A novel de novo synonymous variant in GREB1L impacts the mRNA splicing associated with aplasia of the urogenital system.

GREB1-like retinoic acid receptor coactivator (GREB1L) gene is associated with autosomal dominant renal hypodysplasia/aplasia 3 (RHDA3) and deafness, autosomal dominant 80 (DFNA80). Among the GREB1L variants reported, most of them are missense or frameshift, while no pathogenic synonymous variants have been recorded. Classical theory paid little attention to synonymous variants and classified it as nonpathogenic; however, recent studies suggest that the variants might be equally important. Here, we report a 7-year-old girl with new symptoms of clitoromegaly, uterovaginal, and ovarian agenesis as well as right kidney missing. A novel de novo GREB1L synonymous variant (NM_001142966: c.4731C>T, p.G1577=) was identified via whole exome sequencing. The variant was predicted to be disease-causing through in silico analysis and was classified as likely pathogenic. Minigene splicing assays confirmed a 6 bp deletion in mutant cDNA comparing with the wild type, leading to two amino acids lost in GREB1L protein. Secondary and tertiary structure modeling showed alterations in protein structure. Our finding reveals a novel GREB1L variant with a new phenotype of urogenital system and is the first to report a pathogenic synonymous variant in GREB1L which affects mRNA splicing, suggesting synonymous variants cannot be ignored in prenatal diagnosis and genetic counseling.

BvCGT1-mediated differential distribution of flavonoid C-glycosides contributes to plant's response to UV-B stress.

C-glycosides are a predominant class of flavonoids that demonstrate diverse medical properties and plant physiological functions. The chemical stability, structural diversity, and differential aboveground distribution of these compounds in plants make them ideal protectants. However, little is known about the transcriptional regulatory mechanisms that play these diverse roles in plant physiology. In this study, chard was selected from 69 families for its significantly different flavonoid C-glycosides distributions between the aboveground and underground parts to investigate the role and regulatory mechanism of flavonoid C-glycosides in plants. Our results indicate that flavonoid C-glycosides are affected by various stressors, especially UV-B. Through cloning and validation of key biosynthetic genes of flavonoid C-glycosides in chard (BvCGT1), we observed significant effects induced by UV-B radiation. This finding was further confirmed by resistance testing in BvCGT1 silenced chard lines and in Arabidopsis plants with BvCGT1 overexpression. Yeast one-hybrid and dual-luciferase assays were employed to determine the underlying regulatory mechanisms of BvCGT1 in withstanding UV-B stress. These results indicate a potential regulatory role of BvDof8 and BvDof13 in modulating flavonoid C-glycosides content, through their influence on BvCGT1. In conclusion, we have effectively demonstrated the regulation of BvCGT1 by BvDof8 and BvDof13, highlighting their crucial role in plant adaptation to UV-B radiation. Additionally, we have outlined a comprehensive transcriptional regulatory network involving BvDof8 and BvDof13 in response to UV-B radiation.

The impact of diabetes mellitus on cardiac function assessed by magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

BACKGROUND: The adverse prognostic impact of diabetes on hypertrophic cardiomyopathy (HCM) is poorly understood. We sought to explore the underlying mechanisms in terms of structural and functional remodelling in HCM patients with coexisting diabetes (HCM-DM). METHODS: A total of 45 HCM-DM patients were retrospectively included. Isolated HCM controls (HCM patients without diabetes) were matched to HCM-DM patients in terms of maximal wall thickness, age, and gender distribution. Left ventricular (LV) and atrial (LA) performance were evaluated using cardiac magnetic resonance feature tracking strain analyses. The associations between diabetes and LV/LA impairment were investigated by univariable and multivariable linear regression. RESULTS: Compared with the isolated HCM controls, the HCM-DM patients had smaller end-diastolic volume and stroke volume, lower ejection fraction, larger mass/volume ratio and impaired strains in all three directions (all P < 0.05). In terms of the LA parameters, HCM-DM patients presented impaired LA reservoir and conduit strain/strain rate (all P < 0.05). Among all HCM patients, comorbidity with diabetes was independently associated with a low LV ejection fraction (ß = - 6.05, P < 0.001) and impaired global longitudinal strain (ß = 1.40, P = 0.007). Moreover, compared with the isolated HCM controls, HCM-DM patients presented with more myocardial fibrosis according to late gadolinium enhancement, which was an independent predictor of impaired LV global radial strain (ß = - 45.81, P = 0.008), LV global circumferential strain (ß = 18.25, P = 0.003), LA reservoir strain (ß = - 59.20, P < 0.001) and strain rate (ß = - 2.90, P = 0.002). CONCLUSIONS: Diabetes has adverse effects on LV and LA function in HCM patients, which may be important contributors to severe manifestations and outcomes in those patients. The present study strengthened the evidence of the prevention and management of diabetes in HCM patients.

