Gut-liver axis: Potential mechanisms of action of food-derived extracellular vesicles.

Food-derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non-gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non-gastrointestinal diseases via the gut-liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut-liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non-alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut-liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases.

Alantolactone attenuates high-fat diet-induced inflammation and oxidative stress in non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear. METHODS: C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis. RESULTS: Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress. CONCLUSIONS: The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.

Oxygen Vacancy-Laden Confinement Impact on Degradation of Metal Complexes.

Oxygen vacancies (Vo) have been recognized as the superior active site for PS-mediated environmental remediation; however, the formation and activation of Vo associated with the effects of chemical and spatial environments remain ambiguous. Herein, attributing to the low defect-formation energy of Vo in the presence of sulfonate groups, an in situ nucleating Vo-laden CuO nanosheet was deliberately fabricated inside the phase of a sulfonated mesoporous polystyrene substrate (Vo-CuO@SPM). The as-prepared nanocomposite demonstrated an excellent treatment efficiency toward metal complexes [Cu-EDTA as a case] with ignorable Cu(II) leaching, and it can be repeatedly employed for 25 recycles (not limited). Mechanistically, the electron transfer and the mass transport for PDS nonradical activation were proved to be substantially enhanced by the delocalized electrons and with the assistance of the microchannel environment. This work not only establishes insight into the formation of oxygen vacancies but also reveals the PS activation mechanism in the spatially confined sites.

The prognostic value of metabolic dysfunction-associated steatotic liver disease in acute myocardial infarction: A propensity score-matched analysis.

AIM: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined. METHODS: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan-Meier curve was constructed for long-term all-cause mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality. RESULTS: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow-up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all-cause mortality (6.8% vs. 3.6%, p < .001) at 30 days, with unfavourable mortality rates sustained in the long-term (18.3% vs. 14.5%, p = .001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long-term all-cause mortality (hazard ratio 1.330, 95% confidence interval 1.106-1.598, p = .002). CONCLUSION: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long-term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI.

Practice of standardization of CLSI M45 A3 antimicrobial susceptibility testing of Infrequently Isolated or Fastidious Bacteria strains isolated from blood specimens in Guangdong Province 2017-2021.

The concentration of antimicrobial agents in environments like water and food has increased rapidly, which led to a rapid increase in antimicrobial resistance levels in the environment. Monitoring of bacterial resistance levels is considered as a necessary means to control the bacterial resistance. Reference standards are critical for antimicrobial susceptibility testing. CLSI M45 A3 standard defines pathogenic microorganisms that cause infections less frequently than those covered by CLSI M02, M07, and M100 as Infrequently Isolated or Fastidious Bacteria and specifies antimicrobial susceptibility testing methods. Our study investigated the epidemiology and antimicrobial susceptibility testing data of Infrequently Isolated or Fastidious Bacteria strains isolated from blood specimens in 70 hospitals in Guangdong Province between 2017 and 2021. We defined testing methods other than those specified in CLSI M45 A3 as "Non-Standardized." The proportion of standardized antimicrobial susceptibility testing for penicillin increased significantly (Corynebacterium spp. 17.4% vs. 50.0% p < 0.05; Micrococcus spp. 50.0% vs. 77.8% p < 0.05; Abiotrophia spp. and Granulicatella spp. 21.4% vs. 90.9% p < 0.001), while for cefotaxime (Corynebacterium spp. 0.0% vs. 45.2% p < 0.05; Abiotrophia spp. and Granulicatella spp. 0.0% vs. 14.3% p = 0.515) and vancomycin increased finitely. Non-standardized methods were used for all other antimicrobials. Due to limitations in the economic and medical environment, some clinical laboratories are unable to fully comply with CLSI M45 A3 standard. We recommend that CLSI should add breakpoints for disk diffusion method to improve the standardization of antimicrobial susceptibility testing.

Higher-order topological phases in crystalline and non-crystalline systems: a review.

