MYBL2 regulates de novo purine synthesis by transcriptionally activating IMPDH1 in hepatocellular carcinoma cells.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer, alteration of nucleotide metabolism of hepatocellular carcinoma (HCC) is not well-understood. MYBL2 regulates cell cycle progression and hepatocarcinogenesis, its role in metabolic regulation remains elusive. PATIENTS AND METHODS: Copy number, mRNA and protein level of MYBL2 and IMPDH1 were analyzed in HCC, and correlated with patient survival. Chromatin Immunoprecipitation sequencing (Chip-seq) and Chromatin Immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) were used to explore the relationship between MYBL2 and IMPDH1. Metabolomics were used to analyze how MYBL2 affected purine metabolism. The regulating effect of MYBL2 in HCC was further validated in vivo using xenograft models. RESULTS: The Results showed that copy-number alterations of MYBL2 occur in about 10% of human HCC. Expression of MYBL2, IMPDH1, or combination of both were significantly upregulated and associated with poor prognosis in HCC. Correlation, ChIP-seq and ChIP-qPCR analysis revealed that MYBL2 activates transcription of IMPDH1, while knock-out of MYBL2 retarded IMPDH1 expression and inhibited proliferation of HCC cells. Metabolomic analysis post knocking-out of MYBL2 demonstrated that it was essential in de novo purine synthesis, especially guanine nucleotides. In vivo analysis using xenograft tumors also revealed MYBL2 regulated purine synthesis by regulating IMPDH1, and thus, influencing tumor progression. CONCLUSION: MYBL2 is a key regulator of purine synthesis and promotes HCC progression by transcriptionally activating IMPDH1, it could be a potential candidate for targeted therapy for HCC.

Impact of multiple cardiovascular medications on mortality after an incidence of ischemic stroke or transient ischemic attack.

BACKGROUND: To manage the risk factors and to improve clinical outcomes, patients with stroke commonly receive multiple cardiovascular medications. However, there is a lack of evidence on the optimum combination of medication therapy in the primary care setting after ischemic stroke. Therefore, this study aimed to investigate the effect of multiple cardiovascular medications on long-term survival after an incident stroke event (ischemic stroke or transient ischemic attack (TIA)). METHODS: This study consisted of 52,619 patients aged 45 and above with an incident stroke event between 2007 and 2016 in The Health Improvement Network database. We estimated the risk of all-cause mortality in patients with multiple cardiovascular medications versus monotherapy using a marginal structural model. RESULTS: During an average follow-up of 3.6 years, there were 9230 deaths (7635 in multiple cardiovascular medication groups and 1595 in the monotherapy group). Compared with patients prescribed monotherapy only, the HRs of mortality were 0.82 (95% CI 0.75-0.89) for two medications, 0.65 (0.59-0.70) for three medications, 0.61 (0.56-0.67) for four medications, 0.60 (0.54-0.66) for five medications and 0.66 (0.59-0.74) for ≥ six medications. Patients with any four classes of antiplatelet agents (APAs), lipid-regulating medications (LRMs), angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), beta-blockers, diuretics and calcium channel blockers (CCBs) had the lowest risk of mortality (HR 0.51, 95% CI 0.46-0.57) versus any one class. The combination containing APAs, LRMs, ACEIs/ARBs and CCBs was associated with a 61% (95% CI 53-68%) lower risk of mortality compared with APAs alone. CONCLUSION: Our results suggested that combination therapy of four or five cardiovascular medications may be optimal to improve long-term survival after incident ischemic stroke or TIA. APAs, LRMs, ACEIs/ARBs and CCBs were the optimal constituents of combination therapy in the present study.

Global trends in symptomatic medication use against dementia in 66 countries/regions from 2008 to 2018.

