The mechano-chemical circuit in fibroblasts and dendritic cells drives basal cell proliferation in psoriasis.

Psoriasis is an intractable immune-mediated disorder that disrupts the skin barrier. While studies have dissected the mechanism by which immune cells directly regulate epidermal cell proliferation, the involvement of dermal fibroblasts in the progression of psoriasis remains unclear. Here, we identified that signals from dendritic cells (DCs) that migrate to the dermal-epidermal junction region enhance dermal stiffness by increasing extracellular matrix (ECM) expression, which further promotes basal epidermal cell hyperproliferation. We analyzed cell-cell interactions and observed stronger interactions between DCs and fibroblasts than between DCs and epidermal cells. Using single-cell RNA (scRNA) sequencing, spatial transcriptomics, immunostaining, and stiffness measurement, we found that DC-secreted LGALS9 can be received by CD44+ dermal fibroblasts, leading to increased ECM expression that creates a stiffer dermal environment. By employing mouse psoriasis and skin organoid models, we discovered a mechano-chemical signaling pathway that originates from DCs, extends to dermal fibroblasts, and ultimately enhances basal cell proliferation in psoriatic skin.

The effect of a split-dose intravenous dexamethasone and a single high-dose on postoperative blood glucose after total joint arthroplasty: a randomized double-blind placebo-controlled trial.

BACKGROUND: In patients undergoing total joint arthroplasty (TJA), the administration of dexamethasone may contribute to perioperative blood glucose (BG) disturbances, potentially resulting in complications, even in patients without diabetes. This study aimed to demonstrate the impact of different administration regimens of dexamethasone in postoperative BG levels. METHODS: In this randomized, controlled, double-blind trial, 136 patients without diabetes scheduled for TJA were randomly assigned to three groups: two perioperative saline injections (Group A, placebo); a single preoperative injection of 20 mg dexamethasone and a postoperative saline injection (Group B), and two perioperative injections of 10 mg dexamethasone (Group C). Primary outcomes were the postoperative fasting blood glucose (FBG) levels. Secondary outcome parameters were the postoperative postprandial blood glucose (PBG) levels. Postoperative complications within 90 days were also recorded. Risk factors for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl were investigated. RESULTS: Compared to Group A, there were transient increases in FBG and PBG on postoperative days (PODs) 0 and 1 in Groups B and C. Statistical differences in FBG and PBG among the three groups were nearly absent from POD 1 onward. Both dexamethasone regimens did not increase the risk for postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl. Elevated preoperative HbA1c levels may increase the risk of postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl, respectively. CONCLUSION: Perioperative intravenous high-dose dexamethasone to patients without diabetes has transient effects on increasing BG levels after TJA. However, no differences were found between the split-dose and single high-dose regimens. The elevated preoperative HbA1c, but not the dexamethasone regimens were the risk factor for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl. TRIAL REGISTRATION: Chinese Clinical Trail Registry, ChiCTR2300069473. Registered 17 March 2023, https://www.chictr.org.cn/showproj.html?proj=186760 .

Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair.

Fibroblast activation and extracellular matrix (ECM) deposition play an important role in the tracheal abnormal repair process and fibrosis. As a transcription factor, SOX9 is involved in fibroblast activation and ECM deposition. However, the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear. We investigated the role of SOX9 in TGF-ß1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast (RTF) cells. SOX9 overexpression adenovirus (Ad-SOX9) and siRNA were transfected into RTF cells. We found that SOX9 expression was up-regulated in RTF cells treated with TGF-ß1. SOX9 overexpression activated fibroblasts and promoted ECM deposition. Silencing SOX9 inhibited cell proliferation, migration, and ECM deposition, induced G2 arrest, and increased apoptosis in RTF cells. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) assays identified MMP10, a matrix metalloproteinase involved in ECM deposition, as a direct target of SOX9, which promotes ECM degradation by increasing MMP10 expression through the Wnt/ß-catenin signaling pathway. Furthermore, in vivo, SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis, as manifested by reduced tracheal stenosis. In conclusion, our findings indicate that SOX9 can drive fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/ß-catenin signaling pathway. The SOX9-MMP10-ECM biosynthesis axis plays an important role in tracheal injury and repair. Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

Conversion of Retinoids along the Marine Food Chain Contributes to Adverse Impacts on the Spine, Liver, and Intestinal Health of the Marine Medaka (Oryzias melastigma).

