Therapeutic effects of natural compounds against diabetic complications via targeted modulation of ferroptosis.

Diabetes mellitus, a chronic metabolic disorder, can result in serious tissue and organ damage due to long-term metabolic dysfunction, leading to various complications. Therefore, exploring the pathogenesis of diabetic complications and developing effective prevention and treatment drugs is crucial. The role of ferroptosis in diabetic complications has emerged as a significant area of research in recent years. Ferroptosis, a recently discovered form of regulated cell death closely linked to iron metabolism imbalance and lipid peroxidation, has garnered increasing attention in studies exploring the potential role of natural products in its regulation. This review provides an overview of the mechanisms underlying ferroptosis, outlines detection methods, and synthesizes information from natural product databases. It also summarizes current research on how natural products may regulate ferroptosis in diabetic complications. Studies have shown that these products can modulate the ferroptosis process by influencing iron ion balance and combating oxidative stress. This highlights the potential of natural products in treating diabetic complications by regulating ferroptosis, offering a new strategy for managing such complications.

Precise diagnosis of tumor cells and hemocytes using ultrasensitive, stable, selective cuprous oxide composite SERS bioprobes assisted with high-efficiency separation microfluidic chips.

Efficient enrichment and accurate diagnosis of cancer cells from biological samples can guide effective treatment strategies. However, the accessibility and accuracy of rapid identification of tumor cells have been hampered due to the overlap of white blood cells (WBCs) and cancer cells in size. Therefore, a diagnosis system for the identification of tumor cells using reliable surface-enhanced Raman spectroscopy (SERS) bioprobes assisted with high-efficiency microfluidic chips for rapid enrichment of cancer cells was developed. According to this, a homogeneous flower-like Cu2O@Ag composite with high SERS performance was constructed. It showed a favorable spectral stability of 5.81% and can detect trace alizarin red (10-9 mol L-1). Finite-difference time-domain (FDTD) simulation of Cu2O, Ag and Cu2O@Ag, decreased the fluorescence lifetime of methylene blue after adsorption on Cu2O@Ag, and surface defects of Cu2O observed using a spherical aberration-corrected transmission electron microscope (AC-TEM) demonstrated that the combined effects of electromagnetic enhancement and promoted charge transfer endowed the Cu2O@Ag with good SERS activity. In addition, the modulation of the absorption properties of flower-like Cu2O@Ag composites significantly improved electromagnetic enhancement and charge transfer effects at 532 nm, providing a reliable basis for the label-free SERS detection. After the cancer cells in blood were separated by a spiral inertial microfluidic chip (purity >80%), machine learning-assisted linear discriminant analysis (LDA) successfully distinguished three types of cancer cells and WBCs with high accuracy (>90%). In conclusion, this study provides a profound reference for the rational design of SERS probes and the efficient diagnosis of malignant tumors.

FOXO4 suppresses cisplatin resistance of Triple-Negative Breast Cancer by inhibiting autophagy.

BACKGROUND: Resistance to chemotherapy containing cisplatin (DDP) is a main challenge in the treatment of triple-negative breast cancer (TNBC). Forkhead box O4 (FOXO4) is frequently downregulated in DDP-resistant cells. However, it is unclear whether FOXO4 down-regulation is related to DDP resistance. Here, we investigated the relationship between FOXO4 and DDP resistance in TNBC. METHODS: We established the DDP-resistant cell lines MDA-MB-231/DDP and BT-549/DDP through in vitro selection. CCK-8 and colony formation assays analyzed cell growth. The resistance index was calculated. Cell autophagy was evaluated. Western blotting and qRT-PCR measured protein and gene expression. The binding between FOXO4 and TGF-ß1 was determined by the dual-luciferase reporter assay. RESULTS: FOXO4 expression was significantly lower in MDA-MB-231/DDP and BT-549/DDP cells. FOXO4 overexpression increased the sensitivity of TNBC cells to DDP. The PI3K class Ⅲ and Beclin-1 levels and LC3-II/LC3-I ratio elevated significantly in DDP-resistant cells. Moreover, the autophagic flux was enhanced in DDP-resistant cells. 3-MA enhanced the sensitivity of TNBC cells to DDP by inhibiting autophagy. Overexpression of FOXO4, treatment with 3-MA, and their combination significantly reduced the drug resistance index. FOXO4 directly targeted TGF-ß1. Additionally, TGF-ß1 knockdown inhibited autophagy and restored the sensitivity of DDP-resistant cells to DDP. Mechanistically, FOXO4 affected TNBC resistance to DDP by regulating autophagy and TGF-ß1. CONCLUSION: FOXO4 overexpression, in combination with autophagy inhibitors, can significantly improve the sensitivity of TNBC-resistant cells to DDP. These findings reveal the role and mechanism of FOXO4 in DDP sensitivity and may provide evidence for the development of TNBC therapies.

