CRADD and cIAP1 antagonistically regulate caspase-9-mediated apoptosis in teleost.

Caspase 9 (CASP9) is a well-known initiator caspase of intrinsic apoptosis. In humans, cIAP1 binds and induces degradation of the activated form of CASP9, but not pro-CASP9. In fish, the activity and regulation of CASP9 remain unknown. In this work, using flounder Paralichthys olivaceus as a representative species, we examined the regulatory mechanism of CASP9 in teleost. P. olivaceus CASP9 (PoCASP9) induced robust apoptosis, which was inhibited by P. olivaceus cIAP1 (PocIAP1). Unlike human cIAP1, PocIAP1 bound both pro- and active PoCASP9 and induced their degradation via the RING domain-involved proteasome pathway. In humans, the adaptor molecule CRADD cannot interact with CASP9. In contrast, P. olivaceus CRADD (PoCRADD) bound both pro- and active PoCASP9 via CARD-CARD interaction and enhanced apoptosis by promoting the cellular levels of pro- and active PoCASP9. Furthermore, PoCRADD abrogated the inhibition of PoCASP9 by PocIAP1 by preventing PocIAP1-PoCASP9 interaction. Together these results reveal a CASP9 regulation mechanism in teleost that differs from that in humans and demonstrate that teleost CASP9 is tightly and directly controlled by both negative and positive regulators that exert a regulation effect both before and after CASP9 activation. These findings advance our understanding of the regulation of CASP9-mediated apoptosis in vertebrates.

N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.

CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC50 values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC50 values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.

Clinicopathological characteristics, prognostic factors, and outcomes of elderly patients with lymphoma-associated hemophagocytic lymphohistiocytosis: A multicenter analysis.

BACKGROUND: Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma-associated HLH (LA-HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA-HLH in the elderly population. METHODS: We retrospectively analyzed a multicenter cohort of elderly patients with LA-HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. RESULTS: A total of 173 elderly patients with LA-HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B-cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p < 0.001) while T/NK-cell lymphoma was more common in young patients (65.3% vs. 35.3%, p < 0.001). The median survival of elderly patients with LA-HLH was only 92 days. The prior use of HLH therapy or etoposide-containing HLH therapy was not associated with improved overall survival. T/NK-cell subtype, a lower platelet count (≤53 × 109/L), a lower albumin level (≤32.1 g/L), a higher LDH level (>1407 U/L), and a higher creatinine level (>96.8 µmol/L) were independent predictors of decreased overall survival and 60-day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60-day survival of elderly patients with LA-HLH. CONCLUSIONS: LA-HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA-HLH.

A high-efficiency strategy for fruit preservation using green, natural raw materials.

Straw is an abundant renewable biomass resource material. Lignin contained in straw is a unique natural aromatic compound in nature. At present, it is urgent to find ways to realize the higher value of natural lignin resources. In this study, alkali lignin was separated from rice straw by hydrothermal method in NaOH solution, which was prepared lignin nanoparticles by a simple green anti-solvent method. The obtained lignin nanoparticles had excellent anti-tyrosinase activity (IC50 = 0.329 mg mL-1) and anti-oxidation performance (IC50 = 0.0451 mg mL-1). Meanwhile, through the analysis of tyrosinase inhibition kinetics, it is concluded that the tyrosinase inhibition by lignin nanoparticles belongs to mixed inhibition. The affinity of lignin nanoparticles to the free enzyme is greater than that of enzyme and substrate complex. In addition, lignin nanoparticles were added to chitosan solution for compounding, then the composite films for fruit preservation were prepared by casting method. The experimental results show that the composite membrane can effectively extend the shelf life of fruits, which is expected to achieve a broader application in the field of fruit preservation and food packaging.

METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor.

The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes.