In recent years, higher-order topological phases have attracted great interest in various fields of physics. These phases have protected boundary states at lower-dimensional boundaries than the conventional first-order topological phases due to the higher-order bulk-boundary correspondence. In this review, we summarize current research progress on higher-order topological phases in both crystalline and non-crystalline systems. We firstly introduce prototypical models of higher-order topological phases in crystals and their topological characterizations. We then discuss effects of quenched disorder on higher-order topology and demonstrate disorder-induced higher-order topological insulators. We also review the theoretical studies on higher-order topological insulators in amorphous systems without any crystalline symmetry and higher-order topological phases in non-periodic lattices including quasicrystals, hyperbolic lattices, and fractals, which have no crystalline counterparts. We conclude the review by a summary of experimental realizations of higher-order topological phases and discussions on potential directions for future study.

[Retracted] MicroRNA­25 protects nucleus pulposus cells against apoptosis via targeting SUMO2 in intervertebral disc degeneration.

Following the publication of this paper, the authors requested that the paper be retracted, specifically on account of deficiencies that were identified both in the documentation of patient records and in written consent pertaining to the data presented in Fig. 1. After having considered the authors' request, the Editor of Molecular Medicine Reports has agreed that this paper should be retracted from the Journal. All the authors are in agreement with the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 24: 724, 2021; DOI: 10.3892/mmr.2021.12363].

Insight into Impacts of π-π Assembly on Phthalocyanine Based Heterogeneous Molecular Electrocatalysis.

Electrochemical CO2 reduction (CO2R) to feedstocks competes with the hydrogen evolution reaction (HER). Cobalt phthalocyanine (CoPc) immobilized onto carbon driven by π-π interaction represents a classical type of heterogeneous molecular catalyst for CO2R. However, the impacts of π conjugation on the electrocatalysis have not been clarified. Herein, the electrochemical properties of CoPc were investigated by comparison of its analogue to 2,3-naphthalocyanine cobalt (NapCo) having extended π conjugation. It is found that CoPc is redox-active on carbon to provide low oxidized Co sites for improving the CO2R activity and selectivity, while NapCo on carbon turned out to be redox-inert leading to lower performance. In addition, the redox-mediated mechanism for CO2R on CoPc tends to operate with increasing electrolyte alkalinity, which further enhances the reaction selectivity. We speculated that moderate π conjugation allows the redox-mediated mechanism on CoPc, which is critical to promote CO2R performance while depressing the competing HER.

Flavokawain B inhibits NF-κB inflammatory signaling pathway activation in inflammatory bowel disease by targeting TLR2.

Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.

Recommended 10-Year Follow-Up Strategy for Small Hepatocellular Carcinoma After Radiofrequency Ablation: A Cost-Effectiveness Evaluation.

INTRODUCTION: An optimal follow-up schedule for small (≤3-cm) hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains unclear in clinical guidelines. We aimed to assess the cost-effectiveness of follow-up strategies in patients with small HCC after RFA. METHODS: In total, 11,243 patients were collected from global institutions to calculate recurrence rates. Subsequently, a Markov model covering a 10-year period was developed to compare 25 surveillance strategies involving different surveillance techniques (computed tomography [CT], magnetic resonance imaging or ultrasonography [US], and α-fetoprotein [AFP]) and intervals (3 or 6 months). The study endpoint was incremental cost-effectiveness ratio (ICER), which represented additional cost per incremental quality-adjusted life year. Sensitivity analysis was conducted by varying the values of input parameters to observe the ICER. RESULTS: In a base case analysis, the dominant strategy was CT every 3 months during an initial 2 years, followed by semiannual CT, and then switch to biannual the combination of US screening and AFP testing after 5 years (m3_CT-m6_CT-m6_USAFP), with an ICER of $68,570.92 compared with the "not followed" strategy. One-way sensitivity analysis showed the ICER consistently remained below the willingness-to-pay threshold of $100,000.00. In a probabilistic sensitivity analysis, m3_CT-m6_CT-m6_USAFP was the most cost-effective approach in 95.6% of simulated scenarios at a willingness-to-pay threshold. DISCUSSION: For small HCC after RFA, the recommended follow-up strategy is CT, with scans scheduled every 3 months for the first 2 years, every 6 months thereafter, and transition to biannual the combination of US screening and AFP testing after 5 years.

