Neurotoxicity of fine and ultrafine particulate matter: A comprehensive review using a toxicity pathway-oriented adverse outcome pathway framework.

Fine particulate matter (PM2.5) can cause brain damage and diseases. Of note, ultrafine particles (UFPs) with an aerodynamic diameter less than or equal to 100 nm are a growing concern. Evidence has suggested toxic effects of PM2.5 and UFPs on the brain and links to neurological diseases. However, the underlying mechanism has not yet been fully illustrated due to the variety of the study models, different endpoints, etc. The adverse outcome pathway (AOP) framework is a pathway-based approach that could systematize mechanistic knowledge to assist health risk assessment of pollutants. Here, we constructed AOPs by collecting molecular mechanisms in PM-induced neurotoxicity assessments. We chose particulate matter (PM) as a stressor in the Comparative Toxicogenomics Database (CTD) and identified the critical toxicity pathways based on Ingenuity Pathway Analysis (IPA). We found 65 studies investigating the potential mechanisms linking PM2.5 and UFPs to neurotoxicity, which contained 2, 675 genes in all. IPA analysis showed that neuroinflammation signaling and glucocorticoid receptor signaling were the common toxicity pathways. The upstream regulator analysis (URA) of PM2.5 and UFPs demonstrated that the neuroinflammation signaling was the most initially triggered upstream event. Therefore, neuroinflammation was recognized as the MIE. Strikingly, there is a clear sequence of activation of downstream signaling pathways with UFPs, but not with PM2.5. Moreover, we found that inflammation response and homeostasis imbalance were key cellular events in PM2.5 and emphasized lipid metabolism and mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in UFPs. Previous AOPs, which only focused on phenotypic changes in neurotoxicity upon PM exposure, we for the first time propose AOP framework in which PM2.5 and UFPs may activate pathway cascade reactions, resulting in adverse outcomes associated with neurotoxicity. Our toxicity pathway-based approach not only advances risk assessment for PM-induced neurotoxicity but shines a spotlight on constructing AOP frameworks for new chemicals.

Comparable cerebral cortex activity and gait performance in elderly hypertensive and healthy individuals during dual-task walking: A fNIRS study.

BACKGROUND: Hypertension increases the risk of cognitive impairment and related dementia, causing impaired executive function and unusual gait parameters. However, the mechanism of neural function illustrating this is unclear. Our research aimed to explore the differences of cerebral cortex activation, gait parameters, and working memory performance between healthy older adults (HA) and older hypertensive (HT) patients when performing cognitive and walking tasks. METHOD: A total of 36 subjects, including 12 healthy older adults and 24 older hypertensive patients were asked to perform series conditions including single cognitive task (SC), single walking task (SW), and dual-task (DT), wearing functional near-infrared spectroscopy (fNIRS) equipment and Intelligent Device for Energy Expenditure and Activity equipment to record cortical hemodynamic reactions and various gait parameters. RESULTS: The left somatosensory cortex (L-S1) and bilateral supplementary motor area (SMA) showed higher cortical activation (p < .05) than HA when HT performed DT. The intragroup comparison showed that HT had higher cortical activation (p < .05) when performing DT as SW. The cognitive performance of HT was significantly worse (p < .05) than HA when executing SC. The activation of the L-S1, L-M1, and bilateral SMA in HT were significantly higher during SW (p < .05). CONCLUSION: Hypertension can lead to cognitive impairment in the elderly, including executive function and walking function decline. As a result of these functional declines, elderly patients with hypertension are unable to efficiently allocate brain resources to support more difficult cognitive interference tasks and need to meet more complex task demands by activating more brain regions.

Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306).

Background & Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. Results: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). Conclusions: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Direct comparison of bone marrow biopsy and PET/CT for the detection of bone marrow infiltration in patients with non-Hodgkin lymphoma: a meta-analysis.

