Discretizing Continuous Action Space With Unimodal Probability Distributions for On-Policy Reinforcement Learning.

For on-policy reinforcement learning (RL), discretizing action space for continuous control can easily express multiple modes and is straightforward to optimize. However, without considering the inherent ordering between the discrete atomic actions, the explosion in the number of discrete actions can possess undesired properties and induce a higher variance for the policy gradient (PG) estimator. In this article, we introduce a straightforward architecture that addresses this issue by constraining the discrete policy to be unimodal using Poisson probability distributions. This unimodal architecture can better leverage the continuity in the underlying continuous action space using explicit unimodal probability distributions. We conduct extensive experiments to show that the discrete policy with the unimodal probability distribution provides significantly faster convergence and higher performance for on-policy RL algorithms in challenging control tasks, especially in highly complex tasks such as Humanoid. We provide theoretical analysis on the variance of the PG estimator, which suggests that our attentively designed unimodal discrete policy can retain a lower variance and yield a stable learning process.

Predictive value of number of metastatic lymph nodes and lymph node ratio for prognosis of patients with FIGO 2018 stage IIICp cervical cancer: a multi-center retrospective study.

BACKGROUND: To identify the cut-off values for the number of metastatic lymph nodes (nMLN) and lymph node ratio (LNR) that can predict outcomes in patients with FIGO 2018 IIICp cervical cancer (CC). METHODS: Patients with CC who underwent radical hysterectomy with pelvic lymphadenectomy were identified for a propensity score-matched (PSM) cohort study. A receiver operating characteristic (ROC) curve analysis was performed to determine the critical nMLN and LNR values. Five-year overall survival (OS) and disease-free survival (DFS) rates were compared using Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: This study included 3,135 CC patients with stage FIGO 2018 IIICp from 47 Chinese hospitals between 2004 and 2018. Based on ROC curve analysis, the cut-off values for nMLN and LNR were 3.5 and 0.11, respectively. The final cohort consisted of nMLN ≤ 3 (n = 2,378) and nMLN > 3 (n = 757) groups and LNR ≤ 0.11 (n = 1,748) and LNR > 0.11 (n = 1,387) groups. Significant differences were found in survival between the nMLN ≤ 3 vs the nMLN > 3 (post-PSM, OS: 76.8% vs 67.9%, P = 0.003; hazard ratio [HR]: 1.411, 95% confidence interval [CI]: 1.108-1.798, P = 0.005; DFS: 65.5% vs 55.3%, P < 0.001; HR: 1.428, 95% CI: 1.175-1.735, P < 0.001), and the LNR ≤ 0.11 and LNR > 0.11 (post-PSM, OS: 82.5% vs 76.9%, P = 0.010; HR: 1.407, 95% CI: 1.103-1.794, P = 0.006; DFS: 72.8% vs 65.1%, P = 0.002; HR: 1.347, 95% CI: 1.110-1.633, P = 0.002) groups. CONCLUSIONS: This study found that nMLN > 3 and LNR > 0.11 were associated with poor prognosis in CC patients.

Three-Dimensional Computed Tomography Scanning Study of the Superior Labial Artery in Chinese Individuals for Assessing Filler Injection Safety.

BACKGROUND: Lip filler injection is one of the most common minimally invasive cosmetic procedures involving the face; however, vascular complications are not uncommon. The aim of this study was to investigate the anatomy of the superior labial artery (SLA) and provide precise topographic information for dermal filler injection into the lips. METHODS: Computed tomography (CT) scans of 52 cadaveric heads injected with lead oxide were obtained. We then used Mimics software to construct 3D images of the SLA described by a coordinate system based on the bilateral external auditory canal and the left orbit. This study aimed to classify the SLA in the Han Chinese population, measure its diameter at specific points, and determine the thickness of the lip at those points. Ultimately, we utilized a thermal imaging technique to illustrate the course and depth of the SLA within the lip. The objective of this study was to provide safe guidance for clinical injections. RESULTS: In this study, the SLA was successfully identified in all cadavers. The mean overall diameter of the superior labial arteries was 1.36 ± 0.28 mm. The superior labial artery showed a general course from deep to shallow with an average depth of 5.68 ± 1.68 mm from the oral commissure to the midline. CONCLUSIONS: There are anatomical differences in the superior labial arteries among Chinese people. Furthermore, 3D CT images can digitally elucidate the exact positions of the superior labial artery via a coordinate system, improving the safety of upper lip filler injections in clinical settings. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ferroelectric polarization and magnetic structure at domain walls in a multiferroic film.

