the lowest CC, CK was in adverse; and chemical control was in intervenient. Biological control had the highest ratio of profit to cost, and suggesting that this control measure is an optimal and recommendable measure in controlling A. artemisiifolia.

[Screening, identification, and antagonism assessment, of dominant bacteria in Ageratina adenophora Sprengel rhizosphere soil].

By using isolation and culture method, 25 strains of dominant bacteria in Ageratina adenophora rhizosphere soil were isolated and identified, of which, 8 strains were assessed for their antagonistic activity. The results showed that Bacillus and Pseudomonas were highly abundant in A. adenophora rhizosphere soil, of which, B. subtilis and B. megaterium were most abundant and occupied 55.6% of the total identified bacteria. These dominant bacteria had different level antagonistic activity to Fusarium oxysporum and Ralstonia solanacearum, and B. subtilis BS-5 and B. thuringiensis BT-1 had the strongest antagonistic effect on F. oxysporum, with the antagonistic activity of their metabolic products being 85.5% and 83.8%, respectively. The metabolic products of the dominant antagonistic bacteria had even more stronger antagonistic effect on pathogens than the dominant antagonistic bacteria themselves. The existence of abundant bacterial groups with strong antagonistic activity in A. adenophora rhizosphere soil could help A. adenophora to resist harmful soil-borne diseases and escape its natural enemies. Through the feedback actions of the beneficial rhizosphere microbes, A. adenophora probably earned its competition superiority directly or indirectly, being favorable to its rapid expansion.