Search

Background: Previous studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel has a role in sepsis, but it is unclear whether its effect on survival and immune response is beneficial or harmful.Methods: We studied the effects of genetic (Trpv1-knockout vs. wild-type [WT] mice) and pharmacologic disruption of TRPV1 with resiniferatoxin (an agonist) or capsazepine (an antagonist) on mortality, bacterial clearance, and cytokine expression during lipopolysaccharide or cecal ligation and puncture-induced sepsis.Results: After cecal ligation and puncture, genetic disruption of TRPV1 in Trpv1-knockout versus WT mice was associated with increased mortality risk (hazard ratio, 2.17; 95% CI, 1.23-3.81; P = 0.01). Furthermore, pharmacologic disruption of TRPV1 with intrathecal resiniferatoxin, compared with vehicle, increased mortality risk (hazard ratio, 1.80; 95% CI, 1.05-3.2; P = 0.03) in WT, but not in Trpv1-knockout, mice. After lipopolysaccharide, neither genetic (Trpv1 knockout) nor pharmacologic disruption of TRPV1 with resiniferatoxin had significant effect on survival compared with respective controls. In contrast, after lipopolysaccharide, pharmacologic disruption of TRPV1 with capsazepine, compared with vehicle, increased mortality risk (hazard ratio, 1.92; 95% CI, 1.02-3.61; P = 0.04) in WT animals. Furthermore, after cecal ligation and puncture, increased mortality in resiniferatoxin-treated WT animals was associated with higher blood bacterial count (P = 0.0004) and higher nitrate/nitrite concentrations and down-regulation of tumor necrosis factor α expression (P = 0.004) compared with controls.Conclusions: Genetic or pharmacologic disruption of TRPV1 can affect mortality, blood bacteria clearance, and cytokine response in sepsis in patterns that may vary according to the sepsis-inducing event and the method of TRPV1 disruption. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although phytochemical curcumin has been shown to possess anti-inflammatory properties, it remains unknown whether this agent has any beneficial effects in sepsis. The purpose of this study was to demonstrate whether curcumin protects septic animals and, if so, whether activation of peroxisome proliferator-activated receptor (PPAR)-gamma, an anti-inflammatory nuclear receptor, plays any role. DESIGN: Prospective, controlled, and randomized animal study. SETTING: A research institute laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: A bolus injection of 0.2 micromol of curcumin was given intravenously to male adult rats, followed by continuous infusion of curcumin (0.24 micromol/day) for 3 days via a primed 2-mL mini-pump. The rats were then subjected to sepsis by cecal ligation and puncture (CLP). MEASUREMENTS AND MAIN RESULTS: Serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase), lactate, albumin, and tumor necrosis factor (TNF)-alpha were measured at 20 hrs after CLP (i.e., late stage of sepsis). In addition, a 10-day survival curve was conducted following CLP and cecal excision with or without curcumin treatment. Furthermore, macrophages cell line RAW 264.7 cells were treated with curcumin followed by stimulation with endotoxin. TNF-alpha and PPAR-gamma expression were then measured. The results indicate that intravenous administration of curcumin before the onset of sepsis attenuated tissue injury, reduced mortality, and decreased the expression of TNF-alpha in septic animals. Similar results were also found when curcumin was administered after the onset of sepsis. Moreover, the down-regulated PPAR-gamma in the liver at 20 hrs after CLP was significantly improved by curcumin treatment. Concurrent administration of curcumin and GW9662, a specific PPAR-gamma antagonist, completely abolished the beneficial effects of curcumin under such conditions. In cultured RAW 264.7 cells, curcumin inhibited endotoxin-induced increases in TNF-alpha expression and markedly up-regulated PPAR-gamma expression without affecting cell viability. Curcumin also prevented morphologic alterations in macrophages induced by endotoxin. CONCLUSIONS: The protective effect of curcumin makes it or its analogues strong candidates as a novel therapy for sepsis. The beneficial effect of curcumin appears to be mediated by up-regulation of nuclear receptor PPAR-gamma. [ABSTRACT FROM AUTHOR]

Abstract: Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors ( Cnr1 and Oprm1 ) is coexpressed across different neuron clusters. Myc-CB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain., (Copyright © 2024 International Association for the Study of Pain.)

Background: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown., Methods: Patients with acute myocardial infarction receiving percutaneous coronary intervention (PCI) were recruited independently in the discovery cohort (103 patients) and validation cohort (334 patients), and major adverse cardiovascular events were recorded. Plasma samples were collected before and after PCI (6 and 24 h) for RIPK3 concentration measurement. Cultured neonatal rat ventricular myocytes, macrophages and endothelial cells, and in vivo mouse models with myocardial injury induced by I/R (or hypoxia/reoxygenation) were used to investigate the role and mechanisms of extracellular RIPK3. Another cohort including patients with acute myocardial infarction receiving PCI and healthy volunteers was recruited to further explore the mechanisms of extracellular RIPK3., Results: In the discovery cohort, elevated plasma RIPK3 levels after PCI are associated with poorer short- and long-term outcomes in patients with acute myocardial infarction, as confirmed in the validation cohort. In both cultured cells and in vivo mouse models, recombinant RIPK3 protein exaggerated myocardial I/R (or hypoxia/reoxygenation) injury, which was alleviated by the RIPK3 antibody. Mechanistically, RIPK3 acted as a damage-associated molecular pattern and bound with RAGE (receptor of advanced glycation end-products), subsequently activating CaMKII (Ca 2+ /calmodulin-dependent kinase II) to elicit the detrimental effects. The positive correlation between plasma RIPK3 concentrations and CaMKII phosphorylation in human peripheral blood mononuclear cells was confirmed., Conclusions: We identified the positive relationship between plasma RIPK3 concentrations and the risk of major adverse cardiovascular events in patients with acute myocardial infarction receiving PCI. As a damage-associated molecular pattern, extracellular RIPK3 plays a causal role in multiple pathological conditions during cardiac I/R injury through RAGE/CaMKII signaling. These findings expand our understanding of the physiological and pathological roles of RIPK3, and also provide a promising therapeutic target for myocardial I/R injury and the associated complications.

