Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Nuclear F-actin assembly on damaged chromatin is regulated by DYRK1A and Spir1 phosphorylation.

Nuclear actin-based movements support DNA double-strand break (DSB) repair. However, molecular determinants that promote filamentous actin (F-actin) formation on the damaged chromatin remain undefined. Here we describe the DYRK1A kinase as a nuclear activity that promotes local F-actin assembly to support DSB mobility and repair, accomplished in part by its targeting of actin nucleator spire homolog 1 (Spir1). Indeed, perturbing DYRK1A-dependent phosphorylation of S482 mis-regulated Spir1 accumulation at damaged-modified chromatin, and led to compromised DSB-associated actin polymerization and attenuated DNA repair. Our findings uncover a role of the DYRK1A-Spir1 axis in nuclear actin dynamics during early DSB responses, and highlight the intricate details of nuclear cytoskeletal network in DSB repair and genome stability maintenance.

Field performance of 15 rain gardens in different cities in Taiwan.

Rain gardens are widely used for low impact development (LID) or as a nature-based solution (NbS). They help to reduce runoff, mitigate hot temperatures, create habitats for plants and insects, and beautify landscapes. Rain gardens are increasingly being established in urban areas. In Taiwan, the Ministry of Environment (MoE) initiated a rain garden project in Taipei city in 2018, and 15 rain gardens have since been constructed in different cities. These Taiwanese-style rain gardens contain an underground storage tank to collect the filtrated rainwater, which can be used for irrigation. Moreover, the 15 rain gardens are equipped with sensors to monitor temperature, rainfall, and underground water levels. The monitoring data were transmitted with Internet of Things (IoT) technology, enabling the capture and export of real-time values. The water retention, temperature mitigation, water quality, and ecological indices of the rain gardens were quantified using field data. The results from the young rain gardens (1-3 years) showed that nearly 100 % of the rainfall was retained onsite and did not flow out from the rain gardens; however, if the stored water was not used and the tanks were full, the rainwater from subsequent storms could not be stored, and the tanks overflowed. The surface temperatures of the rain garden and nearby impermeable pavement differed by an average of 2-4 °C. This difference exceeded 20 °C in summer at noon. The water in the underground storage tanks had very low levels of SS and BOD, with averages of 1.6 mg/L and 5.6 mg/L, respectively. However, the E. coli concentrations were high, and the average was 6283 CFU/100 mL; therefore, washing or drinking water is not recommended. The ecological indices, i.e., the Shannon and Simpson indices, demonstrated the good flora status of the rain gardens after one year. Although the weather differed by city, the performance of the rain gardens in terms of water retention, temperature mitigation, rainwater harvesting, and providing biological habitats was consistent. However, maintenance influences rain garden performance. If the stored water is not frequently used, the stored volume is reduced, and the stored water quality degrades.

Global prevalence, clinical characteristics, surveillance, treatment allocation, and outcomes of alcohol-associated hepatocellular carcinoma.

BACKGROUND AND AIMS: Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS: Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS: Of 4,824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (CI: 24.0%-37.7%) of HCC were alcohol-associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male, but similar in age and comorbidities, compared to other causes. 20.8% (CI: 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared to 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P<0.05). Alcohol-associated HCC had a lower likelihood of BCLC stage (0/A) (OR: 0.7, CI: 0.6-0.9; P=0.018) and curative therapy (24.5% vs 33.9%; OR 0.7, CI: 0.5-0.9; P=0.003), and higher mortality (HR: 1.3, CI: 1.1-1.5, P=0.012) when compared to other causes. CONCLUSIONS: Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.

Overexpression of AcWRKY31 Increases Sensitivity to Salt and Drought and Improves Tolerance to Mealybugs in Pineapple.

Pineapple is a globally significant tropical fruit, but its cultivation faces numerous challenges due to abiotic and biotic stresses, affecting its quality and quantity. WRKY transcription factors are known regulators of stress responses, however, their specific functions in pineapple are not fully understood. This study investigates the role of AcWRKY31 by overexpressing it in pineapple and Arabidopsis. Transgenic pineapple lines were obtained using Agrobacterium-mediated transformation methods and abiotic and biotic stress treatments. Transgenic AcWRKY31-OE pineapple plants showed an increased sensitivity to salt and drought stress and an increased resistance to biotic stress from pineapple mealybugs compared to that of WT plants. Similar experiments in AcWRKY31-OE, AtWRKY53-OE, and the Arabidopsis Atwrky53 mutant were performed and consistently confirmed these findings. A comparative transcriptomic analysis revealed 5357 upregulated genes in AcWRKY31-OE pineapple, with 30 genes related to disease and pathogen response. Notably, 18 of these genes contained a W-box sequence in their promoter region. A KEGG analysis of RNA-Seq data showed that upregulated DEG genes are mostly involved in translation, protein kinases, peptidases and inhibitors, membrane trafficking, folding, sorting, and degradation, while the downregulated genes are involved in metabolism, protein families, signaling, and cellular processes. RT-qPCR assays of selected genes confirmed the transcriptomic results. In summary, the AcWRKY31 gene is promising for the improvement of stress responses in pineapple, and it could be a valuable tool for plant breeders to develop stress-tolerant crops in the future.

