New clinical application prospects of artemisinin and its derivatives: a scoping review.

BACKGROUND: Recent research has suggested that artemisinin and its derivatives may have therapeutic effects on parasites, viruses, tumors, inflammation and skin diseases. This study aimed to review clinical research on artemisinin and its derivatives except anti-malaria and explore possible priority areas for future development. METHODS: Relevant articles in English and Chinese published before 28 October 2021 were reviewed. All articles were retrieved and obtained from databases including WanFang, PubMed/MEDLINE, the Cochrane Library, China National Knowledge International, Embase, OpenGrey, the Grey Literature Report, Grey Horizon, and ClinicalTrials.gov. Studies were selected for final inclusion based on predefined criteria. Information was then extracted and analyzed by region, disease, outcome, and time to identify relevant knowledge gaps. RESULTS: Seventy-seven studies on anti-parasitic (35), anti-tumor (16), anti-inflammatory (12), anti-viral (8), and dermatological treatments (7) focused on the safety and efficacy of artemisinin and its derivatives. The anti-parasitic clinical research developed rapidly, with a large number of trials, rapid clinical progress, and multiple research topics. In contrast, anti-viral research was limited and mainly stayed in phase I clinical trials (37.50%). Most of the studies were conducted in Asia (60%), followed by Africa (27%), Europe (8%), and the Americas (5%). Anti-parasite and anti-inflammatory research were mainly distributed in less developed continents such as Asia and Africa, while cutting-edge research such as anti-tumor has attracted more attention in Europe and the United States. At the safety level, 58 articles mentioned the adverse reactions of artemisinin and its derivatives, with only one study showing a Grade 3 adverse event, while the other studies did not show any related adverse reactions or required discontinuation. Most studies have discovered therapeutic effects of artemisinin or its derivatives on anti-parasitic (27), anti-tumor (9), anti-inflammatory (9) and dermatological treatment (6). However, the efficacy of artemisinin-based combination therapies (ACTs) for parasitic diseases (non-malaria) is still controversial. CONCLUSIONS: Recent clinical studies suggest that artemisinin and its derivatives may be safe and effective candidates for anti-tumor, anti-parasitic, anti-inflammatory and dermatological drugs. More phase II/III clinical trials of artemisinin and its derivatives on antiviral effects are needed.

CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR+/-) mice, whereas the DCM was alleviated in DICAR-overexpressed DICARTg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.

Time trends in tuberculosis mortality across the BRICS: an age-period-cohort analysis for the GBD 2019.

Background: Tuberculosis is the leading cause of death from a single infectious agent among the HIV-negative population and ranks first among the HIV-positive population. However, few studies have assessed tuberculosis trends in Brazil, Russia, India, China and South Africa (BRICS) or with an emphasis on HIV status. This study assesses the time trends of tuberculosis mortality across the BRICS with an emphasis on HIV status from 1990 to 2019. Methods: We obtained tuberculosis data from the Global Burden of Disease 2019 study (GBD 2019). We calculated the relative proportion of tuberculosis to all communicable, maternal, neonatal, and nutritional diseases by HIV status across the BRICS. We used age-period-cohort modelling to estimate cohort and period effects in tuberculosis from 1990 to 2019, and calculated net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks. Findings: There were 549,522 tuberculosis deaths across the BRICS in 2019, accounting for 39.3% of global deaths. Among HIV-negative populations, the age-standardised mortality rate (ASMR) of tuberculosis in BRICS remained far higher than that of high-income Asia Pacific countries, especially in India (36.1 per 100 000 in 2019, 95% UI [30.7, 42.6]) and South Africa (40.1 per 100 000 in 2019, 95% UI [36.8, 43.7]). China had the fastest ASMR reduction across the BRICS, while India maintained the largest tuberculosis death numbers with an annual decrease much slower than China's (-4.1 vs -8.0%). Among HIV-positive populations, the ASMR in BRICS surged from 0.24 per 100 000 in 1990 to 5.63 per 100 000 in 2005, and then dropped quickly to 1.70 per 100 000 in 2019. Brazil was the first country to reverse the upward trend of HIV/AIDS-tuberculosis (HIV-TB) mortality in 1995, and achieved the most significant reduction (-3.32% per year). The HIV-TB mortality in South Africa has realised much progress since 2006, but still has the heaviest HIV-TB burden across the BRICS (ASMR: 70.0 per 100 000 in 2019). We also found unfavourable trends among HIV-negative middle-aged (35-55) adults of India, men over 50 in the HIV-negative population and whole HIV-positive population of South Africa, and women aged 45-55 years of Russia. China had little progress in its HIV-positive population with worsening period risks from 2010 to 2019, and higher risks in the younger cohorts born after 1980. Interpretation: BRICS' actions on controlling tuberculosis achieved positive results, but the overall improvements were less than those in high-income Asia Pacific countries. BRICS and other high-burden countries should strengthen specified public health approaches and policies targeted at different priority groups in each country. Funding: National Natural Science Foundation of China (82073573; 72074009), Peking University Global Health and Infectious Diseases Group.

