Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT04288102). METHODS: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). FINDINGS: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. INTERPRETATION: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. FUNDING: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).

Response of organic aerosol characteristics to emission reduction in Yangtze River Delta region.

Organic aerosol (OA) is a major component of atmospheric particulate matter (PM) with complex composition and formation processes influenced by various factors. Emission reduction can alter both precursors and oxidants which further affects secondary OA formation. Here we provide an observational analysis of secondary OA (SOA) variation properties in Yangtze River Delta (YRD) of eastern China in response to large scale of emission reduction during Chinese New Year (CNY) holidays from 2015 to 2020, and the COVID-19 pandemic period from January to March, 2020. We found a 17% increase of SOA proportion during the COVID lockdown. The relative enrichment of SOA is also found during multi-year CNY holidays with dramatic reduction of anthropogenic emissions. Two types of oxygenated OA (OOA) influenced by mixed emissions and SOA formation were found to be the dominant components during the lockdown in YRD region. Our results highlight that these emission-reduction-induced changes in organic aerosol need to be considered in the future to optimize air pollution control measures. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s11783-023-1714-0 and is accessible for authorized users.

Transformation of chronic disease management: Before and after the COVID-19 outbreak.

Adults with chronic diseases often experience a decline in their quality of life along with frequent exacerbations. These diseases can cause anxiety and impose a significant economic burden. Self-management is a crucial aspect of treatment outside of the hospital and can improve quality of life and reduce the financial burden resulting from unexpected hospitalizations. With the COVID-19 pandemic, telehealth has become a vital tool for both medical professionals and patients; many in-person appointments have been canceled due to the pandemic, leading to increased reliance on online resources. This article aimed to discuss various methods of chronic disease management, both traditional self-management and modern telehealth strategies, comparing before and after the COVID-19 outbreak and highlighting challenges that have emerged.

An inactivated recombinant rabies virus chimerically expressed RBD induces humoral and cellular immunity against SARS-CoV-2 and RABV.

Many studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various animals and transmit among animals, and even to humans, posing a threat to humans and animals. There is an urgent need to develop inexpensive and efficient animal vaccines to prevent and control coronavirus disease 2019 (COVID-19) in animals. Rabies virus (RABV) is another important zoonotic pathogen that infects almost all warm-blooded animals and poses a great public health threat. The present study constructed two recombinant chimeric viruses expressing the S1 and RBD proteins of the SARS-CoV-2 Wuhan01 strain based on a reverse genetic system of the RABV SRV9 strain and evaluated their immunogenicity in mice, cats and dogs. The results showed that both inactivated recombinant viruses induced durable neutralizing antibodies against SARS-CoV-2 and RABV and a strong cellular immune response in mice. Notably, inactivated SRV-nCoV-RBD induced earlier antibody production than SRV-nCoV-S1, which was maintained at high levels for longer periods. Inactivated SRV-nCoV-RBD induced neutralizing antibodies against both SARS-CoV-2 and RABV in cats and dogs, with a relatively broad-spectrum cross-neutralization capability against the SARS-CoV-2 pseudoviruses including Alpha, Beta, Gamma, Delta, and Omicron, showing potential to be used as a safe bivalent vaccine candidate against COVID-19 and rabies in animals.

The effects of lipoic acid on respiratory diseases

Respiratory diseases, including lung cancer, pulmonary fibrosis, asthma, and the recently emerging fatal coronavirus disease-19 (COVID-19), are the leading causes of illness and death worldwide. The increasing incidence and mortality rates have attracted much attention to the prevention and treatment of these conditions. Lipoic acid (LA), a naturally occurring organosulfur compound, is not only essential for mitochondrial aerobic metabolism but also shows therapeutic potential via certain pharmacological effects (e.g., antioxidative and anti-inflammatory effects). In recent years, accumulating evidence (animal experiments and in vitro studies) has suggested a role of LA in ameliorating many respiratory diseases (e.g., lung cancer, fibrosis, asthma, acute lung injury and smoking-induced lung injury). Therefore, this review will provide an overview of the present investigational evidence on the therapeutic effect of LA against respiratory diseases in vitro and in vivo. We also summarize the corresponding mechanisms of action to inspire further basic studies and clinical trials to confirm the health benefits of LA in the context of respiratory diseases.