Tumour cell senescence can be induced by various factors, including DNA damage, inflammatory signals, genetic toxins, ionising radiation and nutrient metabolism. The senescence-associated secretory phenotype (SASP), secreted by senescent tumour cells, possesses the capacity to modulate various immune cells, including macrophages, T cells, natural killer cells and myeloid-derived suppressor cells, as well as vascular endothelial cells and fibroblasts within the tumour microenvironment (TME), and this modulation can result in either the promotion or suppression of tumorigenesis and progression. Exploring the impact of SASP on the TME could identify potential therapeutic targets, yet limited studies have dissected its functions. In this review, we delve into the causes and mechanisms of tumour cell senescence. We then concentrate on the influence of SASP on the tumour immune microenvironment, angiogenesis, extracellular matrix and the reprogramming of cancer stem cells, along with their associated tumour outcomes. Last, we present a comprehensive overview of the diverse array of senotherapeutics, highlighting their prospective advantages and challenge for the treatment of cancer patients. KEY POINTS: Senescence-associated secretory phenotype (SASP) secretion from senescent tumour cells significantly impacts cancer progression and biology. SASP is involved in regulating the remodelling of the tumour microenvironment, including immune microenvironment, vascular, extracellular matrix and cancer stem cells. Senotherapeutics, such as senolytic, senomorphic, nanotherapy and senolytic vaccines, hold promise for enhancing cancer treatment efficacy.

Systematic synthesis and identification of monolignol pathway metabolites.

Monolignol serves as the building blocks to constitute lignin, the second abundant polymer on Earth. Despite two decades of diligent efforts, complete identification of all metabolites in the currently proposed monolignol biosynthesis pathway has proven elusive. This limitation also hampers their potential application. One of the primary obstacles is the challenge of assembling a collection of all molecules, because many are commercially unavailable or prohibitively costly. In this study, we established systematic pipelines to synthesize all 24 molecules through the conversions between functional groups on a core structure followed by the application to other core structures. We successfully identified all of them in Populus trichocarpa and Eucalyptus grandis, two representative species respectively from malpighiales and myrtales in angiosperms. Knowledge about monolignol metabolite chemosynthesis and identification will form the foundation for future studies.

The AST/ALT ratio predicts survival and improves oncological therapy decisions in patients with non-small cell lung cancer receiving immunotherapy with or without radiotherapy.

Background and purpose: Immunotherapy, with or without radiotherapy (iRT or ICIs-nonRT), is the standard treatment for non-small cell lung cancer (NSCLC). Nonetheless, the response to the treatment varies among patients. Given the established role of aspartate aminotransferase/alanine transaminase (AST/ALT) ratio in predicting cancer prognosis, we sought to identify whether the pre-treatment AST/ALT ratio has the potential to serve as a prognostic factor for NSCLC patients receiving ICIs-nonRT and iRT. Materials and methods: We retrospectively analyzed NSCLC patients who received immunotherapy between April 2018 and March 2021. Patients were classified into iRT group and ICIs-nonRT group and further classified based on AST/ALT ratio cut-off values. The Kaplan-Meier (KM) method estimated the time-to-event endpoints (progression-free survival (PFS) and overall survival (OS). Results: Of the cohort, 239 underwent ICIs-nonRT and 155 received iRT. Higher AST/ALT ratios correlated with worse outcomes in the ICIs-nonRT group but indicated better outcomes in those who received iRT. Multivariate analysis validated AST/ALT ratio as an independent prognostic factor. For AST/ALT ratios between 0.67-1.7, both ICIs-nonRT and iRT yielded similar treatment outcomes; with AST/ALT ratios greater than 1.7, iRT could be a more favorable treatment option (P=0.038). Conversely, for ratios less than 0.67, ICIs-nonRT could be a more favorable treatment option (P=0.073). Conclusions: The pre-treatment AST/ALT ratio demonstrates potential as a prognostic marker for treatment outcomes in NSCLC patients receiving either ICIs-nonRT or iRT. This finding could help guide clinicians in selecting more effective treatment protocols, thereby enhancing patient prognosis.

Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation.

Background: In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined. Objective: In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards. Methods: The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: "Graft Selection" and "Clinical Outcome Evaluation" during the second part of the consensus development. Results: This focused discussion ultimately led to a strong consensus on nine specific consensus terms. Conclusion: The consensus clearly states that ACL reconstruction has no definitive "gold standard" graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.