Effectiveness of influenza vaccination on in-hospital death and recurrent hospitalization in older adults with cardiovascular diseases.

OBJECTIVES: There is limited evidence on the effectiveness of influenza vaccination on hospitalization outcomes by cardiovascular disease (CVD) subtypes or comorbidities. METHODS: This study involved 713,488 records of hospitalization of adults ≥60 years with CVD from the Beijing Urban Employee Basic Medical Insurance database. Logistic regression with generalized estimating equations was conducted to estimate the effectiveness of influenza vaccination on in-hospital death and recurrent hospitalization, adjusting for unmeasured confounders. RESULTS: The coverage of influenza vaccination was only 13.3% among older adults hospitalized for CVD. Influenza vaccination was associated with 15% (odds ratios 0.85 [0.74, 0.99]) lower risk of in-hospital death among patients with CVD, with stronger associations in patients with stroke. Influenza vaccination was associated with 6% (0.94 [0.88, 0.99]) and 28% (0.72 [0.56, 0.93]) lower risks of recurrent hospitalization for ischemic heart disease (IHD) and respiratory disease in patients with IHD, but there were no clear associations in patients with stroke. For in-hospital death, the protective association of influenza vaccination was stronger in patients with fewer comorbidities and was similar to that of joint vaccinations of influenza and pneumococcal vaccinations. CONCLUSION: The protective association of influenza vaccination on CVD hospitalization outcomes serves as the evidence base to increase the uptake of influenza vaccination among older adults in China.

Research and development of traditional medicines in low- and middle-income countries: A case study of artemisinin discovery in China.

Though traditional medicines have been developed through practice for thousands of years, limited research has discussed the research and development (R&D) pattern of traditional medicines. China's discovery of artemisinin accumulated valuable experiences to explore traditional medicine under low-resource settings. With limited R&D resources, China mobilized all domestic research units at different levels and departments to develop artemisinin collaboratively. The discovery of artemisinin not only based on valuable experiential wisdom of traditional medicine, but also relied on excellent synergy among all units. In this study, we reviewed the story of how artemisinin was discovered in China, summarized key factors for new drug development from traditional medicines under limited resources, and raised suggestions to utilize traditional medicines in low- and middle-income countries. This case suggested that the vitality of traditional medicine could be extended by promoting new drug development based on modern methods and collaboration.

Barriers and facilitators to uptake and promotion of influenza vaccination among health care workers in the community in Beijing, China: A qualitative study.

BACKGROUND: In the prevention and control of influenza, it is important for healthcare workers (HCWs) to be vaccinated and recommend influenza vaccines to their patients. However, there is limited evidence on the factors influencing uptake and promotion of influenza vaccination to patients among HCWs in China. METHODS: We conducted in-depth interviews among HCWs in community health centers, including general practitioners (GPs) and preventive health workers (PHWs), during January to February 2017. A total of 21 individuals, purposively selected from six community health centers covering central districts and remote suburbs in Beijing, were interviewed using semi-structured topic guides. Thematic analysis was used to analyze the interviews and coding framework was developed both inductively and deductively. RESULTS: Identified factors influencing influenza vaccine uptake included knowledge, perception and recognition, and prior experience of vaccine uptake. All PHWs conservatively recommended influenza vaccine because of concerns about potential patient-doctor disputes. GPs rarely recommended vaccination under their own initiative because vaccine promotion was not their duties. Notably, we found that the division of work was an underlying reason for the different behaviors regarding vaccine uptake and promotion between GPs and PHWs. CONCLUSIONS: Our findings highlighted a combination of misconceptions and cognitive biases limiting influenza vaccine uptake among HCWs in China. Our findings indicate that promotion of health education regarding influenza vaccination should be implemented among HCWs. Importantly, the division of work greatly affects the behaviors of HCWs. GPs, who are at the front line in the doctor-patient relationship, have a critical role in influenza vaccination programs.