Prediction of postoperative mortality in older surgical patients by clinical frailty scale: A systematic review and meta-analysis.

AIMS: To systematically evaluate the predictive efficacy of clinical frailty scale (CFS) for postoperative mortality older surgical patients, and to evaluate the prevalence of frailty in the included studies. DESIGN: A systematic review and meta-analysis of observational studies was conducted, utilizing the MOOSE guidelines for the evaluation of both. Quality assessment of the articles was also performed. DATA SOURCES: The protocol was registered (CRD42023423552). Relevant English and Chinese language studies published until October 20th, 2023 were retrieved from PubMed, Web of Science, Embase, Medline, CINAHL,Cochrane, WAN FANG DATA, VIP Information, CNKI, and SinoMed databases. REVIEW METHODS: Study were included in which frailty was measured by the CFS and postoperative mortality was reported for older surgery patients. A meta-analysis to predict postoperative mortality and frailty prevalence was performed using STATA 17.0 software. RESULTS: Sixteen cohort studies were included (5,864 participants) from 1,513 records. All studies' Newcastle-Ottawa Scale (NOS) scores were above 6 points. It was found that the prevalence of surgical frailty in the older was 0.36(CI 0.20-0.52). Patients assessed as frail by the CFS were associated with higher all-cause mortality (OR:4.01; CI 2.59-6.23). Subgroup analysis shows that frailty was associated with1-month mortality (OR:3.85; CI 1.11-13.45) and 1-year mortality (OR:4.43; CI 2.18-8.99). CONCLUSIONS: The prevalence of frailty is high in older surgical patients, and CFS can effectively predict the mortality of older surgical patients with frailty.

Syringin: a naturally occurring compound with medicinal properties.

Syringin, a phenylpropanoid glycoside, is widely distributed in various plants, such as Acanthopanax senticosus (Rupr. et Maxim.) Harms, Syringa reticulata (BL) Hara var. mandshurica (Maxim.) Hara, and Ilex rotunda Thumb. It serves as the main ingredient in numerous listed medicines, health products, and foods with immunomodulatory, anti-tumor, antihyperglycemic, and antihyperlipidemic effects. This review aims to systematically summarize syringin, including its physicochemical properties, plant sources, extraction and separation methods, total synthesis approaches, pharmacological activities, drug safety profiles, and preparations and applications. It will also cover the pharmacokinetics of syringin, followed by suggestions for future application prospects. The information on syringin was obtained from internationally recognized scientific databases through the Internet (PubMed, CNKI, Google Scholar, Baidu Scholar, Web of Science, Medline Plus, ACS Elsevier, and Flora of China) and libraries. Syringin, extraction and separation, pharmacological activities, preparations and applications, and pharmacokinetics were chosen as the keywords. According to statistics, syringin can be found in 23 families more than 60 genera, and over 100 species of plants. As a key component in many Chinese herbal medicines, syringin holds significant research value due to its unique sinapyl alcohol structure. Its diverse pharmacological effects include immunomodulatory activity, tumor suppression, hypoglycemic action, and hypolipidemic effects. Additionally, it has been shown to provide neuroprotection, liver protection, radiation protection, cardioprotection, and bone protection. Related preparations such as Aidi injection, compound cantharidin capsule, and Tanreqing injection have been widely used in clinical settings. Other studies on syringin such as extraction and isolation, total synthesis, safety profile assessment, and pharmacokinetics have also made progress. It is crucial for medical research to deeply explore its mechanism of action, especially regarding immunity and tumor therapy. Meanwhile, more robust support is needed to improve the utilization of plant resources and to develop extraction means adapted to the needs of industrial biochemistry to further promote economic development while protecting people's health.

