Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

BACKGROUND AND AIMS: Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference between SDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. METHODS: Patients who had CTEPH (n = 80) or CTEPD without PH (n = 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. RESULTS: SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). CONCLUSION: Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

Recruitment of HAB1 and SnRK2.2 by C2-domain protein CAR1 in plasma membrane ABA signaling.

Plasma membrane (PM)-associated abscisic acid (ABA) signal transduction is an important component of ABA signaling. The C2-domain ABA-related (CAR) proteins have been reported to play a crucial role in recruiting ABA receptor PYR1/PYL/RCAR (PYLs) to the PM. However, the molecular details of the involvement of CAR proteins in membrane-delimited ABA signal transduction remain unclear. For instance, where this response process takes place and whether any additional members besides PYL are taking part in this signaling process. Here, the GUS-tagged materials for all Arabidopsis CAR members were used to comprehensively visualize the extensive expression patterns of the CAR family genes. Based on the representativeness of CAR1 in response to ABA, we determined to use it as a target to study the function of CAR proteins in PM-associated ABA signaling. Single-particle tracking showed that ABA affected the spatiotemporal dynamics of CAR1. The presence of ABA prolonged the dwell time of CAR1 on the membrane and showed faster lateral mobility. Surprisingly, we verified that CAR1 could directly recruit hypersensitive to ABA1 (HAB1) and SNF1-related protein kinase 2.2 (SnRK2.2) to the PM at both the bulk and single-molecule levels. Furthermore, PM localization of CAR1 was demonstrated to be related to membrane microdomains. Collectively, our study revealed that CARs recruited the three main components of ABA signaling to the PM to respond positively to ABA. This study deepens our understanding of ABA signal transduction.

Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Bio-Polyethylene and Polyethylene Biocomposites: An Alternative toward a Sustainable Future.

Polyethylene (PE), a highly prevalent non-biodegradable polymer in the field of plastics, presents a waste management issue. To alleviate this issue, bio-based PE (bio-PE), derived from renewable resources like corn and sugarcane, offers an environmentally friendly alternative. This review discusses various production methods of bio-PE, including fermentation, gasification, and catalytic conversion of biomass. Interestingly, the bio-PE production volumes and market are expanding due to the growing environmental concerns and regulatory pressures. Additionally, the production of PE and bio-PE biocomposites using agricultural waste as filler materials, highlights the growing demand for sustainable alternatives to conventional plastics. According to previous studies, addition of ≈50% defibrillated corn and abaca fibers into bio-PE matrix and a compatibilizer, results in the highest Young's modulus of 4.61 and 5.81 GPa, respectively. These biocomposites have potential applications in automotive, building construction, and furniture industries. Moreover, the advancement made in abiotic and biotic degradation of PE and PE biocomposites is elucidated to address their environmental impacts. Finally, the paper concludes with insights into the opportunities, challenges, and future perspectives in the sustainable production and utilization of PE and bio-PE biocomposites. In summary, production of PE and bio-PE biocomposites can contribute to a cleaner and sustainable future.

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OBJECTIVES: To explore the risk factors associated with cow's milk protein allergy (CMPA) in infants. METHODS: This study was a multicenter prospective nested case-control study conducted in seven medical centers in Beijing, China. Infants aged 0-12 months were included, with 200 cases of CMPA infants and 799 control infants without CMPA. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for the occurrence of CMPA. RESULTS: Univariate logistic regression analysis showed that preterm birth, low birth weight, birth from the first pregnancy, firstborn, spring birth, summer birth, mixed/artificial feeding, and parental history of allergic diseases were associated with an increased risk of CMPA in infants (P<0.05). Multivariate logistic regression analysis revealed that firstborn (OR=1.89, 95%CI: 1.14-3.13), spring birth (OR=3.42, 95%CI: 1.70-6.58), summer birth (OR=2.29, 95%CI: 1.22-4.27), mixed/artificial feeding (OR=1.57, 95%CI: 1.10-2.26), parental history of allergies (OR=2.13, 95%CI: 1.51-3.02), and both parents having allergies (OR=3.15, 95%CI: 1.78-5.56) were risk factors for CMPA in infants (P<0.05). CONCLUSIONS: Firstborn, spring birth, summer birth, mixed/artificial feeding, and a family history of allergies are associated with an increased risk of CMPA in infants.

Clinical observation of extraction-site incisional hernia after laparoscopic colorectal surgery.