Objective: The value of the transformation zone (TZ) is often overlooked in clinical settings. This study aims to assess TZ distribution, associated factors, and its impact on colposcopic diagnosis., Methods: χ2 tests were used to analyze demographics, clinical history, and tissue samples to examine the differences in TZ distribution. Factors affecting the TZ were explored using logistic regression, and diagnostic indicators were calculated., Results: A total of 5,302 individual datasets were finally included. TZ1, TZ2, and TZ3 accounted for 31.6%, 38.5%, and 30.0%, respectively. Age is the most important factor that influences the location of the TZ. The proportion of TZ3 steadily increased with age, comprising over 55% in women over 50. The colposcopic diagnostic performance shows that high-grade squamous intraepithelial lesion or worse (HSIL+) sensitivity of TZ3 (58.1%, 95% confidence interval [CI] = 52.9-63.4) is significantly lower than that of TZ1 (69.8%, 95% CI = 65.5-74.1) and TZ2 (73.2%, 95% CI = 69.7-76.8). The HSIL+ specificity of TZ3 (96.3, 95% CI = 95.3-97.4) was higher than that of TZ1 (96.3, 95% CI = 95.2-97.3) and TZ2 (92.5, 95% CI = 91.1-93.9). The HSIL+ positive predictive value (81.3%, 95% CI = 76.4-86.2) and negative predictive value (89.3%, 95% CI = 87.6-90.9) for TZ3 are high, with no significant differences when compared with TZ1 and TZ2., Conclusions: Age predominantly influences TZ location, with TZ3 being most frequently found in women over 50. While TZ3 poses a higher risk of missed diagnosis during colposcopy, it remains clinically valuable in identifying diseased and nondiseased status. Increasing colposcopists' awareness of TZ importance is needed in clinical practice., Competing Interests: Conflicts of Interest: Funding received from the American Society for Colposcopy and Cervical Pathology (ASCCP), as reported in the author Copyright Transfer Agreements for Ye, Xue, Jiang, and Qiao, has been included in this study., (Copyright © 2024, ASCCP.)

Rationale: Hepatic angiosarcoma (HSA) has a poor prognosis. Our understanding of its clinical features, diagnosis, treatment, and prognosis remains limited. In certain cases, vascular tumors such as HSA can induce bleeding complications due to thrombocytopenia, known as Kasabach-Merritt syndrome (KMS). When KMS symptoms occur in the lungs, its clinical manifestations closely resemble those of ARDS, leading to misdiagnosis and poor outcomes. Unfortunately, this condition is extremely rare and there is a lack of relevant case reports, which further adds to the difficulty of its diagnosis and treatment., Patient Concerns: This case report describes a patient who initially presented with symptoms of ARDS. Due to the unique nature of these symptoms, the patient underwent a complex diagnostic and treatment process before finally being diagnosed with HSA complicated by KMS through pathological examination., Diagnoses: The patient was eventually diagnosed with HSA by pathology and KMS with multiorgan hemorrhage., Interventions: Highly misleading clinical manifestations were recorded during the diagnosis and treatment, which, to our knowledge, have not been previously reported., Outcomes: The patient died from a massive pulmonary hemorrhage., Lessons: Dysfunction of a single organ or system may be the external manifestation of a multi-system clinical disease. Therefore, in the clinical diagnosis and treatment process, especially during early diagnosis, while it is important to focus on the primary or typical clinical symptoms, it is equally crucial not to underestimate or ignore accompanying symptoms that lack specificity. When diagnosis and treatment reach an impasse, these "atypical" symptoms often prove to be key in solving the puzzle., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

High-throughput immune repertoire (IR) sequencing provides direct insight into the diversity of B cell receptor (BCR) and T cell receptor (TCR), with great potential to revolutionize the diagnosis, monitoring, and prevention of immune system-related disorders. In this study, multiplex PCR was applied to amplify the complementarity-determining regions of BCR and TCR, followed by comprehensive analysis by high-throughput sequencing. We compare the TCR (BCR) of bone marrow fluid (BMF) and peripheral blood (PB) samples from 17 patients in the Epstein-Barr and immunodeficiency groups, respectively. Our study shows that the diversity of the IR of blood samples is very similar to that of bone marrow samples statistically. However, the distributions of the monoclonal genes are significantly different in these 2 samples of most patients. This suggests that the BMFs can be replaced by the PB samples in diversity detection of IR to monitor the immune status of the body, while the detection of the BMFs is unreplaceable when the monoclonal change occurs. We used high-throughput sequencing to assess the TCR and BCR of the patients and provide a basis for the clinical analysis of PB and bone marrow samples and selection of disease diagnosis and monitoring methods., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Spinal cord stimulation (SCS) is an effective modality for pain treatment, yet its underlying mechanisms remain elusive. Neurokinin 1 receptor-positive (NK1R+) neurons in spinal lamina I play a pivotal role in pain transmission. To enhance our mechanistic understanding of SCS-induced analgesia, we investigated how different SCS