Domain walls affect significantly ferroelectric and magnetic properties of magnetoelectric multiferroics. The stereotype is that the ferroelectric polarization will reduce at the domain walls due to the incomplete shielding of depolarization field or the effects of gradient energy. By combining transmission electron microscopy and first-principles calculations, we demonstrate that the ferroelectric polarization of tail-to-tail 180° domain walls in ε-Fe2O3 is regulated by the bound charge density. A huge enhancement (43%) of ferroelectric polarization is observed in the type I domain wall with a low bound charge density, while the ferroelectric polarization is reduced to almost zero at the type II domain wall with a high bound charge density. The magnetic coupling across the type I and type II ferroelectric domain walls are antiferromagnetic and ferromagnetic, respectively. Revealing mechanisms for enhancing ferroelectric polarization and magnetic behaviors at ferroelectric domain walls may promote the fundamental research and potential applications of magnetoelectric multiferroics.

Hierarchical lncRNA regulatory network in early-onset severe preeclampsia.

BACKGROUND: Recent studies have shown that several long non-coding RNAs (lncRNAs) in the placenta are associated with preeclampsia (PE). However, the extent to which lncRNAs may contribute to the pathological progression of PE is unclear. RESULTS: Here, we report a hierarchical regulatory network involved in early-onset severe PE (EOSPE). We have carried out transcriptome sequencing on the placentae from patients and normal subjects to identify the differentially expressed genes (DEGs), including some lncRNAs (DElncRNAs). We then constructed a high-quality hierarchical regulatory network of lncRNAs, transcription factors (TFs), and target DEGs, containing 1851 lncRNA-TF interactions and 6901 TF-promoter interactions. The lncRNA-to-target regulatory interactions were further validated by the triplex structures between the DElncRNAs and the promoters of the target DEGs. The DElncRNAs in the regulatory network were clustered into 3 clusters, one containing DElncRNAs correlated with the blood pressure, including FLNB-AS1 with targeting 27.89% (869/3116) DEGs in EOSPE. We further demonstrated that FLNB-AS1 could bind the transcription factor JUNB to regulate a series members of the HIF-1 signaling pathway in trophoblast cells. CONCLUSIONS: Our results suggest that the differential expression of lncRNAs may perturb the lncRNA-TF-DEG hierarchical regulatory network, leading to the dysregulation of many genes involved in EOSPE. Our study provides a new strategy and a valuable resource for studying the mechanism underlying gene dysregulation in EOSPE patients.

5-Hydroxymethylfurfural and its Downstream Chemicals: A Review of Catalytic Routes.

Biomass assumes an increasingly vital role in the realm of renewable energy and sustainable development due to its abundant availability, renewability, and minimal environmental impact. Within this context, 5-hydroxymethylfurfural (HMF), derived from sugar dehydration, stands out as a critical bio-derived product. It serves as a pivotal multifunctional platform compound, integral in synthesizing various vital chemicals, including furan-based polymers, fine chemicals, and biofuels. The high reactivity of HMF, attributed to its highly active aldehyde, hydroxyl, and furan ring, underscores the challenge of selectively regulating its conversion to obtain the desired products. This review highlights the research progress on efficient catalytic systems for HMF synthesis, oxidation, reduction, and etherification. Additionally, it outlines the techno-economic analysis (TEA) and prospective research directions for the production of furan-based chemicals. Despite significant progress in catalysis research, and certain process routes demonstrating substantial economics, with key indicators surpassing petroleum-based products, a gap persists between fundamental research and large-scale industrialization. This is due to the lack of comprehensive engineering research on bio-based chemicals, making the commercialization process a distant goal. These findings provide valuable insights for further development of this field.

Clinical Observation of Posterior-Chamber Phakic Implantable Collamer Lens V4c Implantation in Myopic Patients with Shallow Anterior Chamber Depth: A Retrospective, Consecutive Observational Study.