BACKGROUND: Laparoscopic colorectal cancer surgery increases the risk of incisional hernia (IH) at the tumor extraction site. AIM: To investigate the incidence of IH at extraction sites following laparoscopic colorectal cancer surgery and identify the risk factors for IH incidence. METHODS: This study retrospectively analyzed the data of 1614 patients who underwent laparoscopic radical colorectal cancer surgery with tumor extraction through the abdominal wall at our center between January 2017 and December 2022. Differences in the incidence of postoperative IH at different extraction sites and the risk factors for IH incidence were investigated. RESULTS: Among the 1614 patients who underwent laparoscopic radical colorectal cancer surgery, 303 (18.8%), 923 (57.2%), 171 (10.6%), and 217 (13.4%) tumors were extracted through supraumbilical midline, infraumbilical midline, umbilical, and off-midline incisions. Of these, 52 patients developed IH in the abdominal wall, with an incidence of 3.2%. The incidence of postoperative IH was significantly higher in the off-midline incision group (8.8%) than in the middle incision groups [the supraumbilical midline (2.6%), infraumbilical midline (2.2%), and umbilical incision (2.9%) groups] (χ2 = 24.985; P < 0.05). Univariate analysis showed that IH occurrence was associated with age, obesity, sex, chronic cough, incision infection, and combined diabetes, anemia, and hypoproteinemia (P < 0.05). Similarly, multivariate analysis showed that off-midline incision, age, sex (female), obesity, incision infection, combined chronic cough, and hypoproteinemia were independent risk factors for IH at the site of laparoscopic colorectal cancer surgery (P < 0.05). CONCLUSION: The incidence of postoperative IH differs between extraction sites for laparoscopic colorectal cancer surgery. The infraumbilical midline incision is associated with a lower hernia rate and is thus a suitable tumor extraction site.

Therapeutic advantage of teriparatide in very elderly patients with proximal femoral fractures: a functional and BMD analysis.

BACKGROUND: Teriparatide, a recombinant parathyroid hormone, is pivotal in osteoporosis treatment, particularly in post-surgical recovery for hip fractures. This study investigates its efficacy in functional recovery post-hip fracture surgery in elderly patients, a demographic particularly susceptible to osteoporotic fractures. METHODS: In this retrospective cohort study, 150 elderly patients with proximal femoral fractures undergoing open reduction and internal fixation were enrolled. They were categorized into two groups: receiving 20 µg of daily teriparatide injections for 18 months and receiving standard antiresorptive medications during a 24-month follow-up. Detailed records of patient demographics, Fracture Risk Assessment Tool scores, and comorbidities were kept. Key outcomes, including bone mineral density (BMD) and functional scores (Barthel Index and Visual Analog Scale for hip pain), were evaluated at 3 and 24 months post-surgery. RESULTS: Out of the original cohort, 126 patients (20 men and 106 women with an average age of 85.5 ± 9.3 years) completed the study. The teriparatide group exhibited significant enhancements in both functional scores and BMD when compared to the control group. Notably, functional improvements were less pronounced in male patients compared to female patients. Additionally, the incidence of new fractures was markedly lower in the teriparatide group. CONCLUSION: Administering teriparatide daily for 18 months post-surgery for proximal femoral fractures significantly benefits very elderly patients by improving functionality and bone density, with observed differences in recovery between genders. These results reinforce the efficacy of teriparatide as a potent option for treating osteoporosis-related fractures in the elderly and highlight the importance of considering gender-specific treatment and rehabilitation strategies.

Association analyses between the variants of SNAP25, SV2C and ST3GAL2 and the efficacy of botulinum toxin A in the treatment of the primary Meige syndrome.