paradigms modulate the activation of NK1R+ neurons, by developing NK1R-Cre;GCaMP6s transgenic mice and using in vivo calcium imaging of superficial NK1R+ neurons under anesthesia (1.5% isoflurane). Neurokinin 1 receptor-positive neurons in the lumbar spinal cord (L4-5) showed a greater activation by electrical test stimulation (TS, 3.0 mA, 1 Hz) at the hindpaw at 2 weeks after tibia-sparing nerve injury (SNI-t) than in naïve mice. Spinal cord stimulation was then delivered through a bipolar plate electrode placed epidurally at L1-2 level. The short-term 50-Hz high-intensity SCS (80% motor threshold [MoT], 10 minutes) induced robust and prolonged inhibition of NK1R+ neuronal responses to TS in both naïve and SNI-t mice. The 30-minute 50-Hz and 900-Hz SCS applied at moderate intensity (50% MoT) also significantly inhibited neuronal responses in SNI-t mice. However, at low intensity (20% MoT), the 30-minute 900-Hz SCS only induced persistent neuronal inhibition in naïve mice, but not in SNI-t mice. In conclusion, both 10-minute high-intensity SCS and 30-minute SCS at moderate intensity inhibit the activation of superficial NK1R+ neurons, potentially attenuating spinal nociceptive transmission. Furthermore, in vivo calcium imaging of NK1R+ neurons provides a new approach for exploring the spinal neuronal mechanisms of pain inhibition by neuromodulation pain therapies., (Copyright © 2024 International Association for the Study of Pain.)

Atherosclerosis (AS) causes thickening and hardening of the arterial wall due to accumulation of extracellular matrix, cholesterol, and cells. In this study, we used comprehensive bioinformatics tools and machine learning approaches to explore key genes and molecular network mechanisms underlying AS in multiple data sets. Next, we analyzed the correlation between AS and immune fine cell infiltration, and finally performed drug prediction for the disease. We downloaded GSE20129 and GSE90074 datasets from the Gene expression Omnibus database, then employed the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts algorithm to analyze 22 immune cells. To enrich for functional characteristics, the black module correlated most strongly with T cells was screened with weighted gene co-expression networks analysis. Functional enrichment analysis revealed that the genes were mainly enriched in cell adhesion and T-cell-related pathways, as well as NF-κ B signaling. We employed the Lasso regression and random forest algorithms to screen out 5 intersection genes (CCDC106, RASL11A, RIC3, SPON1, and TMEM144). Pathway analysis in gene set variation analysis and gene set enrichment analysis revealed that the key genes were mainly enriched in inflammation, and immunity, among others. The selected key genes were analyzed by single-cell RNA sequencing technology. We also analyzed differential expression between these 5 key genes and those involved in iron death. We found that ferroptosis genes ACSL4, CBS, FTH1 and TFRC were differentially expressed between AS and the control groups, RIC3 and FTH1 were significantly negatively correlated, whereas SPON1 and VDAC3 were significantly positively correlated. Finally, we used the Connectivity Map database for drug prediction. These results provide new insights into AS genetic regulation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Ischemic stroke (IS) is a major cause of disability and mortality worldwide. Increasing evidence suggests a strong association between blood pressure, blood glucose, circulating lipids, and IS. Nonetheless, the genetic association of these 3 risk factors with IS remains elusive., Methods: We screened genetic instruments related to blood pressure, blood glucose, and circulating lipids and paired them with IS genome-wide association study data to conduct Mendelian randomization analysis. Positive Mendelian randomization findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus data set to perform differential expression analysis, aiming to identify differentially expressed associated genes. We determined the importance scores of these differentially expressed associated genes through 4 machine learning models and constructed a nomogram based on these findings., Results: The combined results of the Mendelian randomization analysis indicate that blood pressure (systolic blood pressure: odds ratio [OR], 1.02 [95% CI, 1.01-1.02]; diastolic blood pressure: OR, 1.03 [95% CI, 1.03-1.04]) and some circulating lipids (low-density lipoprotein cholesterol: OR, 1.06 [95% CI, 1.01-1.12]; apoA1: OR, 0.95 [95% CI, 0.92-0.98]; apoB: OR, 1.05 [95% CI, 1.01-1.09]; eicosapentaenoic acid: OR, 2.36 [95% CI, 1.41-3.96]) have causal relationships with the risk of IS onset. We identified 73 genes that are linked to blood pressure and circulating lipids in the context of IS, and 16 are differentially expressed associated genes. FURIN , MAN2A2 , HDDC3 , ALDH2 , and TOMM40 were identified as feature genes for constructing the nomogram that provides a quantitative prediction of the risk of IS onset., Conclusions: This study indicates that there are causal links between blood pressure, certain circulating lipids, and the development of IS. The potential mechanisms underlying these causal relationships involve the regulation of lipid metabolism, blood pressure, DNA repair and methylation, cell apoptosis and autophagy, immune inflammation, and neuronal protection, among others., Competing Interests: Disclosures None.

