Long Non-coding RNA PCED1B Antisense RNA 1 Promotes Cell Proliferation and Invasion in Hepatocellular Carcinoma by Regulating the MicroRNA-34a/CD44 Axis.

OBJECTIVE: This study aimed to examine the role of long non-coding RNA PCED1B antisense RNA 1 (PCED1B-AS1) in the development of hepatocellular carcinoma (HCC). METHODS: A total of 62 pairs of HCC tissues and adjacent non-tumor tissues were obtained from 62 HCC patients. The interactions of PCED1B-AS1 and microRNA-34a (miR-34a) were detected by dual luciferase activity assay and RNA pull-down assay. The RNA expression levels of PCED1B-AS1, miR-34a and CD44 were detected by RT-qPCR, and the protein expression level of CD44 was determined by Western blotting. The cell proliferation was detected by cell proliferation assay, and the cell invasion and migration by transwell invasion assay. The HCC tumor growth after PCED1B-AS1 was downregulated was determined by in vivo animal study. RESULTS: PCED1B-AS1 was highly expressed in HCC tissues, which was associated with poor survival of HCC patients. Furthermore, PCED1B-AS1 interacted with miR-34a in HCC cells, but they did not regulate the expression of each other. Additionally, PCED1B-AS1 increased the expression level of CD44, which was targeted by miR-34a. The cell proliferation and invasion assay revealed that miR-34a inhibited the proliferation and invasion of HCC in vitro, while CD44 exhibited the opposite effects. Furthermore, PCED1B-AS1 suppressed the role of miR-34a. Moreover, the knockdown of PCED1B-AS1 repressed the HCC tumor growth in nude mice in vivo. CONCLUSION: PCED1B-AS1 may play an oncogenic role by regulating the miR-34a/CD44 axis in HCC.

Type VII secretion system extracellular protein B targets STING to evade host anti-Staphylococcus aureus immunity.

Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.

Clinical Effects of Ultrasound-Guided Acupotomy in Knee Osteoarthritis Treatment.

The protocol presented here demonstrates the operation method of ultrasound-guided acupotomy for knee osteoarthritis (KOA), including patient recruitment, preoperative preparation, manual operation, and postoperative care. The purpose of this protocol is to relieve pain and improve knee function in patients with KOA. A total of 60 patients with KOA admitted between June 2022 and June 2023 were treated with ultrasound-guided acupotomy. Pathological changes and knee function scores were compared before and after the treatment. After 1 week of treatment, the synovial thickness of the suprapatellar bursae was significantly lesser than before treatment (p < 0.05), the Hospital for Special Surgery Knee Score (HSS) was significantly higher than before treatment (p < 0.05), the Visual analogue scale (VAS) was significantly lower than those of the control group (p < 0.05) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were significantly lower than those of the control group (p < 0.05). Therefore, ultrasound-guided acupotomy for the treatment of KOA can reduce synovial thickness, relieve pain, improve knee joint function, and have a remarkable curative effect.

Expression and localization of the mechanosensitive/osmosensitive ion channel TMEM63B in the mouse urinary tract.

The epithelial cells that line the kidneys and lower urinary tract are exposed to mechanical forces including shear stress and wall tension; however, the mechanosensors that detect and respond to these stimuli remain obscure. Candidates include the OSCA/TMEM63 family of ion channels, which can function as mechanosensors and osmosensors. Using Tmem63bHA-fl/HA-fl reporter mice, we assessed the localization of HA-tagged-TMEM63B within the urinary tract by immunofluorescence coupled with confocal microscopy. In the kidneys, HA-TMEM63B was expressed by proximal tubule epithelial cells, by the intercalated cells of the collecting duct, and by the epithelial cells lining the thick ascending limb of the medulla. In the urinary tract, HA-TMEM63B was expressed by the urothelium lining the renal pelvis, ureters, bladder, and urethra. HA-TMEM63B was also expressed in closely allied organs including the epithelial cells lining the seminal vesicles, vas deferens, and lateral prostate glands of male mice and the vaginal epithelium of female mice. Our studies reveal that TMEM63B is expressed by subsets of kidney and lower urinary tract epithelial cells, which we hypothesize are sites of TMEM63B mechanosensation or osmosensation, or both.