Efficacy of robot-assisted thoracoscopic surgery in the treatment of pulmonary sequestration in children.

Objective: This study was performed to evaluate the efficacy of robot-assisted thoracoscopic surgery (RATS) in the treatment of pulmonary sequestration (PS) in children. Methods: All video-assisted thoracoscopic surgery (VATS) and RAST performed on patients with PS at a single center from May 2019 to July 2023 were identified. The χ 2 and Wilcoxon tests were used to compare the perioperative outcomes between VATS and RATS groups. Results: Ninety-three patients underwent RATS while 77 patients underwent VATS. In both two groups, one patient converted to thoracotomy and no surgical mortality case. The median operation time was longer for the RATS group compared with the VATS group (75 min vs. 60 min, p <0.001). A lower ratio of chest tube indwelling (61.3% vs. 90.9%, p <0.001), fewer drainage days (1.0 day vs. 2.0 days, p <0.001), and a shorter postoperative length of stay (5.0 days vs. 6.0 days, p <0.001) were found in the RATS group than that in the VATS group. No significant difference was found in the incidence of short-term postoperative complications (hydrothorax and pneumothorax) between two groups. Conclusions: RATS was safe and effective in children with PS over 6 months old and more than 7 kg. Furthermore, RATS led to better short-time postoperative outcome than VATS. Multi-institutional studies are warranted to compare differences in long-term outcomes between RATS and VATS.

Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design.

Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc-/glutathione peroxidase 4 (GPX4), lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.

The regulating mechanisms of Triton X-100 affected oxidation of PAHs in site soil aggregates using sodium citrate assisted Fe2+-persulfate.

Here, we present a first investigation of the inhibition mechanism of surfactant Triton X-100 (TX-100) on the oxidation degradation of polycyclic aromatic hydrocarbons (PAHs) in site soil aggregates using sodium citrate assisted Fe2+-activated persulfate (SC/Fe2+/PS). First, TX-100 was not only competed the adsorption sites of soil aggregates with PS, but also consumed PS, which inhibit the PAHs remediation rate in the TX-100 elution followed by the SC/Fe2+/PS oxidation system from 55.6 % in the oxidation system to 50.3 %. Furthermore, in the oxidation followed by elution system, PAHs was adsorbed on the iron minerals produced during the oxidation, which would be form a bound PAHs that was difficult to react with PS, and then re-eluted to the soil by the TX-100. Additionally, it was found that the oxidative and the elution efficiency of PAHs exhibited negative correlations with aggregate particle sizes. Finally, soil microorganism communities were more strongly changed by SC/Fe2+/PS oxidation and PAHs concentration than that of TX-100 elution, with obvious alterations bacteria than fungi, the effects of SC/Fe2+/PS and PAHs concentration on microorganism communities were opposite. This study provided a proof of regulating mechanisms for the site soil remediation using surfactants combined with the iron-PS system.

Effectiveness of onsite and online education in enhancing knowledge and use of human immunodeficiency virus pre- and post-exposure prophylaxis.