Marine microalgae serve as an aquaculture bait. To enhance algal cell growth and breeding profits, high-intensity light conditions are standard for cultivating bait microalgae, potentially altering microalgal metabolite production. This research revealed that Thalassiosira pseudonana, when subjected to high-intensity light conditions, accumulated significant quantities of retinal (RAL) that transferred through the food chain and transformed into all-trans retinoic acid (atRA) in marine medaka. The study further explored the toxic effects on individual fish and specific tissues, as well as the mechanisms behind this toxicity. The accumulation of atRA in the liver, intestine, and spinal column resulted in structural damage and tissue inflammation, as well as oxidative stress. It also down-regulated the gene transcription levels of key pathways involved in immune function and growth. Furthermore, it disrupted the homeostasis of the intestinal microbial communities. The implications for wildlife and human health, which are influenced by the regulation of microalgal metabolite accumulation and their transfer via the food chain, require further investigation and could hold broader significance.

Real-time evolution characteristics and potential reactions of contaminants in commuter bus cabin air.

Despite the increasing use of motor vehicles, the impact of airborne pollutants and their health risks inside public transportation, such as commuter buses, is not well understood. This study assessed air quality inside an urban commuter bus by continuously monitoring PM10, PM2.5, and CO concentrations during both driving and parking periods. Our findings revealed that the ventilation system of the bus significantly reduced the infiltration of outdoor particulate matter and water vapor. However, CO concentrations were considerably higher inside the bus than outside, primarily due to vehicular self-emission. The ineffection of the ventilation system to remove CO potentially increases long-term exposure risks for passengers. The study identified ozone as a key oxidant in the cabin. Besides vehicle emissions, C3-C10 saturated aldehydes and carbonyl compounds were detected, including acetone, propanal, and hexanal. The presence of 6-MHO, an oxidation product of squalene, suggests that passengers contribute to VOCs load through direct emissions or skin surface reactions. Additionally, human respiration was found to significantly contribute to isoprene levels, estimated at 81.7 %. This research underscores the need for further investigation into the cumulative effects of stable compounds in cabin air and provides insights for developing healthier public transportation systems.

Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.

The sigma-1 receptor (σ1R) is a non-opioid membrane receptor, which responds to a diverse array of synthetic ligands to exert various pharmacological effects. Meanwhile, candidates for endogenous ligands of σ1R have also been identified. However, how endogenous ligands bind to σ1R remains unknown. Here, we present crystal structures of σ1R from Xenopus laevis (xlσ1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09 Å resolutions. Both neurosteroids bind to a similar location in xlσ1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xlσ1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xlσ1R-neurosteroid complex structures. Furthermore, molecular dynamics simulations and structural data reveal a potential water entry pathway. Our results provide insight into binding of two endogenous neurosteroid ligands to σ1R.

Prevalence of mental health symptoms and associated risk factors among healthcare workers in specialized COVID-19 hospitals in Anyang, China: A cross-sectional survey.