The purpose of this study is to investigate the serum inflammatory factors in patients with high-altitude polycythemia (HAPC) and their correlation with cognitive function. The subjects were recruited and placed into a HAPC group and control group. Serum samples were collected, and inflammatory factors (interleukin-1beta [IL-1β], monocyte chemoattractant protein-1 [MCP-1], and tumor necrosis factor-alpha [TNF-α]) were measured using ELISA kits. The mini-mental State Examination (MMSE) was used to assess cognitive function. According to the MMSE scores, HAPC group was further divided into normal cognitive function group (HNCF) and cognitive dysfunction group (HCDF). In comparison with the control group, the MMSE scores in the HAPC group were significantly low (P < .05), whereas the serum levels of IL-1β, MCP-1, and TNF-α were significantly high (P < .01). Among the HAPC group (n = 60), 21 belonged to the HCDF and 39 belonged to the HNCF. Compared with the HNCF, the IL-1β, MCP-1, and TNF-α in the HCDF were significantly increased (P < .01). The Pearson correlation analysis showed that inflammatory factors were positively correlated with hemoglobin, and negatively correlated with MMSE. Serum inflammatory cytokines IL-1, MCP-1, and TNF-α were increased in HAPC, and HAPC exhibited cognitive dysfunction. Considering chronic hypoxia environment influences the change of the red blood cell metabolic and inflammatory factor, red blood cells and inflammatory factor in plateau is likely to be affected by patients with vascular lesions, increase cognitive impairment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To identify neutrophil extracellular trap (NET)-associated gene features in the blood of patients with myocardial infarction (MI) using bioinformatics and machine learning, with the aim of exploring potential diagnostic utility in atherosclerosis. The datasets GSE66360 and GSE48060 were downloaded from the Gene Expression Omnibus (GEO) public database. GSE66360 was used as the training set, and GSE48060 was used as an independent validation set. Differential genes related to NETs were screened using R software. Machine learning was performed based on the differential expression of NET-related genes across different samples. The advantages and disadvantages of 4 machine learning algorithms (Random Forest [RF], Extreme Gradient Boosting [XGBoost, XGB], Generalized Linear Models [GLM], and Support Vector Machine-Recursive Feature Elimination [SVM-RFE]) were compared, and the optimal method was used to screen feature genes and construct diagnostic models, which were then validated in the external validation dataset. Correlations between feature genes and immune cells were analyzed, and samples were reclustered based on the expression of feature genes. Differences in downstream molecular mechanisms and immune responses were explored for different clusters. Weighted Gene Co-expression Network Analysis was performed on different clusters, and disease-related NET genes were extracted, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Finally, Mendelian randomization was employed to further investigate the causal relationship between the expression of model genes and the occurrence of MI. Forty-seven NET-related differential genes were obtained, and after comparing the 4 machine learning methods, support vector machine was used to screen ATG7, MMP9, interleukin 6 (IL6), DNASE1, and PDE4B as key genes for the construction of diagnostic models. The diagnostic value of the model was validated in an independent external validation dataset. These five genes showed strong correlations with neutrophils. Different sample clusters also demonstrated differential enrichment in pathways such as nitrogen metabolism, complement and coagulation cascades, cytokine-cytokine receptor interaction, renin-angiotensin system, and steroid biosynthesis. The Mendelian randomization results demonstrate a causal relationship between the expression of ATG7 and the incidence of myocardial infarction. The feature genes ATG7, MMP9, IL6, DNASE1, and PDE4B, identified using bioinformatics, may serve as potential diagnostic biomarkers and therapeutic targets for Myocardial infarction. Specifically, the expression of ATG7 could potentially be a significant factor in the occurrence of MI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The purpose of the study was to evaluate the routine clinical application of total-body PET with quarter-dose 18 F-FDG., Methods: The contrast recovery coefficient (CRC) and coefficient of variation (COV) were evaluated among full-, half-, and quarter-dose groups with an acquisition duration of 10-, 5-, 3-, and 1-min in the NEMA (IQ) phantom test. Fifty patients undergoing total-body PET/CT with quarter-dose (0.925MBq/kg) of 18 F-FDG were included in the prospective study. The acquisition time was 10 min, divided into duration groups of 5-, 3-, and 1-min, referred to as G10, G5, G3, and G1. Visual scores were assessed based on overall visual assessment, noise scoring, and lesion conspicuity. Lesion SUV max and TBR were evaluated in semi-quantitative analysis. G10 was used as the gold reference to evaluate lesion detectability., Results: In the phantom study, the COV value of the images with quarter-dose 18 F-FDG and 10-min acquisition time was 11.52%. For spheres with 10 mm diameter, the CRC of quarter-dose PET images was relatively stable compared to that of full-dose groups with all acquisition durations. In the human study, the visual score in G10, G5, and G3 was significantly higher than that in G1. The differences in lesion SUV max and TBR for G1-G10 were significantly higher than that for G5-G10 and G3-G10. All lesions in G10 could be identified in G5 and G3., Conclusion: The phantom and human findings demonstrated the feasibility of quarter-dose 18 F-FDG PET with 3-min acquisition time, which can maintain image quality with reduced radiation dose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine demographic and clinical precursors to pregnancy-associated deaths overall and when pregnancy-related deaths are excluded., Methods: We conducted a retrospective cohort study based on a Massachusetts population-based data system linking data from live birth and fetal