BACKGROUND: Enhancing awareness and use of pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) is vital to curb human immunodeficiency virus (HIV) spread. High-risk behaviors prevalent among sexually transmitted infection clinic outpatients underscore the need for increased PrEP/PEP education in this group. AIM: To investigate the effects of both onsite and online health education on the knowledge of, and willingness to use, PrEP and PEP among individuals receiving PEP services. METHODS: Participants were drawn from a cohort study on PEP service intervention at an STD/AIDS outpatient clinic in designated HIV/AIDS hospitals in Beijing, conducted from January 1 to June 30, 2022. Health education was provided both onsite and online during follow-up. Surveys assessing knowledge of, and willingness to use, PrEP/PEP were administered at baseline and again at 24 wk post-intervention. RESULTS: A total of 112 participants were enrolled in the study; 105 completed the follow-up at week 24. The percentage of participants with adequate knowledge of, and willingness to use, PrEP significantly increased from 65.2% and 69.6% at baseline to 83.8% and 82.9% at the end of the intervention (both P < 0.05). Similarly, those with adequate knowledge of, and willingness to use, PEP increased from 74.1% and 77.7% at baseline to 92.4% and 89.5% at week 24 (P < 0.05). Being between 31 years and 40 years of age, having a postgraduate degree or higher, and reporting a monthly expenditure of RMB 5000 or more were found to be significantly associated with knowledge of PrEP and PEP (both P < 0.05). CONCLUSION: The findings show that both onsite and online health education significantly improved the knowledge of, and increased willingness to use, PrEP and PEP in individuals utilizing PEP services.

Chromosome-level genome assembly of marmalade hoverfly Episyrphus balteatus (Diptera: Syrphidae).

Episyrphus balteatus can provide dual ecosystem services including pest control and pollination, which the larvae are excellent predators of aphid pest whereas adults are efficient pollinator. In this study, we assembled a high-quality genome of E. balteatus from northern China geographical population at the chromosome level by using Illumina, PacBio long reads, and Hi-C technologies. The 467.42 Mb genome was obtained from 723 contigs, with a contig N50 of 9.16 Mb and Scaffold N50 of 118.85 Mb, and 90.25% (431.75 Mb) of the assembly was anchored to 4 pseudo-autosomes and one pseudo-heterosome. In total, 14,848 protein-coding genes were annotated, and 95.14% of genes were fully represented in NR, GO, KEGG databases. Besides, we also obtained the mitochondrial genome of E. balteatus of 16, 837 bp in length with 37 typical mitochondrial genes. Overall, this high-quality genome is valuable for evolutionary and genetic studies of E. balteatus and other Syrphidae hoverfly species.

miR-106b-5p protects against drug-induced liver injury by targeting vimentin to stimulate liver regeneration.

Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR-106b-5p protects mice from liver injury. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR-106b-5p by dual luciferase reporter and siRNA assays. Furthermore, single-cell RNA-sequencing analysis of toosendanin-injured mouse liver revealed a cluster of Vim + hepatocytes; nonetheless declined following miR-106b-5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR-106b-5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR-106b-5p safeguards restorative tissue repair by targeting vimentin.

Deep learning architecture with shunted transformer and 3D deformable convolution for voxel-level dose prediction of head and neck tumors.

Intensity-modulated radiation therapy (IMRT) has been widely used in treating head and neck tumors. However, due to the complex anatomical structures in the head and neck region, it is challenging for the plan optimizer to rapidly generate clinically acceptable IMRT treatment plans. A novel deep learning multi-scale Transformer (MST) model was developed in the current study aiming to accelerate the IMRT planning for head and neck tumors while generating more precise prediction of the voxel-level dose distribution. The proposed end-to-end MST model employs the shunted Transformer to capture multi-scale features and learn a global dependency, and utilizes 3D deformable convolution bottleneck blocks to extract shape-aware feature and compensate the loss of spatial information in the patch merging layers. Moreover, data augmentation and self-knowledge distillation are used to further improve the prediction performance of the model. The MST model was trained and evaluated on the OpenKBP Challenge dataset. Its prediction accuracy was compared with three previous dose prediction models: C3D, TrDosePred, and TSNet. The predicted dose distributions of our proposed MST model in the tumor region are closest to the original clinical dose distribution. The MST model achieves the dose score of 2.23 Gy and the DVH score of 1.34 Gy on the test dataset, outperforming the other three models by 8%-17%. For clinical-related DVH dosimetric metrics, the prediction accuracy in terms of mean absolute error (MAE) is 2.04% for D 99 , 1.54% for D 95 , 1.87% for D 1 , 1.87% for D mean , 1.89% for D 0.1 c c , respectively, superior to the other three models. The quantitative results demonstrated that the proposed MST model achieved more accurate voxel-level dose prediction than the previous models for head and neck tumors. The MST model has a great potential to be applied to other disease sites to further improve the quality and efficiency of radiotherapy planning.