Drug research and development opportunities in low- and middle-income countries: accelerating traditional medicine through systematic utilization and comprehensive synergy.

BACKGROUND: Though the utilization of traditional medicine has been proposed for modern drug research and development (R&D), limited research has discussed its feasible paths. In this commentary, we summarized key factors for new drug R&D under limited resources by reviewing China's discovery of artemisinin, and raised suggestions to utilize traditional medicines in low- and middle-income countries (LMICs). MAIN TEXT: We suggested that systematic utilization of traditional medicine, outstanding synergy of research units at all levels and timely information-sharing mechanism should be achieved to establish a comprehensive and efficient R&D system, especially under low-resource settings. In the case of artemisinin discovery, Chinese scientists integrated documented traditional medicine experiences and modern approaches to develop drug candidates timely. Due to limited R&D resources, China adopted a collaborative way, motivating nearly all domestic research units at different levels, to develop antimalarial products. Moreover, the excellent synergy among all units through efficient information-sharing mechanisms greatly avoided work repetition and accelerated the R&D process. CONCLUSION: Traditional medicines inspires drug discoveries in LMICs, while a comprehensive and efficient R&D system could accelerate its R&D process and save investment. The discovery of artemisinin in China gave a reliable pattern to promote sustainable development of traditional medicines and a good example to realize R&D of traditional medicine under low-resource settings.

Cx22: A new publicly available dataset for deep learning-based segmentation of cervical cytology images.

The segmentation of cervical cytology images plays an important role in the automatic analysis of cervical cytology screening. Although deep learning-based segmentation methods are well-developed in other image segmentation areas, their application in the segmentation of cervical cytology images is still in the early stage. The most important reason for the slow progress is the lack of publicly available and high-quality datasets, and the study on the deep learning-based segmentation methods may be hampered by the present datasets which are either artificial or plagued by the issue of false-negative objects. In this paper, we develop a new dataset of cervical cytology images named Cx22, which consists of the completely annotated labels of the cellular instances based on the open-source images released by our institute previously. Firstly, we meticulously delineate the contours of 14,946 cellular instances in1320 images that are generated by our proposed ROI-based label cropping algorithm. Then, we propose the baseline methods for the deep learning-based semantic and instance segmentation tasks based on Cx22. Finally, through the experiments, we validate the task suitability of Cx22, and the results reveal the impact of false-negative objects on the performance of the baseline methods. Based on our work, Cx22 can provide a foundation for fellow researchers to develop high-performance deep learning-based methods for the segmentation of cervical cytology images. Other detailed information and step-by-step guidance on accessing the dataset are made available to fellow researchers at https://github.com/LGQ330/Cx22.

Comprehensive evaluation of water resources carrying capacity and analysis of obstacle factors in Weifang City based on hierarchical cluster analysis-VIKOR method.

This study uses hierarchical cluster analysis (HCA) to screen the evaluation indexes and establishes a comprehensive evaluation index system for water resources carrying capacity (WRCC), based on the VIKOR method and the obstacle degree model for the identification of the main factors affecting the WRCC of Weifang City. The results show that the WRCC of Weifang City has steadily increased from 2008 to 2018. The subsystems referred to society and water environment are currently the main obstacles affecting Weifang's WRCC, but there is still space for improvement in the future. The areas with low WRCC was Kuiwen District in 2018, which was in a seriously overloaded state, mostly affected by the water resources subsystem. The implementation of measures such as efficiently improving the level of water resources management and the development of water conservancy projects is prominent in water resource planning in Kuiwen District. This study analyzes the current situation of water resources management in order to consider it in strategic decision-making in promoting the improvement of WRCC, which in turn may ensure the realization of a green and sustainable development strategy in the future for Weifang City.

Knowledge, Attitudes, and Practices Related to COVID-19 Among Malawi Adults: A Community-Based Survey.

