Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens.

Substance use disorder is characterized by a maladaptive imbalance wherein drug seeking persists despite negative consequences or drug unavailability. This imbalance correlates with neurobiological alterations some of which are amplified during forced abstinence, thereby compromising the capacity of extinction-based approaches to prevent relapse. Cocaine use disorder (CUD) exemplifies this phenomenon in which neurobiological modifications hijack brain reward regions such as the nucleus accumbens (NAc) to manifest craving and withdrawal-like symptoms. While increasing evidence links transcriptional changes in the NAc to specific phases of addiction, genome-wide changes in gene expression during withdrawal vs. extinction (WD/Ext) have not been examined in a context- and NAc-subregion-specific manner. Here, we used cocaine self-administration (SA) in rats combined with RNA-sequencing (RNA-seq) of NAc subregions (core and shell) to transcriptionally profile the impact of experiencing withdrawal in the home cage or in the previous drug context or experiencing extinction training. As expected, home-cage withdrawal maintained drug seeking in the previous drug context, whereas extinction training reduced it. By contrast, withdrawal involving repetitive exposure to the previous drug context increased drug-seeking behavior. Bioinformatic analyses of RNA-seq data revealed gene expression patterns, networks, motifs, and biological functions specific to these behavioral conditions and NAc subregions. Comparing transcriptomic analysis of the NAc of patients with CUD highlighted conserved gene signatures, especially with rats that were repetitively exposed to the previous drug context. Collectively, these behavioral and transcriptional correlates of several withdrawal-extinction settings reveal fundamental and translational information about potential molecular mechanisms to attenuate drug-associated memories.

Suppression of AGRN enhances CD8+ T cell recruitment and inhibits breast cancer progression.

Breast cancer (BC) stands as a prominent contributor to global cancer-related mortality, with an increasing incidence annually. This study aims to investigate AGRN gene expression in BC, as well as explore its influence on the tumor immune microenvironment. AGRN displayed a pronounced upregulation in BC tissues relative to paracancerous tissues. Single-cell RNA analysis highlighted AGRN-specific elevation within cancer cell clusters and also showed expression expressed in stromal as well as immune cell clusters. AGRN upregulation was positively correlated with clinicopathological stage and negatively correlated with BC prognosis. As revealed by the in vitro experiment, AGRN knockdown effectively hinders BC cells in terms of proliferation, invasion as well as migration. AGRN protein, which may interact with EXT1, LRP4, RAPSN, etc., was primarily distributed in the cell cytoplasm. Notably, immune factors might interact with AGRN in BC, evidenced by its discernible associations with immunofactors like IL10, CD274, and PVRL2. Mass spectrometry and immunohistochemistry revealed that the reduction of AGRN led to an increase in CD8+ T cells with triple-negative breast cancer (TNBC). Mechanistically, the connection between TRIM7 and PD-L1 is improved by AGRN, acting as a scaffold, thereby facilitating the accelerated degradation of PD-L1 by TRIM7. Downregulation of AGRN inhibits BC progression and increases CD8+ T cell recruitment. Targeting AGRN may contribute to BC treatment. The biomarker AGRN, serving as a therapeutic target for BC, emerges as a prospective avenue for enhancing both diagnosis and prognosis in BC cases.

Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis.

Disulfidptosis was recently reported to be caused by abnormal disulfide accumulation in cells with high SLC7A11 levels subjected to glucose starvation, suggesting that targeting disulfidptosis was a potential strategy for cancer treatment. We analyzed the relationships between gene expression and mutations and prognoses of patients. In addition, the correlation between gene expression and immune cell infiltration was explored. The potential regulatory mechanisms of these genes were assessed by investigating their related signaling pathways involved in cancer, their expression patterns, and their cellular localization. Most cancer types showed a negative correlation between the gene-set variation analysis (GSVA) scores and infiltration of B cells and neutrophils, and a positive correlation between GSVA scores and infiltration of natural killer T and induced regulatory T cells. Single-cell analysis revealed that ACTB, DSTN, and MYL6 were highly expressed in different bladder urothelial carcinoma subtypes, but MYH10 showed a low expression. Immunofluorescence staining showed that actin cytoskeleton proteins were mainly localized in the actin filaments and plasma membrane. Notably, IQGAP1 was localized in the cell junctions. In conclusion, this study provided an overview of disulfidptosis-related actin cytoskeleton genes in pan-cancer. These genes were associated with the survival of patients and might be involved in cancer-related pathways.