BACKGROUND AND PURPOSE: The aim was to determine trends and patterns of symptomatic medication used against dementia in 66 countries and regions. METHODS: This was a cross-sectional study that used the wholesale data from the IQVIA Multinational Integrated Data Analysis System database. Sale data for symptomatic medication against dementia from 66 countries and regions from 2008 to 2018 were analysed and stratified by income level (low/middle-income countries [LMICs], n = 27; high-income countries [HICs], n = 37; regions, n = 2). The medication use volume was estimated by defined daily dose (DDD) per 1000 inhabitants per day (World Health Organization DDD harmonized the size, strength and form of each pack and reflects average dosing). Changes in medication use over time were quantified as percentage changes in compound annual growth rates (CAGRs). RESULTS: Total symptomatic medication against dementia sales increased from 0.85 to 1.33 DDD per 1000 inhabitants per day between 2008 and 2018 (LMICs 0.094-0.396; HICs 3.88-5.04), which is an increase of CAGR of 4.53% per year. The increase was mainly driven by the LMICs (CAGR = 15.42%) in comparison to the HICs (CAGR = 2.65%). The overall medication use from 2008 to 2018 increased for all four agents: memantine (CAGR = 8.51%), rivastigmine (CAGR = 6.91%), donepezil (CAGR = 2.72%) and galantamine (CAGR = 0.695%). In 2018, the most commonly used medication globally was donepezil, contributing to 49.8% of total use volume, followed by memantine (32.7%), rivastigmine (11.24%) and galantamine (6.36%). CONCLUSION: There was an increasing trend in the use of symptomatic medications against dementia globally, but the use remained low in LMICs. Interventions may be needed to support the medication use in some countries.

Initial cardiovascular treatment patterns during the first 90 days following an incident cardiovascular event.

AIMS: The aim of this study was to investigate the initial cardiovascular prescription patterns in patients after their first cardiovascular events, and to identify factors associated with cardiovascular polypharmacy. METHODS: This was a cross-sectional study including patients aged ≥ 45 years with the first record of coronary heart disease (CHD) or stroke between 2007 and 2016 using The Health Improvement Network database. This study investigated the patterns of cardiovascular drugs prescribed during the first 90 days after the first cardiovascular events. Logistic regression was used to examine the association between patients' baseline characteristics and cardiovascular polypharmacy (≥5 cardiovascular drugs). RESULTS: A total of 121,600 (59,843 CHD and 61,757 stroke) patients were included in the study. The mean age was 69.5 ± 11.9 years. The proportion of patients who were prescribed 0-1, 2-3, 4-5 drugs and ≥6 drugs were 11.0%, 29.8%, 38.6% and 20.5%, respectively. Factors associated with cardiovascular polypharmacy were sex (female: OR 0.74, 95% CI 0.72-0.76 vs male), age (75-84 years old: OR 0.50, 0.47-0.53 vs 45-54 years old), smoking status (current smoking: OR 1.29, 1.15-1.24 vs never), body mass index (obesity: OR 1.38, 1.34-1.43 vs normal), deprivation status (most deprived: OR 1.09, 1.04-1.14 vs least deprived) and Charlson comorbidity index (index ≥5: OR 1.25, 1.16-1.35 vs index 0). CONCLUSION: Multiple cardiovascular drugs treatment was common in patients with CVD in the UK. High-risk factors of CVD were also associated with cardiovascular polypharmacy. Further studies are warranted to assess the impact of cardiovascular polypharmacy and its interaction on CVD recurrence and mortality.

Small nucleolar RNA of silkworm can translocate from the nucleolus to the cytoplasm under abiotic stress.

Small nucleolar RNAs (snoRNAs) are thought to be exclusively nuclear and guide nucleotide modifications of ribosomal RNAs. Recently, more and more evidence has suggested that the nucleolus is a stress sensor for changes in growth status and that snoRNAs may orchestrate the response to environmental stress through molecular interactions outside of the nucleus. We previously showed that a box C/D snoRNA Bm-15 had both nuclear and cytoplasmic location in BmN4 cell line of the silkworm, Bombyx mori. To further study the functional roles of Bm-15, changes in expression level and cellular location of Bm-15 were examined in BmN4 cells subjected to serum starvation and ultraviolet (UV) ray radiation. Results indicated that total RNA level of Bm-15 was unchanged after 24 h serum starvation, but exhibited 3-fold increases in the cytoplasm, and the nuclear-to-cytosolic distribution ratio was reduced from 5:1 to 2:1. Moreover, UV radiation also causes rapid decline in nuclear Bm-15 and progressive cytoplasmic accumulation with a percentage of 22% and 57% after 6 and 24 h UV radiation. UV treatment results in a dramatic decrease in Bm-15 nuclear-to-cytosolic ratio from 7:1 to 2:1 and 2:1 to 1:20 after 6 and 24 h UV radiation, respectively. We show here for the first time that box C/D snoRNAs can translocate from the nucleus to the cytoplasm under the abiotic stress of nutritional deficiency and UV radiation. The rapid translocation of snoRNAs from nucleus to cytoplasm may slow down the maturation of rRNAs and synthesis of ribosomes to enhance the stress resistance of cells.