Discovery of candidate genes involved in ethylene biosynthesis and signal transduction pathways related to peach bud cold resistance.

Background: Low temperature pose significant challenges to peach cultivation, causing severe damage to peach buds and restricting production and distribution. Ethylene, an important phytohormone, plays a critical role in enhancing plant cold resistance. Structural genes and transcription factors involved in ethylene biosynthesis and signal transduction pathways are associated with cold resistance. However, no research has specifically addressed their roles in peach cold resistance. Methods: In this study, we aimed for cold-resistance gene discovery in cold-sensitive peach cultivar "21Shiji" (21SJ) and cold-resistance cultivar "Shijizhixing" (SJZX) using RNA-seq and gas chromatography. Results: The findings revealed that under cold stress conditions, ethylene biosynthesis in "SJZX" was significantly induced. Subsequently, a structural gene, PpACO1-1, involved in ethylene biosynthesis in peach buds was significantly upregulated and showed a higher correlation with ethylene release rate. To identify potential transcription factors associated with PpACO1-1 expression and ethylene signal transduction, weighted gene co-expression network analysis was conducted using RNA-seq data. Four transcription factors: PpERF2, PpNAC078, PpWRKY65 and PpbHLH112, were identified. Conclusion: These findings provide valuable theoretical insights for investigating the regulatory mechanisms of peach cold resistance and guiding breeding strategies.

Prediction of clinical prognosis and drug sensitivity in hepatocellular carcinoma through the combination of multiple cell death pathways.

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor, highlighting a significant need for reliable predictive models to assess clinical prognosis, disease progression, and drug sensitivity. Recent studies have highlighted the critical role of various programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, NETotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, in tumor development. Therefore, by investigating these pathways, we aimed to develop a predictive model for HCC prognosis and drug sensitivity. We analyzed transcriptome, single-cell transcriptome, genomic, and clinical information using data from the TCGA-LIHC, GSE14520, GSE45436, and GSE166635 datasets. Machine learning algorithms were used to establish a cell death index (CDI) with seven gene signatures, which was validated across three independent datasets, showing that high CDI correlates with poorer prognosis. Unsupervised clustering revealed three molecular subtypes of HCC with distinct biological processes. Furthermore, a nomogram integrating CDI and clinical information demonstrated good predictive performance. CDI was associated with immune checkpoint genes and tumor microenvironment components using single-cell transcriptome analysis. Drug sensitivity analysis indicated that patients with high CDI may be resistant to oxaliplatin and cisplatin but sensitive to axitinib and sorafenib. In summary, our model offers a precise prediction of clinical outcomes and drug sensitivity for patients with HCC, providing valuable insights for personalized treatment strategies.