BACKGROUND: The diagnostic utility of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) compared to bone marrow biopsy (BMB) in patients with non-Hodgkin lymphoma (NHL) remained to be confirmed. This study aimed to compare BMB and PET/CT for bone marrow infiltration (BMI) in patients with NHL. METHODS: PubMed, Embase, and the Cochrane library were searched for papers published up to October 2021. The outcomes were the true positive and negative and false positive and negative rates for BMB and PET/CT. The summarized sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratios (DOR) were calculated. RESULTS: Thirteen studies with a total of 2396 patients were included. Significant differences are observed between BMB and PET/CT for sensitivity (relative ratio: 0.749; 95% CI: 0.586-0.956; P=0.020) and NLR (relative ratio: 1.839; 95% CI: 1.106-3.058; P=0.019), but not for specificity (P=0.819), PLR (P=0.802), and DOR (P=0.150). The summary area under the receiver operating characteristic curves for BMB is 0.692 (SE: 0.170) and 0.977 (SE: 0.021) for PET/CT. CONCLUSIONS: PET/CT presents a better sensitivity and NLR for the detection of BMI in patients with NHL, whereas no differences are found regarding specificity, PLR, and DOR compared with BMB.

Bioinformatics and systems biology approach to identify the pathogenetic link of neurological pain and major depressive disorder.

Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8+ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.

Efficacy, safety, and serum cytokine modulation by olopatadine hydrochloride and desloratadine citrate disodium combination therapy in urticaria.

OBJECTIVES: To assess the efficacy, safety, and impact on serum cytokines of olopatadine hydrochloride (OLP) combined with desloratadine citrate disodium (DES) in treating urticaria. METHODS: We retrospectively analyzed 114 urticaria patients treated at the Affiliated Hospital of Xinyang Vocational and Technical College from March 2020 to March 2023. The control group (55 patients) received DES, while the research group (59 patients) received OLP+DES combination therapy. We compared efficacy, safety (including epigastric pain, dry mouth, lethargy, dizziness, and fatigue), changes in serum cytokines (interleukin [IL]-2, IL-4, and interferon [IFN]-γ), symptom resolution (wheal number, wheal size, and itching degree), and 3-month recurrence rates. A univariate analysis was also conducted to identify factors influencing urticaria recurrence. RESULTS: The research group exhibited a significantly higher overall efficacy rate, lower incidence of adverse events, and reduced recurrence rates at 3 months (all P<0.05) compared to the control group. Post-treatment, the research group showed significant increases in IL-2 and IFN-γ levels and reductions in IL-4 levels, wheal number, wheal size, and itching degree (all P<0.05). Factors such as history of drinking/smoking, IL-2 levels, and treatment method were associated with urticaria recurrence (all P<0.05). CONCLUSIONS: The combination of OLP and DES is an effective and safe treatment option for urticaria, significantly improving serum cytokine profiles, alleviating symptoms, and reducing recurrence risk.

Sex disparities of the effect of the COVID-19 pandemic on mortality among patients living with tuberculosis in the United States.

Background: We aimed to determine the trend of TB-related deaths during the COVID-19 pandemic. Methods: TB-related mortality data of decedents aged ≥25 years from 2006 to 2021 were analyzed. Excess deaths were estimated by determining the difference between observed and projected mortality rates during the pandemic. Results: A total of 18,628 TB-related deaths were documented from 2006 to 2021. TB-related age-standardized mortality rates (ASMRs) were 0.51 in 2020 and 0.52 in 2021, corresponding to an excess mortality of 10.22 and 9.19%, respectively. Female patients with TB demonstrated a higher relative increase in mortality (26.33 vs. 2.17% in 2020; 21.48 vs. 3.23% in 2021) when compared to male. Female aged 45-64 years old showed a surge in mortality, with an annual percent change (APC) of -2.2% pre-pandemic to 22.8% (95% CI: -1.7 to 68.7%) during the pandemic, corresponding to excess mortalities of 62.165 and 99.16% in 2020 and 2021, respectively; these excess mortality rates were higher than those observed in the overall female population ages 45-64 years in 2020 (17.53%) and 2021 (33.79%). Conclusion: The steady decline in TB-related mortality in the United States has been reversed by COVID-19. Female with TB were disproportionately affected by the pandemic.

Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Effect of ultrasound-guided injection of botulinum toxin type A into shoulder joint cavity on shoulder pain in poststroke patients: study protocol for a randomized controlled trial.