Synthesis of Polycyclic Aromatic Compounds by Electrocyclization-Dehydrogenation of Diradicaloids.

Herein, we present a novel and efficient method for the synthesis of two new polycyclic aromatic hydrocarbons, 1 and 2, through the electrocyclization-dehydrogenation of diradicaloids. The proposed oxidative electrocyclization via intermediate diradicaloids is monitored by electron paramagnetic resonance and ultraviolet-visible spectroscopy. Interestingly, 1 exhibits chirality because of its inherent helical skeleton, and 2 features long-wavelength absorption and near-infrared emission properties due to its extended π-conjugation.

[Mechanism of Paeoniae Radix Rubra and Aconiti Lateralis Radix Praeparata herbal pair in promoting hepatocellular regeneration in chronic acute liver failure based on HGF/PI3K/Akt signaling axis].

Based on the hepatocyte growth factor(HGF)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling axis, this study investigated the therapeutic effect of Paeoniae Radix Rubra and Aconiti Lateralis Radix Praeparata(PRR-ALRP) her-bal pair on acute-on-chronic liver failure(ACLF) rats and its impact on hepatocellular regeneration. The rat model of ACLF was constructed by subcutaneous and tail vein injection of bovine serum albumin combined with intraperitoneal injection of lipopolysaccharides(LPS)+D-galactosamine(D-GalN). The rats were divided into normal control(NC) group, model(vehicle) group, PRR-ALRP(5.85 g·kg~(-1)) group, and hepatocyte growth factor granules(HGFG, 4.05 g·kg~(-1)) group. Hematoxylin-eosin(HE) staining was used to observe pathological changes in rat liver tissues. Serum alanine aminotransferase(ALT), aspartate transaminase(AST), and total bilirubin(TBIL) were detected using an automatic biochemical analyzer. The levels of interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) inflammatory factors were detected by ELISA. Immunofluorescence staining was used to detect the positive expression of proliferating cell nuclear antigen(PCNA), antigen identified by monoclonal antibody(Ki67), and cell cycle protein B1(CyclinB1). Real-time fluorescence-based quantitative polymerase chain reaction(RT-qPCR) and Western blot were used to detect the mRNA and protein expression levels of HGF, growth factor receptor-bound protein 1(Gab1), PI3K, Akt, phosphorylated PI3K(p-PI3K), and phosphorylated Akt(p-Akt). The results showed that compared with the vehicle group, the PRR-ALRP group had reduced liver tissue pathological scores, improved liver function, and reduced inflammatory response, with enhanced PCNA, Ki67, and CyclinB1 fluorescence expression. Furthermore, compared with the model group, the PRR-ALRP group showed upregulated expression of HGF and Gab1 proteins, as well as activation of PI3K and Akt phosphorylation. These findings suggest that PRR-ALRP herbal pair exerts anti-liver failure effects by alleviating hepatocyte inflammatory damage and promoting hepatocellular regeneration, and its specific regulatory mechanism may be related to the activation of the HGF/PI3K/Akt signaling pathway.

Rapid discovery of natural antioxidants in Hypericum japonicum: Dual roles of the liquid phase mobile phase as extraction and separation solvent.

Hypericum japonicum is a traditional folk medicine with various bioactivities such as hepatoprotective, antioxidant, and anti-tumorous. The antioxidant effect of H. japonicum is one of the most prominent effects due to its responsibility for many of its activities. To clarify active natural substance, the antioxidant properties of H. japonicum were preliminarily assessed by ferric reducing-antioxidant power (FRAP), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and Oxygen radical absorbance capacity (ORAC), as well as superoxide dismutase (SOD). Then, a straightforward and effective method named online liquid extraction-high performance liquid chromatography combined with ABTS antioxidant assay and mass spectrometry (OLE-HPLC-ABTS/Q-TOF-MS) was developed to swiftly and directly discover the antioxidants in H. japonicum. Using mobile phase as extraction and separation reagent, coupled with online activity analysis and compounds identification by high-resolution MS, the online system enables rapid screening of natural antioxidant bioactives from complex mixture. By using it, a total of 9 compounds including flavonoids and phenolic acids characterized by retention time, precise mass, and fragmentation ions in MS/MS spectra showed antioxidant action. Finally, the antioxidant and SOD activity of main found active compounds were validated by in vitro experiment assay and molecular docking. In summary, these results suggested that H. japonicum could be considered as a potential source of natural antioxidants, and the online integrated system might become a promising candidate for the natural antioxidants discovery in the future.