Wine- and stir-frying processing of Cuscutae Semen enhance its ability to alleviate oxidative stress and apoptosis via the Keap 1-Nrf2/HO-1 and PI3K/AKT pathways in H2O2-challenged KGN human granulosa cell line.

BACKGROUND: Cuscutae Semen (CS) has been prescribed in traditional Chinese medicine (TCM) for millennia as an aging inhibitor, an anti-inflammatory agent, a pain reliever, and an aphrodisiac. Its three main forms include crude Cuscutae Semen (CCS), wine-processed CS (WCS), and stir-frying-processed CS (SFCS). Premature ovarian insufficiency (POI) is a globally occurring medical condition. The present work sought a highly efficacious multi-target therapeutic approach against POI with minimal side effects. Finally, it analyzed the relative differences among CCS, WCS and SFCS in terms of their therapeutic efficacy and modes of action against H2O2-challenged KGN human granulosa cell line. METHODS: In this study, ultrahigh-performance liquid chromatography (UPLC)-Q-ExactiveTM Orbitrap-mass spectrometry (MS), oxidative stress indices, reactive oxygen species (ROS), Mitochondrial membrane potential (MMP), real-time PCR, Western blotting, and molecular docking were used to investigate the protective effect of CCS, WCS and SFCS on KGN cells oxidative stress and apoptosis mechanisms. RESULTS: The results confirmed that pretreatment with CCS, WCS and SFCS reduced H2O2-induced oxidative damage, accompanied by declining ROS levels and malondialdehyde (MDA) accumulation in the KGN cells. CCS, WCS and SFCS upregulated the expression of antioxidative levels (GSH, GSH/GSSG ratio, SOD, T-AOC),mitochondrial membrane potential (MMP) and the relative mRNA(Nrf2, Keap1, NQO-1, HO-1, SOD-1, CAT). They inhibited apoptosis by upregulating Bcl-2, downregulating Bax, cleaved caspase-9, and cleaved caspase-3, and lowering the Bax/Bcl-2 ratio. They also exerted antioxidant efficacy by partially activating the PI3K/Akt and Keap1-Nrf2/HO-1 signaling pathways. CONCLUSIONS: The results of the present work demonstrated the inhibitory efficacy of CCS, WCS and SFCS against H2O2-induced oxidative stress and apoptosis in KGN cells and showed that the associated mechanisms included Keap1-Nrf2/HO-1 activation, P-PI3K upregulation, and P-Akt-mediated PI3K-Akt pathway induction.

The Prevalence of Difficult Airway and Associated Risk Factors in Pediatric Patients: A Cross-sessional Observational Study.

BACKGROUND: Difficult airway remains a great challenge in pediatric anesthesia practice. Previously published data show the prevalence of difficult airways in pediatric population varies in a wide range. However, there is a lack of studies in the Asian region. METHODS: This cross-sectional single-center study was conducted in a tertiary pediatric hospital in China from October 2022 to October 2023. The patients who underwent elective surgery under general anesthesia with tracheal intubation were recruited consecutively. Data on patient characteristics, airway assessment, and airway management information were collected. Multivariable logistic regression analysis was performed to detect the independent variables of difficult airway in pediatric patients. RESULTS: A total of 18,491 pediatric patients were included in this study. The overall incidence of difficult airways was 0.22%, 39% of whom were unanticipated. Very few previous airway management information was available in the patients presented with a known difficult airway. Patients with younger age, higher American Society of Anesthesiologists (ASA) physical status classification grade, and presented for craniofacial and thoracic surgery were associated with higher incidence of difficult airway. Further multivariable logistic regression analysis revealed that age ≤28 days (OR=50.48), age between 28days and 1 year (OR=6.053), craniofacial surgery (OR=1.81), and thoracic surgery (OR=0.2465) were independent risk factors of increased incidence of difficult airway. CONCLUSIONS: Our study showed the prevalence of difficult airways in pediatric surgical patients. Patient characteristics, age, and type of surgery were identified as the independent factors associated with increased occurrence of difficult airways. Unanticipated difficult airway was not unusual in our study population, even for the patients with previous surgical history.

Aspirin/amoxicillin loaded chitosan microparticles and polydopamine modified titanium implants to combat infections and promote osteogenesis.