Rapid and Visual Detection of SARS-CoV-2 RNA Based on Reverse Transcription-Recombinase Polymerase Amplification with Closed Vertical Flow Visualization Strip Assay.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially identified in 2019, after which it spread rapidly throughout the world. With the progression of the epidemic, new variants of SARS-CoV-2 with faster transmission speeds and higher infectivity have constantly emerged. The proportions of people asymptomatically infected or reinfected after vaccination have increased correspondingly, making the prevention and control of COVID-19 extremely difficult. There is therefore an urgent need for rapid, convenient, and inexpensive detection methods. In this paper, we established a nucleic acid visualization assay targeting the SARS-CoV-2 nucleoprotein (N) gene by combining reverse transcription-recombinase polymerase amplification with closed vertical flow visualization strip (RT-RPA-VF). This method had high sensitivity, comparable to that of reverse transcription-quantitative PCR (RT-qPCR), and the concordance between RT-RPA-VF and RT-qPCR methods was 100%. This detection method is highly specific and is not compatible with bat coronavirus HKU4, human coronaviruses 229E, OC43, and HKU1-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), or other respiratory pathogens. However, multiple SARS-CoV-2 variants are detectable within 25 min at 42°C using this visual method, including RNA transcripts of the Wuhan-Hu-1 strain at levels as low as 1 copy/µL, the Delta strain at 1 copy/µL, and the Omicron strain at 0.77 copies/µL. The RT-RPA-VF method is a simple operation for the rapid diagnosis of COVID-19 that is safe and free from aerosol contamination and could be an affordable and attractive choice for governments seeking to promote their emergency preparedness and better their responses to the continuing COVID-19 epidemic. In addition, this method also has great potential for early monitoring and warning of the epidemic situation at on-site-nursing points. IMPORTANCE The global COVID-19 epidemic, ongoing since the initial outbreak in 2019, has caused panic and huge economic losses worldwide. Due to the continuous emergence of new variants, COVID-19 has been responsible for a higher proportion of asymptomatic patients than the previously identified SARS and MERS, which makes early diagnosis and prevention more difficult. In this manuscript, we describe a rapid, sensitive, and specific detection tool, RT-RPA-VF. This tool provides a new alternative for the detection of SARS-CoV-2 variants in a range as low as 1 to 0.77 copies/µL RNA transcripts. RT-RPA-VF has great potential to ease the pressure of medical diagnosis and the accurate identification of patients with suspected COVID-19 at point-of-care.

Treat the "Untreatable" by a Photothermal Agent: Triggering Heat and Immunological Responses for Rabies Virus Inactivation.

Rabies is a fatal neurological zoonotic disease caused by the rabies virus (RABV), and the approved post-exposure prophylaxis (PEP) procedure remains unavailable in areas with inadequate medical systems. Although strategies have been proposed for PEP and postinfection treatment (PIT), because of the complexity of the treatment procedures and the limited curative outcome, developing an effective treatment strategy remains a holy grail in rabies research. Herein, a facile approach is proposed involving photothermal therapy (PTT) and photothermally triggered immunological effects to realize effective PEP and PIT simultaneously. The designed photothermal agent (N+ TT-mCB nanoparticles) featured positively charged functional groups and high photo-to-heat efficiency, which are favorable for virus targeting and inactivation. The level of the virus at the site of infection in mice is significantly decreased upon treatment with orthotopic PTT, and the transfer of the virus to the brain is significantly inhibited. Furthermore, the survival ratio of the mice three days postinfection is increased by intracranial injection of N+ TT-mCB and laser irradiation. Overall, this work provides a platform for the effective treatment of RABV and opens a new avenue for future antiviral studies.