The NAD kinase OsNADK1 affects the intracellular redox balance and enhances the tolerance of rice to drought.

BACKGROUND: NAD kinases (NADKs) are the only known enzymes that directly phosphorylate NAD(H) to generate NADP(H) in different subcellular compartments. They participate in multiple life activities, such as modulating the NADP/NAD ratio, maintaining the intracellular redox balance and responding to environmental stresses. However, the functions of individual NADK in plants are still under investigation. Here, a rice NADK, namely, OsNADK1, was identified, and its functions in plant growth regulation and stress tolerance were analysed by employing a series of transgenic plant lines. RESULTS: OsNADK1 is a cytosol-localized NADK in rice. It was expressed in all rice tissues examined, and its transcriptional expression could be stimulated by a number of environmental stress treatments. Compared with wild-type (WT) rice, the mutant plant osnadk1 in which OsNADK1 was knocked out was a dwarf at the heading stage and had decreased NADP(H)/NAD(H), ascorbic acid (ASA)/dehydroascorbate (DHA) and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios, which led to increased oxidation states in the rice cells and sensitivity to drought. Moreover, certain stress-related genes showed differential expression patterns in osnadk1 under both normal growth and drought-stress conditions compared with WT. Among these genes, OsDREB1B and several WRKY family transcription factors, e.g., OsWRKY21 and OsWRKY42, showed correlated co-expression patterns with OsNADK1 in osnadk1 and the plants overexpressing or underexpressing OsNADK1, implying roles for these transcription factors in OsNADK1-mediated processes. In addition, overexpression of OsNADK1 enhanced the drought tolerance of rice plants, whereas loss of function of the gene reduced the tolerance. Furthermore, the proline content was dramatically increased in the leaves of the OsNADK1-overexpressing lines under drought conditions. CONCLUSIONS: Altogether, the results suggest that an OsNADK1-mediated intracellular redox balance is involved in the tolerance of rice plants to drought.

Platelets release proinflammatory microparticles in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: The biological functions of the platelets contributing to ANCA-associated vasculitis (AAV) are largely unclear. The current study aimed to investigate the potential role of platelet-derived microparticles (PMPs) in AAV. METHODS: In the current study, microparticles in AAV patients were analysed by flow cytometry, and PMPs were probed for relative levels of 640 bioactive proteins secreted from patients' platelets using antibody microarrays. These data were then correlated with clinical and pathological parameters. RESULTS: PMPs were significantly increased in 69 AAV patients, predominantly MPO-ANCA positive patients in active stage compared with in remission [4406.8/µl (2135.4, 5485.0) vs 549.7/µl (350, 708.5), P < 0.0001], and 43% of microparticles in active AAV were PMPs. Compared with 15 patients in remission, highly expressed proinflammatory molecules in the microparticles from platelets in 15 AAV patients in active stage revealed that potential functions of PMPs were promotion of the effect of chemotaxis, adhesion, growth and apoptosis (all the patients for array analysis were MPO-ANCA positive). The level of PMPs had a significant association with disease activity, inflammation, and renal damage. CONCLUSION: PMPs may serve as inflammatory propagators through their wide production of proinflammatory cytokines in AAV, potentially providing a novel therapeutic target.

Engineering of molecularly imprinted cavity within 3D covalent organic frameworks: An innovation for enhanced extraction and removal of microcystins.

The scarcity of selective adsorbents for efficient extraction and removal of microcystins (MCs) from complex samples greatly limits the precise detection and effective control of MCs. Three-dimensional covalent organic frameworks (3D COFs), characterized by their large specific surface areas and highly ordered rigid structure, are promising candidates, but suffer from lack of specific recognition. Herein, we design to engineer molecularly imprinted cavities within 3D COFs via molecularly imprinted technology, creating a novel adsorbent with exceptional selectivity, kinetics and capacity for the efficient extraction and removal of MCs. As proof-of-concept, a new CC bond-containing 3D COF, designated JNU-7, is designed and prepared for copolymerization with methacrylic acid, the pseudo template L-arginine and ethylene dimethacrylate to yield the JNU-7 based molecularly imprinted polymer (JNU-7-MIP). The JNU-7-MIP exhibits a great adsorption capacity (156 mg g-1) for L-arginine. Subsequently, the JNU-7-MIP based solid-phase extraction coupled with high performance liquid chromatography-mass spectrometry achieves low detection limit of 0.008 ng mL-1, wide linear range of 0.025-100 ng mL-1, high enrichment factor of 186, rapid extraction of 10 min, and good recoveries of 92.4%-106.5% for MC-LR. Moreover, the JNU-7-MIP can rapidly remove the MC-LR from 1 mg L-1 to levels (0.26-0.35 µg L-1) lower than the WHO recommended limit for drinking water (1 µg L-1). This work reveals the considerable potential of 3D COF based MIPs as promising adsorbents for the extraction and removal of contaminants in complex real samples.