BACKGROUND: Hemiplegic shoulder pain (HSP) is a common complication after stroke. It severely affects the recovery of upper limb motor function. Early shoulder pain in hemiplegic patients is mainly neuropathic caused by central nerve injury or neuroplasticity. Commonly used corticosteroid injections in the shoulder joint can reduce shoulder pain; however, the side effects also include soft tissue degeneration or increased tendon fragility, and the long-term effects remain controversial. Botulinum toxin injections are relatively new and are thought to block the transmission of pain receptors in the shoulder joint cavity and inhibit the production of neuropathogenic substances to reduce neurogenic inflammation. Some studies suggest that the shoulder pain of hemiplegia after stroke is caused by changes in the central system related to shoulder joint pain, and persistent pain may induce the reorganization of the cortical sensory center or motor center. However, there is no conclusive evidence as to whether or not the amelioration of pain by botulinum toxin affects brain function. In previous studies of botulinum toxin versus glucocorticoids (triamcinolone acetonide injection) in the treatment of shoulder pain, there is a lack of observation of differences in changes in brain function. As the content of previous assessments of pain improvement was predominantly subjective, objective quantitative assessment indicators were lacking. Functional near-infrared imaging (fNIRS) can remedy this problem. METHODS: This study protocol is designed for a double-blind, randomized controlled clinical trial of patients with post-stroke HSP without biceps longus tenosynovitis or acromion bursitis. Seventy-eight patients will be randomly assigned to either the botulinum toxin type A or glucocorticoid group. At baseline, patients in each group will receive shoulder cavity injections of either botulinum toxin or glucocorticoids and will be followed for 1 and 4 weeks. The primary outcome is change in shoulder pain on the visual analog scale (VAS). The secondary outcome is the assessment of changes in oxyhemoglobin levels in the corresponding brain regions by fNIRS imaging, shoulder flexion, external rotation range of motion, upper extremity Fugl-Meyer, and modified Ashworth score. DISCUSSION: Ultrasound-guided botulinum toxin type A shoulder joint cavity injections may provide evidence of pain improvement in patients with HSP. The results of this trial are also help to analyze the correlation between changes in shoulder pain and changes in cerebral hemodynamics and shoulder joint motor function. TRIAL REGISTRATION: Chinese clinical Trial Registry, ChiCTR2300070132. Registered 03 April 2023, https://www.chictr.org.cn/showproj.html?proj=193722 .

Prognosis and diagnosis of prostate cancer based on hypergraph regularization sparse least partial squares regression algorithm.

BACKGROUND: Prostate cancer (PCa) is a malignant tumor of the male reproductive system, and its incidence has increased significantly in recent years. This study aimed to further identify candidate biomarkers with prognostic and diagnostic significance by integrating gene expression and DNA methylation data from PCa patients through association analysis. MATERIAL AND METHODS: To this end, this paper proposes a sparse partial least squares regression algorithm based on hypergraph regularization (HR-SPLS) by integrating and clustering two kinds of data. Next, module 2, with the most significant weight, was selected for further analysis according to the weight of each module related to DNA methylation and mRNAs. Based on the DNA methylation sites in module 2, this paper uses multiple machine learning methods to construct a PCa diagnosis-related model of 10-DNA methylation sites. RESULTS: The results of Receiver Operating Characteristic (ROC) analysis showed that the DNA methylation-related diagnostic model we constructed could diagnose PCa patients with high accuracy. Subsequently, based on the mRNAs in module 2, we constructed a prognostic model for 7-mRNAs (MYH11, ACTG2, DDR2, CDC42EP3, MARCKSL1, LMOD1, and MYLK) using multivariate Cox regression analysis. The prognostic model could predict the disease free survival of PCa patients with moderate to high accuracy (area under the curve (AUC) =0.761). In addition, Gene Set EnrichmentAnalysis (GSEA) and immune analysis indicated that the prognosis of patients in the risk group might be related to immune cell infiltration. CONCLUSIONS: Our findings may provide new methods and insights for identifying disease-related biomarkers by integrating DNA methylation and gene expression data.

Machine learning-based models for advanced fibrosis and cirrhosis diagnosis in chronic hepatitis B patients with hepatic steatosis.

BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants non-invasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in ten medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from Shapley Additive exPlanations, were compared to Fibrosis-4 Index (FIB-4), Nonalcoholic fatty liver disease Fibrosis Score (NFS), and Aspartate transaminase to platelet ratio index (APRI) using the area under receiver operating characteristic curve (AUROC), and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest (RF) model achieved AUROCs of 0.778 [95% confidence interval (CI) 0.749-0.807] for diagnosing advanced fibrosis (RF-AF model) and 0.777 (95%CI 0.748-0.806) for diagnosing cirrhosis (RF-C model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the RF-AF model obtained an AUROC of 0.825 (95% CI 0.787-0.862) in patients with HBV DNA ≥105 IU/ml, and RF-C model had an AUROC of 0.828 (95% CI 0.774-0.883) in female patients. The two models outperformed FIB-4, NFS, and APRI in the training cohort, and also performed well in the validation cohort. CONCLUSION: The RF models provide reliable, non-invasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the co-management of the two diseases.

