Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Personalized starting age of gastric cancer screening based on individuals' risk profiles: a population-based prospective study.

BACKGROUND: The current recommended starting age for gastric cancer (GC) lacks unified guideline and individualized criteria. We aimed to determine risk-stratified starting age for GC screening in China based on individuals' risk profiles, and develop an online calculator for clinical application. METHODS: In this multi-center population-based prospective study, we divided participants enrolled during 2015-2017 (n = 59,771, aged 40-69) into screened and unscreened groups and observed them for primary endpoints-GC occurrence, all-cause and GC-specific deaths. The median follow-up was 6.07 years. To determine the reference starting age, the effectiveness of GC screening was assessed by age-groups after propensity-score-matching. Further, we categorized the calculated individual risk scores (using well-established risk factors) by quantiles. Subsequently, we used age-specific 10-year cumulative risk curves to estimate the risk-stratified starting age-when the individual's risk level matches reference starting age risk threshold. RESULTS: During follow-up, 475 GC cases, 182 GC deaths and 1,860 all-cause deaths occurred. All-cause and GC-specific mortality decreased among screened individuals aged ≥45 and 50-59 years, respectively. Thus, the average population (reference) starting age was set as 50 years. The 10-year cumulative risk of GC in average population aged 50 was 1.147%. We stratified the starting age using eight risk factors, and categorized participants as low-, medium-, and high-risk individuals, whose risk-stratified starting age was 58, 50, and 46, respectively. CONCLUSION: While high-risk individuals warrant 3-5 years earlier GC screening than average population (age 50), low-risk individuals can tolerate delayed screening. Our online, personalized starting-age calculator will help risk-adapted GC screening (https://web.consultech.com.cn/gastric/#/).

Semaglutide for the prevention of atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is reported to have cardiac benefits, but its effects on preventing atrial fibrillation (AF) remain inconclusive. This study aimed to investigate whether semaglutide can prevent AF occurrence in patients with type 2 diabetes mellitus (T2DM), obesity, or overweight. METHODS: We searched MEDLINE, EMBASE, the Cochrane CENTRAL database, and clinicaltrials.gov from inception to December 29, 2023. Randomized controlled trials of semaglutide in patients with T2DM, obesity, or overweight were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95 % confidence intervals (CIs) were calculated for the overall population and subgroups. RESULTS: Twenty-one trials comprising 25957 patients were included. In the overall pooled analysis, semaglutide decreased AF occurrence compared to control drugs (RR 0.70, 95 % CI 0.52-0.95). This result was consistent in trials using other antihyperglycemic medications as controls (RR 0.43, 95 % CI 0.21-0.89), but not in placebo-controlled trials (RR 0.77, 95 % CI 0.56-1.07). The outcome was favorable for patients with T2DM (RR 0.71, 95 % CI 0.52-0.97), but not for patients with overweight or obesity (RR 0.56, 95 % CI 0.18-1.73). Results varied by type of semaglutide, with oral semaglutide showing an RR of 0.49 (95 % CI 0.25-0.97) and subcutaneous semaglutide showing an RR of 0.77 (95 % CI 0.55-1.07). CONCLUSION: Semaglutide was associated with a reduced risk of AF occurrence in the overall analysis. Favorable outcomes were observed in subsets using other antihyperglycemic medications as controls, in patients with T2DM, and with oral semaglutide.

Association between coronary artery stenosis and myocardial injury in patients with acute pulmonary embolism: A case-control study.

BACKGROUND: The potential impact of pre-existing coronary artery stenosis (CAS) on acute pulmonary embolism (PE) episodes remains underexplored. This study aimed to investigate the association between pre-existing CAS and the elevation of high-sensitivity cardiac troponin I (hs-cTnI) levels in patients with PE. METHODS: In this multicenter, prospective case-control study, 88 cases and 163 controls matched for age, sex, and study center were enrolled. Cases were patients with PE with elevated hs-cTnI. Controls were patients with PE with normal hs-cTnI. Coronary artery assessment utilized coronary computed tomographic angiography or invasive coronary angiography. CAS was defined as ≥50% stenosis of the lumen diameter in any coronary vessel >2.0 mm in diameter. Conditional logistic regression was used to evaluate the association between CAS and hs-cTnI elevation. RESULTS: The percentage of CAS was higher in the case group compared to the control group (44.3% [39/88] vs. 30.1% [49/163]; P = 0.024). In multivariable conditional logistic regression model 1, CAS (adjusted odds ratio [OR], 2.680; 95% confidence interval [CI], 1.243-5.779), heart rate >75 beats/min (OR, 2.306; 95% CI, 1.056-5.036) and N-terminal pro-B type natriuretic peptide (NT-proBNP) >420 pg/mL (OR, 12.169; 95% CI, 4.792-30.900) were independently associated with elevated hs-cTnI. In model 2, right CAS (OR, 3.615; 95% CI, 1.467-8.909) and NT-proBNP >420 pg/mL (OR, 13.890; 95% CI, 5.288-36.484) were independently associated with elevated hs-cTnI. CONCLUSIONS: CAS was independently associated with myocardial injury in patients with PE. Vigilance towards CAS is warranted in patients with PE with elevated cardiac troponin levels.