Photochromic radical states in 3D covalent organic frameworks with zyg topology for enhanced photocatalysis.

Covalent-organic frameworks (COFs) with photoinduced donor-acceptor (D-A) radical pairs show enhanced photocatalytic activity in principle. However, achieving long-lived charge separation in COFs proves challenging due to the rapid charge recombination. Here, we develop a novel strategy by combining [6 + 4] nodes to construct zyg-type 3D COFs, first reported in COF chemistry. This structure type exhibits a fused Olympic-rings-like shape, which provides a platform for stabilizing the photoinduced D-A radical pairs. The zyg-type COFs containing catalytically active moieties such as triphenylamine and phenothiazine (PTZ) show superior photocatalytic production rates of hydrogen peroxide (H2O2). Significantly, the photochromic radical states of these COFs show up to 400% enhancement in photocatalytic activity compared to the parent states, achieving a remarkable H2O2 synthesis rate of 3324 µmol g-1 h-1, which makes the PTZ-COF one of the best crystalline porous photocatalysts in H2O2 production. This work will shed light on the synthesis of efficient 3D COF photocatalysts built on topologies that can facilitate photogenerating D-A radical pairs for enhanced photocatalysis.

Effectiveness and Respiratory Adverse Events Following Inactivated and mRNA COVID-19 Vaccines in Patients with COPD and Asthma: A Chinese Population-Based Study.

INTRODUCTION: Effectiveness and respiratory adverse events following coronavirus disease-2019 (COVID-19) vaccines have not been well investigated in Chinese patients with chronic obstructive pulmonary disease (COPD) and asthma. METHODS: Using electronic health care records in Hong Kong, we included adults with COPD or asthma or both and hospitalised for severe respiratory exacerbation in a self-controlled case series (SCCS) study between 23/02/2021 and 30/11/2022. Conditional Poisson regression models were used to estimate the incidence of outcomes within exposure periods (28 days after each dose) compared with baseline periods. Cox proportional hazard models evaluated vaccine effectiveness (VE) against COVID-related mortality, hospitalisation, and severe complications, including admission to intensive care units or ventilatory support. The VE assessment was based on vaccine types and the number of doses. RESULTS: In the SCCS, 343 CoronaVac recipients and 212 BNT162b2 recipients were included. No increased risk of outcomes was observed within the exposure periods. In the cohort study, 108,423 and 83,323 patients received ≥ 2 doses of CoronaVac and BNT162b2, respectively. The VE (95% CI) against COVID-related mortality, hospitalisation, and severe complications after two-dose CoronaVac was 77% (74-80%), 18% (6-23%), and 29% (12-43%), respectively, while for the two-dose regimen of BNT162b2, it was 92% (91-94%), 33% (30-37%), and 57% (45-66%), respectively. Higher VE against COVID-related mortality, hospitalisation, and severe complications was found for the three-dose regimen of CoronaVac (94%, 40%, and 71%) and BNT162b2 (98%, 65%, and 83%). Administering a fourth dose of either vaccine showed additional reductions in COVID-related outcomes. CONCLUSIONS: Among people with COPD and asthma, the COVID-19 vaccines CoronaVac and BNT162b2 did not increase severe exacerbations and achieved moderate-to-high effectiveness against COVID-related outcomes. COVID-19 vaccination remains essential and should be encouraged to protect this vulnerable population in future epidemic waves.

Trifluoromethyl-Functionalized 2D Covalent Organic Framework for High-Resolution Separation of Isomers.