death certificates to corresponding delivery hospital discharge records and a birthing individual's nonbirth hospital contacts and associated death records. Exposures included maternal demographics, severe maternal morbidity (without transfusion), hospitalizations in the 3 years before pregnancy, comorbidities during pregnancy, and opioid use. In cases of postpartum deaths, hospitalization between delivery and death was examined. The primary outcome measure was pregnancy-associated death , defined as death during pregnancy or up to 1 year postpartum., Results: There were 1,291,626 deliveries between 2002 and 2019, of which 384 were linked to pregnancy-associated deaths. Pregnancy-associated but not pregnancy-related deaths (per 100,000 deliveries) were highest for birthing people with opioid use before pregnancy (498.3), severe maternal morbidity (387.3), a comorbidity (106.3), or a prior hospitalization (88.9). In multivariable analysis, the adjusted risk ratios associated with severe maternal morbidity (9.37, 95% CI, 6.14-14.31) and opioid use (6.49, 95%, CI, 3.71-11.35) were highest. Individuals with pregnancy-associated deaths were also more likely to have been hospitalized before or during pregnancy (2.30, 95% CI, 1.62-3.26). Among postpartum deaths, more than two-thirds (69.9%) of birthing people had a hospital contact after delivery and before their death., Conclusion: Severe maternal morbidity and opioid use disorder were precursors to pregnancy-associated deaths. Individuals with pregnancy-associated but not pregnancy-related deaths experienced a history of hospital contacts during and after pregnancy before death., Competing Interests: Financial Disclosure Ndidiamaka Amutah-Onukagha reports money was paid to their institution from the National Institute on Minority Health and Health Disparities. Audra Meadows reports money was paid to their institution from Robert Wood Johnson Foundation and the Massachusetts Department of Public Health. She received a speaker fee from Optum Health Education and she received payment from the Institute for Healthcare Improvement Institute for Perinatal Quality March of Dimes. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Currently, there is no gold standard for monitoring noxious stimulation during surgery, and the surgical pleth index (SPI) is only one of many monitoring methods. It is commonly used in the monitoring of conventional opiate anesthesia, but its effectiveness in opioid-free anesthesia (OFA) has not been evaluated. Therefore, the aim of this study was to observe the guidance value of the surgical pleth index in opioid-free anesthesia for patients undergoing lower abdominal or pelvic surgery., Methods: A total of 122 patients who underwent lower abdominal or pelvic surgery in our hospital between March 2021 and July 2022 were selected and equally divided into OFA (F) and control (C) groups according to the random number table method. Both groups underwent ultrasound-guided unilateral/bilateral quadratus lumborum block in the supine position according to the surgical field. In group F, 0.50% lidocaine and 0.20% ropivacaine (in 20 mL of 0.9% normal saline) were injected on each side. In group C, 20 mL 0.9% normal saline was injected on each side. Group F received general anesthesia without opioids and group C received general anesthesia with opioids. BP, pulse oxygen saturation, PETCO2, reactionentropy, stateentropy, and SPI values; Steward score; dosage of propofol, dexmedetomidine, rocuronium, and diltiazem; extubation time; and awake time were monitored in both groups., Results: There were no significant differences in the general data between the 2 groups (P > .05). There were no significant differences in SPI values at T0, T1, T2, T3, T4, and T5 or the number of cases requiring additional remifentanil, propofol, and diltiazem between the 2 groups (P > .05). The stateentropy, reactionentropy, and Steward scores were higher in group F than in group C at T4 and T5, while the extubation and awake times were lower in group F than in group C (P < .05). The heart rate and SPI of group F were lower than that of group C at T3 (P < .05)., Conclusion: The guiding value of SPI in OFA was similar to its use in opiated anesthesia. Its clinical efficacy is exact, vital signs are stable, enabling rapid, and complete regaining of consciousness., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aimed to investigate the research hotspots and global trends of acupuncture in the treatment of headaches from 1974 to 2022. The Web of Science core collection database and literature related to acupuncture for headache treatment were retrieved. The CiteSpace (version 5.1.R8) and VOSviewer (version 1.6.19) software perform collaborative network analysis on the information of countries, academic institutions, authors, and co-occurrence network analysis on keywords, co-cited journals, and references. A total of 841 studies were included. Overall, the number of publications has increased over the past 5 decades. We identified and analyzed the countries, institutions, authors, and journals that were most active in the domain of acupuncture treatment for headaches. The most productive countries were the United States and China. Chengdu University of Traditional Chinese Medicine was the most productive institution and Linde Klaus was the most productive author. Cephalalgia was the most productive and co-cited journal, whereas Lancet had the highest impact factor. The research hotspots mainly focus on headache, migraine, tension headache, electroacupuncture, and acupuncture. Research trends have mainly focused on acupuncture therapy and its curative effects, migraine without aura, paroxysmal migraine, and the mechanism of acupuncture treatment. The main research hotspots and frontier trends were the therapeutic effect and mechanism of acupuncture for headaches. The mechanism of acupuncture in the treatment of headache mainly focused on the neural mechanism by multimodal MRI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A patient, with a mental disorder caused by an intracranial infection, treated with olanzapine, fluvoxamine, and buspirone. The plasma exposure of olanzapine was too high at standard doses, with evidence indicating