Aspirin suppresses hepatocellular carcinoma progression by inhibiting platelet activity.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. Platelets (PLTs) are known to play a key role in the maintenance of liver homeostasis and the pathophysiological processes of a variety of liver diseases. Aspirin is the most classic antiplatelet agent. However, the molecular mechanism of platelet action and whether aspirin can affect HCC progression by inhibiting platelet activity need further study. AIM: To explore the impact of the antiplatelet effect of aspirin on the development of HCC. METHODS: Platelet-rich plasma, platelet plasma, pure platelet, and platelet lysate were prepared, and a coculture model of PLTs and HCC cells was established. CCK-8 analysis, apoptosis analysis, Transwell analysis, and real-time polymerase chain reaction (RT-PCR) were used to analyze the effects of PLTs on the growth, metastasis, and inflammatory microenvironment of HCC. RT-PCR and Western blot were used to detect the effects of platelet activation on tumor-related signaling pathways. Aspirin was used to block the activation and aggregation of PLTs both in vitro and in vivo, and the effect of PLTs on the progression of HCC was detected. RESULTS: PLTs significantly promoted the growth, invasion, epithelial-mesenchymal transition, and formation of an inflammatory microenvironment in HCC cells. Activated PLTs promoted HCC progression by activating the mitogen-activated protein kinase/protein kinase B/signal transducer and activator of transcription three (MAPK/ AKT/STAT3) signaling axis. Additionally, aspirin inhibited HCC progression in vitro and in vivo by inhibiting platelet activation. CONCLUSION: PLTs play an important role in the pathogenesis of HCC, and aspirin can affect HCC progression by inhibiting platelet activity. These results suggest that antiplatelet therapy has promising application prospects in the treatment and combined treatment of HCC.

Colorimetric detection of neomycin sulfate in serum based on ultra-small gold nanoparticles with peroxidase-like activity.

Neomycin sulfate (NEO) is a kind of aminoglycoside antibiotics. Because of its strong ototoxicity, nephrotoxicity and other side effects, its content in the body should be strictly monitored during use. In this paper, a rapid colorimetric detection method for NEO based on ultrasmall polyvinylpyrrolidone modified gold nanoparticles (PVP/Au NPs) with peroxidase-like activity was developed. Firstly, ultra small PVP/Au NPs with weak peroxidase-like activity were synthetized. When they were mixed with NEO, strong hydrogen bonds were formed between NEO and PVP, resulting in the aggregation of PVP/Au NPs, and the aggregated PVP/Au NPs showed stronger peroxidase-like activity. Therefore, rapid colorimetric detection of NEO was achieved by utilizing the enhanced peroxidase-like activity mechanism caused by the aggregation of ultra small PVP/Au NPs. The naked eye detection limit of this method is 50 nM. Within the range of 1 nM-300 nM, there was a good linear relationship between NEO concentration and the change in absorbance intensity of PVP/Au NPs-H2O2-TMB solution at 652 nm, with the regression curve of y = 0.0045x + 0.0525 (R2 = 0.998), and the detection limit is 1 nM. In addition, this method was successfully applied to the detection of NEO in mouse serum. The recoveries were 104.4 % -107.6 % compared with HPLC assay results, indicating that this method for NEO detection based on PVP/Au NPs has great potential in actual detection of NEO in serum.

Short- and long-term effects of different forage types supplemented in preweaning dairy calves on performance and milk production into first lactation.

We investigated the short- and long-term effects of different forage types supplemented in preweaning dairy calves on growth performance, blood metabolites, rumen fermentation, bacterial community, and milk production during first lactation. A total of 60 healthy 30-d-old female Holstein calves were blocked by birth date and body weight and randomly assigned to 1 of 3 groups (n = 20): normal milk and pelleted starter feeding (CON), supplemented with chopped oat hay (OAH; 75.0 g/d per calf [DM basis]), or alfalfa hay (ALF; 75.0 g/d per calf [DM basis]). The forage supplementation started when calves were 30 d old (d 1 of the experimental period) and ended when they were 73 d old (d 44 of the experimental period, when calves were weaned). Milk and feed intakes and fecal consistency scores were recorded daily. Growth performance, rumen fluid, and blood samples were collected biweekly. After weaning, all the calves were integrated with the same barn and diets. After calving, the milk production was recorded daily. During the experimental period, the OAH group had greater solid feed and total DM intakes and greater rumen pH than the CON group (P ≤ 0.04), but had lower forage intake and CP digestibility than the ALF group (P ≤ 0.04). The ALF group had higher rumen pH and blood BHB concentration (P ≤ 0.04), lower fecal score (P = 0.02), and greater ether extract digestibility (P = 0.02) than the CON group. The ALF and OAH groups had lower concentrations of ruminal total VFA (P = 0.01). Still, the ALF group had a greater proportion of acetate and a relative abundance of cellulose degradation-related bacteria (Lachnoclostridium_1 and Oribacterium) and a lower relative abundance of inflammation-related bacteria (Erysipelotrichaceae_UCG-009) in the rumen compared with CON. Interestingly, the average milk production from 6 to 200 DIM was greater in the ALF group (P < 0.01), even though no significant effects were found on the rumen fermentation parameters and blood metabolites at 200 DIM. Generally, alfalfa hay supplementation in preweaning dairy calves had positive effects in the short- and long-term for rumen development, health status, and future milk production.

Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

African American patients have a higher probability of cognitive impairment after incident stroke: An analysis of national electronic health record data.

BACKGROUND: Cognitive impairment (CI) and stroke are diseases with significant disparities in race and geography. Post stroke cognitive impairment (PSCI) can be as high as 15-70 % but few studies have utilized large administrative or electronic health records (EHR) to evaluate trends in PSCI. We utilized an EHR database to evaluate for disparities in PSCI in a large sample of patients after first recorded stroke to evaluate for disparities in race. METHODS: This is a retrospective cohort analysis of Cerner Health Facts® EHR database, which is comprised of EHR data from hundreds of hospitals/clinics in the US from 2009-2018. We evaluated patients ≥40 years of age with a first time ischemic stroke (IS) diagnosis for PSCI using ICD9/10 codes for both conditions. Patients with first stroke in the Cerner database and no pre-existing cognitive impairment were included, we compared hazard ratios for developing PSCI for patient characteristics RESULTS: A total of 150,142 IS patients with follow-up data and no pre-existing evidence of CI were evaluated. Traditional risk factors of age, female sex, kidney injury, hypertension, and hyperlipidemia were associated with PSCI. Only African American stroke survivors had a higher probability of developing PSCI compared to White survivors (HR 1.347, 95 % CI (1.270, 1.428)) and this difference was most prominent in the South. Among those to develop PSCI, median time to documentation was 1.8 years in African American survivors. CONCLUSION: In a large national database, African American stroke survivors had a higher probability of PSCI five years after stroke than White survivors.

Dietary fat and carbohydrate-balancing the lactation performance and methane emissions in the dairy cow industry: A meta-analysis.

For the agroecosystems of the dairy cow industry, dietary carbohydrate (starch, neutral detergent fiber [NDF]) and fat could directly affect rumen methane emissions and host energy utilization. However, the relationships among diet, lactation performance, and methane emissions need to be further determined to assist dairy farms to adjust diet formulations and feeding strategies for environmental and production management. A meta-analysis was conducted in the current study to explore quantitative patterns of dietary fat and carbohydrate at different levels in balancing lactation performance and environment sustainability of dairy cows, and to establish a methane emission prediction model using the artificial neural network (ANN) model. The results showed that the regression relationship between dietary fat, carbohydrate and methane emissions could be shown by the following models: methane = 106.78 + (14.86 × DMI), R2 = 0.80; methane = 443.17 - (46.41 × starch/NDF), R2 = 0.76; and methane = 388.91 + (31.40 × fat) - (5.42 × fat2), R2 = 0.80. The regression relationships between dietary fat, carbohydrate and lactation performance could be shown by the following models: milk fat yield = 1.08 + (0.43 × starch/NDF) - [0.34 × (starch/NDF)2], R2 = 0.79; milk protein yield = 0.68 + (0.15 × fat) - (0.016 × fat2), R2 = 0.82. In the structural equation model, we found that when formulating dietary carbohydrates and fats, it was necessary to balance the relationship between methane emissions and lactation performance. Specifically, dietary starch/NDF was lower than 0.63 (extremum point) and dietary fat was between 2.89% and 4.69% (extremum point), it could ensure that the aim of methane emission reduction (methane emissions decrease with increasing dietary starch/NDF and fat) was achieved without losing lactation performance of dairy cows (lactation performance increase with increasing dietary starch/NDF and fat). Finally, we established the ANN model to predict methane emissions (training set: R2 = 0.62; validation set: R2 = 0.61).