Joint effect of atrial fibrillation and obesity on mortality in critically ill patients.

BACKGROUND: The interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population. METHODS: Utilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods. RESULTS: The study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF. CONCLUSIONS: AF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF.

Attributable liver cancer deaths and disability-adjusted life years in China and worldwide: profiles and changing trends.

OBJECTIVE: Liver cancer is a major health concern globally and in China. This analysis investigated deaths and disability-adjusted life years (DALYs) with respect to etiologies and risk factors for liver cancer in China and worldwide. METHODS: Global and China-specific data were collected on liver cancer deaths, DALYs, and age-standardized rates (ASRs) from the Global Burden of Disease Study 2019 database. Liver cancer etiologies were classified into five groups and risk factors were categorized into three levels. Each proportion of liver cancer burden was calculated in different geographic regions. The joinpoint regression model were used to assess the trends from 1990-2019. RESULTS: Liver cancer accounted for 484,577 deaths worldwide in 2019 with an ASR of 5.9 per 100,000 population. China had an elevated liver cancer death ASR in 2019 and males had an ASR 1.7 times the global rate. The global ASR for DALYs peaked at 75-79 years of age but peaked earlier in China. Hepatitis B virus was the prominent etiology globally (39.5%) and in China (62.5%), followed by hepatitis C virus and alcohol consumption. In high sociodemographic index countries, non-alcoholic steatohepatitis has gained an increasing contribution as an etiologic factor. The liver cancer burden due to various etiologies has decreased globally in both genders. However, metabolic risk factors, particularly obesity, have had a growing contribution to the liver cancer burden, especially among males. CONCLUSIONS: Despite an overall decreasing trend in the liver cancer burden in China and worldwide, there has been a rising contribution from metabolic risk factors, highlighting the importance of implementing targeted prevention and control strategies that address regional and gender disparities.

Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain.

Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.

Apigenin alleviates doxorubicin-induced myocardial pyroptosis by inhibiting glycogen synthase kinase-3ß in vitro and in vivo.

Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti-cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK-3ß and the effects of apigenin in DOX-induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX-induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis-related factors. Furthermore, the phosphorylation of GSK-3ß was enhanced while the phosphorylation of nuclear factor-kB (NF-κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA-GSK-3ß-transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK-3ß. Therefore, our study confirmed that the inhibition of GSK-3ß and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX-stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK-3ß expression and subsequent reduction in NF-κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK-3ß may offer a promising therapeutic approach for alleviating DOX-induced cardiotoxicity.

The current infection with Helicobacter pylori and association with upper gastrointestinal lesions and risk of upper gastrointestinal cancer: Insights from multicenter population-based cohort study.

The relationship between Helicobacter pylori (H. pylori) infection and upper gastrointestinal (UGI) cancers is complex. This multicenter, population-based cohort study conducted in seven areas in China aimed to assess the correlation between current H. pylori infection and the severity of UGI lesions, as well as its association with the risk of gastric cancer (GC) and esophageal cancer (EC). From 2015 to 2017, 27,085 participants (aged 40-69) completed a standardized questionnaire, and underwent a 13C-urea breath test. Then a subset underwent UGI endoscopy to assess the UGI lesion detection rates. All individuals were followed up until December 2021 to calculate the hazard ratios (HRs) for UGI cancers. H. pylori infection prevalence was 45.9%, and among endoscopy participants, 22.2% had gastric lesions, 19.2% had esophageal lesions. Higher detection rates of gastric lesions were noted in the H. pylori-positive population across all lesion severity levels. Over a median follow-up of 6.3 years, 104 EC and 179 GC cases were observed, including 103 non-cardia gastric cancer (NCGC) cases and 76 cardia gastric cancer (CGC) cases. H. pylori-infected individuals exhibited a 1.78-fold increased risk of GC (HR 1.78, 95% confidence interval [CI] 1.32-2.40) but no significant increase in EC risk (HR 1.07, 95% CI 0.73-1.57). Notably, there was a higher risk for both NCGC and CGC in H. pylori-infected individuals. This population-based cohort study provides valuable evidence supporting the association between current H. pylori infection and the risk of both NCGC and CGC. These findings contribute to the empirical basis for risk stratification and recommendations for UGI cancer screening.