Background: The novel coronavirus disease 2019 (COVID-19) pandemic spread worldwide and brought unprecedented challenges to healthcare systems. Healthcare workers experienced tremendous pressure and psychological issues. Methods: A cross-sectional online survey was conducted from January 2022 to April 2022 among healthcare workers in Anyang, Henan Province, China. Insomnia, anxiety, depression, post-traumatic stress disorder (PTSD), and problematic internet use (PIU) were evaluated. Logistic regression analyses were used to explore the factors that were associated with mental health problems. Results: A total of 242 participants (mean [SD] age, 34.7 [6.6] years, 187 female [77.3 %]) were included in the study. The prevalence of symptoms of insomnia, anxiety, depression, PTSD and PIU during the COVID-19 pandemic in China was 53.7 %, 100.0 %, 7.0 %, 20.3 %, and 19.4 %, respectively. Participants who smoked, used sedative-hypnotic drugs and may need psychological assistance were at a higher risk for mental health problems. Respondents who were older than 45 years and were married displayed a lower risk of insomnia and PTSD, respectively. Conclusions: Mental health symptoms are pervasive among healthcare workers in specialized COVID-19 hospitals during the outbreak. Risk factors include smoking, sedative-hypnotic drug use, and the need for psychological assistance, while protective factors include age and marital status. Developing social media platforms and providing psychological assistance may be effective interventions for healthcare workers.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Exosomes derived from cord blood Treg cells promote diabetic wound healing by targeting monocytes.

Chronic nonhealing diabetic wounds are a critical clinical challenge. Regulatory T cells (Tregs) are immunosuppressive modulators affecting wound healing progression by controlling the inflammatory response. The current study attempted to investigate whether the exosomes derived from cord blood (CB) Tregs can accelerate the healing process. Exosomes were isolated from CB-Treg cultures using ultracentrifugation and validated with different specific markers of exosomes. The purified CB-Treg-derived exosomes were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes. The migration-promoting effect of CB-Treg-derived exosomes on fibroblasts and endothelial cells was investigated. We used thermosensitive Pluronic F-127 hydrogel (PF-127) loaded with CB-Treg-derived exosomes in a diabetic wound healing mouse model. CB-Treg-derived exosomes with 30-120 nm diameters revealed exosome-specific markers, such as TSG101, Alix, and CD63. CB-Treg-derived exosomes were mainly bound to the monocytes when co-cultured with PBMCs, and promoted monocyte polarization to the anti-inflammatory phenotype (M2) in vitro. CB-Treg-derived exosomes enhanced the migration of endothelial cells and fibroblasts. Furthermore, CB-Treg-derived exosomes treatment accelerated wound healing by downregulating inflammatory factor levels and upregulating the M2 macrophage ratio in vivo. Our findings indicated that CB-Treg-derived exosomes could be a promising cell-free therapeutic strategy for diabetic wound healing, partly by targeting monocytes.

Associations of ambient air pollution exposure and lifestyle factors with incident dementia in the elderly: A prospective study in the UK Biobank.

OBJECTIVE: Dementia is an important disease burden among the elderly, and its occurrence may be profoundly affected by environmental factors. Evidence of the relationship between air pollution and dementia is emerging, but the extent to which this can be offset by lifestyle factors remains ambiguous. METHODS: This study comprised 155,828 elder adults aged 60 years and above in the UK Biobank who were dementia-free at baseline. Cox proportional hazard models were conducted to examine the associations of annual average levels of air pollutants in 2010, including nitrogen dioxide (NO2), nitrogen oxides (NOX), particulate matter (PM2.5, PM10, and PMcoarse) and lifestyle factors recorded at baseline [physical activity (PA), sleep patterns, or smoking status] with incident risk of dementia, and their interactions on both multiplicative and additive scales. RESULTS: During a 12-year period of follow-up, 4,389 incidents of all-cause dementia were identified. For each standarddeviationincrease in ambient NO2, NOX or PM2.5, all-cause dementia risk increases by 1.07-fold [hazard ratio (HR) and 95 % confidence interval (CI) = 1.07 (1.04, 1.10)], 1.05-fold (95 % CI: 1.02, 1.08) and 1.07-fold (95 % CI: 1.04, 1.10), whereas low levels of PA, poor sleep patterns, and smoking are associated with an elevated risk of dementia [HR (95 % CI) = 1.17 (1.09, 1.26), 1.13 (1.00, 1.27), and 1.14 (1.07, 1.21), respectively]. Furthermore, these air pollutants show joint effects with low PA, poor sleep patterns, and smoking on the onset of dementia. The moderate to high levels of PA could significantly or marginally significantly modify the associations between NO2, NOX or PM2.5 (P-int = 0.067, 0.036, and 0.067, respectively) and Alzheimer's disease (AD), but no significant modification effects are found for sleep patterns or smoking status. CONCLUSION: The increased exposures of NO2, NOX, or PM2.5 are associated with elevated risk of dementia among elderly UK Biobank population. These air pollutants take joint effects with low PA, poor sleep patterns, and smoking on the development of dementia. In addition, moderate to high levels of PA could attenuate the incident risk of AD caused by air pollution. Further prospective researches among other cohort populations are warranted to validate these findings.