Objective: Individual differences were observed in the clinical efficacy of Botulinum toxin A (BoNT-A) in the treatment of the primary Meige syndrome. Our study aimed to explore the potential associations between the clinical efficacy of BoNT-A in the treatment of the primary Meige syndrome and variants of SNAP25, SV2C and ST3GAL2, which are involving in the translocation of the BoNT-A in vivo. Methods: Patients with the primary Meige syndrome treated with BoNT-A were enrolled. Clinical efficacy was evaluated by the maximum improvement rate of motor symptoms and the duration of efficacy. Variants of SNAP25, SV2C and ST3GAL2 were obtained by Sanger sequencing. Another cohort diagnosed with primary cervical dystonia was also enrolled in the replication stage. Results: Among the 104 primary Meige syndrome patients, 80 patients (76.9%) had a good efficacy (the maximum improvement rate of motor symptoms ≥30%) and 24 (23. 1%) had a poor (the maximum improvement rate of motor symptoms <30%). As to the duration of efficacy, 52 patients (50.0%) had a long duration of efficacy (≥4 months), and 52 (50.0%) had a short (<4 months). In terms of primary Meige syndrome, SNAP25 rs6104571 was found associating with the maximum improvement rate of motor symptoms (Genotype: P = 0.02, OR = 0.26; Allele: P = 0.013, OR = 0.29), and SV2C rs31244 was found associating with the duration of efficacy (Genotype: P = 0.024, OR = 0.13; Allele: P = 0.012, OR = 0.13). Besides, we also conducted the association analyses between the variants and BoNT-A-related adverse reactions. Although, there was no statistical difference between the allele of SV2C rs31244 and BoNT-A-related adverse reactions, there was a trend (P = 0.077, OR = 2.56). In the replication stage, we included 39 patients with primary cervical dystonia to further expanding the samples' size. Among the 39 primary cervical dystonia patients, 25 patients (64.1%) had a good efficacy (the maximum improvement rate of motor symptoms ≥50%) and 14 (35.9%) had a poor (the maximum improvement rate of motor symptoms <50%). As to the duration of efficacy, 32 patients (82.1%) had a long duration of efficacy (≥6 months), and 7 (17.9%) had a short (<6 months). Integrating primary Meige syndrome and primary cervical dystonia, SV2C rs31244 was still found associating with the duration of efficacy (Genotype: P = 0.002, OR = 0. 23; Allele: P = 0.001, OR = 0. 25). Conclusion: In our study, SNAP25 rs6104571 was associated with the maximum improvement rate of motor symptoms in patients with primary Meige syndrome treated with BoNT-A, and patients carrying this variant had a lower improvement rate of motor symptoms. SV2C rs31244 was associated with duration of treatment in patients with primary Meige syndrome treated with BoNT-A and patients carrying this variant had a shorter duration of treatment. Patients with primary Meige syndrome carrying SV2C rs31244 G allele have an increase likelihood of BoNT-A-related adverse reactions. Involving 39 patients with primary cervical dystonia, the results further verify that SV2C rs31244 was associated with duration of treatment and patients carrying this variant had a shorter duration of treatment.

A meta-analysis of the association between RBP4 rs3758539 genotype and metabolic syndrome factors.

AIM: To explore the link between the RBP4 rs3758539 genotype and metabolic syndrome risk factors and whether the impact of this genetic variation displays any potential race discrepancy. MATERIALS AND METHODS: This meta-analysis followed the PRISMA guidelines and was registered with PROSPERO (registration no. CRD42023407999). PubMed, Web of Science, Embase, Cochrane Library, Google Scholar, Airiti Library and CINAHL databases were used for the study search until October 2023. We evaluated the methodological quality using the Joanna Briggs Institute checklist and determined the correlation using a random-effects meta-analysis. RESULTS: The results indicated that individuals with the rs3758539 GA/AA genotype had a higher risk profile, including lower high-density lipoprotein levels [correlation: -0.045, 95% confidence interval (CI): -0.080 to -0.009, p = .015, I2 = 46.9%] and higher body mass index (correlation: 0.117, 95% CI: 0.036-0.197, p = .005, I2 = 82.0%), body fat (correlation: 0.098, 95% CI: 0.004-0.191, p = .041, I2 = 64.0%), and low-density lipoprotein levels (correlation: 0.074, 95% CI: 0.010-0.139, p = .024, I2 = 0%), of developing metabolic syndrome than those with the GG genotype. The subgroup analysis maintained a significantly positive correlation between the rs3758539 GA/AA genotype and body mass index (correlation: 0.163, 95% CI: 0.031-0.289, p = .016, I2 = 88.9%) but a negative correlation with high-density lipoprotein levels (correlation: -0.047, 95% CI: -0.087 to -0.006, p = .025, I2 = 65.7%) in the Asian group only. CONCLUSION: The current meta-analysis supports a significant link between the RBP4 rs3758539 GA/AA genotype and the metabolic syndrome.

Breast Tumor Tissue Image Classification Using Single-Task Meta Learning with Auxiliary Network.