Mesonephric-type adenocarcinomas of the ovary: prevalence, diagnostic reproducibility, outcome, and value of PAX2.

Mesonephric-type (or -like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four-marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four-marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376-0.727) with the integration of the four-marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first-line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62-5.85; p < 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended.

Temporal lobe malacia as a rare cause of gelastic seizure: A case report.

BACKGROUND: Gelastic seizure (GS) is a rare type of epilepsy that most commonly appears in patients with hypothalamic hamartoma. It is rarely associated with other types of brain damage. This particular type of epilepsy is relatively rare and has few links to other brain lesions. Temporal lobe malacia is mostly caused by cerebral infarction or cerebral hemorrhage, which can lead to seizures. We report a case of GS in a woman with temporal lobe malacia which was reported for the first time in the literature. CASE SUMMARY: A 73-year-old female, diagnosed case of GS, presented with repetitive stereotyped laughter a month prior to presentation, happening multiple times daily and with each time lasting for 5-15s. Electroencephalogram displayed a focal seizure seen in the right temporal region. Magnetic resonance imaging head with contrast showed a right temporal lobe malacia. The patient was started on levetiracetam daily. The patient indicated that they had fully recovered and were not experiencing any recurrent or stereotyped laughter during their daily routines. These results remained consistent even after a one-year follow-up period. CONCLUSION: GS can be caused by temporal lobe malacia, which is an uncommon but potentially grave condition. The outcome of this present case exhibited the importance of the temporal lobe in the genesis of GS.

Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: Systematic review and network meta-analysis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. Dynamic changes in magnetic resonance imaging (MRI) proton-density-fat fraction (PDFF) are associated with MASH resolution. We aimed to determine the relative efficacy of therapeutic agents for reducing hepatic fat, assessed by magnetic resonance imaging (MRI) proton-density-fat fraction (PDFF). APPROACH AND RESULTS: In this systematic review and network meta-analysis, we searched MEDLINE and Embase from inception until Dec 26, 2023, for published randomized-controlled trials (RCTs) comparing pharmacological interventions in patients with MASH that assessed changes in MRI-PDFF. The primary outcome was the absolute change in MRI-PDFF. The secondary outcome was a ≥30% decline in MRI-PDFF. A surface under-the-curve cumulative ranking probabilities (SUCRA) analysis was performed. Of 1550 records, a total of 39 RCTs (3311 participants) met the inclusion criteria. For MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were ranked the most effective interventions. At 24-weeks, efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were ranked the most effective interventions for achieving a ≥30% decline in MRI-PDFF. CONCLUSIONS: This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist selection of combination therapy.

Lipopolysaccharide-Induced Lysosomal Cell Death Through Reactive Oxygen Species in Rat Liver Cell Clone 9.

In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.

Evaluation of the SpotChecks contrast sensitivity test in healthy adults.

PURPOSE: SpotChecks is a new contrast sensitivity (CS) test designed for self-monitoring of vision. This study assessed the test-retest repeatability of take-home SpotChecks, in-office SpotChecks and near Pelli-Robson charts in healthy adults. METHODS: One eye of 61 healthy adults with near visual acuity (VA) of 6/9 or better (age range 22-84, mean 49 [18] years) was tested during two office visits (mean 10 [8] days apart). Each visit included high-contrast VA, then 12 randomly ordered CS tests (6 different SpotChecks and 6 different Pelli-Robson) under the same lighting (luminance 110 cd/m2), all at near in the same eye with habitual correction. The same eye was self-tested with take-home SpotChecks once a day on 6 days between the office visits. SpotChecks was scored by the logCS at the highest line with ≥2 errors. Pelli-Robson was scored by [0.05 × number of letters read correctly - 0.15]. Repeatability of logCS was defined as 1.96 2 $$ \sqrt{2} $$ Sw, Sw representing within-subject standard deviation. Comparison for repeatability was performed with Bootstrap hypothesis test. RESULTS: SpotChecks and Pelli-Robson showed similar intra-session or inter-visit repeatability (p = 0.14-0.81). Inter-day repeatability for take-home SpotChecks was 0.18 logCS, the same as that from the first measurements of two office visits with SpotChecks or Pelli-Robson. Inter-visit repeatability improved to 0.15 by using the average of two repeated measurements for SpotChecks (p = 0.02) or three repeated measurements for Pelli-Robson (p = 0.04). Age showed a small effect on logCS (-0.015/decade, p = 0.02) for both SpotChecks and Pelli-Robson. Mean logCS was 0.05 lower in those ≥50 years (SpotChecks 1.84 [0.10] and Pelli-Robson 1.77 [0.10]) compared with those <50 years of age (SpotChecks 1.89 [0.07] and Pelli-Robson 1.83 [0.07]). CONCLUSIONS: SpotChecks showed good repeatability with take-home and in-office testing in healthy adults, making it a promising tool for monitoring disease progression at home.