Molecular architectures of iron complexes for oxygen reduction catalysis-Activity enhancement by hydroxide ions coupling.

Developing cost-effective and high-performance electrocatalysts for oxygen reduction reaction (ORR) is critical for clean energy generation. Here, we propose an approach to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and selective electrocatalyst for ORR. The performance is significantly superior to FePc in randomly aggregated and molecularly dispersed states, as well as the commercial Pt/C catalyst. When FePc NTs are anchored on graphene, the resulting architecture shifts the ORR potentials above the redox potentials of Fe2+/3+ sites. This does not obey the redox-mediated mechanism operative on conventional FePc with a Fe2+-N moiety serving as the active sites. Pourbaix analysis shows that the redox of Fe2+/3+ sites couples with HO- ions transfer, forming a HO-Fe3+-N moiety serving as the ORR active sites under the turnover condition. The chemisorption of ORR intermediates is appropriately weakened on the HO-Fe3+-N moiety compared to the Fe2+-N state and thus is intrinsically more ORR active.

A First-Principles Study of Mechanical and Electronic Properties of Cr0.5-xAl0.5TMxN Hard Coatings (TM = Ti, V, Y, Zr, Hf, and Ta).

The structural, mechanical, and electronic properties of cubic Cr0.5-xAl0.5TMxN, doped with TM (transition metal) elements (TM = Ti, V, Y, Zr, Hf, and Ta) at low concentrations (x = 0.03 and 0.06), was investigated by first-principles calculations. The results of the structural properties calculations reveal that the addition of Ti, Y, Hf, Zr, and Ta expand the volume, while V has the opposite effect. All doped compounds are thermodynamically stable, and Cr0.5-xAl0.5TMxN with TM = Ti is energetically more favorable than other doped compounds. At the same doping concentration, Cr0.5-xAl0.5VxN possesses the highest stiffness, hardness, and resistance to external forces due to its greatest mechanical properties, and Cr0.5-xAl0.5TaxN possesses the highest elastic anisotropy and the lowest Young's modulus. Substituting Cr atoms with TM atoms in a stepwise manner results in a decrease in the bulk modulus, shear modulus, Young's modulus, and theoretical hardness of Cr0.5-xAl0.5TMxN, while increasing its toughness. Based on the calculation results of the total and partial density of states of Cr0.5Al0.5N and Cr0.47Al0.5TM0.03N, all compounds exhibit metallic behavior as indicated by the finite density of states at the Fermi level. The contribution of Ti-3d, V-3d, and Ta-3d orbitals at Fermi level is significantly higher than that of other TM atoms, resulting in a more pronounced metallic character for Cr0.47Al0.5Ti0.03N, Cr0.47Al0.5V0.03N, and Cr0.47Al0.5Ta0.03N.

Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors and Economic Burden Among Patients with Bloodstream Infections.

Introduction: Although Extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) significantly contribute to bloodstream infections, their economic repercussions remain largely unquantified. Data Source and Methods: We performed a retrospective analysis of inpatients diagnosed with Escherichia coli or Klebsiella pneumoniae bacteremia in a tertiary hospital from January 2020 to December 2022 in Guangzhou, China. We employed the chi-square test to examine ESBL risk factors and utilized propensity score matching (PSM) to negate baseline confounding factors, assessing economic burden through disability-adjusted life years (DALYs), hospital costs and productivity losses. We employed mediation analysis to eliminate confounding factors and better identify ESBL sources of burden related. Results: We found 166 ESBL-EC/KP BSI patients (52.2% of the total examined 318 patients). Post-PSM analysis revealed that ESBL-producing EC/KP will reduce the effectiveness of empirical medication by 19.8%, extend the total length of hospitalization by an average of 3 days, and increase the patient's financial burden by US$2047. No significant disparity was found in overall mortality and mean DALYs between the groups. Mediation analysis showed that the link between ESBL and hospital costs is predominantly, if not entirely, influenced by the appropriateness of empirical antibiotic treatment and length of hospital stay. Conclusion: Patients with BSI due to ESBL-producing ESBL-EK incur higher costs compared to those with non-ESBL-EK BSI. This cost disparity is rooted in varying rates of effective empirical antimicrobial therapy and differences in hospital stay durations. A nuanced approach, incorporating a thorough understanding of regional epidemiological trends and judicious antibiotic use, is crucial for mitigating the financial impact on patients.