FABEL: Forecasting Animal Behavioral Events with Deep Learning-Based Computer Vision.

Behavioral neuroscience aims to provide a connection between neural phenomena and emergent organism-level behaviors. This requires perturbing the nervous system and observing behavioral outcomes, and comparing observed post-perturbation behavior with predicted counterfactual behavior and therefore accurate behavioral forecasts. In this study we present FABEL, a deep learning method for forecasting future animal behaviors and locomotion trajectories from historical locomotion alone. We train an offline pose estimation network to predict animal body-part locations in behavioral video; then sequences of pose vectors are input to deep learning time-series forecasting models. Specifically, we train an LSTM network that predicts a future food interaction event in a specified time window, and a Temporal Fusion Transformer that predicts future trajectories of animal body-parts, which are then converted into probabilistic label forecasts. Importantly, accurate prediction of food interaction provides a basis for neurobehavioral intervention in the context of compulsive eating. We show promising results on forecasting tasks between 100 milliseconds and 5 seconds timescales. Because the model takes only behavioral video as input, it can be adapted to any behavioral task and does not require specific physiological readouts. Simultaneously, these deep learning models may serve as extensible modules that can accommodate diverse signals, such as in-vivo fluorescence imaging and electrophysiology, which may improve behavior forecasts and elucidate invervention targets for desired behavioral change.

Identifying Shared Neuroanatomic Architecture between Cognitive Traits through Multiscale Morphometric Correlation Analysis.

We introduce an informative metric, called morphometric correlation, as a measure of shared neuroanatomic similarity between two cognitive traits. Traditional estimates of trait correlations can be confounded by factors beyond brain morphology. To exclude these confounding factors, we adopt a Gaussian kernel to measure the morphological similarity between individuals and compare pure neuroanatomic correlations among cognitive traits. In our empirical study, we employ a multiscale strategy. Given a set of cognitive traits, we first perform morphometric correlation analysis for each pair of traits to reveal their shared neuroanatomic correlation at the whole brain (or global) level. After that, we extend our whole brain concept to regional morphometric correlation and estimate shared neuroanatomic similarity between two cognitive traits at the regional (or local) level. Our results demonstrate that morphometric correlation can provide insights into shared neuroanatomic architecture between cognitive traits. Furthermore, we also estimate the morphometricity of each cognitive trait at both global and local levels, which can be used to better understand how neuroanatomic changes influence individuals' cognitive status.

Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRß.

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction. Vascular smooth muscle cells (VSMCs), the main components of atherosclerotic plaque, switch from contractile to synthetic phenotypes during atherogenesis. Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis, and it can be reversely regulated by deubiquitinases. However, the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated. In this study, RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases, which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch. Further in vivo studies using Apoe-/- mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype. Moreover, VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro. Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation, adhesion, and proliferation. Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated. Mechanistically, we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRß with its catalytic triad, thereby reducing the K48-linked ubiquitylation of PDGFRß. Inhibiting OTUB1 in VSMCs could promote PDGFRß degradation via the ubiquitin-proteasome pathway, so it was beneficial in preventing VSMCs' phenotype switch. These findings revealed that knocking down OTUB1 ameliorated VSMCs' phenotype switch and atherosclerosis progression, indicating that OTUB1 could be a valuable translational therapeutic target in the future.

The Alzheimer's Knowledge Base: A Knowledge Graph for Alzheimer Disease Research.

BACKGROUND: As global populations age and become susceptible to neurodegenerative illnesses, new therapies for Alzheimer disease (AD) are urgently needed. Existing data resources for drug discovery and repurposing fail to capture relationships central to the disease's etiology and response to drugs. OBJECTIVE: We designed the Alzheimer's Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics. METHODS: We designed the AlzKB as a large, heterogeneous graph knowledge base assembled using 22 diverse external data sources describing biological and pharmaceutical entities at different levels of organization (eg, chemicals, genes, anatomy, and diseases). AlzKB uses a Web Ontology Language 2 ontology to enforce semantic consistency and allow for ontological inference. We provide a public version of AlzKB and allow users to run and modify local versions of the knowledge base. RESULTS: AlzKB is freely available on the web and currently contains 118,902 entities with 1,309,527 relationships between those entities. To demonstrate its value, we used graph data science and machine learning to (1) propose new therapeutic targets based on similarities of AD to Parkinson disease and (2) repurpose existing drugs that may treat AD. For each use case, AlzKB recovers known therapeutic associations while proposing biologically plausible new ones. CONCLUSIONS: AlzKB is a new, publicly available knowledge resource that enables researchers to discover complex translational associations for AD drug discovery. Through 2 use cases, we show that it is a valuable tool for proposing novel therapeutic hypotheses based on public biomedical knowledge.