Retrosplenial cortex and aversive conditioning.

The retrosplenial cortex (RSC) is well-known for its contribution to episodic memory, as well as contextual and spatial learning and memory. However, two literatures have also emerged examining the role of the RSC in aversive conditioning. The purpose of this manuscript is to review, and attempt to integrate, these two literatures. We focus on studies in which discrete cues, such as tones, predict the occurrence of aversive outcomes, such as mild shocks. Using both electrophysiological recordings and lesion methods, the first literature has examined RSC contributions to discriminative avoidance conditioning. The second, and more recent literature, has focused on the role of the RSC in Pavlovian fear conditioning. We discuss both literatures in terms of the type of information processed by the RSC, the role of the RSC in memory storage, and how the aversive conditioning literature might be consistent with a role for the RSC in contextual learning and memory.

Dual protection by Bcp1 and Rkm1 ensures incorporation of uL14 into pre-60S ribosomal subunits.

Eukaryotic ribosomal proteins contain extended regions essential for translation coordination. Dedicated chaperones stabilize the associated ribosomal proteins. We identified Bcp1 as the chaperone of uL14 in Saccharomyces cerevisiae. Rkm1, the lysine methyltransferase of uL14, forms a ternary complex with Bcp1 and uL14 to protect uL14. Rkm1 is transported with uL14 by importins to the nucleus, and Bcp1 disassembles Rkm1 and importin from uL14 simultaneously in a RanGTP-independent manner. Molecular docking, guided by crosslinking mass spectrometry and validated by a low-resolution cryo-EM map, reveals the correlation between Bcp1, Rkm1, and uL14, demonstrating the protection model. In addition, the ternary complex also serves as a surveillance point, whereas incorrect uL14 is retained on Rkm1 and prevented from loading to the pre-60S ribosomal subunits. This study reveals the molecular mechanism of how uL14 is protected and quality checked by serial steps to ensure its safe delivery from the cytoplasm until its incorporation into the 60S ribosomal subunit.

The Impact of Neoadjuvant Chemotherapy on Patients With T1N0M0 Triple-Negative and HER-2 Positive Breast Cancer: A Retrospective Analysis Based on the SEER Database.

BACKGROUND: The utilization of neoadjuvant chemotherapy (NAC) originated in the treatment of locally advanced breast cancer (BC). Our study is designed to elucidate the effects of NAC on patients with T1N0M0 triple-negative and HER-2 positive BC. METHODS: This study involved the selection of 10,614 patients diagnosed with T1N0M0 triple-negative and HER-2 positive breast cancer (BC) from the surveillance, epidemiology, and end results (SEER) database. To ascertain the impact of neoadjuvant chemotherapy (NAC) on T1a, T1b, and T1c N0M0 BC, we conducted multivariate Cox regression analyses. Similarly, we performed multivariate Cox regression analyses to compare the effects of neoadjuvant chemotherapy against adjuvant chemotherapy on T1N0M0 BC. The Kaplan-Meier method was employed to delineate survival curves for different molecular subtypes and clinical stages. RESULTS: The data results from the SEER database reveal a significant enhancement of overall survival (OS) in T1c BC patients as a result of NAC. For T1b BC patients, NAC does not present any significant effect. Contrarily, NAC seems to adversely impact the OS of T1a triple-negative BC patients. However, the prognosis comparison between neoadjuvant and adjuvant chemotherapy for T1N0M0 breast cancer did not show any significant difference, with the exception of T1a triple-negative BC. CONCLUSIONS: Patients with T1cN0M0 triple-negative and HER-2 positive BC may derive OS benefits from NAC. Additionally, NAC could be detrimental to T1a triple-negative BC.

Application of Multi-Channel Synchronized Dynamic Strain Gauges in Monitoring the Neutral Axis Position and Prestress Loss of Box Girder Bridges.