Purpose: The reference range for the preoperative anterior chamber angle width for ICL surgery is unclear. Our objective was to assess the clinical effect and the range of anterior chamber angle width of posterior-chamber implantable collamer lens V4c (ICL V4c) implantation in patients with anterior chamber depth (ACD) < 2.8 mm. Methods: Patients who underwent ICL V4c implantation with shallow ACD were included in this retrospective study. The patients' uncorrected and corrected distance visual acuity, angle of trabecular-iris (TIA), angle-opening distance (AOD500), trabecular-iris space area (TISA500), corneal endothelial cell density, vault, retinal nerve fiber layer thickness, intraocular pressure, visual field, and complications were analyzed. Results: Forty-one patients (68 eyes) completed at least 12 months of follow-up (median follow-up, 30 months). The effectiveness and safety indices were 1.09 ± 0.13 and 1.04 ± 0.21, respectively. The preoperative TIA values on the nasal and temporal sides were 39.78 ± 7.68 degree (range, 25.8-65.1 degree) and 41.54 ± 8.03 degree (range, 28.5-63.00 degree). Forty-seven eyes had uncorrected distance visual acuity ≥1.0, and 55 had corrected distance visual acuity ≥1.0 at the last follow-up visit. The TIA, AOD500, and TISA500 on the nasal and temporal sides were significantly reduced compared to those before surgery (all P < 0.01); no eye had an angle closure or elevated intraocular pressure. The ICL V4c vault was 290.88 ± 153.36 µm (range, 60.0-880.0 µm). No severe complications occurred in any patient. Conclusions: In patients with myopia with shallow ACD (2.55-2.79 mm), a preoperative TIA >25.8° is safe and effective for a relatively long time after surgery; however, an extended long-term close follow-up is needed.

Layer-by-layer phase transformation in Ti3O5 revealed by machine-learning molecular dynamics simulations.

Reconstructive phase transitions involving breaking and reconstruction of primary chemical bonds are ubiquitous and important for many technological applications. In contrast to displacive phase transitions, the dynamics of reconstructive phase transitions are usually slow due to the large energy barrier. Nevertheless, the reconstructive phase transformation from ß- to λ-Ti3O5 exhibits an ultrafast and reversible behavior. Despite extensive studies, the underlying microscopic mechanism remains unclear. Here, we discover a kinetically favorable in-plane nucleated layer-by-layer transformation mechanism through metadynamics and large-scale molecular dynamics simulations. This is enabled by developing an efficient machine learning potential with near first-principles accuracy through an on-the-fly active learning method and an advanced sampling technique. Our results reveal that the ß-λ phase transformation initiates with the formation of two-dimensional nuclei in the ab-plane and then proceeds layer-by-layer through a multistep barrier-lowering kinetic process via intermediate metastable phases. Our work not only provides important insight into the ultrafast and reversible nature of the ß-λ transition, but also presents useful strategies and methods for tackling other complex structural phase transitions.

Perineural invasion in cervical cancer: A multicenter retrospective study.

OBJECTIVE: The study aimed to evaluate the accuracy of perineural invasion (PNI) diagnosis in cervical cancer, and to analyze the impact of PNI on the prognosis and postoperative adjuvant treatment decisions for cervical cancer. METHODS: A retrospective pathological review of PNI in cervical cancer was conducted from 2004 to 2016 in 15 hospitals. RESULTS: This study included a total of 1208 cases, comprising 273 cases with PNI and 935 cases without. The false positive rate and false negative rate of PNI diagnosis were 5.35% (50/935) and 33.33% (91/273), respectively. Adenocarcinoma, deep stromal invasion, lymphovascular space invasion (LVSI) (+), and margin involvement were independent risk factors for PNI. Both 5-year overall survival rate (OS) and 5-year disease-free survival rate (DFS) of PNI group were worse than non-PNI group. PNI was an independent risk factor for 5-year OS and 5-year DFS. In cases receiving standard postoperative adjuvant treatment, among those with two intermediate-risk factors, both 5-year OS and DFS were worse in the PNI group. Among cases with three intermediate-risk factors or at least one high-risk factor, there was no difference in 5-year OS between the two groups, but 5-year DFS was worse in the PNI group. CONCLUSION: The diagnosis of PNI in cervical cancer was not accurate. Adenocarcinoma, deep stromal invasion, LVSI, and margin involvement were independent risk factors for PNI. PNI was an independent risk factor for 5-year OS and DFS. PNI has the potential to serve as a new high-risk factor, thus providing guidance for postoperative adjuvant therapy.

Iodide-umpolung catalytic system for non-traditional amide coupling from nitroalkanes and amines.

An N-iodosuccinimide (NIS) catalyst was developed for use in the non-traditional synthesis of amide derivatives from nitroalkanes and amines. In contrast to traditional oxidative catalysis, this catalytic system involves reversing the polarities of two catalytic components (umpolung) by means of a hypervalent iodine reagent. A variety of functional groups were tolerated in the reaction, suggesting that they have the potential for use in other types of oxidative catalytic reactions.

A comparative study of two pelvimetry methods: 3D models based on CT and MRI.