It is known that titanium (Ti) implant surfaces exhibit poor antibacterial properties and osteogenesis. In this study, chitosan particles loaded with aspirin, amoxicillin or aspirin + amoxicillin were synthesized and coated onto implant surfaces. In addition to analysing the surface characteristics of the modified Ti surfaces, the effects of the modified Ti surfaces on the adhesion and viability of rat bone marrow-derived stem cells (rBMSCs) were evaluated. The metabolic activities of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilms on the modified Ti surfaces were also measured in vitro. Moreover, S. aureus was tested for its antibacterial effect by coating it in vivo. Using water as the droplet medium, the contact angles of the modified Ti surfaces increased from 44.12 ± 1.75° to 58.37 ± 4.15°. In comparison to those of the other groups tested, significant increases in rBMSC adhesion and proliferation were observed in the presence of aspirin + amoxicillin-loaded microspheres, whereas a significant reduction in the metabolic level of biofilms was observed in the presence of aspirin + amoxicillin-loaded microspheres both in vitro and in vivo. Aspirin and amoxicillin could be used in combination to coat implant surfaces to mitigate bacterial activities and promote osteogenesis.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Amino acid transporter SLC7A5 regulates cell proliferation and secretary cell differentiation and distribution in the mouse intestine.

The intestine is critical for not only processing nutrients but also protecting the organism from the environment. These functions are mainly carried out by the epithelium, which is constantly being self-renewed. Many genes and pathways can influence intestinal epithelial cell proliferation. Among them is mTORC1, whose activation increases cell proliferation. Here, we report the first intestinal epithelial cell (IEC)-specific knockout (ΔIEC) of an amino acid transporter capable of activating mTORC1. We show that the transporter, SLC7A5, is highly expressed in mouse intestinal crypt and Slc7a5ΔIEC reduces mTORC1 signaling. Surprisingly, adult Slc7a5ΔIEC intestinal crypts have increased cell proliferation but reduced mature Paneth cells. Goblet cells, the other major secretory cell type in the small intestine, are increased in the crypts but reduced in the villi. Analyses with scRNA-seq and electron microscopy have revealed dedifferentiation of Paneth cells in Slc7a5ΔIEC mice, leading to markedly reduced secretory granules with little effect on Paneth cell number. Thus, SLC7A5 likely regulates secretory cell differentiation to affect stem cell niche and indirectly regulate cell proliferation.

A novel member of drug/metabolite transporter (DMT) family efflux pump, SA00565, contributes to tetracycline antibiotics resistance in Staphylococcus aureus USA300.

Drug efflux systems have recently been recognized as a significant mechanism responsible for multidrug resistance in bacteria. In this study, we described the identification and characterization of a new chromosomally encoded efflux pump (SA00565) in Staphylococcus aureus. SA00565, which belongs to the drug/metabolite transporter (DMT) superfamily, was predicted to be a 10-transmembrane segment transporter. To evaluate the role of sa00565 in resistance, we generated sa00565 gene deletion mutant (Δsa00565) and assessed its susceptibility to 35 different antibiotic treatments. Our results demonstrated that the Δsa00565 mutant exhibited reduced resistance to tetracycline and doxycycline, with 64-fold and 12-fold decreased MICs, respectively. The mechanism of SA00565-mediated tetracycline resistance was demonstrated that SA00565 possesses the capability to efficiently extrud intracellular tetracycline into the environment. The efflux activity of SA00565 was further validated using EtBr accumulation and efflux assays. In summary, our study uncovered a previously unknown function of a DMT family transporter, which serves as a tetracycline efflux pump, thereby contributing to tetracycline resistance in S. aureus.IMPORTANCEIn this study, we addressed the significance of drug efflux systems in multidrug resistance of Staphylococcus aureus, focusing on the unexplored efflux pump SA00565 in the drug/metabolite transporter (DMT) superfamily. Through phylogenetic analysis, gene knockout, and overexpression experiments, we identified the role of SA00565 in antibiotic resistance. The Δsa00565 mutant showed increased susceptibility to tetracycline and doxycycline in disk diffusion assays, with significantly lower MICs compared to the WT. Remarkably, intracellular tetracycline concentration in the mutant was two- to threefold higher, indicating SA00565 actively eliminates intracellular tetracycline. Our findings emphasize the pivotal contribution of SA00565 to tetracycline antibiotic resistance in S. aureus, shedding light on its functional attributes within the DMT superfamily and providing valuable insights for combating multidrug resistance.