A practical risk stratification system based on ultrasonography and clinical characteristics for predicting the malignancy of soft tissue masses.

OBJECTIVE: To establish a practical risk stratification system (RSS) based on ultrasonography (US) and clinical characteristics for predicting soft tissue masses (STMs) malignancy. METHODS: This retrospective multicenter study included patients with STMs who underwent US and pathological examinations between April 2018 and April 2023. Chi-square tests and multivariable logistic regression analyses were performed to assess the association of US and clinical characteristics with the malignancy of STMs in the training set. The RSS was constructed based on the scores of risk factors and validated externally. RESULTS: The training and validation sets included 1027 STMs (mean age, 50.90 ± 16.64, 442 benign and 585 malignant) and 120 STMs (mean age, 51.93 ± 17.90, 69 benign and 51 malignant), respectively. The RSS was constructed based on three clinical characteristics (age, duration, and history of malignancy) and six US characteristics (size, shape, margin, echogenicity, bone invasion, and vascularity). STMs were assigned to six categories in the RSS, including no abnormal findings, benign, probably benign (fitted probabilities [FP] for malignancy: 0.001-0.008), low suspicion (FP: 0.008-0.365), moderate suspicion (FP: 0.189-0.911), and high suspicion (FP: 0.798-0.999) for malignancy. The RSS displayed good diagnostic performance in the training and validation sets with area under the receiver operating characteristic curve (AUC) values of 0.883 and 0.849, respectively. CONCLUSION: The practical RSS based on US and clinical characteristics could be useful for predicting STM malignancy, thereby providing the benefit of timely treatment strategy management to STM patients. CRITICAL RELEVANCE STATEMENT: With the help of the RSS, better communication between radiologists and clinicians can be realized, thus facilitating tumor management. KEY POINTS: There is no recognized grading system for STM management. A stratification system based on US and clinical features was built. The system realized great communication between radiologists and clinicians in tumor management.

Maternal autoimmune disease and offspring risk of haematological malignancies: a case-control study.

Background: Autoimmune diseases are known to be associated with an increased risk of cancer. Whether maternal immune dysregulation can have an impact on the development of haematological malignancies in offspring remains uncertain. Therefore, we explored the association between offspring risk of haematological malignancies and maternal autoimmune disease using a real-world nationwide population-based study. Methods: In this case-control study, we identified 2172 children with haematological malignancies between 2004 and 2019 from Taiwan's National Health Insurance program and compared them with population-based controls without haematologic malignancies, who were matched with each individual at a ratio of 1:4. The medical information of the autoimmune mothers were obtained from the Taiwan Maternal and Child Health Database. Conditional logistic regression was used to estimate the odds ratio for haematologic malignancy in offspring. Furthermore, subgroup and stratified analyses were conducted. Findings: Among the rheumatologic diseases in our study, Crohn's disease was the most common disease both in the haematological malignancy group (1.1%) and the control group (0.9%). In multivariable analysis, the odds ratio for haematological malignancy in offspring with maternal autoimmune diseases was 1.2 (95% confidence interval [CI] 0.91-1.58). The overall risk of haematologic malignancy was not significantly higher when adjusted for specific risk factors, including neonatal age, maternal age, family income, urbanization, maternal occupation, birth weight, or maternal comorbidity, except for prematurity. When comparing different autoimmune diseases among haematological malignancies and the control group, maternal psoriatic arthritis/psoriasis had the highest adjusted overall risk for haematological malignancies (adjusted OR 2.11, CI 0.89-5), followed by ankylosing spondylitis (adjusted OR 1.45, CI 0.7-3), autoimmune thyroiditis (OR 1.26, CI 0.57-2.81), systemic lupus erythematosus (OR 1.21, CI 0.48-3.02), Crohn's disease (OR 1.19, CI 0.75-1.9), and Sjogren's syndrome (OR 1.18, CI 0.65-2.15), but no significance was reached in these analyses. Multivariable analysis of risk factors associated with haematological malignancy subtypes was done. It showed no associations between maternal autoimmune disease and childhood haematological malignancies. Interpretation: We found no significant relationship between maternal autoimmune disease and childhood haematological malignancies. The influence of maternal immune dysregulation on the next generation with respect to haematological malignancies development may be limited. Funding: There was no funding source for this study.