Breast cancer has a high mortality rate among cancers. If the type of breast tumor can be correctly diagnosed at an early stage, the survival rate of the patients will be greatly improved. Considering the actual clinical needs, the classification model of breast pathology images needs to have the ability to make a correct classification, even in facing image data with different characteristics. The existing convolutional neural network (CNN)-based models for the classification of breast tumor pathology images lack the requisite generalization capability to maintain high accuracy when confronted with pathology images of varied characteristics. Consequently, this study introduces a new classification model, STMLAN (Single-Task Meta Learning with Auxiliary Network), which integrates Meta Learning and an auxiliary network. Single-Task Meta Learning was proposed to endow the model with generalization ability, and the auxiliary network was used to enhance the feature characteristics of breast pathology images. The experimental results demonstrate that the STMLAN model proposed in this study improves accuracy by at least 1.85% in challenging multi-classification tasks compared to the existing methods. Furthermore, the Silhouette Score corresponding to the features learned by the model has increased by 31.85%, reflecting that the proposed model can learn more discriminative features, and the generalization ability of the overall model is also improved.

Factors Associated With Early Palliative Care Among Patients With Heart Failure.

Background: Heart failure (HF) is a progressive, life-limiting illness for which palliative care (PC) is considered standard of care. Among patients that do receive PC, consultation tends to occur late in the illness course. Objective: Our primary aim was to examine patient factors associated with receiving PC in HF. Secondarily, we sought to determine factors associated with early PC encounters. Design: This was a retrospective cohort study of U.S. Veterans with prior hospitalization who died between January 1, 2011 and December 31, 2020. Setting/Subjects: Subjects were Veterans with HF who died with a prior admission to a Veterans Affairs hospital in the United States. Measurements: We calculated the time from PC encounter to death. We characterized HF patients who died without PC, with late PC (≤90 days before death), and with early PC (>90 days before death). Results: We identified 232,079 Veterans with a mean age of (76.5 ± 10.7) years. Within the cohort, 56.5% (n = 131,122) of Veterans died with no PC, 22.5% (n = 52,114) had PC <90 days before death, and 21.0% (n = 48,843) had PC >90 days before death. Veterans who died without PC tended to be younger with fewer comorbidities. Conclusions: While more than 20% of HF patients in our cohort had PC well in advance of death, more than half died without PC. PC involvement seemed to be driven by comorbidities rather than HF. Effective collaboration with Cardiology is needed to identify patients who would benefit from earlier PC involvement.

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

The extracellular vesicles in HIV infection and progression: mechanisms, and theranostic implications.

Extracellular vesicles (EVs), these minute yet mighty cellular messengers are redefining our understanding of a spectrum of diseases, from cancer to cardiovascular ailments, neurodegenerative disorders, and even infectious diseases like HIV. Central to cellular communication, EVs emerge as both potent facilitators and insightful biomarkers in immune response and the trajectory of disease progression. This review ventures deep into the realm of EVs in HIV-unraveling their pivotal roles in diagnosis, disease mechanism unravelling, and therapeutic innovation. With a focus on HIV, we will highlights the transformative potential of EVs in both diagnosing and treating this formidable virus. Unveiling the intricate dance between EVs and HIV, the review aims to shed light on novel therapeutic strategies that could significantly benefit HIV therapy, potentially even leading to the eradication of HIV.

Live-cell imaging reveals the trade-off between target search flexibility and efficiency for Cas9 and Cas12a.

CRISPR-Cas systems have widely been adopted as genome editing tools, with two frequently employed Cas nucleases being SpyCas9 and LbCas12a. Although both nucleases use RNA guides to find and cleave target DNA sites, the two enzymes differ in terms of protospacer-adjacent motif (PAM) requirements, guide architecture and cleavage mechanism. In the last years, rational engineering led to the creation of PAM-relaxed variants SpRYCas9 and impLbCas12a to broaden the targetable DNA space. By employing their catalytically inactive variants (dCas9/dCas12a), we quantified how the protein-specific characteristics impact the target search process. To allow quantification, we fused these nucleases to the photoactivatable fluorescent protein PAmCherry2.1 and performed single-particle tracking in cells of Escherichia coli. From our tracking analysis, we derived kinetic parameters for each nuclease with a non-targeting RNA guide, strongly suggesting that interrogation of DNA by LbdCas12a variants proceeds faster than that of SpydCas9. In the presence of a targeting RNA guide, both simulations and imaging of cells confirmed that LbdCas12a variants are faster and more efficient in finding a specific target site. Our work demonstrates the trade-off of relaxing PAM requirements in SpydCas9 and LbdCas12a using a powerful framework, which can be applied to other nucleases to quantify their DNA target search.

Harnessing Ash for Sustainable CO2 Absorption: Current Strategies and Future Prospects.