INTRODUCTION AND HYPOTHESIS: To compare 3D models based on magnetic resonance imaging (MRI) and 3D models based on computed tomography (CT) in pelvimetry. METHODS: A retrospective analysis of 141 patients who underwent both pelvic 3D MRI and 3D CT pelvimetry for gynecological diseases from December 2009 to October 2020 was performed. The two pelvimetry methods were compared by paired Student's t test, Pearson's correlation coefficient, Bland-Altman analysis and intraclass correlation coefficient (ICC). RESULTS: The differences between methods for each diameter were statistically significant, except for those of the posterior sagittal diameter of the pelvic inlet (t:-0.71, P = 0.5) and the anteroposterior pelvic outlet diameter (t:0.02, P = 0.98). 3D MRI and 3D CT pelvimetry strongly correlated with each other (r: min 0.7, max: 0.96, P < 0.01). The Bland-Altman results indicate that the difference points of each pelvic diameter line greater than 95 % are within the 95 % limits of agreement. The ICC was good to very good for all pelvimetric measurements using either MRI-3D (ICC: 0.64-0.98) or CT-3D (ICC: 0.72-0.98) between the two readers. CONCLUSIONS: 3D MRI and 3D CT pelvimetry have good agreement and reproducibility, indicating that 3D MRI is reliable for pelvimetry.

Mechanism of Qingchang compound against coccidiosis based on network pharmacology-molecular docking.

The aim of this study was to investigate the anti-Eimeria tenella mechanism of Qingchang Compound (QCC) and provide a basis for its clinical application. The active ingredients, active ingredient-disease intersection targets, and possible pathways of QCC for the treatment of chicken coccidiosis were analyzed, the binding ability of pharmacodynamic components and target proteins was determined by network pharmacology and the molecular docking, and a model of infection with coccidiosis was constructed to verify and analyze the mechanism of action of QCC against coccidiosis. Among the 57 components that met the screening conditions, the main bioactive components were quercetin, dichroine, and artemisinin, with IL-1ß, IL-6, IL-10, IFN-γ, and IL-8 as the core targets. Simultaneously, the KEGG signaling pathway of QCC anti-coccidiosis in chickens was enriched, including cytokine-cytokine receptor interactions. The results showed that the main pharmacodynamic components of QCC and the core targets could bind well; artemisinin and alpine possessed the largest negative binding energies and presented the most stable binding states. In addition, in vivo studies showed that QCC reduced blood stool in chickens with coccidiosis, restored cecal injury, and significantly reduced the mRNA and protein expression levels of IL-1ß, IL-10, and IFN-γ in ceca (p < 0.01). Our results suggest that the main active ingredients of QCC are artemisinin and alpine and its mechanism of action against coccidiosis may be related to the reduction of the inflammatory response by acting on specific cytokines.

Exploring T7 RNA polymerase-assisted CRISPR/Cas13a amplification for the detection of BNP via electrochemiluminescence sensing platform.

Brain natriuretic peptide (BNP) is considered to be an important biomarker of heart failure (HF) attracting attention. However, its low concentration and short half-life in blood lead to a low-sensitivity detection of BNP, which is a challenge that has to be overcome. In this work, we propose a highly specific, highly sensitive T7 RNA polymerase-assisted clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13a system to detect BNP via an electrochemiluminescence (ECL) sensing platform and incorporate exonuclease III (Exo III)-hairpin and dumbbell-shaped hybridization chain reaction (HCR) technologies. In this detection scheme, the ECL sensing platform possesses low background signal and high sensitivity. Firstly, the T7 promoter-initiated T7 RNA polymerase acts as a signal amplification technique to generate large amounts of RNAs that can activate CRISPR/Cas13a activity. Secondly, CRISPR/Cas13a is able to trans-cleave the surrounding trigger strand to produce DNA1. Thirdly, DNA1 is involved in the co-amplification reaction of Exo III and hairpin DNA, which subsequently triggers a dumbbell-shaped HCR technology. Eventually, a large number of Ru (II) molecules are inserted into the interstitial space of the dumbbell-shaped HCR to generate a strong ECL signal. The CRISPR/Cas13a possesses outstanding specificity for a single base and increased sensitivity. The tightly conformed dumbbell-shaped HCR provides higher sensitivity than the traditional linear HCR amplification technique. Ultimately, the clever combination of several amplification reactions enables the limit of detection (LOD) as low as 3.2 fg/mL. It showed promise for clinical sample testing, with recovery rates ranging from 98.4% to 103% in 5% human serum samples. This detection method offered a valuable tool for early HF detection, emphasizing the synergy of amplification strategies and specificity conferred by CRISPR/Cas13a technology.