Upregulation of ZMAT3 is Associated with the Poor Prognosis of Breast Cancer.

Background: Breast cancer is the leading cause of cancer-related deaths among women worldwide. Identifying robust biomarkers for predicting outcomes is essential for improving patient care and reducing fatalities. ZMAT3, a zinc finger protein with potential carcinogenic properties, has been associated with various cancers. However, its role in breast cancer prognosis remains unclear. Methods: We investigated the expression level of ZMAT3 in breast cancer tissues and its association with clinical outcomes through bioinformatics analysis and experimental validation. We examined the correlation between ZMAT3 expression and immune characteristics. ZMAT3 mRNA expression data from The Cancer Genome Atlas (TCGA) were analysed in relation to overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in patients with breast cancer. Immunohistochemistry (IHC) was performed on breast cancer tissues to assess ZMAT3 protein levels, with findings validated using qPCR and cell experiments. Results: ZMAT3 mRNA levels were significantly upregulated in breast cancer samples compared to normal tissues. High ZMAT3 expression was significantly correlated with the poor OS, DSS and PFI. A significant positive correlation was observed between high ZMAT3 mRNA levels and the abundance of tumour-infiltrating lymphocytes (TILs), especially CD8+T cells and regulatory T cells (Tregs). Multivariate Cox regression analysis identified ZMAT3 as an independent prognostic factor for breast cancer. IHC staining confirmed increased ZMAT3 protein expression in breast cancer tissues, which was further validated by qPCR and cell function tests. Conclusion: Our findings suggest that ZMAT3 is a prognostic biomarker linked to immune invasion in breast cancer. Elevated ZMAT3 expression correlates with adverse clinical outcomes, indicating its potential role in disease progression.

Trend and driving factors in burden of age-related macular degeneration in older adults aged 60-89 years: a global analysis over three decades.

BACKGROUND: To explore temporal trends and determine driving factors of age-related macular degeneration (AMD) burden in older adults aged 60-89 years at global, regional and national levels from 1990 to 2019. METHODS: Prevalence and years lived with disability (YLDs) were extracted. Joinpoint regression analysis was adopted to calculate average annual percentage change and to identify the year with the most significant changes. Global trends were stratified by sex, age and sociodemographic index, and regional and national trends were explored. Decomposition analysis was conducted to determine what extent the forces of population size, age structure and epidemiologic change driving alterations of AMD burden. RESULTS: Globally, prevalence rate slightly increased whereas YLDs rate decreased. The year 2005 marked a turning point where both prevalence and YLDs started to decline. Regionally, Western Sub-Saharan Africa had the highest prevalence and YLDs rates in 2019, with East Asia experiencing the most notable rise in prevalence from 1990 to 2019. Global decomposition revealed that the increased case number was primarily driven by population growth and ageing, and epidemiological change was only detected to lessen but far from offset these impacts. CONCLUSIONS: Although there was only slight increase or even decrease in prevalence and YLDs rates of AMD in older adults, the case number still nearly doubled, which may be primarily attributed to population growth and ageing, coupled with the emerging growing pattern of prevalence rate from 2015, collectively suggesting a huge challenge in control and management of AMD.