Multifunctional polyaniline modified calcium alginate aerogel membrane with antibacterial, oil-water separation, dye and heavy metal ions removal properties for complex water purification.

With the rapid development of urbanization, the discharge of industrial wastewater has led to increasingly critical water pollution issues. Additionally, heavy metals, organic dyes, microorganisms and oil pollution often coexist and have persistence and harmfulness. Developing materials that can treat these complex pollutants simultaneously has important practical significance. In this study, a calcium alginate-based aerogel membrane (PANI@CA membrane) was prepared by spraying, polymerization, Ca2+ cross-linking and freeze-drying using aniline and sodium alginate as raw materials. Oil-water emulsion can be separated by PANI@CA membrane only under gravity, and the separation efficiency was as high as 99 %. At the same time, the membrane can effectively intercept or adsorb organic dyes and heavy metal ions. The removal rates of methylene blue and Congo red were above 92 % and 63 % respectively even after ten times of cyclic filtration. The removal rate of Pb2+ was up to 95 %. In addition, PANI@CA membrane shows excellent photothermal conversion ability, and it can effectively kill Staphylococcus aureus under 808 nm laser irradiation. PANI@CA membrane has the advantages of low cost, simple preparation, good stability and high recycling ability, and has potential application prospects in wastewater treatment.

Identification of Mycoviruses in the Pathogens of Fragrant Pear Valsa Canker from Xinjiang in China.

As a common disease, canker seriously affects the yield and quality of fragrant pear due to the lack of effective control measures. Some fungi have been reported to harbor rich reservoirs of viral resources, and some mycoviruses can be used as biocontrol agents against plant diseases. In this study, 199 isolates were obtained from diseased branches of fragrant pear in the main production areas of Xinjiang. Among them, 134 belonged to Valsa spp., identified using morphological and molecular biological techniques, in which V. mali was the dominant species. The mycoviruses in Valsa spp. were further identified using metatranscriptomic sequencing and RT-PCR. The results revealed that a total of seven mycoviruses were identified, belonging to Botourmiaviridae, Endornaviridae, Fusariviridae, Hypoviridae, Mitoviridae, and Narnaviridae, among which Phomopsis longicolla hypovirus (PlHV) was dominant in all the sample collection regions. The Cryphonectria hypovirus 3-XJ1 (CHV3-XJ1), Botourmiaviridae sp.-XJ1 (BVsp-XJ1), and Fusariviridae sp.-XJ1 (Fvsp-XJ1) were new mycoviruses discovered within the Valsa spp. More importantly, compared with those in the virus-free Valsa spp. strain, the growth rate and virulence of the VN-5 strain co-infected with PlHV and CHV3-XJ1 were reduced by 59% and 75%, respectively, and the growth rate and virulence of the VN-34 strain infected with PlHV were reduced by 42% and 55%, respectively. On the other hand, the horizontal transmission efficiency of PlHV decreased when PlHV was co-infected with CHV3-XJ1, indicating that PlHV and CHV3-XJ1 were antagonistic. In summary, the mycoviruses in Valsa spp. were identified in Xinjiang for the first time, and three of them were newly discovered mycoviruses, with two strains yielding good results. These results will offer potential biocontrol resources for managing pear canker disease and provide a theoretical basis for the control of fruit tree Valsa canker disease.

Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities.