One-Component Cationic Lipids for Systemic mRNA Delivery to Splenic T Cells.

Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four-component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non-liver mRNA delivery systems. Herein, we report the rational design of one-component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine-based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy.

Optimizing preparation of low-NaCl protein gels from goose meat and understanding synergistic effects of pH/NaCl in improving gel characteristics.

This study explored the feasibility of partially substituting NaCl with MgCl2 in preparing gel products from goose meat. Furthermore, the effects of synergistic interaction between different pH levels and NaCl concentrations on the structure and characteristics of the gels were explored by analyzing their secondary structure, microstructure, and water-distribution properties. The results showed that NaCl could be partially substituted by MgCl2, with the optimal preparation conditions: NaCl (0.83 mol/L), pH (7.3), MgCl2 (0.04 mol/L), heating temperature (79 °C), heating time (20 min), and solid-liquid ratio (1:3). Furthermore, the pH had a more significant impact on the gels' structure and characteristics than did NaCl concentration. Thus, our optimized method can reduce the usage of NaCl in the gel products while at the same time improving the characteristics of gel products under low-NaCl conditions by lowering pH, laying a solid theoretical foundation for producing low-NaCl protein gel products from goose meat.

The application of encapsulation technology in the food Industry: Classifications, recent Advances, and perspectives.

Encapsulation technology has been extensively used to enhance the stability, specificity, and bioavailability of essential food ingredients. Additionally, it plays a vital role in improving product quality and reducing production costs. This study presents a comprehensive classification of encapsulation techniques based on the state of different cores (solid, liquid, and gaseous) and offers a detailed description and analysis of these encapsulation methods. Specifically, it introduces the diverse applications of encapsulation technology in food, encompassing areas such as antioxidant, protein activity, physical stability, controlled release, delivery, antibacterial, and probiotics. The potential impact of encapsulation technology is expected to make encapsulation technology a major process and research hotspot in the food industry. Future research directions include applications of encapsulation for enzymes, microencapsulation of biosensors, and novel technologies such as self-assembly. This study provides a valuable theoretical reference for the in-depth research and wide application of encapsulation technology in the food industry.

Preparation, Characterization, and Bioactivity Evaluation of Lambda-Cyhalothrin Microcapsules for Slow-Controlled Release System.

The utilization of interfacial polymerization in the preparation of microcapsules with a slow-controlled release has been shown to effectively improve pesticide efficacy and reduce environmental pollution. In this study, polyurea microcapsules loaded with lambda-cyhalothrin were prepared by an interfacial polymerization method using modified isocyanate (MDI) as the wall material and GT-34 as the initiator. The microcapsules were fully characterized by optical microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, etc., and release behaviors were investigated. The results indicated that the microcapsules had a smooth surface and uniform distribution, the average particle size of the microcapsules was 1.97 µm, and the encapsulation efficiency of lambda-cyhalothrin microcapsules could reach 91.48%. Compared with other commercial formulations, the microcapsules exhibited an excellent sustained release property (>7 days) in a 50% acetonitrile aqueous solution (v/v). Subsequently, in vitro release studies showed that the lambda-cyhalothrin microcapsules could consistently control the release of the core materials at different pH, temperature, and MDI addition amount conditions. The release of lambda-cyhalothrin microcapsules was in accordance with the first-order model release, which was mainly by the Fickian diffusion mechanism. Furthermore, the biological activity on Myzus persicae showed that the microcapsules' persistence period was above 21 days, which was longer than that for the emulsifiable concentrate formulation.

From amino acid analysis to improved gel properties: The role of dl-valine in Landaise goose myofibrillar protein.