that it was caused by drug-drug interactions., Methods: Using pharmacogenomics and therapeutic drug monitoring to guide drug dose adjustment for a patient in clinical practice., Results: The patient underwent pharmacogenetic testing in addition to therapeutic drug monitoring as part of a pharmacist-led comprehensive evaluation of medication therapy management in a clinical setting, resulting in improved clinical efficacy that allowed discharge from a psychiatric hospital., Conclusions: This case study demonstrates that therapeutic drug monitoring combined with pharmacogenetic-guided dose adjustment can aid in the management of patients receiving complex pharmacological treatments., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Dyslipidemia, characterized by elevated total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C), as well as decreased high-density lipoprotein cholesterol (HDL-C), has long been recognized as a major risk factor for age-related diseases. Recent studies have shown that exercise can be effective in mitigating dyslipidemia in older adults. The aim of this study was to systematically evaluate the effects of different exercise modalities (aerobic exercise [AE], resistance exercise [RE], aerobic+resistance exercise [AE+RE], and high-intensity interval training) on lipid profile in the elderly population, in order to identify the most effective exercise modality for maintaining lipid profile health in older adults., Methods: A comprehensive database search of PubMed, EBSCO, Web of Science, China National Knowledge Infrastructure, and Wanfang database. Eligible studies were individually assessed according to the Cochrane Risk of Bias Tool version 2, and the data were analyzed and processed using RevMan 5.4.1 analysis software., Results: This study identified 20 randomized controlled trials with a total of 988 subjects, of which 541 were in the exercise group and 447 in the control group. Our analysis showed that AE significantly reduced TC (P < .05), triglycerides (P < .01), and LDL-C (P < .01), while increasing HDL-C (P < .01) in the elderly population. RE significantly reduced the elevation of TC (P < .01) and LDL-C (P < .05) indices in the elderly population, while AE+RE had a significant effect on decreasing TC (P < .01) and LDL-C (P < .01) indices., Conclusion: Our analysis indicates that AE is the most effective exercise modality for reducing dyslipidemia in older adults, compared to RE, AE+RE, and high-intensity interval training. These findings suggest that AE should be promoted as an important lifestyle intervention to improve lipid profile health in the elderly population. However, further research is needed to investigate the optimal duration, frequency, and intensity of AE required to achieve the most beneficial effects on lipid profile health in older adults., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The triglyceride-glucose (TyG) index has been proposed as a new marker for insulin resistance, which is associated with a risk of major depressive disorder (MDD). This study aims to explore whether the TyG index is correlated with MDD. In total, 321 patients with MDD and 325 non-MDD patients were included in the study. The presence of MDD was identified by trained clinical psychiatrists using the International Classification of Diseases 10th Revision. The TyG index was calculated as follows: Ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). The results revealed that the MDD group presented higher TyG index values than the non-MDD group (8.77 [8.34-9.17] vs 8.62 [8.18-9.01], P < .001). We also found significantly higher morbidity of MDD in the highest TyG index group than in the lower TyG index group (59.9% vs 41.4%, P < .001). Binary logistic regression revealed that TyG was an independent risk factor for MDD (odds ratio [OR] 1.750, 95% confidence interval: 1.284-2.384, P < .001). We further assessed the effect of TyG on depression in sex subgroups. The OR was 3.872 (OR 2.014, 95% confidence interval: 1.282-3.164, P = .002) for the subgroup of men. It is suggested that the TyG index could be closely associated with morbidity in MDD patients; thus, it may be a valuable marker for identifying MDD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pyroptosis is a newly identified mode of programmed cell death, but the potential role in patients with acute myocardial infarction (AMI) remains unclear. In this study, bioinformatics methods were used to identify differentially expressed genes from peripheral blood transcriptome data between normal subjects and patients with AMI which were downloaded by the Gene Expression Omnibus database. Comparing Random Forest (RF) and Support Vector Machine (SVM) training algorithms were used to identify pyroptosis-related genes, predicting patients with AMI by nomogram based on informative genes. Moreover, clustering was used to amplify the feature of pyroptosis, in order to facilitate analysis distinct biological differences. Diversity analysis indicated that a majority of pyroptosis-related genes are expressed at higher levels in patients with AMI. The receiver operating characteristic curves show that the RF model is more responsive than the SVM machine learning model to the pyroptosis characteristics of these patients in vivo. We obtained a column line graph diagnostic model which was developed based on 19 genes established by the RF model. After the consensus clustering algorithm of single sample Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, the results for them found that pyroptosis-related genes mediate the activation of multiple immune cells and many inflammatory pathways in the body. We used RF and SVM algorithms to determine 19 pyroptosis-related genes and evaluate their immunological effects in patients with AMI. We also constructed a series of by nomogram related to pyroptosis-related genes to predict the risk of developing AMI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Preventing contrast-induced acute kidney injury (CI-AKI) is critical because of its association with poor clinical outcomes, including extended hospital stays and increased mortality. The effects of probucol on preventing CI-AKI have been controversial. Therefore, this systematic review