Acupuncture versus tricyclic antidepressants in the prophylactic treatment of tension-type headaches: an indirect treatment comparison meta-analysis.

BACKGROUND: Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. METHODS: We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. RESULTS: A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). CONCLUSION: Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence.

Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline.

INTRODUCTION: Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined. METHODS: Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function. RESULTS: NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs. DISCUSSION: Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline. HIGHLIGHTS: Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.

Fire acupuncture for plaque psoriasis case series.

OBJECTIVE: To investigate the clinical efficacy of fire acupuncture (FA) on plaque psoriasis (PP), exploring its suitable syndrome types, in order to achieve better therapeutic effects, accelerate the possibility of psoriasis skin lesion recovery, and provide assistance for clinical treatment. METHODS: A total of 8 patients with PP aged between 18 and 60 years were recruited and treated with FA once a week, and the lesion area and severity index (PASI), visual analog scale and pruritus were measured before, 2, 4 and 8 weeks after treatment and at the follow-up period (week 12), respectively. Visual analog scale, and dermoscopy were used for assessment. RESULTS: All patients showed improvement in pruritus after 1 FA treatment, and lesions were reduced to varying degrees after 2 weeks. Except for patients 5 and 8, who only achieved effective results due to severe disease, all other patients with psoriasis achieved significant results at 8 weeks after treatment. CONCLUSION: FA can significantly control the development of lesions, reduce the symptoms of PP lesions and pruritus, and help prevent psoriasis recurrence.

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson's Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway.

Parkinson's disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

Comprehensive quantitative determination of aquifer confinement based on tidal response of well water level and its application in North China.

Aquifer confinement represents a pivotal property that significantly influences the vulnerability and contamination risk of groundwater resources. Several methods have been proposed for determining aquifer confinement by analyzing the response of well water level to Earth tides and atmospheric tides. In this study, we evaluated the performance of the existing single methods and put forward an optimized comprehensive approach. We compared the determination results of the three single methods with those of a comprehensive method using water-level data from 39 earthquake precursor monitoring wells in North China. The results demonstrate that the comprehensive method effectively determined aquifer confinement, significantly reducing the uncertainty associated with the three single methods. The application of the comprehensive method in North China reveals that aquifer confinement may undergo temporal variations during long-term continuous observation, especially in areas where the confining properties of aquifers may vary due to human activities and earthquakes. In such areas, the comprehensive method facilitates accurate assessment of groundwater vulnerability, as well as the potential dispersion of underground pollutants.

Preliminary establishment and validation of the inversion method for growth and remodeling parameters of patient-specific abdominal aortic aneurysm.

Traditional medical imaging and biomechanical studies have challenges in analyzing the long-term evolution process of abdominal aortic aneurysm (AAA). The homogenized constrained mixture theory (HCMT) allows for quantitative analysis of the changes in the multidimensional morphology and composition of AAA. However, the accuracy of HCMT still requires further clinical verification. This study aims to establish a patient-specific AAA growth model based on HCMT, simulate the long-term growth and remodeling (G&R) process of AAA, and validate the feasibility and accuracy of the method using two additional AAA cases with five follow-up datasets. The media and adventitia layers of AAA were modeled as mixtures composed of elastin, collagen fibers, and smooth muscle cells (SMCs). The strain energy function was used to describe the continuous deposition and degradation effect of the mixture during the AAA evolution. Multiple sets of growth parameters were applied to finite element simulations, and the simulation results were compared with the follow-up data for gradually selecting the optimal growth parameters. Two additional AAA patients with different growth rates were used for validating this method, the optimal growth parameters were obtained using the first two follow-up imaging data, and the growth model was applied to simulate the subsequent four time points. The differences between the simulated diameters and the follow-up diameters of AAA were compared to validate the accuracy of the mechanistic model. The growth parameters, especially the stress-mediated substance deposition gain factor, are highly related to the AAA G&R process. When setting the optimal growth parameters to simulate AAA growth, the proportion of simulation results within the distance of less than 0.5 mm from the baseline models is above 80%. For the validating cases, the mean difference rates between the simulated diameter and the real-world diameter are within 2.5%, which basically meets the clinical demand for quantitatively predicting the AAA growth in maximum diameters. This study simulated the growth process of AAA, and validated the accuracy of this mechanistic model. This method was proved to be used to predict the G&R process of AAA caused by dynamic changes in the mixtures of the AAA vessel wall during long-term, assisting accurately and quantitatively predicting the multidimensional morphological development and mixtures evolution process of AAA in the clinic.