Changing ozone sensitivity in Fujian Province, China, during 2012-2021: Importance of controlling VOC emissions.

In the troposphere, ozone (O3) formation can be limited by NOx, VOCs, or both, complicating efforts to reduce O3 by controlling its precursors. This study used formaldehyde (HCHO) data and nitrogen dioxide (NO2) data from the Ozone Monitoring Instrument (OMI) to analyze O3 formation sensitivity in Fujian from 2012 to 2021. Over the past decade, an 8.7% reduction in NO2 VCDs and a 9.91% increase in HCHO VCDs were observed. Due to differences in the primary driving factors, HCHO VCDs exhibit a characteristic seasonal pattern with higher in summer and lower in winter, whereas NO2 VCDs show the opposite trend. O3 formation chemistry was accurately diagnosed by combining satellite-based data and ground-based O3 data. A new threshold value (3.3-4.6) was derived to determine the transition from VOC-limited to NOx-limited O3 formation regimes. Results showed that O3 sensitivity exhibited pronounced seasonal variations. The VOC-limited regime predominates throughout the entire Fujian region in winter, whereas it occupies only 5% of the area in summer. A VOC-limited region was found widely across Fujian on an annual average, but it decreased by 24% over 10 years. Transitional areas experienced a 19% increase. In two natural emission reduction cases (reductions during the Chinese Lunar New Year holiday and reductions in weekend traffic emissions compared to weekdays), ground-level O3 effectively captured the impacts of sensitivity changes. The impact suggests that when Fujian is in the VOC control region, a significant reduction in NOx, without effective VOC control, might lead to an O3 increase. The importance of controlling VOC emissions is highlighted in Fujian. This study enhances the understanding of O3 formation regimes in southeastern China, which is crucial for developing O3 prevention and control strategies.

Versatile Fabrication of Biocompatible Antimicrobial Materials Enabled by Cationic Peptide Bundles.

Antimicrobial peptides (AMPs) are expected to be an alternative promising solution to the global public health problem of antibiotic resistance due to their unique antimicrobial mechanism. However, extensive efforts are still needed to improve the shortcomings of traditional AMPs, such as rapid proteolysis, hemolysis, slow response, toxicity, etc., by exploring AMP-based new antimicrobial strategies. Here, we develop cationic peptide bundles into novel antimicrobial architectures that can rapidly kill multiple types of bacteria including drug-resistant bacteria. Remarkably, cationic peptide bundles can be used as polymerization units to cross-link with other polymers through simple two-component polymerization to produce diverse antimicrobial materials. For the proof of concept, three materials were fabricated and investigated, including an antimicrobial hydrogel that can significantly accelerate the healing of infected wounds, a multifunctional antimicrobial bioadhesive that shows promise in antimicrobial coatings for medical devices, and a photo-cross-linked antimicrobial gelatin hydrogel with broad application potential. The integration of antimicrobial units into the materials' backbone endows their biocompatibility. Cationic peptide bundles not only represent a new antimicrobial strategy but also provide a versatile and promising processing method to create diversified, multifunctional, and biocompatible antimicrobial materials.

Nanocrystals: Versatile Platform for Traditional Chinese Medicine Delivery.