Thymosin alpha1 use in adult COVID-19 patients: A systematic review and meta-analysis on clinical outcomes.

OBJECTIVE: Thymosin alpha1 (Ta1) is widely used to treat patients with coronavirus disease 2019 (COVID-19), however, its effect remains unclear. This systematic review and meta-analysis aimed to evaluate the effect of Ta1 as a COVID-19 therapy. METHODS: PubMed, EMBASE, the Cochrane library, Web of Science, and the reference lists of relevant articles were searched to identify eligible studies. Assessment of heterogeneity was done using the I-squared (I2) test and random/fixed effect analysis was done to determine the risk ratio (RR). We polled the data related to mortality mainly by using Review Manager 5.4. Predefined subgroup analyses and sensitivity analyses were also performed. RESULTS: A total of 9 studies were included, on a total of 5352 (Ta1 = 1152, control = 4200) patient outcomes. Meta-analysis results indicated that Ta1 therapy had no statistically significant effect on mortality [RR 1.03 (0.60, 1.75), p = 0.92, I2 = 90 %]. Subgroup analyses demonstrated that the beneficial effect in mortality was associated with mean age＞60 years in the Tα1 group [RR 0.68 (0.58, 0.78), p < 0.0000.1, I2 = 0 %], the proportion of female ≤ 40 % in the Tα1 group [RR 0.67 (0.58, 0.77), p < 0.0000.1, I2 = 0 %], and severe/critical COVID-19 patients [RR 0.66 (0.57, 0.76), p < 0.0000.1, I2 = 0 %]. Sensitivity analysis further demonstrated the results to be robust. CONCLUSIONS: The results of this meta-analysis do not support the use of Ta1 in hospitalized adult COVID-19 patients.

Bioinformatics-based SARS-CoV-2 epitopes design and the impact of spike protein mutants on epitope humoral immunities.

BACKGROUND: Epitope selection is the key to peptide vaccines development. Bioinformatics tools can efficiently improve the screening of antigenic epitopes and help to choose the right ones. OBJECTIVE: To predict, synthesize and testify peptide epitopes at spike protein, assess the effect of mutations on epitope humoral immunity, thus provide clues for the design and development of epitope peptide vaccines against SARS-CoV-2. METHODS: Bioinformatics servers and immunological tools were used to identify the helper T lymphocyte, cytotoxic T lymphocyte, and linear B lymphocyte epitopes on the S protein of SARS-CoV-2. Physicochemical properties of candidate epitopes were analyzed using IEDB, VaxiJen, and AllerTOP online software. Three candidate epitopes were synthesized and their antigenic responses were evaluated by binding antibody detection. RESULTS: A total of 20 antigenic, non-toxic and non-allergenic candidate epitopes were identified from 1502 epitopes, including 6 helper T-cell epitopes, 13 cytotoxic T-cell epitopes, and 1 linear B cell epitope. After immunization with antigen containing candidate epitopes S206-221, S403-425, and S1157-1170 in rabbits, the binding titers of serum antibody to the corresponding peptide, S protein, receptor-binding domain protein were (415044, 2582, 209.3), (852819, 45238, 457767) and (357897, 10528, 13.79), respectively. The binding titers to Omicron S protein were 642, 12,878 and 7750, respectively, showing that N211L, DEL212 and K417N mutations cause the reduction of the antibody binding activity. CONCLUSIONS: Bioinformatic methods are effective in peptide epitopes design. Certain mutations of the Omicron would lead to the loss of antibody affinity to Omicron S protein.

Self-cleaning wearable masks for respiratory infectious pathogen inactivation by type I and type II AIE photosensitizer.