Enhanced predictive validity of integrative models for refractory hyperthyroidism considering baseline and early therapy characteristics: a prospective cohort study.

BACKGROUND: A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. METHODS: A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. RESULTS: Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD. CONCLUSION: Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

Outcomes of Excimer Laser Ablation Combined with Drug-coated Balloon in Atherosclerotic Lesions of the Popliteal Artery.

BACKGROUND: The treatment of atherosclerotic lesions in the popliteal artery is challenging. This study aims to investigate the efficacy and safety of excimer laser ablation (ELA) combined with drug-coated balloon (DCB) for these lesions. METHODS: From June 2019 to December 2021, data of patients who underwent ELA combined with DCB in the popliteal artery were retrospectively reviewed. Demographics, lesion characteristics, periprocedural complications, and follow-up information were analyzed. The primary endpoint was primary patency. Secondary endpoints included major amputation-free survival rate, technical success, bailout stenting, clinically-driven target lesion reintervention, improvement of ankle-brachial index (ABI), and Rutherford class. RESULTS: A total of 61 patients were enrolled. The mean age was 73.4 ± 11.7 years. 20 (32.8%) patients had stenotic lesions, while 41 (67.2%) patients had chronic total occlusions. The mean length of these lesions was 7.3 ± 2.8 cm. Procedure technical success rate was 95.1%. Bailout stent was performed in 3 (4.9%) patients. Intraprocedural distal embolization occurred in 3 (4.9%) patients, while flow limiting dissections occurred in 3 (4.9%) patients. The mean ABI was significantly improved from 0.45 ± 0.13 at baseline to 0.90 ± 0.12 after ELA, 0.88 ± 0.11 at 6 months and 0.85 ± 0.12 at 12 months during the follow-up period. The median follow-up time was 28.2 ± 6.1 months. Reintervention was performed in 5 (8.2%) patients. The 2-year primary patency was 83.5%. CONCLUSIONS: ELA combined with DCB is a safe and effective strategy in the treatment of popliteal artery atherosclerotic lesions with low rates of bail-out stenting and high primary patency.

Dynamics of Perceived Social Isolation, Secondary Conditions, and Daily Activity Patterns Among Individuals With Stroke: A Network Analysis of Ecological Momentary Assessment Data.

OBJECTIVE: To assess contemporaneous and temporal dynamics of perceived social isolation (PSI), secondary conditions, and daily activity patterns in individuals post-stroke. DESIGN: Longitudinal observational study using ecological momentary assessment (EMA) as a real-time assessment of an individual's lived experiences. We conducted dynamic network analyses to examine longitudinal associations among EMA variables. SETTINGS: Home and Community. PARTICIPANTS: 202 individuals with mild-to-moderate chronic stroke (median age=60 years; 45% women; 44% black; 90% ischemic stroke; median NIHSS score=2; N=202). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: EMA questions measured PSI, secondary conditions (pain, tiredness, stress, anxiety, worthlessness, difficulty concentrating, and cheerfulness), and daily activity patterns (being at home, being alone, and participating in productive activities). RESULTS: The median EMA response rate was 84%. The contemporaneous model showed that PSI was associated with being home, alone, and all symptoms except pain. The temporal model revealed a pathway indicating that feelings of worthlessness predicted PSI (regression coefficient=0.06, P=.019), followed by stress (regression coefficient=0.06, P=.024), and then by being not at home (regression coefficient=-0.04, P=.013). CONCLUSION: Implementing dynamic network analyses on EMA data can uncover dynamic connections among PSI, secondary conditions, and daily activity patterns after stroke. This study found a significant temporal association between PSI and negative emotions. Feeling isolated was followed by feeling stressed, which was followed by a tendency to be out of home, indicating adaptive behaviors in individuals with stroke. These findings highlight the importance of engaging in out-of-home or outdoor activities to mitigate PSI and negative emotions.