Low-loss tantalum pentoxide photonics with a CMOS-compatible process.

We report a Ta2O5 photonic platform with a propagation loss of 0.49 dB/cm at 1550 nm, of 0.86 dB/cm at 780 nm, and of 3.76 dB/cm at 2000 nm. The thermal bistability measurement is conducted in the entire C-band for the first time to reveal the absorption loss of Ta2O5 waveguides, offering guidelines for further reduction of the waveguide loss. We also characterize the Ta2O5 waveguide temperature response, which shows favorable thermal stability. The fabrication process temperature is below 350°C, which is friendly to integration with active optoelectronic components.

Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model.

Objective: Combination immunotherapy strategies targeting OX40, a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation, differentiation, and effector function of tumor-infiltrating T cells, have attracted much attention for their excellent therapeutic effects. In this study, we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core virus-like particles (HBc VLPs) therapy using a mouse colon cancer model. Methods: Humanized B-hOX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-hOX40 antibody. Tumor growth was monitored. Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors. Results: The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth, suggesting that a potent antitumor immunity was induced by the combination therapy. Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells (Teffs) and a significant decrease in regulatory T cells (Tregs) in the tumor microenvironment (TME), which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs. Conclusion: Combination therapy of anti-hOX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice, which may represent a potential design strategy for cancer immunotherapy.

Establishing and Validating an Innovative Focal Adhesion-Linked Gene Signature for Enhanced Prognostic Assessment in Endometrial Cancer.

Studies have highlighted the significant role of focal adhesion signaling in cancer. Nevertheless, its specific involvement in the pathogenesis of endometrial cancer and its clinical significance remains uncertain. We analyzed TCGA-UCEC and GSE119041 datasets with corresponding clinical data to investigate focal adhesion-related gene expression and their clinical significance. A signature, "FA-riskScore," was developed using LASSO regression in the TCGA cohort and validated in the GSE dataset. The FA-riskScore was compared with four existing models in terms of their prediction performance. We employed univariate and multivariate Cox regression analyses towards FA-riskScore to assess its independent prognostic value. A prognostic evaluation nomogram based on our model and clinical indexes was established subsequently. Biological and immune differences between high- and low-risk groups were explored through functional enrichment, PPI network analysis, mutation mining, TME evaluation, and single-cell analysis. Sensitivity tests on commonly targeted drugs were performed on both groups, and Connectivity MAP identified potentially effective molecules for high-risk patients. qRT-PCR validated the expressions of FA-riskScore genes. FA-riskScore, based on FN1, RELN, PARVG, and PTEN, indicated a poorer prognosis for high-risk patients. Compared with published models, FA-riskScore achieved better and more stable performance. High-risk groups exhibited a more challenging TME and suppressive immune status. qRT-PCR showed differential expression in FN1, RELN, and PTEN. Connectivity MAP analysis suggested that BU-239, potassium-canrenoate, and tubocurarine are effective for high-risk patients. This study introduces a novel prognostic model for endometrial cancer and offers insights into focal adhesion's role in cancer pathogenesis.

Expressions and Clinical Significance of Met and YAP in Gastric Cancer Tissue Microarray.