The aim of this paper was to explore the application of multi-channel synchronized dynamic strain gauges in monitoring the neutral axis (N.A.) position of prestressed concrete box girders. The N.A. position has recently been proposed as an indicator for monitoring the health of bridge structures. Laboratory experiments were conducted on a prestressed T-beam under different prestress level conditions to investigate the correlation between the prestress magnitude and the N.A. position. In the development of the multi-channel synchronized dynamic strain gauges, edge computing was employed to significantly reduce the amount of data transmitted from the sensor nodes on-site. In edge computing, only the dynamic strain response caused by the maximum vehicle load in each minute is transmitted. This approach greatly enhances the monitoring efficiency and enables the realization of on-site non-computer-based monitoring systems. The laboratory test results of the prestressed T-beam showed that the N.A. position tends to move slightly downward as the prestress force increases. In other words, when the prestress force decreases due to loss, the N.A. position exhibits a slight upward movement. This study selected a newly constructed prestressed box girder as the subject for on-site measurement of the N.A. position using multi-channel synchronized dynamic strain gauges shortly after the prestress was applied. The on-site monitoring data indeed revealed a gradual upward movement of the N.A. position. This phenomenon confirmed that soon after the completion of prestressed concrete bridges, there is a gradual loss of prestress due to the significant shrinkage and creep effects of the early-age concrete. The on-site monitoring result aligned with the findings from the laboratory experiments, where the N.A. position was observed to move upward as the prestress decreased.

Structural, Ionic, and Electronic Properties of Solid-State Phthalimide-Containing Polymers for All-Organic Batteries.

Redox-active polymers serving as the active materials in solid-state electrodes offer a promising path toward realizing all-organic batteries. While both cathodic and anodic redox-active polymers are needed, the diversity of the available anodic materials is limited. Here, we predict solid-state structural, ionic, and electronic properties of anodic, phthalimide-containing polymers using a multiscale approach that combines atomistic molecular dynamics, electronic structure calculations, and machine learning surrogate models. Importantly, by combining information from each of these scales, we are able to bridge the gap between bottom-up molecular characteristics and macroscopic properties such as apparent diffusion coefficients of electron transport (D app). We investigate the impact of different polymer backbones and of two critical factors during battery operation: state of charge and polymer swelling. Our findings reveal that the state of charge significantly influences solid-state packing and the thermophysical properties of the polymers, which, in turn, affect ionic and electronic transport. A combination of molecular-level properties (such as the reorganization energy) and condensed-phase properties (such as effective electron hopping distances) determine the predicted ranking of electron transport capabilities of the polymers. We predict D app for the phthalimide-based polymers and for a reference nitroxide radical-based polymer, finding a 3 orders of magnitude increase in D app (≈10-6 cm2 s-1) with respect to the reference. This study underscores the promise of phthalimide-containing polymers as highly capable redox-active polymers for anodic materials in all-organic batteries, due to their exceptional predicted electron transport capabilities.

Sex-based Disparities in Liver Transplantation for Hepatocellular Carcinoma and the Impact of the Growing Burden of NASH.

Background: The cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC. Methods: Data were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men. Results: A total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P < 0.01), followed by alcohol-associated liver disease. NASH overtook chronic hepatitis C as the leading cause of liver disease in 2020 and 2022 among waitlisted women and men with HCC, respectively. Female patients with HCC spent a significantly longer time on the LT waitlist compared with male patients (ß: 8.73; 95% confidence interval [CI], 2.91-14.54). Female patients with HCC from alcohol-associated liver disease also have a lower probability of receiving LT (subdistribution hazard ratio: 0.90; 95% CI, 0.82-0.99). Among transplant recipients with NASH HCC, female sex was associated with lower posttransplant mortality compared with male sex (hazard ratio: 0.79; 95% CI, 0.70-0.89; P < 0.01). Conclusions: Women have a significantly longer waitlist duration compared with men. NASH is now the leading cause of liver disease among both female and male LT candidates and recipients with HCC.