Development of novel functional materials for effective isomer separation is of great significance in environmental science, chemical industry, and life science due to the different functions of isomers. However, the similar physicochemical properties of isomers make their separation greatly challenging. Here, we report the fabrication of trifluoromethyl-functionalized 2D covalent organic framework (COF) TpTFMB with 2,2'-bis(trifluoromethyl)benzidine (TFMB) and 1,3,5-triformylphloroglucinol (Tp) for the separation of isomers. TpTFMB was in situ-grown on the inner surface of a capillary for the high-resolution separation of isomers. The introduction of hydroxyl and trifluoromethyl functional groups with uniform distribution in 2D COFs is a powerful tactic to endow TpTFMB with various functions such as hydrogen bonding, dipole interaction, and steric effect. The prepared TpTFMB capillary column enabled the baseline separation of positional isomers such as ethylbenzene and xylene, chlorotoluene, carbon chain isomers such as butylbenzene and ethyl butanoate, and cis-trans isomers 1,3-dichloropropene. The hydrogen-bonding, dipole, and π-π interactions as well as the structure of COF significantly contribute to the isomer separation. This work provides a new strategy for designing functional 2D COFs for the efficient separation of isomers.

Attention-deficit/hyperactivity disorder medication consumption in 64 countries and regions from 2015 to 2019: a longitudinal study.

Background: Timely recognition and appropriate treatment of attention-deficit/hyperactivity disorder (ADHD) are essential to enhance long-term outcomes of individuals with ADHD. This study aimed to evaluate the multinational trends and patterns of ADHD medication consumption. Methods: In this longitudinal trend study, we used pharmaceutical sales data of ADHD medication from the IQVIA-Multinational Integrated Data Analysis System between 2015 and 2019, covering 64 countries across the world. Consumption rates of ADHD medication were expressed as defined daily dose per 1000 child and adolescent inhabitants (aged 5-19) per day (DDD/TID). Linear mixed models were used to estimate the multinational, regional, and income level trend changes. Findings: The results showed that multinational ADHD medication consumption increased by +9.72% (95% confidence interval [CI], +6.25%, +13.31%) per year, from 1.19 DDD/TID in 2015 to 1.43 DDD/TID in 2019 across the 64 countries with marked differences between geographical locations. When stratified by countries' income levels, increases in ADHD medication consumption were observed in high-income countries but not in middle-income countries. In 2019, the pooled consumption rates of ADHD medication were 6.39 DDD/TID (95% CI, 4.63, 8.84) in high-income countries, 0.37 DDD/TID (95% CI, 0.23, 0.58) in upper-middle-income countries and 0.02 DDD/TID (95% CI, 0.01, 0.05) in lower-middle-income countries. Interpretation: Current ADHD prevalence estimates and rates of ADHD medication consumption in most middle-income countries are lower than the global epidemiological prevalence. It is therefore imperative to evaluate the potential barriers to diagnosis and treatment in these countries to minimise the risk of negative outcomes from undiagnosed and untreated ADHD. Funding: This project was funded by a grant from the Hong Kong Research Grants Council Collaborative Research Fund (project number C7009-19G).

Global trends in the consumption of benzodiazepines and Z-drugs in 67 countries and regions from 2008 to 2018: a sales data analysis.

STUDY OBJECTIVES: To investigate the trends in the consumption of benzodiazepines (BZDs) and Z-drugs at global, regional, and national levels from 2008 to 2018, across 67 countries and regions. METHODS: This cross-sectional descriptive study investigated the consumption of BZDs and Z-drugs analyzed by global pharmaceutical sales data from the IQVIA-Multinational Integrated Data Analysis System database between 2008 and 2018. Consumption was measured in defined daily dose (DDD) per 1000 inhabitants per day (DDD/TID). The global, regional, and national trends were estimated using linear mixed models. Additional analyses were conducted by grouping countries by income level. The association between consumption and Gross Domestic Product (GDP) and the prevalence of different medical conditions was explored in univariable linear models. RESULTS: BZD consumption decreased annually by -1.88% (95% CI: -2.27%, -1.48%), and Z-drugs increased by + 3.28% (+2.55%, +4.01%). In 2008, the top ten countries for BZD and Z-drug consumption were all European, ranging from 63.69 to 128.24 DDD/TID. Very low levels were found in Russia, Kuwait, United Arab Emirates, Saudi Arabia, French West Africa, and the Philippines, with DDD/TID < 1. The consumption in high-income countries was much higher than in middle-income countries. The results showed that increased consumption of BZDs and Z-drugs was statistically associated (p < 0.05) with higher GDP and increased prevalence of anxiety, self-harm, neurological disorders, chronic respiratory diseases, cardiovascular diseases, and cancers. CONCLUSIONS: Distinct differences in consumption and trends of BZDs and Z-drugs were found across different countries and regions. Further exploration is needed to understand the association and safety of the use of BZDs and Z-drugs in patients with comorbidities.