INTRODUCTION: It is well-recognized that containing COVID-19 successfully is determined by people's prevention measures which are related to their knowledge, attitudes, and practices (KAP). This perception has attracted attention in low- and middle-income countries (LMIC) due to their fragile health systems and economies. The objective of this study was to understand how residents in Malawi perceived COVID-19, to determine the factors related to KAP. METHODS: A semi-structured questionnaire was used for the data collection. A field-based survey was conducted among adult residents in Lilongwe, Malawi. Descriptive statistic, linear regression, the Chi-square test, and Pearson's correlation statistics were used for data analysis. RESULTS: A total of 580 questionnaires were involved. The mean knowledge, attitude, and practice (KAP) scores were 10 (SD = ±3, range: 3-19), 16 (SD = ±4, range: 5-25), and 2 (SD = ±1, range: 0-5), respectively. Lack of money and resources (39%) was the biggest challenge for people who practice prevention measures. Among the participants, the radio (70%) and friends/family (56%) were the main sources of information. A higher economic status was associated with better KAP. CONCLUSIONS: A low level of KAP was detected among the population. The people faced challenges regarding a lack of necessary preventive resources and formal information channels. The situation was worse considering vulnerable population who had low economic status. Further all-round health education is urgently needed along with providing adequate health supplies and ensuring proper information management.

Association between 4-dimension lifestyle pattern and 10-year mortality risk in Chinese individuals older than 65: a population-based cohort study.

While the impact of a 4-dimension lifestyle pattern (4DL) on older people's mortality (aged ≥65 years) has been reported in high-income countries, few studies investigated the association between lifestyle pattern and disease-accompanied mortality, or examined the difference among different age or gender groups in low- and middle-income countries. We followed up 16,954 Chinese older participants from 2008 to 2018 and adopted the Cox proportional hazard model to evaluate the protective effect of 4DL. After adjustment for confounders, individuals with 3-4 4DL scores had a 38% reduction in all-cause mortality risk, and up to 36%, 42% and 41% reduced risk of mortality accompanied by hypertension, respiratory disease and dementia, respectively in contrast with those scored 0. Compared with octogenarians, nonagenarians, and centenarians, adhering to 3-4 4DL could further reduce the mortality risks in the younger elderly (aged 65-79 years). This study shows that among the elderly population in China, participants who adhered to 4DL had a lower all-cause mortality risk than those who did not. Additionally, hypertension, respiratory disease, or dementia accompanied mortality risk was also reduced significantly. The findings indicated that the positive effects of 4DL on longevity should be acknowledged in China's older population, especially for the younger elderly.

In silico-determined compound from the root of Pueraria lobate alleviates synaptic plasticity injury induced by Alzheimer's disease via the p38MAPK-CREB signaling pathway.

Pueraria lobata is utilized as a food source in China. The aim of this study is to combine virtual screening and molecular dynamics predictive model to screen out the potential synaptic plasticity-maintaining components from the root of P. lobate and to verify it by employing the amyloid ß-injected rats' model. Eighteen compounds were identified by HPLC-MS/MS; puerarin manifested the most potential to form a stable complex with calcium/calmodulin kinase IIα (CaMK IIα), which is the key protein in synaptic plasticity by the in silico study. The further in vivo assay showed that puerarin could elevate the synaptic thickness, density, and length, relieve calcium overload, regulate the expression of CaMK IIα, and other p38MAPK-CREB signaling pathway-related biochemical criteria. The behavioral test also verified the results. Results have confirmed that the root of P. lobate can work anti-AD by maintaining the synaptic plasticity and proved the reliability of using the in silico predictive model to determine active ingredients from the natural product.

The effect of miR-471-3p on macrophage polarization in the development of diabetic cardiomyopathy.

AIMS: The imbalance of M1/M2 macrophage ratio promotes the occurrence of diabetic cardiomyopathy (DCM), but the precise mechanisms are not fully understood. The aim of this study was to investigate whether miR-471-3p/silent information regulator 1 (SIRT1) pathway is involved in the macrophage polarization during the development of DCM. METHODS: Immunohistochemical staining was used to detect M1 and M2 macrophages infiltration in the heart tissue. Flow cytometry was used to detect the proportion of M1 and M2 macrophages. Expression of miR-471-3p was quantified by real time quantitative-PCR. Transfection of miRNA inhibitor into RAW264.7 cells was performed to investigate the underlying mechanisms. Bioinformatics methods and western blotting were used to explore the target gene of miR-471-3p and further confirmed by dual luciferase reporter assay. KEY FINDINGS: We observed that M1 macrophages infiltration in the heart of tissue in DCM while M2 type was decreased. M1/M2 ratio was increased significantly in bone marrow-derived macrophages (BMDMs) from db/db mice and in RAW264.7 cells treated with advanced glycation end products (AGEs). Meanwhile, miR-471-3p was significantly upregulated in RAW264.7 cells induced by AGEs and inhibition of miR-471-3p could reduce the inflammatory polarization of macrophages. Bioinformatics analysis identified SIRT1 as a target of miR-471-3p. Both dual luciferase reporter assay and western blotting verified that miR-471-3p negatively regulated SIRT1 expression. SIRT1 agonist resveratrol could downregulate the increased proportion of M1 macrophages induced by AGEs. CONCLUSION: Our results indicated that the development of DCM was related to AGEs-induced macrophage polarized to M1 type through a mechanism involving the miR-471-3p/SIRT1 pathway.