ApoE maintains neuronal integrity via microRNA and H3K27me3-mediated repression.

ApoE regulates neurogenesis, although how it influences genetic programs remains elusive. Cortical neurons induced from isogenic control and ApoE-/- human neural stem cells (NSCs) recapitulated key transcriptomic signatures of in vivo counterparts identified from single-cell human midbrain. Surprisingly, ApoE expression in NSC and neural progenitor cells (NPCs) is not required for differentiation. Instead, ApoE prevents the over-proliferation of non-neuronal cells during extended neuronal culture when it is not expressed. Elevated miR-199a-5p level in ApoE-/- cells lowers the EZH1 protein and the repressive H3K27me3 mark, a phenotype rescued by miR-199a-5p steric inhibitor. Reduced H3K27me3 at genes linked to extracellular matrix organization and angiogenesis in ApoE-/- NPC correlates with their aberrant expression and phenotypes in neurons. Interestingly, the ApoE coding sequence, which contains many predicted miR-199a-5p binding sites, can repress miR-199a-5p without translating into protein. This suggests that ApoE maintains neurons integrity through the target-directed miRNA degradation of miR-199a-5p, imparting the H3K27me3-mediated repression of non-neuronal genes during differentiation.

Targeted platelet with hydrogen peroxide responsive behavior for non-alcoholic steatohepatitis detection.

The most common chronic liver illness, non-alcoholic fatty liver disease (NAFLD), refers to a range of abnormalities of the liver with varying degrees of steatosis. When the clinical symptoms including liver damage, inflammation, and fibrosis, are added to the initial steatosis, NAFLD becomes non-alcoholic steatohepatitis (NASH), the problematic and severe stage. The diagnosis of NASH at the right time could therefore effectively prevent deterioration of the disease. Considering that platelets (PLTs) could migrate to the sites of inflamed liver sinusoids with oxidative stress during the development of NASH, we purified the PLTs from fresh blood and engineered their surface with hydrogen peroxide (H2O2) responsive fluorescent probe (5-DP) through lipid fusion. The engineered PLT-DPs were recruited and trapped in the inflammation foci of the liver with NASH through interaction with the extracellular matrix, including hyaluronan and Kupffer cells. Additionally, the fluorescence of 5-DP on the surface of PLT-DP was significantly enhanced upon reacting with the elevated level of H2O2 in the NASH liver. Thus, PLT-DP has great promise for NASH fluorescence imaging with high selectivity and sensitivity.

Bicyclol alleviates obesity-induced renal injury by inhibiting JNK and NF-κB-mediated inflammation.

Obesity is recognized as a major risk factor for chronic kidney disease (CKD), which is accompanied by increased renal lipid build-up, fibrosis, inflammation, apoptosis and pyroptosis. Bicyclol (BIC), a Chinese marketed hepatoprotective drug, has shown excellent anti-inflammatory, anti-fibrosis, anti-apoptotic, and lipid regulation effects in different animal models. In this study, we explored the role and mechanism of BIC in high-fat diet (HFD)-induced obesity-related nephropathy. Mice were fed with HFD for 24 weeks to develop obesity-related nephropathy, while mice in the BIC administration group were treated with BIC (50 mg/kg or 100 mg/kg, once every two days) at the last 12 weeks. We found that BIC treatment relieved the impairment of kidney structure and renal dysfunction caused by HFD. In addition, we found that BIC mitigated HFD-induced renal fibrosis, inflammation, apoptosis and pyroptosis by inhibiting JNK and NF-κB pathways. SV40-MES-13 cells treated with palmitate (PA) were used as the in vitro model. Our data show that BIC pre-administration relieved cellular damage caused by PA through suppressing JNK and NF-κB signaling pathways. In conclusion, we demonstrated that BIC attenuated obesity-induced renal injury by inhibiting chronic inflammation, fibrosis, apoptosis and pyroptosis via targeting JNK and NF-κB pathways. Our data suggested that BIC could be potentially used to prevent obesity-associated nephropathy, which warrants future investigation.