Exposure-efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure-efficacy of vedolizumab intravenous (IV) and subcutaneous (SC). METHODS: A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD). RESULTS: Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations. CONCLUSION: Exposure-efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

Comparison of urethral parameters in females presenting cystoceles with and without stress urinary incontinence based on dynamic magnetic resonance imaging: are they different?

PURPOSE: To compare urethral parameters between cystocele patients with and without stress urinary incontinence (SUI) and explore factors influencing SUI in cystocele patients via dynamic MRI. METHODS: The two-dimensional parameters evaluated included the paravaginal defects, levator ani muscle defects, urethral length, urethral funnel shape, bladder neck funnel width, bladder neck funnel depth, urethral angle, posterior vesicourethral angle, and anterior bladder protrusion. The three-dimensional parameters included the proximal urethra rotation angle, the distal urethra rotation angle, bladder neck mobility, urethral midpoint mobility, and external urethral meatus mobility. The independent samples t test was used for continuous variables, and the chi-square test was used for categorical variables. Binary logistic regression was used to identify factors independently associated with SUI in cystocele patients. RESULTS: The baseline parameters were similar between the 2 groups. Cystocele patients with SUI had a significantly higher point Aa (1.63 ± 1.06 cm vs. 0.81 ± 1.51 cm, p = 0.008); more anterior bladder protrusion (33.3% vs. 11.4%, p = 0.017); greater bladder neck mobility (36.38 ± 11.46 mm vs. 28.81 ± 11.72 mm, p = 0.005); mid-urethral mobility (22.94 ± 6.50 mm vs. 19.23 ± 6.65 mm, p = 0.014); and external urethral meatus mobility (22.42 ± 8.16 mm vs. 18.03 ± 8.51 mm, p = 0.022) than did cystocele patients without SUI. The other urethral parameters were similar in the groups (p > 0.05). Binary logistic regression showed that bladder neck mobility was independently associated with SUI in females with cystoceles (odds ratio, 1.06; 95% CI 1.015-1.107; p = 0.009). CONCLUSION: Cystocele patients with SUI have a higher point Aa, more anterior bladder protrusion, and greater urethral mobility than those without SUI. Bladder neck mobility is independently associated with SUI in females with cystoceles. REGISTRATION NUMBER: NCT03146195.

Consensus Guidelines: Best Practices for the Prevention, Detection and Management of Hepatitis B Virus Reactivation in Clinical Trials with Immunosuppressive/Immunomodulatory Therapy.

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker-positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.

Fluoroquinolones upregulate insulin-like growth factor-binding protein 3, inhibit cell growth and insulin-like growth factor signaling.

Fluoroquinolones (FQs), commonly known for their antibiotic properties, exhibit additional pharmacological potential with anti-proliferative effects on various malignant cell types and immunomodulatory responses. Despite these observed effects, the precise mechanisms of action remain elusive. This study elucidates the biological impact of FQs on insulin-like growth factor-binding protein 3 (IGFBP-3) productions in a p53-dependent manner. Cultured cells and mouse models treated with FQs demonstrated increased IGFBP-3 mRNA expression and protein secretion. The FQ-induced IGFBP-3 was identified to impede cell growth by inhibiting IGF-I signaling and exerting effects through an IGF-independent pathway. Notably, FQ-mediated suppression of cell proliferation was reversed in p53-null and p53 knockdown cells, suggesting the pivotal role of p53 in FQ-induced IGFBP-3 production and IGFBP-3-mediated growth inhibition. Additionally, ciprofloxacin, a clinically used FQ, exhibited the induction of tumor cell apoptosis and attenuation of tumor growth in a syngeneic mouse hepatocellular carcinoma (HCC) model. These findings unveil a novel mechanism through which FQs act as anti-proliferative agents, prompting further exploration of their potential utility or derivative compounds in cancer treatment and prevention.

Impact of histological subtypes on clinical outcome of endocervical adenocarcinoma.