Celastrol mediates CAV1 to attenuate pro-tumorigenic effects of senescent cells.

BACKGROUND: Cellular senescence is an emerging hallmark of cancers, primarily fuels cancer progression by expressing senescence-associated secretory phenotype (SASP). Caveolin-1 (CAV1) is a key mediator of cell senescence. Previous studies from our group have evidenced that the expression of CAV1 is downregulated by Celastrol (CeT). PURPOSE: To investigate the impact of CeT on cellular senescence and its subsequent influence on post-senescence-driven invasion, migration, and stemness of clear cell renal cell carcinoma (ccRCC). STUDY DESIGN AND METHODS: The expression levels of CAV1, canonical senescence markers, and markers associated with epithelial-mesenchymal transition (EMT) and stemness in clinical samples were assessed through Pearson correlation analysis. Senescent cell models were induced using DOX, and their impact on migration, invasion, and stemness was evaluated. The effects of CeT treatment on senescent cells and their pro-tumorigenic effects were examined. Subsequently, the underlying mechanism of CeT were explored using lentivirus transfection and CRISPR/Cas9 technology to silence CAV1. RESULTS: In human ccRCC clinical samples, the expression of the canonical senescence markers p53, p21, and p16 are associated with ccRCC progression. Senescent cells facilitated migration, invasion, and enhanced stemness in both ccRCC cells and ccRCC tumor-bearing mice. As expected, CeT treatment reduced senescence markers (p16, p53, p21, SA-ß-gal) and SASP factors (IL6, IL8, CXCL12), alleviating cell cycle arrest. However, it did not restore the proliferation of senescent cells. Additionally, CeT suppressed senescence-driven migration, invasion, and stemness. Further investigations into the underlying mechanism demonstrated that CAV1 is a critical mediator of cell senescence and represents a potential target for CeT to attenuate cellular senescence. CONCLUSIONS: This study presents a pioneering investigation into the intricate interplay between cellular senescence and ccRCC progression. We unveil a novel mechanism of CeT to mitigate cellular senescence by downregulating CAV1, thereby inhibiting the migration, invasion and stemness of ccRCC driven by senescent cells. These findings provide valuable insights into the underlying mechanisms of CeT and its potential as a targeted therapeutic approach for alleviating the aggressive phenotypes associated with senescent cells in ccRCC.

Celastrol nano-emulsions selectively regulate apoptosis of synovial macrophage for alleviating rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammation. Excessive proliferation and inadequate apoptosis of synovial macrophages are the crucial events of RA. Therefore, delivering therapeutic molecules to synovial macrophages specifically to tackle apoptotic insufficiency probably can be an efficient way to reduce joint inflammation and bone erosion. Based on the characteristics of dextran sulphate (DS) specifically binding scavenger receptor A (SR-A) on macrophage and celastrol (CLT) inducing apoptosis, we designed synovial macrophage-targeted nano-emulsions encapsulated with CLT (SR-CLTNEs) and explored their anti-RA effect. After intravenous injection, fluorescence-labelled SR-CLTNEs successfully targeted inflammatory joints and synovial macrophages in a mouse model of RA, with the macrophage targeting efficiency of SR-CLTNEs, CLTNEs and free DID was 20.53%, 13.93% and 9.8%, respectively. In vivo and in vitro studies showed that SR-CLTNEs effectively promoted the apoptosis of macrophages, reshaped the balance between apoptosis and proliferation, and ultimately treated RA in a high efficiency and low toxicity manner. Overall, our work demonstrates the efficacy of using SR-CLTNEs as a novel nanotherapeutic approach for RA therapy and the great translational potential of SR-CLTNEs.

Clinical Presentations and Intense FDG-avidity in Pulmonary Angiomatoid Fibrous Histiocytoma with Potential Diagnostic Pitfalls: A Case Report and Literature Review.