Inkjet-printed flexible V2CTx film electrodes with excellent photoelectric properties and high capacities for energy storage device.

Energy storage devices are progressively advancing in the light-weight, flexible, and wearable direction. Ti3C2Tx flexible film electrodes fabricated via a non-contact, cost-effective, high-efficiency, and large-scale inkjet printing technology were capable of satisfying these demands in our previous report. However, other MXenes that can be employed in flexible energy storage devices remain undiscovered. Herein, flexible V2CTx film electrodes (with the low formula weight vs Ti3C2Tx film electrodes) with both high capacities and excellent photoelectric properties were first fabricated. The area capacitances of V2CTx film electrodes reached 531.3-5787.0 µF⋅cm-2 at 5 mV⋅s-1, corresponding to the figure of merits (FoMs) of 0.07-0.15. Noteworthy, V2CTx film electrode exhibited excellent cyclic stability with the capacitance retention of 83 % after 7,000 consecutive charge-discharge cycles. Furthermore, flexible all solid-state symmetric V2CTx supercapacitor was assembled with the area capacitance of 23.4 µF⋅cm-2 at 5 mV⋅s-1. Inkjet printing technology reaches the combination of excellent photoelectric properties and high capacities of flexible V2CTx film electrodes, which provides a new strategy for manufacturing MXene film electrodes, broadening the application prospect of flexible energy storage devices.

Inclisiran Treatment for Cardiovascular Disease Risk Reduction: A Systematic Review and Meta-Analysis.

This study was a meta-analysis of patient data to investigate the therapeutic effects of inclisiran on LDL-C, PCSK9, and TC in patients with atherosclerosis. Authors searched the Cochrane Library, Pubmed, EMBASE, and Web of Science databases for randomised controlled trials. Data of 4,731 subjects from five randomised clinical trials were included in this analysis. Patients treated with the PCSK9 inhibitor inclisiran had significantly lower LDL-C levels than those treated with placebo or a statin (mean difference (MD) -1.477; 95% CI -1.551 to -1.403; p <0.001; I2 = 7.2%). The average level of PCSK9 was also relatively lower ((MD) -2.579; 95% CI -2.694 to -2.464; p <0.001; I2 = 36%). They exhibited significant reductions in total cholesterol protein levels ((MD) -1.477; 95% CI -1.585 to -1.369; p <0.001; I2 = 46.7%). Inclisiran reduced LDL-C and PCSK9 levels as well as TC and Apo B levels significantly in patients with atherosclerotic cardiovascular disease (ASCVD). Key Words: Inclisiran, Low-density lipoprotein cholesterol, Atherosclerosis, Adverse events, Meta-analysis.

Matrine-loaded self-adhesive swelling microneedle for inflammation regulation to improve eczema treatment.

Eczema is a common chronic dermatological disease. Conventional treatments exhibit limited efficacy due to fast drug release resulting in short-term relief. Development of a new treatment strategy that enables sustained drug release and long-term maintenance on the skin surface is necessary. A self-adhesive swelling microneedle patch (SDSMNs) was designed and constructed using a two-step casting method. The adhesive substrate was prepared by blending gelatin and dopamine via oxidation of NaIO4, so it could adhere onto the skin surface as well as withstand repeated bending movement without detachment. The swelling needles were fabricated using polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), which could swell by absorbing interstitial fluid and release the drug in a controlled manner. SDSMNs also showed desirable antibacterial activities toward E. coli and S. aureus. The adhesive microneedles loaded with matrine (MAT-SDSMNs), an anti-inflammatory Chinese medicine, dramatically relieved eczema symptoms through IL-17 mediated inflammation responses. The use of MAT-SDSMNs significantly decreased the infiltration of inflammation cells and level of inflammatory cytokines, reduced the skin thickness, and increased collagen deposition fraction compared with conventional ointment or subcutaneous injection. The results suggested that MAT-SDSMNs can improve eczema treatment by regulating the local inflammatory microenvironment, providing a simple, self-administered sustainable strategy for eczema treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00235-z.