Although face masks as personal protective equipment (PPE) are recommended to control respiratory diseases with the on-going COVID-19 pandemic, improper handling and disinfection increase the risk of cross-contamination and compromise the effectiveness of PPE. Here, we prepared a self-cleaning mask based on a highly efficient aggregation-induced emission photosensitizer (TTCP-PF6) that can destroy pathogens by generating Type I and Type II reactive oxygen species (ROS). The respiratory pathogens, including influenza A virus H1N1 strain and Streptococcus pneumoniae (S. pneumoniae) can be inactivated within 10 min of ultra-low power (20 W/m2) white light or simulated sunlight irradiation. This TTCP-PF6-based self-cleaning strategy can also be used against other airborne pathogens, providing a strategy for dealing with different microbes.

Effect of COVID-19 lockdown on the characterization and mixing state of carbonaceous particles in the urban atmosphere of Liaocheng, the North China Plain

To investigate the effect of COVID-19 control measures on aerosol chemistry, the chemical compositions, mixing states, and formation mechanisms of carbonaceous particles in the urban atmosphere of Liaocheng in the North China Plain (NCP) were compared before and during the pandemic using a single particle aerosol mass spectrometry (SPAMS). The results showed that the concentrations of five air pollutants including PM2.5, PM10, SO2, NO2, and CO decreased by 41.2%–71.5% during the pandemic compared to those before the pandemic, whereas O3 increased by 1.3 times during the pandemic because of the depressed titration of O3 and more favorable meteorological conditions. The count and percentage contribution of carbonaceous particles in the total detected particles were lower during the pandemic than those before the pandemic. The carbonaceous particles were dominated by elemental and organic carbon (ECOC, 35.9%), followed by elemental carbon-aged (EC-aged, 19.6%) and organic carbon-fresh (OC-fresh, 13.5%) before the pandemic, while EC-aged (25.3%), ECOC (17.9%), and secondary ions-rich (SEC, 17.8%) became the predominant species during the pandemic. The carbonaceous particle sizes during the pandemic showed a broader distribution than that before the pandemic, due to the condensation and coagulation of carbonaceous particles in the aging processes. The relative aerosol acidity (Rra) was smaller before the pandemic than that during the pandemic, indicating the more acidic particle aerosol during the pandemic closely related to the secondary species and relative humidity (RH). More than 95.0% and 86.0% of carbonaceous particles in the whole period were internally mixed with nitrate and sulfate, implying that most of the carbonaceous particles were associated with secondary oxidation during their formation processes. The diurnal variations of oxalate particles and correlation analyses suggested that oxalate particles before the pandemic were derived from aqueous oxidation driven by RH and liquid water content (LWC), while oxalate particles during the pandemic were originated from O3-dominated photochemical oxidation.

Bioinformatics-based SARS-CoV-2 epitopes design and the impact of Spike protein mutants on epitope humoral immunities

Graphical Background Epitope selection is the key to peptide vaccines development. Bioinformatics tools can efficiently improve the screening of antigenic epitopes and help to choose the right ones. Objective To predict, synthesize and testify peptide epitopes at spike protein, assess the effect of mutations on epitope humoral immunity, thus provide clues for the design and development of epitope peptide vaccines against SARS-CoV-2. Methods Bioinformatics servers and immunological tools were used to identify the helper T lymphocyte, cytotoxic T lymphocyte, and linear B lymphocyte epitopes on the S protein of SARS-CoV-2. Physicochemical properties of candidate epitopes were analyzed using IEDB, VaxiJen, and AllerTOP online software. Three candidate epitopes were synthesized and their antigenic responses were evaluated by binding antibody detection. Results A total of 20 antigenic, non-toxic and non-allergenic candidate epitopes were identified from 1502 epitopes, including 6 helper T-cell epitopes, 13 cytotoxic T-cell epitopes, and 1 linear B cell epitope. After immunization with antigen containing candidate epitopes S206-221, S403-425, and S1157-1170 in rabbits, the binding titers of serum antibody to the corresponding peptide, S protein, receptor-binding domain protein were (415044, 2582, 209.3), (852819, 45238, 457767) and (357897, 10528, 13.79), respectively. The binding titers to Omicron S protein were 642, 12878 and 7750, respectively, showing that N211L, DEL212 and K417N mutations cause the reduction of the antibody binding activity. Conclusions Bioinformatic methods are effective in peptide epitopes design. Certain mutations of the Omicron would lead to the loss of antibody affinity to Omicron S protein.