The impact of exogenous limiting amino acids on protein gel formation was investigated to enhance the gelation properties of Landaise goose myofibrillar protein (MP). Amino acid composition and gel properties were analyzed, and homologous protein modeling and molecular docking techniques were used to simulate binding sites. Valine was identified as the first limiting amino acid. The addition of 0.075 % dl-valine proved optimal to enhance the gel strength (59.5 g) and water retention (76.76 %) of MP gels. Hydrophobic interactions and disulfide bonds were found to be the main forces maintaining conformational stability of the MP-dl-valine gels. The propyl group of dl-valine can form hydrophobic interactions with protein, contributing to stable complexes. DL valine could also strengthen chemical bonds and secondary structure, convert free water to immobile water, and improve the microstructure of the gel. Therefore, valine can be utilized as a nutritional and gel enhancer in Landaise goose meat products.

A thermal deformation optimization method for cryogenically cooled silicon crystal monochromators under high heat load.

A method to optimize the thermal deformation of an indirectly cryo-cooled silicon crystal monochromator exposed to intense X-rays at a low-emittance diffraction-limited synchrotron radiation source is presented. The thermal-induced slope error of the monochromator crystal has been studied as a function of heat transfer efficiency, crystal temperature distribution and beam footprint size. A partial cooling method is proposed, which flattens the crystal surface profile within the beam footprint by modifying the cooling contact area to optimize the crystal peak temperature. The optimal temperature varies with different photon energies, which is investigated, and a proper cooling strategy is obtained to fulfil the thermal distortion requirements over the entire photon energy range. At an absorbed power up to 300 W with a maximum power density of 44.8 W mm-2 normal incidence beam from an in-vacuum undulator, the crystal thermal distortion does not exceed 0.3 µrad at 8.33 keV. This method will provide references for the monochromator design on diffraction-limited synchrotron radiation or free-electron laser light sources.

Prognostic significance of quantitative electrocardiographic parameters in patients with non-high-risk pulmonary embolism.

BACKGROUND: Electrocardiogram (ECG) abnormalities indicating right ventricular strain have been reported to have prognostic value in severe cases of acute pulmonary embolism (PE). We aimed to analyze the prognostic significance of other quantitative ECG parameters in non-high-risk acute PE. METHODS: Consecutive patients with non-high-risk acute PE were prospectively enrolled. The following baseline ECG parameters were collected: rhythm, heart rate, QRS axis, right bundle branch block (RBBB) pattern, S1Q3T3 pattern, T-wave inversion, ST-segment elevation, Qr in lead V1, PR Interval, QRS complex duration, QT interval, P-wave amplitude and duration, R- and S-wave amplitudes. The primary endpoint was early discharge within three days. Associations between ECG parameters and early discharge were analyzed. RESULTS: Overall, 383 patients were enrolled (median age: 67 years, 57% female): 277 (72.3%) with low-risk and 106 (27.7%) with intermediate-risk. The two groups of patients differed in several ECG signs of right ventricular strain and many other quantitative parameters like R- and S-wave amplitudes. In the multivariate logistic regression analysis, the S-wave depth in lead V5 (S-V5) was the only independent prognostic factor for early discharge (odds ratio = 0.137, 95% confidence interval = 0.031-0.613, p = 0.009). The optimum cutoff value of S-V5 for predicting early discharge derived from the receiver operative characteristic curve was 0.15 mv (c-statistic = 0.66, p =0.003). CONCLUSIONS: Several ECG signs of right ventricular strain and many other quantitative parameters were associated with disease severity in non-high-risk acute PE. An S-V5 lesser than 0.15 mv was predictive for early discharge in these patients.

Cancer profiles in China and comparisons with the USA: a comprehensive analysis in the incidence, mortality, survival, staging, and attribution to risk factors.

China faces a disproportionate cancer burden to the population size and is undergoing a transition in the cancer spectrum. We extracted data in five aspects of cancer incidence, mortality, survival, staging distributions, and attribution to risk factors in China, the USA and worldwide from open-source databases. We conducted a comprehensive secondary analysis of cancer profiles in China in the above aspects, and compared cancer statistics between China and the USA. A total of 4,546,400 new cancer cases and 2,992,600 deaths occurred in China in 2020, accounting for 25.1% and 30.2% of global cases, respectively. Lifestyle-related cancers including lung cancer, colorectal cancer, and breast cancer showed an upward trend and have been the leading cancer types in China. 41.6% of new cancer cases and 49.3% of cancer deaths occurred in digestive-system cancers in China, and the cancers of esophagus, nasopharynx, liver, and stomach in China accounted for over 40% of global cases. Infection-related cancers showed the highest population-attributable fractions among Chinese adults, and most cancers could be attributed to behavioral and metabolic factors. The proportions of stage I for most cancer types were much higher in the USA than in China, except for esophageal cancer (78.2% vs. 41.1%). The 5-year relative survival rates in China have improved substantially during 2000-2014, whereas survival for most cancer types in the USA was significantly higher than in China, except for upper gastrointestinal cancers. Our findings suggest that although substantial progress has been made in cancer control, especially in digestive system cancers in China, there was still a considerable disparity in cancer burden between China and the USA. More robust policies on risk factors and standardized screening practices are urgently warranted to curb the cancer growth and improve the prognosis for cancer patients.