Objective: This study is aimed at investigating the expression of Met and YAP in gastric cancer and their impact on clinical prognosis. Methods: Tissue samples and clinical data were collected from 89 patients with gastric cancer. Immunohistochemistry was performed to quantify the expression of Met and YAP using tissue microarray. The correlation between the expressions of Met, YAP, and clinicopathological characteristics of patients was determined using a chi-square test. Survival analysis was conducted using the Kaplan-Meier method, while multivariate survival analysis was performed using the Cox proportional hazard model. Bioinformatics analysis was carried out by downloading chip data from TCGA. Results: The expression levels of both Met and YAP were significantly higher in gastric cancer tissues compared to adjacent tissues (P < 0.001). Met expression showed a positive association with P53 and CD133, whereas YAP expression correlated positively with tumor grade and CD133 (P < 0.05). Pearson's analysis revealed a significant correlation between Met expression and VEGFR as well as CD133, while YAP expression correlated with Ki67 and VEGFR (P < 0.05). Patients with high levels of both Met and YAP exhibited decreased survival time (P < 0.01). Furthermore, Met expression, N stage, and VEGFR were identified as independent risk factors for gastric cancer prognosis (P < 0.05), whereas no such association was observed for YAP expression. Bioinformatics analysis demonstrated a significant correlation between the expressions of Met and YAP; both proteins were highly expressed in gastric cancer patients accompanied by markedly reduced survival time. Conclusion: The expressions of Met and YAP are closely associated with the survival outcomes as well as clinicopathological features in patients with gastric cancer. Moreover, our findings highlight that Met serves as an independent prognostic factor for gastric cancer.

Circuit-wide gene network analysis reveals sex-specific roles for phosphodiesterase 1b in cocaine addiction.

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA-sequencing dataset to generate gene co-expression networks across 6 interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (Pde1b), a Ca2+/calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats, but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs, while increasing excitability of D2 MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine.Significance Statement Cocaine use disorder is a major public health challenge without an effective pharmacological treatment. Here, we leverage a combination of genome-wide RNA sequencing, gene co-expression network analysis, and bioinformatic analyses of cocaine self-administration behavior to identify a role for phosphodiesterase 1b (Pde1b) in regulating maladaptive, addiction-like behavior. Our studies reveal cell-type- and sex-specific roles for Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine, yielding insight into the molecular mechanisms by which cocaine induces maladaptive plasticity in the brain's reward circuity to drive addiction-like behavior. These discoveries guide directions for future research investigating the molecular basis of cocaine action and provide a pathway for therapeutic development for cocaine use disorder.

Non-contact wide-field viewing system-assisted scleral buckling surgery for retinal detachment in silicone oil-filled eyes.

AIM: To evaluate scleral buckling (SB) surgery using a non-contact wide-field viewing system and 23-gauge intraocular illumination for the treatment of rhegmatogenous retinal detachment in silicone oil (SO)-filled eyes. METHODS: Totally 9 patients (9 eyes) with retinal detachment in SO-filled eyes were retrospectively analyzed. All patients underwent non-contact wide-field viewing system-assisted buckling surgery with 23-gauge intraocular illumination. SO was removed at an appropriate time based on recovery. The patients were followed up for at least 3mo after SO removal. Retinal reattachment, complications, visual acuity and intraocular pressure (IOP) before and after surgery were observed. RESULTS: Patients were followed up for a mean of 8.22mo (3-22mo) after SO removal. All patients had retinal reattachment. At the final follow-up, visual acuity showed improvement for 8 patients, and no change for 1 patient. The IOP was high in 3 patients before surgery, but it stabilized after treatment; it was not affected in the other patients. None of the patients had infections, hemorrhage, anterior ischemia, or any other complication. CONCLUSION: This new non-contact wide-field viewing system-assisted SB surgery with 23-gauge intraocular illumination is effective and safe for retinal detachment in SO-filled eyes.

Leonurus japonicus Houtt. Modulates Neuronal Apoptosis in Intracerebral Hemorrhage: Insights from Network Pharmacology and Molecular Docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique,molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

Robotic gastrectomy was reliable option for overweight patients with gastric cancer: a propensity score matching study.