Costunolide attenuates high-fat diet-induced inflammation and oxidative stress in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease that can further evolve towards liver fibrosis and hepatocellular carcinoma in the end stage. Costunolide (Cos) is a natural sesquiterpene lactone that exhibits both anti-inflammatory and antioxidant properties. However, the therapeutic effect of Cos on NAFLD is not clear. In this study, we explored the potential protective effect and mechanism of Cos on NAFLD. C57BL/6 mice were fed with high-fat diet (HFD) to induce NAFLD. Cos was administered by gavage to observe the effect of Cos on NAFLD. We demonstrated that oral administration of Cos reduced HFD-induced hepatic fibrosis and the release of inflammatory cytokines, limiting the generation of reactive oxygen species. In vitro experiments revealed that pretreatment with Cos significantly decreased PA-induced production of inflammatory cytokines and fibrosis in AML-12 cells. Mechanism study showed that the effect of Cos was correlated to the induction of Nrf-2 and inhibition of NF-κB pathways. Collectively, these findings indicated that Cos exerts hepatoprotective effect against NAFLD through blocking inflammation and oxidative stress. Our study suggested that Cos might be an effective pharmacotherapy for the treatment of NAFLD.

Toll-like receptor 2 deficiency ameliorates obesity-induced cardiomyopathy via inhibiting NF-κB signaling pathway.

Growing evidence demonstrates that chronic low-grade inflammation, which is induced by high-fat diet (HFD) or saturated fatty acid, plays an important role in the obesity-induced cardiomyopathy (OIC) process. Moreover, obesity is associated with the activation of different inflammatory pathways, including nuclear factor-κB (NF-κB), Toll-like-receptor-2 (TLR2) and Toll-like-receptor-4 (TLR4). In this study, we established an HFD-induced cardiac injury mouse model and palmitate (PA)-induced myocardial cell model to evaluate the role of TLR2 in OIC. Our data show that TLR2 blockade using TLR2 knockout (KO) mice or a TLR2-specific inhibitor, C29, markedly ameliorated HFD- or PA-induced inflammation, myocardial fibrosis, and hypertrophy both in vivo and in vitro. Moreover, the PA-induced myocardial cell injury was mediated via inducing the formation of TLR2-MyD88 complex in a TLR4-independent manner in cardiomyocytes. Our data prove the critical role of cardiac TLR2 in the pathogenesis of HFD- and saturated fatty acid-induced myocarditis, fibrosis, myocardial hypertrophy, and cardiac dysfunction. Inhibition of TLR2 pathway may be a therapeutic strategy of OIC.

Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies.

BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

Rising global burden of cancer attributable to high BMI from 2010 to 2019.

BACKGROUND: High body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear. METHODS: We estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study. RESULTS: From 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest-growing cause of cancer mortality (APC: 1.37 %, 95 % CI 1.25 to 1.49 %) attributable to high BMI. CONCLUSION: The global burden of cancer-related deaths attributable to high BMI has increased substantially from 2010 to 2019. The greatest increase in age-standardized death rates occurred in Southeast Asia, and liver cancer is the fastest-growing cause of cancer mortality attributable to high BMI. Urgent and sustained measures are required at a global and regional level to reverse these trends and slow the growing burden of cancer attributed to high BMI.