A Visual Assay of a Loop-Mediated Isothermal Amplification Based Vertical Immunoassay for SARS-CoV-2 RNA Detection.

SARS-CoV-2 is a novel coronavirus that has caused a global pandemic. To date, 504,907,616 people have been infected and developed coronavirus disease 2019 (COVID-19). A rapid and simple diagnostic method is needed to control this pandemic. In this study, a visual nucleic acid detection method combining reverse transcription loop-mediated isothermal amplification and a vertical flow visualization strip (RT-LAMP-VF) was successfully established and could detect 20 copies/µl of SARS-CoV-2 RNA transcript within 50 min at 61°C. This assay had no cross-reactivity with a variety of coronaviruses, including human coronavirus OC43, 229E, HKU1, NL63, severe acute respiratory syndrome-related coronavirus (SARSr-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and bat coronavirus HKU4, exhibiting very high levels of diagnostic sensitivity and specificity. Most strikingly, this method can be used for detecting multiple SARS-CoV-2 variants, including the Wuhan-Hu-1 strain, Delta, and Omicron variants. Compared with the RT-qPCR method recommended by the World Health Organization (WHO), RT-LAMP-VF does not require special equipment and is easy to perform. As a result, it is more suitable for rapid screening of suspected SARS-CoV-2 samples in the field and local laboratories.

Timeliness of health science popularization in local media of Shanghai during the outbreak of Coronavirus disease 2019

Objective: To analyze the timeliness of health science popularization during the outbreak of coronavirus disease 2019 (COVID-19) and its correlation with the epidemic situation and policies.

The Impact of Social Entrepreneurship, Corporate Social Responsibilities, and Working Capital Management Practices on the Performance of Tourism Small-Medium Enterprises (SMEs) During COVID-19: Moderating Role of Employee Behavior.

The failure or success of an enterprise depends upon its working capital management practices (WCMP) along with effective corporate social responsibilities (CSR) and social entrepreneurship (SE). These factors ensure not only the soundness of financial indicators but also the profitability of an enterprise. Therefore, the objective of this study was to determine the impact of CSR, SE, and WCMP on the performance of small-medium enterprises (SMEs) of tourism sector, during the lockdown period in Malaysia. The goals also include the investigation of moderating role of employee behavior (EB) among the nexus of CSR, SE, WCMP, and performance of SMEs. The survey was performed to find out the practices adopted by the SMEs during corona days. A quantitative research method has been adopted to get data with convenient sampling technique, and PLS-SEM has been exploited to find out the significant nexus among CSR, SE, WCMP, and the performance of SMEs. The results indicate that CSR, SE, and WCMP have a positive association with the performance of SMEs in Malaysia. The results also indicate that EB positively moderates among the nexus of CSR, SE, WCMP, and the performance of SMEs in Malaysia. Stock review strategies by the SMEs during the corona days also exhibit significant differences except for no stock review. Significant differences between the enterprises show a lack of adaptation of the financial indicators that determine enterprise soundness. The study not only provides guidelines for entrepreneurs of SMEs but also helps in maintaining standards for the evaluation of the enterprises.

Cold chain and severe acute respiratory syndrome coronavirus 2 transmission: a review for challenges and coping strategies.

