In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

OBJECTIVE: To explore application value and effectiveness of virtual reality technology combined with isokinetic muscle strength training in the rehabilitation of patients after anterior cruciate ligament (ACL) reconstruction surgery. METHODS: Forty patients who underwent ACL reconstruction surgery from December 2021 to January 2023 were selected and divided into control group and observation group according to treatment methods, 20 patients in each group. Control group was received routine rehabilitation training combined with isokinetic muscle strength training, including 15 males and 5 females, aged from 17 to 44 years old, with an average of (29.10±8.60) years old. Observation group was performed virtual reality technology combined with isokinetic muscle strength training, including 16 males and 4 females, aged from 17 to 45 years old with an average of (30.95±9.11) years old. Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque between two groups at 12 (before training) and 16 weeks (after training) after surgery were compared. RESULTS: All patients were followed up for 1 to 6 months with an average of (3.30±1.42) months. There were no statistically significant difference in Lysholm knee joint score, peak knee extension peak torque, and peak knee flexion peak torque between two groups (P>0.05) before training. After training, Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque of both groups were improved compared to before training (P<0.05);there were significant difference in Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque between two groups(P<0.05). CONCLUSION The application of virtual reality technology combined with isokinetic muscle strength training could promote recovery of knee joint function and enhance muscle strength in patients after ACL reconstruction surgery in further.
Male ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Anterior Cruciate Ligament Injuries/surgery* ; Resistance Training ; Knee Joint/surgery* ; Anterior Cruciate Ligament Reconstruction/methods* ; Knee Injuries/surgery* ; Muscle Strength/physiology*

OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).
Humans ; Male ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Hyperuricemia ; Kidney ; Proteinuria ; Renal Insufficiency, Chronic/complications*

Objective: To investigate the prevalence of dyslipidemia, and to explore the association between extracurricular physical activity and dyslipidemia among primary, middle and high school students in Guangzhou. Methods: This cross-sectional study selected primary and middle school students in Guangzhou by the stratified cluster sampling method from March to December 2019. Physical examination and blood lipid test were performed. Information about students' basic characteristics and extracurricular physical activity was collected by questionnaire. Multivariate logistic regression analysis was used to determine the association between extracurricular physical activity and dyslipidemia in this cohort. Results: A total of 7 797 participants (mean aged (12.2±2.9) years) were included (4 194 (53.79%) boys and 3 603 (46.21%) girls]. The detection rates of high total cholesterol, high triglycerides, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol and dyslipidemia were 12.49% (974/7 797), 6.44% (502/7 797), 6.62% (516/7 797), 11.31% (882/7 797) and 23.83% (1 858/7 797), respectively. Dyslipidemia rate was lower in the junior school students (21.39% (675/3 156)) than in primary school students (25.96% (896/3 451)) and high-school students (24.12% (287/1 190)) (P<0.001). The dyslipidemia rates of boys and girls were similar (23.15% (971/4 194) vs. 24.62% (887/3 603), P>0.05). Dyslipidemia rate was lower in students with extracurricular physical activity than in students without extracurricular physical activity (22.50% (923/4 102) vs. 25.30% (935/3 695), P<0.05). Multivariate logistic regression analysis showed that extracurricular physical activity was associated with lower risk of dyslipidemia (OR=0.88, 95%CI=0.79-0.99, P=0.033). Among all types of extracurricular physical activities, participating in extracurricular large ball game was associated with 28% lower risk among junior school students (OR=0.72, 95%CI=0.57-0.91, P=0.006). Conclusion: The prevalence of dyslipidemia is high among primary, middle and high school students in Guangzhou. Extracurricular physical activity is associated with reduced risk of dyslipidemia in this cohort.

BACKGROUND: Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs. METHODS: We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%. RESULTS: At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group. CONCLUSIONS: The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.
Adult ; Anti-HIV Agents/adverse effects* ; Antiretroviral Therapy, Highly Active ; China ; Drug Therapy, Combination ; HIV Infections/drug therapy* ; HIV-1 ; Humans ; Maleimides ; Peptides ; Ritonavir/therapeutic use* ; Treatment Outcome ; Viral Load

Objective To study neutral particle particle(NEUT-X)change in the solid tumor patients with chemotherapy by granulocyte colony-stimulating factor(G-CSF).Methods Chose that 52 cases of cancer chemotherapy with G-CSF(study group),32 cases of cancer chemotherapy patients without G-CSF(study control group)and 50 cases of healthy(healthy control group).The automatic hematology analyzer Sysmex XE-2100 were been examined the peripheral blood routine and collected the data which wes the morphological parameters of peripheral white blood cell.The changes of neutrophil N-X pa-rameters during chemotherapy were analyzed,and the clinical infection fever rates of three groups were collected to reveal the relationship between leukocyte morphological parameters and body resistance.Results In the study group,study control group and healthy control group,the NEUT-X was 1 324(890.2,1 358.0),1 440(1 397.3,1 466.3)and 1 329(1 295.1, 1 359.4),and the difference was statistically significant between the three groups(F=10.778,P=0.002).In study group, the count of WBC before and after G-CSF was 0.99(0.22,1.75)×109/L and 7.53(1.00,14.05)×109/L respitively and there was the significant difference(Z=-2.395,P=0.005).In study group patients the NEUT-X was 1 382(1 323.6,1 440.4)and 1 324(890.2,1 358.0)respectively and there was a significant difference(Z=-2.832,P=0.004).Between the study group and the study control group,there were 23/52 cases and 4/32 cases infection in patients with fever case(Z=9.14,P=0.002).Conclusion By G-CSF the leukocyte counts increased in patients with chemotherapy,and reduced neu-trophil NEUT-X parameters,and the infection rate was higher than the non G-CSF patients.The neutrophil granularity will be useful for evaluating of patients with chemotherapy for solid tumor immunity.