Cancer statistics for young adults aged 20 to 49 years in China from 2000 to 2017: a population-based registry study.

An increasing cancer incidence among adults younger than 50 years has been reported for several types of cancer in multiple countries. We aimed to report cancer profiles and trends among young adults in China. Data from the China Cancer Registry Annual Report were used to estimate incidence and mortality among young adults (ages 20-49 years) in China in 2017, and an age-period-cohort model was employed to estimate the average annual percent change (AAPC) in incidence and mortality from 2000 to 2017. All 25 cancer types were grouped into obesity- or overweight-associated cancers (12 cancer types) and additional cancers (13 cancer types). In 2017, there were 681,178 new cases and 214,591 cancer deaths among young adults in China. Among young adults, the most common cancers were thyroid, breast, cervical, liver, lung, and colorectal cancer, and the leading causes of cancer deaths were liver, lung, cervical, stomach, breast, and colorectal cancer. From 2000 to 2017, the cancer incidence increased for all cancers combined among young adults, with the highest AAPC (1.46%) for adults aged 20-24 years, while cancer mortality decreased, with the highest AAPC (-1.63%) for those aged 35-39 years. In conclusion, the cancer incidence in China has increased among young adults, while cancer mortality has decreased for nearly all ages. Cancer control measures, such as obesity control and appropriate screening, may contribute to reducing the increasing cancer burden among young adults.

SGLT2 inhibitors for the prevention of atrial fibrillation: a systemic review and meta-analysis.

AIMS: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to have cardiac benefits. The effects of SGLT2 inhibitors on the prevention of atrial fibrillation (AF) remain inconclusive. We aimed to investigate whether SGLT2 inhibitors can prevent AF occurrence in patients with cardiometabolic diseases. METHODS: We searched MEDLINE, EMBASE, and the Cochrane CENTRAL database up to July 1, 2023. Randomized, placebo-controlled trials of SGLT2 inhibitors in patients with diabetes, heart failure, chronic kidney diseases, or cardiometabolic risk factors were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated in the overall population and selected subgroups. RESULTS: Forty-six trials comprising 101 100 patients were included. Overall, no significant risk reduction of AF occurrence was observed with SGLT2 inhibitors, although there was a favorable trend (RR 0.90, 95% CI 0.80-1.01). In trials with follow-up durations of over one year, a similar result was achieved (RR 0.90, 95% CI 0.80-1.01). The results were consistent across different SGLT2 inhibitors, with RRs (95%CIs) of 0.82 (0.60-1.12) for canagliflozin, 0.87 (0.73-1.03) for dapagliflozin, 0.97 (0.78-1.22) for empagliflozin, 0.99 (0.66-1.50) for sotagliflozin, and 0.87 (0.58-1.29) for ertugliflozin. Analyses in different doses of SGLT2 inhibitors yielded similar results. The associations between SGLT2 inhibitors and AF occurrence were also absent in patients with diabetes, heart failure, and chronic kidney diseases. CONCLUSION: For patients with cardiometabolic diseases or risk factors, SGLT2 inhibitors did not decrease the risk of AF occurrence, regardless of follow-up duration, type or dose of the drug, or the patient population.

The effects of SGLT2 inhibitors on the prevention of atrial fibrillation (AF) remain inconclusive. For patients with cardiometabolic diseases or risk factors, SGLT2 inhibitors did not decrease the risk of AF occurrence, regardless of follow-up duration, type or dose of the drug, or the patient population. Further research is warranted to investigate the potential benefit of SGLT2 inhibitors in AF.

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.

BACKGROUND: Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved. METHODS: Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation. FINDINGS: The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice. INTERPRETATION: Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).