Cerebral ischemia-reperfusion (I/R) injury is the predominant causes for the poor prognosis of ischemic stroke patients after reperfusion therapy. Currently, potent therapeutic interventions for cerebral I/R injury are still very limited. Melatonin, an endogenous hormone, was found to be valid in preventing I/R injury in a variety of organs. However, a systematic review covering all neuroprotective effects of melatonin in cerebral I/R injury has not been reported yet. Thus, we perform a comprehensive overview of the influence of melatonin on cerebral I/R injury by collecting all available literature exploring the latent effect of melatonin on cerebral I/R injury as well as ischemic stroke. In this systematic review, we outline the extensive scientific studies and summarize the beneficial functions of melatonin, including reducing infarct volume, decreasing brain edema, improving neurological functions and attenuating blood-brain barrier breakdown, as well as its key protective mechanisms on almost every aspect of cerebral I/R injury, including inhibiting oxidative stress, neuroinflammation, apoptosis, excessive autophagy, glutamate excitotoxicity and mitochondrial dysfunction. Subsequently, we also review the predictive and therapeutic implications of melatonin on ischemic stroke reported in clinical studies. We hope that our systematic review can provide the most comprehensive introduction of current advancements on melatonin in cerebral I/R injury and new insights into personalized diagnosis and treatment of ischemic stroke.

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo. FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

Sex Disparities in Longitudinal Use and Intensification of Guideline-Directed Medical Therapy Among Patients With Newly Diagnosed Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Guideline-directed medical therapies (GDMTs) are the mainstay of treatment for heart failure with reduced ejection fraction (HFrEF), but they are underused. Whether sex differences exist in the initiation and intensification of GDMT for newly diagnosed HFrEF is not well established. METHODS: Patients with incident HFrEF were identified from the 2016 to 2020 Optum deidentified Clinformatics Data Mart Database, which is derived from a database of administrative health claims for members of large commercial and Medicare Advantage health plans. The primary outcome was the use of optimal GDMT within 12 months of HFrEF diagnosis. Consistent with the guideline recommendations during the time period of the study, optimal GDMT was defined as ≥50% of the target dose of evidence-based beta-blocker plus ≥50% of the target dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or any dose of angiotensin receptor neprilysin inhibitor plus any dose of mineralocorticoid receptor antagonist. The probability of achieving optimal GDMT on follow-up and predictors of optimal GDMT were evaluated with time-to-event analysis with adjusted Cox proportional hazard models. RESULTS: The study cohort included 63 759 patients (mean age, 71.3 years; 15.2% non-Hispanic Black race; 56.6% male). Optimal GDMT use was achieved by 6.2% of patients at 12 months after diagnosis. Female (compared with male) patients with HFrEF had lower use across every GDMT class and lower use of optimal GDMT at each time point at follow-up. In an adjusted Cox model, female sex was associated with a 23% lower probability of achieving optimal GDMT after diagnosis (hazard ratio [HR], 0.77 [95% CI, 0.71-0.83]; P<0.001). The sex disparities in GDMT use after HFrEF diagnosis were most pronounced among patients with commercial insurance (females compared with males; HR, 0.66 [95% CI, 0.58-0.76]) compared with Medicare (HR, 0.85 [95% CI, 0.77-0.92]); Pinteraction sex×insurance status=0.005) and for younger patients (age <65 years: HR, 0.65 [95% CI, 0.58-0.74]) compared with older patients (age ≥65 years: HR, 87 [95% CI, 80-96]) Pinteraction sex×age=0.009). CONCLUSIONS: Overall use of optimal GDMT after HFrEF diagnosis was low, with significantly lower use among female (compared with male) patients. These findings highlight the need for implementation efforts directed at improving GDMT initiation and titration.

Evaluating the long-term impact of COVID-19-associated public health interventions on zoonotic and vector-borne diseases in China: an interrupted time series analysis.