Cross-correlation adjustment full-waveform inversion with source encoding in ultrasound computed tomography.

Full-waveform inversion (FWI) is one of the leading-edge techniques in ultrasound computed tomography (USCT). FWI reconstructs the images of sound speed by iteratively minimizing the difference between the predicted and measured signals. The challenges of FWI are to improve its stability and reduce its computational cost. In this paper, a new USCT algorithm based on cross-correlation adjustment FWI with source encoding (CCAFWI-SE) is proposed. In this algorithm, the gradient is adjusted using the intermediate signals as the inversion target rather than the measured signals during iteration. The intermediate signals are generated using the travel time difference calculated by cross-correlation. In the case of conventional FWI failure, using the proposed algorithm, the estimated sound speed can converge toward the ground truth. To reduce the computational cost, an intermittent update strategy is implemented. This strategy only requires one time for the calculation of the travel time difference per stage, so that the source encoding can be used. Simulation and laboratory experiments are implemented to validate this approach. The experiment results show it has successfully recovered the sound speed model, while conventional FWI failed when the initial model greatly differed from the ground truth. This verifies that our approach improves the stability of the reconstruction in USCT. In practice, additional computational costs can be reduced by combining our approach with existing methods. The proposed approach increases the robustness of the FWI and expands its application.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

OBJECTIVE AND DESIGN: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. METHODS: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. RESULTS: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. CONCLUSION: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

Language-Guided 3-D Action Feature Learning Without Ground-Truth Sample Class Label.

This work pays the first research effort to leverage point cloud sequence-based Self-supervised 3-D Action Feature Learning (S3AFL), under text's cross-modality weak supervision. We intend to fill the huge performance gap between point cloud sequence and 3-D skeleton-based manners. The key intuition derives from the observation that skeleton-based manners actually hold the human pose's high-level knowledge that leads to attention on the body's joint-aware local parts. Inspired by this, we propose to introduce the text's weak supervision of high-level semantics into a point cloud sequence-based paradigm. With RGB-point cloud pair sequence acquired via RGB-D camera, text sequence is first generated from RGB component using pretrained image captioning model, as auxiliary weak supervision. Then, S3AFL runs in a cross and intra-modality contrastive learning (CL) way. To resist text's missing and redundant semantics, feature learning is conducted in a multistage way with semantic refinement. Essentially, text is only required for training. To facilitate the feature's representation power on fine-grained actions, a multirank max-pooling (MR-MP) way is also proposed for the point set network to better maintain discriminative clues. Experiments verify that the text's weak supervision can facilitate performance by 10.8%, 10.4%, and 8.0% on NTU RGB + D 60, 120, and N-UCLA at most. The performance gap between point cloud sequence and skeleton-based manners has been remarkably narrowed down. The idea of transferring text's weak supervision to S3AFL can also be applied to a skeleton manner, with strong generality. The source code is available at https://github.com/tangent-T/W3AMT.

Energy competition remodels the metabolic glucose landscape of psoriatic epidermal cells.

Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin. Methods: Bulk- and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models. Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin. Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.