Post-modification of covalent organic framework for gas chromatographic separation of isomers.

Separation of isomers is important in diverse areas such as life science, chemical industry, pharmaceutical and environmental science, but still challenging due to their similar physicochemical properties. Development of new stationary phases is an effective way to improve the performance of chromatography for the separation of isomers. Here, we report the post-modification of a new hydroxyl-functionalized covalent organic framework (COF) TzDHNDA with [(1-phenylethyl)amino]acetic acid (PEAA) via esterification reaction to construct PEAA functionalized COF (TzDHNDA-PEAA). The prepared TzDHNDA-PEAA was stable up to 380 °C and used as stationary phase to make TzDHNDA-PEAA coated capillary column for gas chromatographic separation of isomers. The TzDHNDA-PEAA coated capillary column showed a high column efficiency for n-dodecane (12417 plates m-1, 120 °C) and high resolution separation of the isomers of fluoroaniline (Rm-/o-=3.2, Rp-/m-=2.4), chloroaniline (Rm-/o-=5.7, Rp-/m-=1.8), nitrotoluene (Rp-/o-=2.2, Rm-/p-=1.7), pinene (Rß-/α-=2.4), ionone (Rß-/α-=4.8) and 1,3-dichloropropene (RE-/Z-=2.0). The fabricated column offered better separation of chloroaniline isomers than commercial capillary columns InertCap WAX, InertCap 1701 and InertCap 5. The introduced benzene ring, secondary amine and carbonyl groups of PEAA into the COF TzDHNDA significantly improved the resolution of isomers due to the enhanced hydrogen-bonding and π-π interactions. This work shows that post-modification strategy is an effective way to prepare novel COFs for chromatographic separation of isomers.

[Mechanism of acupuncture and moxibustion in ameliorating liver injury induced by DDP by regulating apoptosis factors Caspase-3, Caspase-8 and Caspase-9].

OBJECTIVE: To investigate the mechanism of the effect of acupuncture and moxibustion on improving liver injury by observing the changes of cysteine protease (Caspase) associated with hepatocyte apoptosis based on cisplatin (DDP) induced liver injury model mice. METHODS: Forty KM mice were randomly divided into control group, model group, acupuncture group and moxibustion group, with 10 mice in each group. The liver injury model was replicated by intraperitoneal injection of DDP. In the acupuncture group and the moxibustion group, acupuncture and moxibustion were performed at"Dazhui"(GV14), and bilateral "Ganshu"(BL18), "Shenshu"(BL23), and "Zusanli"(ST36), respectively, once per day for 5 d. General condition of mice in each group were observed;The activities of AST, ALT and GLDH in mice serum were detected by biochemical method. ELISA and Western blot assay were used to detect Caspase-3, Caspase-8 and Caspase-9 contents and protein expression in the liver tissues of each group of mice, respectively. RESULTS: Compared with the control group, the general condition of the mice in the model group was poorer, and the Caspase-3, Caspase-8 and Caspase-9 contents and protein expressions in liver tissues and the activities of AST, ALT and GLDH in serum were increased (P<0.05). Compared with the model group, the general condition of the mice in the acupuncture and moxibustion groups improved, and the Caspase-3, Caspase-8 and Caspase-9 contents and protein expressions in liver tissues and activities of AST, ALT and GLDH in serum were decreased (P<0.05). CONCLUSION: Acupuncture and moxibustion can reduce liver injury due to DDP chemotherapy by modulating the expression of apoptotic factors Caspase-3, Caspase-8 and Caspase-9 in liver tissues of DDP model mice and improving liver function, which may be one of the mechanisms of the effect of acupuncture and moxibustion to ameliorates liver injury after DDP chemotherapy.

Antipsychotic Medication and Risk of Incident Seizure in People with Autism Spectrum Disorder: Analyses with Cohort and Within Individual Study Designs.