INTRODUCTION: Angiomatoid fibrous histiocytoma (AFH) is a borderline tumor usually affecting the the children or young adults. 18F-Fluorodexoyglucose (FDG) positron emission tomography/computed tomography (PET/CT) investigations of pulmonary AFH are rare, and there are currently no reports of intense FDG uptake in AFH. CASE REPORT: We report an AFH that occurred in the lung of a 57-year-old woman. She presented with paroxysmal cough and occasional bloodshot sputum. 18FFDG PET/CT revealed a right parahilar nodule with intense FDG-avidity, middle lobe atelectasis, and several bilateral axillary lymph nodes with mild hypermetabolic activity. This patient underwent a right middle lobe lobectomy via video-assisted thoracoscopy. Histopathologically, the diagnosis was pulmonary AFH. She had an uneventful postoperative course, and the bilateral axillary lymph nodes regressed during postoperative follow-up. CONCLUSIONS: The clinical presentation and image findings of patients with primary pulmonary AFH may be potential diagnosis pitfalls. The diagnosis of lymph nodes or distant metastases should be approached with caution. To avoid misdiagnosis, biopsy with histological examination and immunohistochemichal staining should be performed as early as possible.

Multiple reports on the causal relationship between various chronic pain and gut microbiota: a two-sample Mendelian randomization study.

Background: Previous evidence suggests a link between gut microbiota and chronic pain, but the causal relationship is not yet fully understood. Methods: We categorized gut microbiota based on phylum, class, order, family, and genus levels and gathered pain-related information from the UKB and FinnGen GWAS project. Then, we conducted MR analysis to explore the potential causal relationship between gut microbiota and chronic pain at 12 specific locations. Results: We have discovered a direct connection between genetic susceptibility in the gut microbiota (gut metabolites) and pain experienced at 12 specific locations. Notably, Serotonin (5-HT) and Glycine were found to be associated with a higher risk of pain in the extremities. On the other hand, certain microbial families and orders were found to have a protective effect against migraines. Specifically, the family Bifidobacteriaceae (IVW, FDR p = 0.013) was associated with a lower risk of migraines. Furthermore, the genus Oxalobacter (IVW, FDR p = 0.044) was found to be linked to an increased risk of low back pain. Importantly, these associations remained significant even after applying the Benjamini-Hochberg correction test. Our analysis did not find any heterogeneity in the data (p > 0.05), as confirmed by the Cochrane's Q-test. Additionally, both the MR-Egger and MR-PRESSO tests indicated no significant evidence of horizontal pleiotropy (p > 0.05). Conclusion: Our MR analysis demonstrated a causal relationship between the gut microbiota and pain, highlighting its potential significance in advancing our understanding of the underlying mechanisms and clinical implications of microbiota-mediated pain.

Automatic segmentation of 15 critical anatomical labels and measurements of cardiac axis and cardiothoracic ratio in fetal four chambers using nnU-NetV2.

BACKGROUND: Accurate segmentation of critical anatomical structures in fetal four-chamber view images is essential for the early detection of congenital heart defects. Current prenatal screening methods rely on manual measurements, which are time-consuming and prone to inter-observer variability. This study develops an AI-based model using the state-of-the-art nnU-NetV2 architecture for automatic segmentation and measurement of key anatomical structures in fetal four-chamber view images. METHODS: A dataset, consisting of 1,083 high-quality fetal four-chamber view images, was annotated with 15 critical anatomical labels and divided into training/validation (867 images) and test (216 images) sets. An AI-based model using the nnU-NetV2 architecture was trained on the annotated images and evaluated using the mean Dice coefficient (mDice) and mean intersection over union (mIoU) metrics. The model's performance in automatically computing the cardiac axis (CAx) and cardiothoracic ratio (CTR) was compared with measurements from sonographers with varying levels of experience. RESULTS: The AI-based model achieved a mDice coefficient of 87.11% and an mIoU of 77.68% for the segmentation of critical anatomical structures. The model's automated CAx and CTR measurements showed strong agreement with those of experienced sonographers, with respective intraclass correlation coefficients (ICCs) of 0.83 and 0.81. Bland-Altman analysis further confirmed the high agreement between the model and experienced sonographers. CONCLUSION: We developed an AI-based model using the nnU-NetV2 architecture for accurate segmentation and automated measurement of critical anatomical structures in fetal four-chamber view images. Our model demonstrated high segmentation accuracy and strong agreement with experienced sonographers in computing clinically relevant parameters. This approach has the potential to improve the efficiency and reliability of prenatal cardiac screening, ultimately contributing to the early detection of congenital heart defects.