and meta-analysis evaluated the influence of probucol combined with hydration on the CI-AKI risk in patients with coronary heart disease undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI)., Methods: We retrieved data from the following databases from their inception to May 29, 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database (Sinomed), Wanfang Database, and Chinese Scientific Journal Database. The methodological quality of the trials was assessed following the Cochrane Handbook guidelines, and Review Manager 5.3 and Stata 14.0 software were used for the data analysis., Results: We included 14 trials comprising 3306 patients in the analysis. All included trials reported the CI-AKI incidence rate (the primary outcome). Probucol with hydration significantly reduced the CI-AKI incidence compared to hydration alone (odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.25-0.44, P < .001). Subgroup analyses were performed based on the contrast medium type (iso-osmolality vs low-osmolality contrast medium [LOCM]) and volume (less than or more than 200 mL); the effects of probucol with hydration versus hydration-only on CI-AKI were comparable within each subgroup. Additionally, the serum creatinine (Scr) concentration 24 hours, 48 hours, and 72 hours and the estimated glomerular filtration rate (eGFR) 72 hours after contrast exposure were better in the probucol with hydration group than the hydration-only group. Finally, major clinical adverse events and adverse drug reactions were comparable between the probucol with hydration and hydration-only groups., Conclusion: Probucol with hydration decreases the CI-AKI incidence compared to hydration only in patients with coronary heart disease undergoing CAG or PCI. However, more high-quality, large-sample, multicenter randomized trials are needed to confirm this conclusion., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Traditional Chinese acupoint therapy has been used for thousands of years on gastrointestinal diseases. In this work, we evaluated the efficiency and safety of traditional Chinese acupoint therapies versus standard therapies, nursing or recovery treatments in the treatment of diabetic gastroparesis.e expect that traditional Chinese medicine acupoint therapy can be noticed by more people, so as to provide more high-quality clinical evidence., Methods: Randomized controlled trials were included in this meta-analysis. The treatment groups received traditional Chinese acupoint therapy, while the control groups received standard therapies, nursing, or recovery treatments. The relative risk and weighted mean difference with 95% confidence interval for the total effective rate, gastrin level, gastric-emptying time, fasting blood glucose level, 2-hour blood glucose level, and glycosylated hemoglobin level were evaluated using RevMan 5.3 software. Bias assessment was performed using the Cochrane risk-of-bias tool., Results: A total of 59 articles were included in the analysis. In comparison with the control groups, the acupoint therapy groups showed higher total effective rates (P < .00001), enhanced gastric-emptying rates (P < .00001), and reduced glycosylated hemoglobin levels., Conclusion: In comparison with Western medicine or conventional care, traditional Chinese acupoint therapies showed a significant advantage in the treatment of diabetic gastroparesis. However, considering the low quality and high risk of the included studies, more high-quality randomized controlled trials are needed to confirm the results., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

To evaluate carotid elasticity by using two-dimensional strain imaging (2DSI) in type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD). 98 patients with T2DM diagnosed in our hospital were selected. All the patients were without carotid plaque, which were proved by carotid ultrasonography. According to the fatty liver classification standard, patients were divided into three groups. There were 35 cases without NAFLD in group A, 33 cases with mild NAFLD in group B and 30 cases with moderate to severe NAFLD in group C. By using two-dimensional and M-mode ultrasound to measure the left carotid intima-media thickness (IMT), common carotid arterial systolic diameter (Ds) and diastolic diameter (Dd). The systolic peak velocity was measured by spectral Doppler ultrasound. The systolic global peak circumferential strain (CS), early and late systolic global circumferential strain rate (CSr) were measured by 2DSI. The stiffness parameters β1 and β2 were calculated by M-mode ultrasound and 2DSI separately. Among three groups, the Ds, Dd and systolic peak velocity showed no significant difference (all P > .05). In group C, IMT and β1 were obviously increased than those of groups A and B (all P < .05). Compared groups A and B, there were no significant difference in IMT and β1 (all P > .05). β2 was higher in groups B and C than those in group A, CS, CSr were lower in groups B and C than those in group A (both P > .05). The carotid elasticity of T2DM patients with NAFLD can be evaluated by 2DSI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To compare the clinical and radiological results of locking plate fixation with and without spine cage for the treatment of unstable proximal humeral fractures in elderly patients., Design: Retrospective study., Setting: Level 1 Trauma Center., Patients/participants: A total of 62 patients with a mean age of 72.68 (60-88) years were included. Thirty-nine patients were treated with only a locking compression plate (LCP group), whereas 23 patients were treated with a locking compression plate and a spine cage (SC group). The mean follow-up was 32.26 (24-46) months., Main Outcome Measures: Radiological outcomes were assessed using the humeral head height and neck-shaft angle. The clinical results were evaluated using a visual analog scale for pain, the Constant-Murley score, the American Shoulder and Elbow score, and shoulder range of motion., Results: The average radiological changes in the humeral head height and neck-shaft angle were significantly higher in the LCP group than in the SC group ( P < 0.001 and P < 0.001, respectively). The final outcome scores were lower in the LCP group than in the