There are many case reports of seizures apparently associated with the prescription of antipsychotics. This study aimed to examine whether there is an association between the prescription of antipsychotics and incident seizures in individuals with autism spectrum disorder using retrospective data based on patients' chart review. A cohort study was conducted to compare the rate of incident seizure between 3923 users of antipsychotics with 10,086 users of other psychotropics. This was followed by a self-controlled case series (SCCS) analysis of 149 patients to eliminate the effect of time-invariant confounders. The results showed no evidence of increased risk of seizure after exposure to antipsychotic agents (Hazard Ratio 1.28, 95% CI 0.74-2.19) compared to other psychotropics.

Global, regional, and national trends in opioid analgesic consumption from 2015 to 2019: a longitudinal study.

BACKGROUND: Previous studies have reported an extremely unbalanced global access to opioid analgesics. We aimed to determine contemporary trends and patterns of opioid analgesic consumption at the global, regional, and national levels. METHODS: We analysed the global pharmaceutical sales data of 66 countries or regions from the IQVIA-Multinational Integrated Data Analysis System database on opioid analgesics between 2015 and 2019. Opioid analgesic consumption was measured in milligram morphine equivalent per 1000 inhabitants per day (MME per 1000/day). The global, regional, and national trend changes were estimated using linear regressions. Factors associated with consumption patterns and trend changes were explored in multivariable linear regression analyses. FINDINGS: Overall opioid analgesic sales in the 66 countries or regions increased from 27·52 MME per 1000/day (16·63-45·54) in 2015 to 29·51 MME per 1000/day (17·85-48·79) in 2019 (difference per year 3·96%, 95% CI 0·26 to 7·80). Sales reduced yearly in North America (-12·84%; 95% CI -15·34 to -10·27) and Oceania (-2·96%; -4·20 to -1·70); increased in South America (28·69%; 7·18 to 54·53), eastern Europe (7·68%; 3·99 to 11·49), Asia (5·74%; 0·61 to 11·14), and western and central Europe (1·64%; 0·52 to 2·78); and did not differ in Africa or central America and the Caribbean. The global opioid consumption patterns were associated with country-level Human Development Index (p=0·040), cancer death rate excluding leukaemia (p=0·0072), and geographical location (p<0·0001). In 2019, opioid analgesic consumption ranged from 0·01 MME per 1000/day to 5·40 MME per 1000/day in the 17 countries and regions in the lowest consumption quartile, despite high income levels and cancer death rates in some of them. INTERPRETATION: Global opioid analgesic consumption increased from 2015 to 2019. The trend changes were distinctive across regions, which could reflect the different actions in response to known issues of opioid use and misuse. Disparities in opioid analgesic consumption remained, indicating potential inadequate access to essential pain relief in countries with low consumption. FUNDING: None.

Trends in lipid-modifying agent use in 83 countries.

BACKGROUND AND AIMS: Lipid-modifying agents (LMAs) are increasingly used to reduce lipid levels and prevent cardiovascular events but the magnitude of their consumption in different world regions is unknown. We aimed to describe recent global trends in LMA consumption and to explore the relationship between country-level LMA consumption and cholesterol concentrations. METHODS: This cross-sectional and ecological study used monthly pharmaceutical sales data from January 2008 to December 2018 for 83 countries from the IQVIA Multinational Integrated Data Analysis System and total and non-high-density lipoprotein (non-HDL) cholesterol concentrations from the NCD Risk Factor Collaboration. Compound annual growth rate (CAGR) was used to assess changes in LMA consumption over time. RESULTS: From 2008 to 2018, use of LMAs increased from 7468 to 11,197 standard units per 1000 inhabitants per year (CAGR 4.13%). An estimated 173 million people used LMAs in 2018. Statins were the most used class of LMA and their market share increased in 75% of countries between 2008 and 2018. From 2013 to 2018, consumption of low-density lipoprotein lowering therapies increased (statins 3.99%; ezetimibe 4.01%; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors 104.47%). Limited evidence supports a clear relationship between country-level changes in LMA consumption and mean total and non-HDL cholesterol concentrations in 2008 versus 2018. CONCLUSIONS: Since 2008, global access to LMAs, especially statins, has improved. In line with international lipid guideline recommendations, recent trends indicate growth in the use of statins, ezetimibe, and PCSK9 inhibitors. Country-level patterns of LMA use and total and non-HDL cholesterol varied considerably.