The medicinal value of Chinese medicines has been recognized since ancient times, and they have also been used to treat various diseases. However, in-depth studies on the active ingredients of Chinese medicines have shown that many of them suffer from poor water-solubility, stability, and bioavailability, which has severely limited their further development. The advent of nanomedicine represents a novel direction and paradigm for addressing these challenges. Particularly, within the framework of nanocrystal technology, enhancements in the water solubility, stability, and bioavailability of Chinese medicines are expected to significantly improve the therapeutic efficiency. This advancement also holds promise for unlocking new therapeutic capabilities. Nanocrystals offer significant advantages in oral, intravenous, intranasal and targeted delivery. The drug loading principle is "all in one", with hydrophobic-drug-in and hydrophilic-drug-out and stabilization by amphiphilic agents. Nanocrystal technology in traditional Chinese medicine (TCM) holds extensive application potential. Continuous refinement of preparation techniques, sound safety assessments, and the promotion of large-scale production are anticipated to augment its pivotal role in TCM formulations, thereby creating novel opportunities for clinical drug therapy.

The multiple mechanisms and therapeutic significance of rutin in metabolic dysfunction-associated fatty liver disease (MAFLD).

The global incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been steadily increasing, making it a leading chronic liver disease. MAFLD refers to a metabolic syndrome linked with type 2 diabetes mellitus, obesity. However, its pathophysiology is complex, there are currently no effective and approved medicines for therapy. Rutin, a naturally occurring polyphenolic flavonoid, is widely distributed in fruits, vegetables, and other plants. It exhibits a plethora of bioactive properties, such as antioxidant, anticancer, and anti-inflammatory and neuroprotective activities, making it an extremely promising phytochemical. Rutin has shown great potential in the treatment of a wide variety of metabolic diseases and received considerable attention in recent years. Fortuitously, various research studies have validated rutin's extensive biological functions in treating metabolic disorders. Despite the fact that the exact pathophysiological mechanisms through which rutin has a hepatoprotective effect on MAFLD are still not fully elucidated. This review comprehensively outlines rutin's multifaceted preventive and therapeutic effects in MAFLD, including the modulation of lipid metabolism, reduction of insulin resistance, diminution of inflammation and oxidative stress, combatting of obesity, and influence on intestinal flora. This paper details the known molecular targets and pathways of rutin in MAFLD pathogenesis. It endeavored to provide new ideas for treating MAFLD and accelerating its translation from bench to bedside.

Melatonin regulates microglial M1/M2 polarization via AMPKα2-mediated mitophagy in attenuating sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a disease characterized by neuroinflammation and cognitive dysfunction caused by systemic infection. Inflammation-induced microglial activation is closely associated with neuroinflammation in SAE. It is widely understood that melatonin has strong anti-inflammatory and immunomodulatory properties beneficial for sepsis-related brain damage. However, the mechanism of melatonin action in SAE has not been fully elucidated. METHODS: The SAE cell model and SAE mouse model were induced by lipopolysaccharide (LPS). Behavioral tests were performed to analyze cognitive function. Microglial markers and M1/M2 markers were measured by immunofluorescence. Mitophagy was assessed by western blot, mt-Keima and transmission electron microscopy experiments. Immunoprecipitation and co-immunoprecipitation assays investigated the interactions between AMP-activated protein kinase α2 (AMPKα2) and PTEN-induced putative kinase 1 (PINK1). RESULTS: Melatonin suppresses LPS-induced microglia M1 polarization by enhancing mitophagy, thereby attenuating LPS-induced neuroinflammation and behavioral deficits. However, inhibition or knockdown of AMPKα2 can inhibit the enhancement of melatonin on mitophagy, then weaken its promotion of microglia polarization towards M2 phenotype, and eliminate its protective effect on brain function. Furthermore, melatonin enhances mitophagy through activating AMPKα2, promotes PINK1 Ser495 site phosphorylation, and ultimately regulates microglial polarization from M1 to M2. CONCLUSIONS: Our findings demonstrate that melatonin facilitates microglia polarization towards M2 phenotype to alleviate LPS-induced neuroinflammation, primarily through AMPKα2-mediated enhancement of mitophagy.

The Effect Of Next Generation Accountable Care Organizations On Medicare Expenditures.