BACKGROUND: The long-term impact of COVID-19-associated public health interventions on zoonotic and vector-borne infectious diseases (ZVBs) remains uncertain. This study sought to examine the changes in ZVBs in China during the COVID-19 pandemic and predict their future trends. METHODS: Monthly incidents of seven ZVBs (Hemorrhagic fever with renal syndrome [HFRS], Rabies, Dengue fever [DF], Human brucellosis [HB], Leptospirosis, Malaria, and Schistosomiasis) were gathered from January 2004 to July 2023. An autoregressive fractionally integrated moving average (ARFIMA) by incorporating the COVID-19-associated public health intervention variables was developed to evaluate the long-term effectiveness of interventions and forecast ZVBs epidemics from August 2023 to December 2025. RESULTS: Over the study period, there were 1,599,647 ZVBs incidents. HFRS and rabies exhibited declining trends, HB showed an upward trajectory, while the others remained relatively stable. The ARFIMA, incorporating a pulse pattern, estimated the average monthly number of changes of - 83 (95% confidence interval [CI] - 353-189) cases, - 3 (95% CI - 33-29) cases, - 468 (95% CI - 1531-597) cases, 2191 (95% CI 1056-3326) cases, 7 (95% CI - 24-38) cases, - 84 (95% CI - 222-55) cases, and - 214 (95% CI - 1036-608) cases for HFRS, rabies, DF, HB, leptospirosis, malaria, and schistosomiasis, respectively, although these changes were not statistically significant besides HB. ARFIMA predicted a decrease in HB cases between August 2023 and December 2025, while indicating a relative plateau for the others. CONCLUSIONS: China's dynamic zero COVID-19 strategy may have exerted a lasting influence on HFRS, rabies, DF, malaria, and schistosomiasis, beyond immediate consequences, but not affect HB and leptospirosis. ARFIMA emerges as a potent tool for intervention analysis, providing valuable insights into the sustained effectiveness of interventions. Consequently, the application of ARFIMA contributes to informed decision-making, the design of effective interventions, and advancements across various fields.

Rhesus monkeys learn to control a directional-key inspired brain machine interface via bio-feedback.

Brain machine interfaces (BMI) connect brains directly to the outside world, bypassing natural neural systems and actuators. Neuronal-activity-to-motion transformation algorithms allow applications such as control of prosthetics or computer cursors. These algorithms lie within a spectrum between bio-mimetic control and bio-feedback control. The bio-mimetic approach relies on increasingly complex algorithms to decode neural activity by mimicking the natural neural system and actuator relationship while focusing on machine learning: the supervised fitting of decoder parameters. On the other hand, the bio-feedback approach uses simple algorithms and relies primarily on user learning, which may take some time, but can facilitate control of novel, non-biological appendages. An increasing amount of work has focused on the arguably more successful bio-mimetic approach. However, as chronic recordings have become more accessible and utilization of novel appendages such as computer cursors have become more universal, users can more easily spend time learning in a bio-feedback control paradigm. We believe a simple approach which leverages user learning and few assumptions will provide users with good control ability. To test the feasibility of this idea, we implemented a simple firing-rate-to-motion correspondence rule, assigned groups of neurons to virtual "directional keys" for control of a 2D cursor. Though not strictly required, to facilitate initial control, we selected neurons with similar preferred directions for each group. The groups of neurons were kept the same across multiple recording sessions to allow learning. Two Rhesus monkeys used this BMI to perform a center-out cursor movement task. After about a week of training, monkeys performed the task better and neuronal signal patterns changed on a group basis, indicating learning. While our experiments did not compare this bio-feedback BMI to bio-mimetic BMIs, the results demonstrate the feasibility of our control paradigm and paves the way for further research in multi-dimensional bio-feedback BMIs.

Pathophysiology and Genetic Associations of Varicose Veins: A Narrative Review.

Varicose veins (VVs) have a high prevalence worldwide and have become a major medical burden. Their pathophysiology involves a complex interplay of inflammation and tissue remodeling, and current treatment is limited by its impact on the pathophysiological mechanisms. In addition, despite clear environmental factors, family history is an important risk factor, suggesting a genetic component to the risk of developing VVs. Our understanding of the pathogenesis of these diseases has benefited greatly from the expansion of population genetic studies, from pioneering family studies to large genome-wide association studies; we now find multiple risk loci for each venous disease. This review considers the pathophysiology of VVs, highlighting the current state of genetic knowledge. We also propose future directions for research.