Since June 2020, the re-emergence of coronavirus disease 2019 (COVID-19) epidemics in parts of China was linked to the cold chain, which attracted extensive attention and heated discussions from the public. According to the typical characteristics of these epidemics, we speculated a possible route of transmission from cold chain to human. A series of factors in the supply chain contributed to the epidemics if the cold chain were contaminated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as temperature, humidity, personal hygiene/protection, and disinfection. The workers who worked in the cold chain at the receiving end faced a higher risk of being infected when they were not well protected. Facing the difficult situation, China put forward targeted and powerful countermeasures to block the cold chain-related risk. However, in the context of the unstable pandemic situation globally, the risk of the cold chain needs to be recognized and evaluated seriously. Hence, in this review, we reviewed the cold chain-related epidemics in China, analyzed the possible mechanisms, introduced the Chinese experience, and suggested coping strategies for the global epidemic prevention and control.

The Impact of Social Entrepreneurship, Corporate Social Responsibilities, and Working Capital Management Practices on the Performance of Tourism Small–Medium Enterprises (SMEs) During COVID-19: Moderating Role of Employee Behavior

The failure or success of an enterprise depends upon its working capital management practices (WCMP) along with effective corporate social responsibilities (CSR) and social entrepreneurship (SE). These factors ensure not only the soundness of financial indicators but also the profitability of an enterprise. Therefore, the objective of this study was to determine the impact of CSR, SE, and WCMP on the performance of small–medium enterprises (SMEs) of tourism sector, during the lockdown period in Malaysia. The goals also include the investigation of moderating role of employee behavior (EB) among the nexus of CSR, SE, WCMP, and performance of SMEs. The survey was performed to find out the practices adopted by the SMEs during corona days. A quantitative research method has been adopted to get data with convenient sampling technique, and PLS-SEM has been exploited to find out the significant nexus among CSR, SE, WCMP, and the performance of SMEs. The results indicate that CSR, SE, and WCMP have a positive association with the performance of SMEs in Malaysia. The results also indicate that EB positively moderates among the nexus of CSR, SE, WCMP, and the performance of SMEs in Malaysia. Stock review strategies by the SMEs during the corona days also exhibit significant differences except for no stock review. Significant differences between the enterprises show a lack of adaptation of the financial indicators that determine enterprise soundness. The study not only provides guidelines for entrepreneurs of SMEs but also helps in maintaining standards for the evaluation of the enterprises.

Clinical features of 51 patients with corona virus disease 2019

Objective: To investigate the clinical characteristics of corona virus disease 2019 (COVID-19) patients in Wuhan City, and the correlation between inflammatory factors and severity.

An overview of COVID-19 aerosol box for preventing droplet and aerosol contaminations in healthcare providers performing airway intubation.

The COVID-19 is caused by the SARS-CoV-2, which is extremely infectious. Numerous virologist suggestions and guidelines advised using P2/N95 masks, gloves, goggles, face-shields, and frocks or gowns as routine specific protective tools during airway management to protect healthcare personnel from infection (PPE). However, numerous imitation research has indicated that conventional PPE cannot adequately protect healthcare personnel. Since then, numerous firms and healthcare professionals have created their personal reformed devices 'aerosol containment devices' (ACD). Their usage has expanded throughout the world without being properly evaluated for usefulness, efficacy, or safety. The practice of 'ACD' has been shown to make tracheal intubation (TI) more problematic in several simulated tests. Furthermore, the device should limit the transmission of droplets from a patient; however, it might put healthcare personnel at danger of being exposed to greater levels of viral aerosols. Consequently, the existing state of information suggests that 'ACD' deprived of a vacuum mechanism can simply protect healthcare personnel against viral transmission to a limited extent. We search various databases for the literature with keywords 'COVID-19,' 'aerosol box,' 'aerosol contaminations,' and 'droplet contaminations.' The current review focused on the aerosol box from various perspectives, including their mechanism, optimum time of use, the spread of aerosol control, current gaps, and future perspective for bridging those gaps.