SC group (Constant-Murley score of 73.26 vs. 78.91 [ P = 0.028] and American Shoulder and Elbow score of 72.36 vs. 78.57 [ P = 0.011]). The SC group showed better forward elevation ( P = 0.005) and abduction ( P = 0.001); however, no significant differences were observed for shoulder external or internal rotation. The number of complications was higher in the LCP group (38.5%) than in the SC group (13.0%) ( P = 0.033)., Conclusions: For unstable proximal humeral fractures with medial comminution in elderly patients, locking plate with an SC is a reasonable option to ensure satisfactory results and lower the postoperative complications., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We aimed to identify differentially methylated genes and related signaling pathways in autism spectrum disorder (ASD)., Methods: First, the DNA methylation profile in the brain samples (GSE131706 and GSE80017) and peripheral blood samples (GSE109905) was downloaded from the Gene Expression Omnibus database (GEO) dataset, followed by identification of differentially methylated genes and functional analysis. Second, the GSE109905 data set was used to further validate the methylation state and test the ability to diagnose disease of identified differentially methylated genes. Third, expression measurement of selected differentially methylated genes was performed in whole blood from an independent sample. Finally, protein-protein interaction (PPI) network of core differentially methylated genes was constructed., Results: Totally, 74 differentially methylated genes were identified in ASD, including 38 hypermethylated genes and 36 hypomethylated genes. 15 differentially methylated genes were further identified after validation in the GSE109905 data set. Among these, major histocompatibility complex (HLA)-DQA1 was involved in the molecular function of myosin heavy chain class II receptor activity; HLA-DRB5 was involved in the signaling pathways of cell adhesion molecules, Epstein-Barr virus infection and antigen processing and presentation. In the PPI analysis, the interaction pairs of HLA-DQA1 and HLA-DRB5, FMN2 and ACTR3, and CALCOCO2 and BAZ2B were identified. Interestingly, FMN2, BAZ2B, HLA-DRB5, CALCOCO2 and DUSP22 had a potential diagnostic value for patients with ASD. The expression result of four differentially methylated genes (HLA-DRB5, NTM, IL16 and COL5A3) in the independent sample was consistent with the integrated analysis., Conclusions: Identified differentially methylated genes and enriched signaling pathway could be associated with ASD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Trazodone (TZD) is a tetracyclic serotonin antagonist and reuptake inhibitor that is used as a second-generation phenylpiperazine antidepressant. However, the plasma concentrations of TZD have shown individual variations in clinical practice. Quantification of TZD plasma concentrations may be an effective and valuable method to balance the clinical efficacy and adverse reactions. This study aimed to establish a novel liquid chromatography coupled with mass spectrometry (LC-MS) assay for measuring TZD concentrations in human plasma for therapeutic drug monitoring (TDM)., Methods: After protein precipitation with acetonitrile, LC-MS quantification of TZD was performed in the multiple reaction monitoring mode with chromatographic separation using a mobile phase of MeOH and 0.1% formic acid in water. This method validation intends to investigate specificity, sensitivity, linearity, precision, accuracy, recovery, matrix effect, and stability according to United states food and drug administration guidelines., Results: This method showed good selectivity because no interfering peaks were observed in the plasma samples during the 2-minute run time. The range of the calibration curve was 1-3000 ng/mL. The detection and quantification limits were 0.3 and 1 ng/mL, respectively. The intraday and interday accuracies were 96.5%-103.4%, with precision relative SD% values of <5%, except for the limit of quality. The mean TZD recovery from human plasma was 95.4%-104.5%. Finally, this method was successfully applied to TDM in 20 patients. The TZD plasma concentrations of the patients ranged between 21.5 and 2267.3 ng/mL., Conclusions: A novel analytical method was established to measure TZD by LC-MS coupled with an automatic 2-dimensional liquid chromatograph mass spectrometer coupler 9500 (LC-MS/MS-Mate 9500), which is superior to the ordinary LC-MS system in separation, transport, anti-interference, sensitivity, and quantitative analysis stability., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Levosimendan and milrinone are 2 effective inotropic drugs used to maintain cardiac output in acute heart failure (AHF). Using data from patients with AHF with and without abnormal renal function, we performed this single-center, retrospective cohort study to compare the effectiveness and safety of milrinone and levosimendan for the initial management of AHF. Patients admitted for heart failure between December 2016 and September 2019 who received levosimendan or milrinone as initial inotrope therapy in the cardiology department were identified. A total of 436 levosimendan and 417 milrinone patients with creatinine clearance (CrCl) ≥30 mL/min and 50 levosimendan and 71 milrinone patients with CrCl <30 mL/min or on dialysis were included. The primary outcome was a composite of changes in clinical status at 15 and 30 days after initial inotrope therapy discontinuation. Between subgroups of patients with CrCl ≥30 mL/min, there were no significant differences in primary outcomes; milrinone was associated with more frequent hypotension and cardiac arrhythmias during the infusion period (P < 0.01), while levosimendan was associated with more frequent cardiac arrhythmias within 48 hours after discontinuation (P < 0.05). Of the patients with CrCl <30 mL/min or on dialysis, more initial levosimendan than milrinone patients and those who switched to alternative inotropes experienced clinical worsening at 15 days and 30 days (P < 0.05). According to our results, patients with AHF with severe renal dysfunction should avoid initial inotrope therapy with levosimendan., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)