Research of the dynamic regulatory mechanism of Compound Danshen Dripping Pills on myocardial infarction based on metabolic trajectory analysis.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease, which presents different pathophysiological changes with the prolongation of the disease. Compound danshen dripping pills (CDDP) has obvious advantages in MI treatment and widely used in the clinic. However, the current studies were mostly focused on the endpoint of CDDP intervention, lacking the dynamic attention to the disease process. It is of great value to establish a dynamic research strategy focused on the changes in pharmacodynamic substances for guiding clinical medication more precisely. PURPOSE: It is aimed to explore the dynamic regulating pattern of CDDP on MI based on metabolic trajectory analysis, and then clarify the variation characteristic biomarkers and pharmacodynamic substances in the intervention process. METHODS: The MI model was successfully prepared by coronary artery left anterior descending branch ligation, and then CDDP intervention was given for 28 days. Endogenous metabolites and the components of CDDP in serum were measured by LC/MS technique simultaneously to identify dynamic the metabolic trajectory and screen the characteristic pharmacodynamic substances at different points. Finally, network pharmacology and molecular docking techniques were used to simulate the core pharmacodynamic substances and core target binding, then validated at the genetic and protein level by Q-PCR and western blotting technology. RESULTS: CDDP performed typical dynamic regulation features on metabolite distribution, biological processes, and pharmacodynamic substances. During 1-7 days, it mainly regulated lipid metabolism and inflammation, the Phosphatidylcholine (PC(18:1(9Z/18:1(9Z)) and Sphingomyelin (SM(d18:1/23:1(9Z)), SM(d18:1/24:1(15Z)), SM(d18:0/16:1(9Z))) were the main characteristic biomarkers. Lipid metabolism was the mainly regulation pathway during 14-21 days, and the characteristic biomarkers were the Lysophosphatidylethanolamine (LysoPE(0:0/20:0), PE-NMe2(22:1(13Z)/15:0)) and Sphingomyelin (SM(d18:1/23:1(9Z))). At 28 days, in addition to inflammatory response and lipid metabolism, fatty acid metabolism also played the most important role. Correspondingly, Lysophosphatidylcholine (LysoPC(20:0/0:0)), Lysophosphatidylserine (LPS(18:0/0:0)) and Fatty acids (Linoelaidic acid) were the characteristic biomarkers. Based on the results of metabolite distribution and biological process, the characteristic pharmacodynamic substances during the intervention were further identified. The results showed that various kinds of Saponins and Tanshinones as the important active ingredients performed a long-range regulating effect on MI. And the other components, such as Tanshinol and Salvianolic acid B affected Phosphatidylcholine and Sphingomyelin through Relaxin Signaling pathway during the early intervention. Protocatechualdehyde and Rosmarinic acid affected Lysophosphatidylethanolamine and Sphingomyelin through EGFR Tyrosine kinase inhibitor resistance during the late intervention. Tanshinone IIB and Isocryptotanshinone via PPAR signaling pathway affected Lysophosphatidylcholine, Lysophosphatidylserine, and Fatty acids. CONCLUSION: The dynamic regulating pattern was taken as the entry point and constructs the dynamic network based on metabolic trajectory analysis, establishes the dynamic correlation between the drug-derived components and the endogenous metabolites, and elucidates the characteristic biomarkers affecting the changes of the pharmacodynamic indexes, systematically and deeply elucidate the pharmacodynamic substance and mechanism of CDDP on MI. It also enriched the understanding of CDDP and provided a methodological reference for the dynamic analysis of complex systems of TCM.

Mental health inequality between urban and rural youth under COVID-19 from survey data from China.