OBJECTIVETo investigate the effects of inhaled short-acting bronchodilators on diaphragm function and neural respiratory drive in patients with chronic obstructive pulmonary disease (COPD) during maximal isocapnic ventilation (MIV).

METHODSForty-seven patient with moderate to severe COPD were randomized into 4 groups: placebo group (n=12), salbutamol group (n=13), ipratropium group (n=10), and combined group (salbutamol and ipratropium, n=12). Each subject received an initial MIV for 3 min at baseline and inhaled placebo (400 µg), salbutamol (400 µg), ipratropium (80 µg), or both salbutamol and ipratropium, followed 30 min later by another 3 min of MIV. The parameters of diaphragm function and neural respiratory drive were monitored continuously and calculated during MIV.

RESULTSDuring the initial MIV, all the patients experienced a linear increase in root mean square (RMS) of diaphragm electromyogram with a gradual decrease in transdiaphragmatic pressure (Pdi), minute ventilation (VE), and VE/RMS, and these parameters all improved significantly after inhalation of the bronchodilators. Compared with the placebo group at the same time point, the 3 bronchodilator-treated groups showed significantly decreased RMS and Borg score and increased Pdi, VE and VE/RMS; VE/RMS was the highest in the combined treatment group (P<0.05). The Delta Borg was significantly correlated with Delta Pdi, Delta VE, Delta RMS, and Delta VE/RMS (P<0.05).

CONCLUSIONSIn COPD patients, inhaled short-acting bronchodilators can alleviate diaphragm fatigue during MIV, increase lung ventilation, reduce neural respiratory drive, and improve neuro-ventilatory coupling to relieve dyspnoea, and the combination of β-2 agonists and anti-muscarinic antagonists produces a stronger efficacy.

Administration, Inhalation ; Albuterol ; therapeutic use ; Bronchodilator Agents ; therapeutic use ; Diaphragm ; drug effects ; Humans ; Ipratropium ; therapeutic use ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; Respiration

AIM:Heart failure is characterized by immune activation leading to production and release of proinflammatory cytokines .Inter-leukin 17A (IL-17A) is a proinflammatory cytokine and multiple lines of evidence from animal and human studies suggest crucial roles of IL-17A in heart failure.Therefore, we investigated whether common polymorphisms of genes IL17A and IL17RA (coding interleukin 17 receptor A) gene contribute to genetic predisposition to heart failure and adverse clinical outcomes associated with it .METHODS AND RESULTS:A total of 1713 adults patients with congestive heart failure and 1713 age-and sex-matched controls were genotyped for promoter SNPs, rs2275913 and rs8193037 in IL17A and rs4819554 in IL17RA, to assess the relationship between individual SNPs and the risk of congestive heart failure .Results showed that rs8193037 in IL17A was associated with the risk of congestive heart failure (P<0.01) after adjustment for multiple cardiovascular risk factors including age , sex, smoking status, diabetes, hypertension and dyslipidemia.This association was evident in both ischemic and non-ischemic heart failure (P<0.05).Furthermore, prospective fol-low-up of 12.7 months for the occurrence of adverse clinical outcomes showed that rs 4819554 in IL17RA was significantly associated with cardiovascular mortality (P<0.05) after adjustments for multiple cardiovascular risk factors and New York Heart Association functional class.CONCLUSION:This study demonstrated associations of rs8193037 in the promoter of IL17A with the risk of conges-tive heart failure, and of rs4819554 in the promoter of IL17RA with the risk of cardiovascular mortality in patients with congestive heart failure.These data lend further support to the notion that immune activation and genetic polymorphisms contribute to heart failure path -ogenesis and progression .

AIM:Mitochondrial DNA (mtDNA) copy number variation (CNV), which reflects the oxidant-induced cell damage, has been observed in a wide range of human diseases .However, whether it correlates with heart failure , which is closely related to oxidative stress, has never been elucidated before .We aimed to systematically investigate the association between leukocyte mtDNA CNV and heart failure risk and prognosis .METHODS: A total of 1 700 hospitalized patients with heart failure and 1 700 age-and gender-matched community population were consecutively enrolled in this observational study , as well as 1 638 ( 96.4%) patients were fol-lowed prospectively for a median of 17 months (12~24 months).The relative mtDNA copy number in leukocyte of peripheral blood or cardiac tissue was measured in triplicate by quantitative real-time PCR method .RESULTS:Patients with heart failure possessed much lower relative mtDNA copy number compared with control subjects (P<0.01), especially for the patients with ischemic etiology (P<0.01).Patients with lower mtDNA copy number exhibited 1.7 times higher risk of heart failure ( P<0.01).Long-term follow-up (median 17 months) showed that decreased mtDNA copy number was significant associated with both increased cardiovascular deaths (P<0.01) and cardiovascular rehospitalization (P<0.01).After adjusted for the conventional risk factors and medications , lower mtDNA copy number were still significantly associated with 50% higher cardiovascular mortality (P <0.05).CONCLUSION:
mtDNA copy number depletion is an independent risk factor for heart failure and predicted higher risk of cardiovascular deaths in patients with heart failure .