Association between pain interference and motoric cognitive risk syndrome in older adults: a population-based cohort study.

OBJECTIVES: Motoric cognitive risk syndrome (MCR) is a pre-dementia condition characterized by subjective complaints in cognition and slow gait. Pain interference has previously been linked with cognitive deterioration; however, its specific relationship with MCR remains unclear. We aimed to examine how pain interference is associated with concurrent and incident MCR. METHODS: This study included older adults aged ≥ 65 years without dementia from the Health and Retirement Study. We combined participants with MCR information in 2006 and 2008 as baseline, and the participants were followed up 4 and 8 years later. The states of pain interference were divided into 3 categories: interfering pain, non-interfering pain, and no pain. Logistic regression analysis was done at baseline to examine the associations between pain interference and concurrent MCR. During the 8-year follow-up, Cox regression analysis was done to investigate the associations between pain interference and incident MCR. RESULTS: The study included 7120 older adults (74.6 ± 6.7 years; 56.8% females) at baseline. The baseline prevalence of MCR was 5.7%. Individuals with interfering pain had a significantly increased risk of MCR (OR = 1.51, 95% CI = 1.17-1.95; p = 0.001). The longitudinal analysis included 4605 participants, and there were 284 (6.2%) MCR cases on follow-up. Participants with interfering pain at baseline had a higher risk for MCR at 8 years of follow-up (HR = 2.02, 95% CI = 1.52-2.69; p < 0.001). CONCLUSIONS: Older adults with interfering pain had a higher risk for MCR versus those with non-interfering pain or without pain. Timely and adequate management of interfering pain may contribute to the prevention and treatment of MCR and its associated adverse outcomes.

Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Analysis of lumbar spine loading during walking in patients with chronic low back pain and healthy controls: An OpenSim-Based study.

Low back pain (LBP) is one of the most prevalent and disabling disease worldwide. However, the specific biomechanical changes due to LBP are still controversial. The purpose of this study was to estimate the lumbar and lower limb kinematics, lumbar moments and loads, muscle forces and activation during walking in healthy adults and LBP. A total of 18 healthy controls and 19 patients with chronic LBP were tested for walking at a comfortable speed. The kinematic and dynamic data of the subjects were collected by 3D motion capture system and force plates respectively, and then the motion simulation was performed by OpenSim. The OpenSim musculoskeletal model was used to calculate lumbar, hip, knee and ankle joint angle variations, lumbar moments and loads, muscle forces and activation of eight major lumbar muscles. In our results, significant lower lumbar axial rotation angle, lumbar flexion/extension and axial rotation moments, as well as the muscle forces of the four muscles and muscle activation of two muscles were found in patients with LBP than those of the healthy controls (p < 0.05). This study may help providing theoretical support for the evaluation and rehabilitation treatment intervention of patients with LBP.

Cytochrome b5 diversity in green lineages preceded the evolution of syringyl lignin biosynthesis.

Lignin production marked a milestone in vascular plant evolution, and the emergence of syringyl (S) lignin is lineage specific. S-lignin biosynthesis in angiosperms, mediated by ferulate 5-hydroxylase (F5H, CYP84A1), has been considered a recent evolutionary event. F5H uniquely requires the cytochrome b5 protein CB5D as an obligatory redox partner for catalysis. However, it remains unclear how CB5D functionality originated and whether it coevolved with F5H. We reveal here the ancient evolution of CB5D-type function supporting F5H-catalyzed S-lignin biosynthesis. CB5D emerged in charophyte algae, the closest relatives of land plants, and is conserved and proliferated in embryophytes, especially in angiosperms, suggesting functional diversification of the CB5 family before terrestrialization. A sequence motif containing acidic amino residues in Helix 5 of the CB5 heme-binding domain contributes to the retention of CB5D function in land plants but not in algae. Notably, CB5s in the S-lignin-producing lycophyte Selaginella lack these residues, resulting in no CB5D-type function. An independently evolved S-lignin biosynthetic F5H (CYP788A1) in Selaginella relies on NADPH-dependent cytochrome P450 reductase as sole redox partner, distinct from angiosperms. These results suggest that angiosperm F5Hs coopted the ancient CB5D, forming a modern cytochrome P450 monooxygenase system for aromatic ring meta-hydroxylation, enabling the reemergence of S-lignin biosynthesis in angiosperms.