OBJECTIVE: This multicenter study aimed to investigate the disparity in clinical features and prognosis among different histopathologic subtypes of endocervical adenocarcinoma (EA) based on the 2014 World Health Organization (WHO) classification. METHODS: We retrieved and analyzed data from the Chinese Four C Database between 2004 and 2018. 672EA patients with radical hysterectomies from 32 institutions were retrospectively reviewed. Clinicopathologic characteristics, five-year overall survival (OS), and disease-free survival (DFS) were compared based on histological subtypes. RESULTS: The 5-year DFS and OS rates for usual, endometrioid, mucinous, gastric, villoglandular, clear cell/serous/mesonephric EAs were as follows: 81.3 %, 89.1 %, 63.0 %, 35.6 %, 88.6 %, 79.9 %, respectively (P < 0.0001); 87.4 %, 96.6 %, 74.7 %, 34.0 %, 96.7 %, 86.3 %, respectively (P < 0.0001). Gastric- and mucinous-type exhibited a higher frequency of lymph node metastasis, deep stromal invasion, uterine corpus invasion, and recurrence than the usual -type (recurrence rate:50.00 % vs 29.90 % vs 15.50 %, P < 0.0001). Multivariate analysis revealed gastric-type was significantly associated with inferior DFS (HR,3.018; 95 % CI, 1.688-5.397; P < 0.0001) and OS(HR, 4.114; 95 % CI, 2.002-8.453; P < 0.0001). Furthermore, compared to the usual -type, mucinous-type demonstrated significantly worse DFS (HR, 1.773; 95 % CI,1.123-2.8; P = 0.014) and OS (HR, 2.168; 95 % CI,1.214-3.873; P = 0.009) whereas endometrioid-type was an identified as independent factor for better DFS (HR, 0.365; 95 % CI,0.143-0.928; P = 0.034). Villoglandular subtype displayed similar features and favorable prognosis as the usual type. CONCLUSIONS: Relevant clinical features and prognosis varied significantly among histological subtypes of EA, thus offering valuable guidance for the development of subtype-specific treatment strategies to optimize EA management.

Monocular Vision Loss After Ear Filler Injection.

Ophthalmic artery occlusion caused by facial hyaluronic acid filler injection has always been a rare but devastating complication. With the pursuit of beauty, people have become more interested in ears and hyaluronic acid fillers. Herein, we report the case of a more serious rare complication of ophthalmic artery occlusion caused by ear filler injection. A 45-year-old woman developed vision loss on the left side immediately after receiving cosmetic hyaluronic acid injection in the ear, with only the visual field at the inferior temporal side remaining. She was diagnosed with central retinal artery occlusion in the left eye. After treatment with hyaluronidase injection, dexamethasone, hyperbaric oxygen, and oral alprostadil, blood flow was partially restored in the left ophthalmic artery, and her vision improved. Vascular complications after ear injections are rare. However, as the demand for ear filler injections increases, the probability of serious vascular complications is predicted to increase. The potential mechanism by which occlusion occurred involved the filler reaching the superficial temporal artery system through the superior auricular artery, thus occluding the ophthalmic artery. Having an understanding of anatomy is an important measure to avoid complications.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of contents or the online Instructions to Authors www.springer.com/00266 .

PD-1 inhibitor combined with Docetaxel exerts synergistic anti-prostate cancer effect in mice by down-regulating the expression of PI3K/AKT/NFKB-P65/PD-L1 signaling pathway.

BACKGROUND: Docetaxel is a yew compound antitumor agent with accurate antitumor efficacy, but its application is limited due to the high and serious adverse effects, and finding effective combination therapy options is a viable strategy. Immune checkpoint inhibitors have become hotspots in enhancing anti-tumor immunity by blocking immune checkpoint signaling pathways, but their response rate to monotherapy use is not high and the efficacy is minimal. OBJECTIVE: To explore the anti-tumor effects and mechanisms of the combination of PD-1 inhibitors and Docetaxel through in vivo experiments and develop a feasible combination treatment for the therapy of prostate cancer. METHODS: Tumor-bearing mice were subcutaneously injected with 0.1 ml RM-1 cells. Treatment were taken when the tumor growed up to 3 mm, after which the tumor and spleen were removed to test the antitumor effect with Flow cytometric (FACS) analysis, Immunohistochemistry, Western Blot. RESULTS: In this experiment, we found that PD-1 inhibitors combined with Docetaxel had a synergistic effect on mouse prostate cancer, inhibited the growth of prostate cancer, improved survival and reduced adverse reactions, increased spleen and tumor infiltrative CD4+ and CD8+ T cells, especially in group combination with low-dose Docetaxel, and were related to the PI3K/AKT/NFKB-P65/PD-L1 signaling pathway. CONCLUSION: Our study confirms that PD-1 inhibitors in combination with Docetaxel are a viable combination strategy and provide a safe and effective combination option for the clinical treatment of prostate cancer.