Background: While health inequality has been the focus of past scholarly discussions, COVID-19's outbreak and spread have provided a new arena for discussing health inequality, particularly in the context of urban-rural disparities in China. This paper explores the impact of COVID-19 on urban-rural health inequality, and the roles played by socioeconomic status and social capital. Methods: A cross-sectional observational collected data on demographics, mental health, socioeconomic status, and social capital. An online survey was administered from August 27 to August 30, 2020, and, 1936 valid samples were received. Mental health was measured using the Brief Symptom Inventory (BSI-18). This study applied the ordinary least squares regression (OLS) model, and data analysis was performed using STATA. Results: There were 1936 participants, with an equal distribution of genders. Multiple regression analysis showed that the mental health levels of rural youth were superior to those of urban youth (p = 0.049), especially when the epidemic was not severe (p = 0.013). Socioeconomic status had a significant positive promotion effect on mental health (p = 0.008), but the interaction effect between socioeconomic status and the urban-rural divide indicated that the promotion effect of socioeconomic status on the mental health of urban youth was greater than that of rural youth (p = 0.04). Social capital had a significant positive promotion effect on mental health (p = 0.000), and the interaction effect indicated that this promoting effect did not differ between urban and rural areas (p > 0.05).

Effect of Oxycodone-Based Multimodal Analgesia on Visceral Pain After Major Laparoscopic Gastrointestinal Surgery: A Randomised, Double-Blind, Controlled Trial.

Purpose: Oxycodone is a potent µ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. Methods: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. Results: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. Conclusion: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2100052085).

Inflammation and coronary microvascular disease: relationship, mechanism and treatment.

Coronary microvascular disease (CMVD) is common in patients with cardiovascular risk factors and is linked to an elevated risk of adverse cardiovascular events. Although modern medicine has made significant strides in researching CMVD, we still lack a comprehensive understanding of its pathophysiological mechanisms due to its complex and somewhat cryptic etiology. This greatly impedes the clinical diagnosis and treatment of CMVD. The primary pathological mechanisms of CMVD are structural abnormalities and/or dysfunction of coronary microvascular endothelial cells. The development of CMVD may also involve a variety of inflammatory factors through the endothelial cell injury pathway. This paper first reviews the correlation between the inflammatory response and CMVD, then summarizes the possible mechanisms of inflammatory response in CMVD, and finally categorizes the drugs used to treat CMVD based on their effect on the inflammatory response. We hope that this paper draws attention to CMVD and provides novel ideas for potential therapeutic strategies based on the inflammatory response.

Prevalence and prognostic value of PD-L1 expression and tumor mutational burden in persistent, recurrent, or metastatic cervical cancer.

OBJECTIVE: To evaluate the prevalence and prognostic role of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in patients with non-immunotherapy-treated advanced cervical cancer. METHODS: Clinical data were retrospectively collected from medical records between January 1, 2008, and December 31, 2016, at Asan Medical Center (Korea); archived tumor samples were assessed for PD-L1 expression (combined positive score [CPS] ≥1) and TMB (≥175 mutations/exome). Overall survival (OS) was defined as time from advanced diagnosis or initiation of first-line or second-line systemic therapy until death/last follow-up. The association of OS with PD-L1 expression and TMB were analyzed using the log-rank test and Cox proportional hazards model adjusted for covariates. RESULTS: Of 267 patients, 76.0% had squamous cell carcinoma (SCC), 24.0% had adenocarcinoma (AC)/adenosquamous carcinoma (ASC), 64.4% had PD-L1 CPS ≥1, and 32.6% had TMB ≥175 mutations/exome. PD-L1 CPS ≥1 and TMB ≥175 mutations/exome were more prevalent in SCC than in AC/ASC (73.9% and 37.2% vs. 34.4% and 17.7%). There was no association between OS and PD-L1 expression (CPS ≥1 vs. <1: adjusted hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.84-1.53 from advanced diagnosis); OS trended shorter for the subgroup with TMB ≥175 versus <175 mutations/exome (adjusted HR=1.29; 95% CI=0.95-1.75). CONCLUSION: Retrospective analysis of non-immunotherapy-treated patients with advanced cervical cancer demonstrated a higher prevalence of PD-L1 CPS ≥1 and TMB ≥175 mutations/exome in SCC versus AC/ASC. PD-L1 CPS ≥1 was not associated with OS; TMB ≥175 mutations/exome showed a trend toward shorter OS. Additional studies are needed to confirm these findings.