This review explores the potential of using different types of ash, namely fly ash, biomass ash, and coal ash etc., as mediums for CO2 capture and sequestration. The diverse origins of these ash types-municipal waste, organic biomass, and coal combustion-impart unique physicochemical properties that influence their suitability and efficiency in CO2 absorption. This review first discusses the environmental and economic implications of using ash wastes, emphasizing the reduction in landfill usage and the transformation of waste into value-added products. Then the chemical/physical treatments of ash wastes and their inherent capabilities in binding or reacting with CO2 are introduced, along with current methodologies utilize these ashes for CO2 sequestration, including mineral carbonation and direct air capture techniques. The application of using ash wastes for CO2 capture are highlighted, followed by the discussion regarding challenges associated with ash-based CO2 absorption approach. Finally, the article projects into the future, proposing innovative approaches and technological advancements needed to enhance the efficacy of ash in combating the increasing CO2 levels. By providing a comprehensive analysis of current strategies and envisioning future prospects, this review aims to contribute to the field of sustainable CO2 absorption and environmental management.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Exercise capacity-hemodynamics mismatch in elderly patients with pulmonary hypertension: A nationwide multicenter study from Taiwan Society of Cardiology Pulmonary Hypertension Registry (TAIPANS).

Background: Demographics of pulmonary hypertension (PH) has changed a lot over the past forty years. Several recent registries noted an increase in mean age of PH but only a few of them investigated the characteristics of elderly patients. Thus, we aimed to analyze the characteristics of PH in such a population in this study. Methods: This multicenter study enrolled patients diagnosed with PH in group 1, 3, 4, and 5 consecutively from January 1, 2019 to December 31, 2020. A total of 490 patients was included, and patients were divided into three groups by age (≤45 years, 45-65 years, and >65 years). Results: The mean age of PH patients diagnosed with PH was 55.3 ± 16.3 years of age. There was higher proportion of elderly patients classified as group 3 PH (≤45: 1.3, 45-65: 4.5, >65: 8.1 %; p = 0.0206) and group 4 PH (≤45: 8.4, 45-65: 14.5, >65: 31.6 %; p < 0.0001) than young patients. Elderly patients had shorter 6-min walking distance (6 MWD) (≤45 vs. >65, mean difference, 77.8 m [95% confidence interval (CI), 2.1-153.6 m]), lower mean pulmonary arterial pressure (mPAP) (≤45 vs. >65, mean difference, 10.8 mmHg [95% CI, 6.37-15.2 mmHg]), and higher pulmonary arterial wedge pressure (PAWP) (≤45 vs. 45-65, mean difference, -2.1 mmHg [95% CI, -3.9 to -0.3 mmHg]) compared to young patients. Elderly patients had a poorer exercise capacity despite lower mPAP level compared to young population, but they received combination therapy less frequently compared to young patients (triple therapy in group 1 PH, ≤45: 16.7, 45-65: 11.3, >65: 3.8 %; p = 0.0005). Age older than 65 years was an independent predictor of high mortality for PH patients. Conclusions: Elderly PH patients possess unique hemodynamic profiles and epidemiologic patterns. They had higher PAWP, lower mPAP, and received combination therapy less frequently. Moreover, ageing is a predictor of high mortality for PH patients. Exercise capacity-hemodynamics mismatch and inadequate treatment are noteworthy in the approach of elderly population with PH.

Advanced brain aging in Parkinson's disease with cognitive impairment.

Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.

Downregulation of HMGB1 carried by macrophage-derived extracellular vesicles delays atherosclerotic plaque formation through Caspase-11-dependent macrophage pyroptosis.

BACKGROUND: Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS: In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1). ApoE-/- mice were used to construct an AS mouse model by a high-fat diet, followed by injection of macrophage-EV/siHMGB1 to assess the in vivo effect of macrophage-EV/siHMGB1 on AS mice. RAW264.7 cells were subjected to ox-LDL, LPS or macrophage-EV/siHMGB1 for analyzing the in vitro effect of macrophage-EV/siHMGB1 on macrophage pyrophosis and inflammation. RESULTS: In silico analysis found that HMGB1 was closely related to the development of AS. Macrophage-EV/siHMGB could inhibit the release of HMGB1 from macrophages to outside cells, and the reduced HMGB1 release could inhibit foam cell formation. Besides, macrophage-EV/siHMGB also inhibited the LPS-induced Caspase-11 activation, thus inhibiting macrophage pyroptosis and preventing atherosclerotic plaque formation. CONCLUSION: Our results proved that macrophage-EV/siHMGB could inhibit foam cell formation and suppress macrophage pyroptosis, finally preventing atherosclerotic plaque formation in AS mice.