Public health preparedness and responses to the coronavirus disease 2019 (COVID-19) pandemic in South Asia: a situation and policy analysis.

Like rest of the world, the South Asian region is facing enormous challenges with the coronavirus disease 2019 (COVID-19) pandemic. The socioeconomic context of the eight South Asian countries is averse to any long-term lockdown program, but the region still observed stringent lockdown close to two months. This paper analyzed major measures in public health preparedness and responses in those countries in the pandemic. The research was based on a situation analysis to discuss appropriate plan for epidemic preparedness, strategies for prevention and control measures, and adequate response management mechanism. Based on the data from March 21 to June 26, 2020, it appeared lockdown program along with other control measures were not as effective to arrest the exponential growth of fortnightly COVID-19 cases in Afghanistan, Bangladesh, India, Nepal and Pakistan. However, Bhutan, Maldives and Sri Lanka have been successfully limiting the spread of the disease. The in-depth analysis of prevention and control measures espoused densely populated context of South Asia needs community-led intervention strategy, such as case containment, in order to reverse the growing trend, and adopt the policy of mitigation instead of suppression to formulate COVID-19 action plan. On the other hand, mechanism for response management encompassed a four-tier approach of governance to weave community-led local bodies with state, national and international governance actors for enhancing the countries' emergency operation system. It is concluded resource-crunch countries in South Asia are unable to cope with the disproportionate demand of capital and skilled health care workforce at the time of the pandemic. Hence, response management needs an approach of governance maximization instead of resource maximization. The epidemiologic management of population coupled with suitable public health prevention and control measures may be a more appropriate strategy to strike a balance between economy and population health during the time of pandemic.

miR-1247-3p mediates apoptosis of cerebral neurons by targeting caspase-2 in stroke.

Brain stroke is one of the leading causes of death worldwide. We explored a potential stroke-related role for a newly found microRNA, miR-1247-3p, and one of its target genes, caspase-2, predicted by TargetScanVert. In the present study, we found that miR-1247-3p was downregulated during ischemia/reperfusion (I/R) and that LV-miR-1247-3p overexpression attenuated brain impairment induced by I/R. Similar results were observed in neuro2a (N2a) cells treated with oxygen-glucose deprivation/reoxygenation (OGD/R). Caspase-2 was upregulated in the I/R and OGD/R model, while Z-VDVAD-FMK - the inhibitor of caspase-2-inhibited apoptosis of N2a cells induced by OGD/R. An miR-1247-3p mimic inhibited caspase-2 expression and attenuated apoptosis of N2a cells induced by OGD/R. Myocardin-related transcription factor-A (MRTF-A) overexpression upregulated miR-1247 and mature miR-1247-3p levels and attenuated apoptosis induced by OGD/R, whereas its anti-apoptotic function could be blocked by a miR-1247-3p inhibitor. Hence, we conclude that miR-1247-3p may protect cells during brain stroke. This study offers insights for the development of effective therapeutics for promoting the survival of cerebral neurons during brain I/R injury.

The in silico and in vivo evaluation of puerarin against Alzheimer's disease.

The root of Pueraria lobata has been utilized as a food source for thousands of years in China. Puerarin is the major bioactive and the most abundant secondary metabolite obtained from the root of P. lobata. The potential therapeutic effect of puerarin against Alzheimer's disease was screened by in silico methods and confirmed by the amyloid ß-peptide-induced Alzheimer's disease (AD) rat model. The in silico study displayed that puerarin had the potential to penetrate across the blood-brain barrier and had high stability in molecular docking and dynamics simulation with acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2) and caspase-3 (C3), which play a central role in the development of AD. The in vivo results showed that puerarin could restrain the AChE activity, restore the activities of antioxidant defense substances toward normal levels, and decrease the expression of inflammatory factors and apoptosis genes in the brain, especially down-regulating the expressions of COX-2 and C3. The histopathological examination of brain sections and behavioral testing also verified the biochemical observations, which further validates the in silico study. These results not only suggest that puerarin, as a potential compound, could relieve AD, but also broaden the applications of puerarin.