Disparities in metabolic dysfunction-associated steatotic liver disease and cardiometabolic conditions in low and lower middle-income countries: a systematic analysis from the global burden of disease study 2019.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic conditions affect populations across economic strata. Nevertheless, there are limited epidemiological studies addressing these diseases in low (LICs) and lower-middle-income countries (lower MICs). Therefore, an analysis of the trend of MASLD and cardiometabolic conditions in these countries is necessary. METHODS: From 2000 to 2019, jointpoint regression analysis was employed to calculate the prevalence, mortality, and disability-adjusted life years (DALYs) for cardiometabolic conditions including MASLD, type 2 diabetes mellitus (T2DM), dyslipidemia (DLP), hypertension (HTN), obesity, peripheral artery disease (PAD), atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), stroke, and chronic kidney disease from HTN and T2DM, in LICs and lower MICs (according to the World Bank Classification 2019) using the Global Burden of Disease 2019 data. RESULTS: Among the eleven cardiometabolic conditions, MASLD (533.65 million), T2DM (162.96 million), and IHD (76.81 million) had the highest prevalence in LICs and Lower MICs in 2019. MASLD represented the largest proportion of global prevalence in these countries (43 %). From 2000 to 2019, mortality in LICs and lower MICs increased in all cardiometabolic conditions, with obesity-related mortality having the highest increase (+134 %). During this timeframe, there were increased age-standardized death rates (ASDR) from obesity, PAD, and AF/AFL. From all conditions, the DALYs-to-prevalence ratio was higher in LICs and lower MICs than the global average. CONCLUSION: The burden of MASLD and cardiometabolic conditions is increasing worldwide, with LICs and lower MICs experiencing higher (DALYs) disability per prevalence. As these conditions are preventable, counteracting these trends requires not only the modification of ongoing actions but also the strategizing of immediate interventions.

Sex and Race-Ethnic Disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis of 40,166 Individuals.

BACKGROUND: To overcome the limitations of the term "non-alcoholic fatty liver disease" (NAFLD), the term metabolic-associated steatotic liver disease (MASLD) was introduced. While epidemiologic studies have been conducted on MASLD, there is limited evidence on its associated sex and ethnic variations. AIMS: This study assesses the differences across sex and race-ethnicity on the prevalence, associated risk factors and adverse outcomes in individuals with MASLD. METHODS: Data retrieved from the National Health and Nutrition Examination Survey between 1999 to 2018 was analyzed. Prevalence, clinical characteristics, and outcomes were evaluated according to sex and race-ethnicity. Adverse outcomes and mortality events were analyzed using multivariate analyses. RESULTS: Of 40,166 individuals included, 37.63% had MASLD. There was a significant increase in MASLD prevalence from 1999 to 2018 among Mexican Americans (Annual Percentage Change [APC] + 1.889%, p < 0.001), other Hispanics (APC + 1.661%, p = 0.013), NH Whites (APC + 1.084%, p = 0.018), NH Blacks (APC + 1.108%, p = 0.007), and females (APC + 0.879%, p = 0.030), but not males. Females with MASLD were at lower risk of all-cause (HR: 0.766, 95%CI 0.711 to 0.825, p < 0.001), cardiovascular disease-related (CVD) (SHR: 0.802, 95% CI 0.698 to 0.922, p = 0.002) and cancer-related mortality (SHR: 0.760, 95% CI 0.662 to 0.873, p < 0.001). Significantly, NH Blacks have the highest risk of all-cause and CVD-related mortality followed by NH Whites then Mexican Americans. CONCLUSION: There has been an increase in prevalence in most race-ethnicities over time. While the change in definition shows no significant differences in previous associations found in NAFLD, the increased mortality in NH Whites relative to Mexican Americans remains to be explored.

Characterization of double-stranded RNA and its silencing efficiency for insects using hybrid deep-learning framework.

RNA interference (RNAi) technology is widely used in the biological prevention and control of terrestrial insects. One of the main factors with the application of RNAi in insects is the difference in RNAi efficiency, which may vary not only in different insects, but also in different genes of the same insect, and even in different double-stranded RNAs (dsRNAs) of the same gene. This work focuses on the last question and establishes a bioinformatics software that can help researchers screen for the most efficient dsRNA targeting target genes. Among insects, the red flour beetle (Tribolium castaneum) is known to be one of the most sensitive to RNAi. From iBeetle-Base, we extracted 12 027 efficient dsRNA sequences with a lethality rate of ≥20% or with experimentation-induced phenotypic changes and processed these data to correspond to specific silence efficiency. Based on the first complied novel benchmark dataset, we specifically designed a deep neural network to identify and characterize efficient dsRNA for RNAi in insects. The dna2vec word embedding model was trained to extract distributed feature representations, and three powerful modules, namely convolutional neural network, bidirectional long short-term memory network, and self-attention mechanism, were integrated to form our predictor model to characterize the extracted dsRNAs and their silencing efficiencies for T. castaneum. Our model dsRNAPredictor showed reliable performance in multiple independent tests based on different species, including both T. castaneum and Aedes aegypti. This indicates that dsRNAPredictor can facilitate prescreening for designing high-efficiency dsRNA targeting target genes of insects in advance.