The Next Generation Accountable Care Organization (NGACO) model (active during 2016-21) tested the effects of high financial risk, payment mechanisms, and flexible care delivery on health care spending and value for fee-for-service Medicare beneficiaries. We used quasi-experimental methods to examine the model's effects on Medicare Parts A and B spending. Sixty-two ACOs with more than 4.2 million beneficiaries and more than 91,000 practitioners participated in the model. The model was associated with a $270 per beneficiary per year, or approximately $1.7 billion, decline in Medicare spending. After shared savings payments to ACOs were included, the model increased net Medicare spending by $56 per beneficiary per year, or $96.7 million. Annual declines in spending for the model grew over time, reflecting exit by poorer-performing NGACOs, improvement among the remaining NGACOs, and the COVID-19 pandemic. Larger declines in spending occurred among physician practice ACOs and ACOs that elected population-based payments and risk caps greater than 5 percent.

Learning Signed Hyper Surfaces for Oriented Point Cloud Normal Estimation.

We propose a novel method called SHS-Net for point cloud normal estimation by learning signed hyper surfaces, which can accurately predict normals with global consistent orientation from various point clouds. Almost all existing methods estimate oriented normals through a two-stage pipeline, i.e., unoriented normal estimation and normal orientation, and each step is implemented by a separate algorithm. However, previous methods are sensitive to parameter settings, resulting in poor results from point clouds with noise, density variations and complex geometries. In this work, we introduce signed hyper surfaces (SHS), which are parameterized by multi-layer perceptron (MLP) layers, to learn to estimate oriented normals from point clouds in an end-to-end manner. The signed hyper surfaces are implicitly learned in a high-dimensional feature space where the local and global information is aggregated. Specifically, we introduce a patch encoding module and a shape encoding module to encode a 3D point cloud into a local latent code and a global latent code, respectively. Then, an attention-weighted normal prediction module is proposed as a decoder, which takes the local and global latent codes as input to predict oriented normals. Experimental results show that our algorithm outperforms the state-of-the-art methods in both unoriented and oriented normal estimation.

Sex differences in clinical profile, left ventricular remodeling and cardiovascular outcomes among diabetic patients with heart failure and reduced ejection fraction: a cardiac-MRI-based study.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with a high rate of mortality and morbidity. Evidence has shown that sex differences may be an important contributor to phenotypic heterogeneity in patients with HFrEF. Although diabetes mellitus (DM) frequently coexists with HFrEF and results in a worse prognosis, there remains a need to identify sex-related differences in the characteristics and outcomes of this population. In this study, we aimed to investigate the between-sex differences in clinical profile, left ventricular (LV) remodeling, and cardiovascular risk factors and outcomes in patients with HFrEF concomitant with DM. METHODS: A total of 273 patients with HFrEF concomitant with DM who underwent cardiac MRI were included in this study. Clinical characteristics, LV remodeling as assessed by cardiac MRI, and cardiovascular risk factors and outcomes were compared between sexes. RESULTS: Women were older, leaner and prone to have anemia and hypoproteinemia but less likely to have ischemic etiology. Cardiac MRI revealed that despite similar LVEFs between the sexes, there was more LV concentric remodeling, less impaired global systolic peak strain in longitudinal and circumferential components and a decreased likelihood of late gadolinium enhancement presence in women than in men. During a median follow-up time of 34.6 months, women exhibited better overall survival than men did (log-rank P = 0.042). Multivariable Cox proportional hazards analysis indicated different risk factors for predicting outcomes between sexes, with hypertension [hazard ratio (HR) = 2.05, 95% confidence interval (CI) 1.05 to 4.85, P = 0.041] and hypoproteinemia (HR = 2.27, 95% CI 1.06 to 4.37, P = 0.039) serving as independent determinants of outcomes in women, whereas ischemic etiology (HR = 1.96, 95% CI 1.11 to 3.48, P = 0.021) and atrial fibrillation (HR = 1.86, 95% CI 1.02 to 3.41, P = 0.044) served as independent determinants of outcomes in men. CONCLUSIONS: Among patients with HFrEF concomitant with DM, women displayed different LV remodeling and risk factors and had better survival than men did. Sex-based phenotypic heterogeneity in patients with HFrEF in the context of DM should be addressed in clinical practice.