BACKGROUND: The role of minimally invasive surgery using robotics versus laparoscopy in resectable gastric cancer patients with a high body mass index (BMI) remains controversial. METHODS: A total of 482 gastric adenocarcinoma patients with BMI ≥ 25 kg/m2 who underwent minimally invasive radical gastrectomy between August 2016 and December 2019 were retrospectively analyzed, including 109 cases in the robotic gastrectomy (RG) group and 321 cases in the laparoscopic gastrectomy (LG) group. Propensity score matching (PSM) with a 1:1 ratio was performed, and the perioperative outcomes, lymph node dissection, and 3-year overall survival (OS) and disease-free survival (DFS) rates were compared. RESULTS: After PSM, 109 patients were included in each of the RG and LG groups, with balanced baseline characteristics. Compared with the LG group, the RG group had similar intraoperative estimated blood loss [median (IQR) 30 (20-50) vs. 35 (30-59) mL, median difference (95%CI) - 5 (- 10 to 0)], postoperative complications [13.8% vs. 18.3%, OR (95%CI) 0.71 (0.342 to 1.473)], postoperative recovery, total harvested lymph nodes [(34.25 ± 13.43 vs. 35.44 ± 14.12, mean difference (95%CI) - 1.19 (- 4.871 to 2.485)] and textbook outcomes [(81.7% vs. 76.1%, OR (95%CI) 1.39 (0.724 to 2.684)]. Among pathological stage II-III patients receiving chemotherapy, the initiation of adjuvant chemotherapy in the RG group was similar to that in the LG group [median (IQR): 28 (25.5-32.5) vs. 32 (27-38.5) days, median difference (95%CI) - 3 (- 6 to 0)]. The 3-year OS (RG vs. LG: 80.7% vs. 81.7%, HR = 1.048, 95%CI 0.591 to 1.857) and DFS (78% vs. 76.1%, HR = 0.996, 95%CI 0.584 to 1.698) were comparable between the two groups. CONCLUSION: RG conferred comparable lymph node dissection, postoperative recovery, and oncologic outcomes in a selected cohort of patients with BMI ≥ 25 kg/m2.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

Effects of sacubitril/valsartan according to polypharmacy status in PARAGON-HF.

AIMS: Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON-HF. METHODS AND RESULTS: In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON-HF. The effects of sacubitril/valsartan, compared with valsartan, were assessed according to the number of medications at baseline: 683 non-polypharmacy (<5 medications); 2750 polypharmacy (5-9 medications), and 1360 hyper-polypharmacy (≥10 medications). The primary outcome was total HF hospitalizations and cardiovascular deaths. Patients with hyper-polypharmacy were older, had more severe limitations due to HF (worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores), and had greater comorbidity. The non-adjusted risk of the primary outcome was significantly higher in patients taking more medications, and similar trends were seen for HF hospitalization and cardiovascular and all-cause death. The effect of sacubitril/valsartan versus valsartan on the primary outcome from the lowest to highest polypharmacy category was (as a rate ratio): 1.19 (0.76-1.85), 0.94 (0.77-1.15), and 0.77 (0.61-0.96) (pinteraction = 0.16). Treatment-related adverse events were more common in patients in the higher polypharmacy categories but not more common with sacubitril/valsartan, versus valsartan, in any polypharmacy category. CONCLUSIONS: Polypharmacy is very common in patients with HFpEF, and those with polypharmacy have worse clinical status and a higher rate of non-fatal and fatal outcomes. The benefit of sacubitril/valsartan was not diminished in patients taking a larger number of medications at baseline.

Comparison of three VST orthokeratology lenses in axial length growth and average corneal reshaping in myopia children: A retrospective self-controlled study.

Purpose: To determine the differences in myopia control efficiency and corneal reshaping between three different brands of orthokeratology (OK) lenses (Lucid, Euclid, and Alpha). Method: We retrospectively reviewed subjects who started simultaneously using different brands of OK lenses. For each participant, every 6 months in the 19 months of following, the changes in axial length (AL), horizontal and vertical maximum distances of the treatment zone (HMDTZ and VMDTZ), width of the high convex zone (WHCZ), distance of decentration, and horizontal and vertical components of the decentration vector were measured. The average values of the above data, the average value of the decentration vector (ADV), and the average value of decentration calculated algebraically (ADA) were calculated. Results: All the three pairs (Lucid (n = 46) vs. Euclid (n = 46): groups Lucid-versus-Euclid-Lucid (LE-L) and LE-E), Lucid (n = 50) vs. Alpha (n = 50): groups LA-L and LA-A), and Euclid (n = 17) vs. Alpha (n = 17): groups EA-E and EA-A) showed good comparability. Regarding the change in AL during 19 months, none of the pairs showed significant differences (LE-L:0.27 ± 0.24 mm, LE-E:0.31 ± 0.24 mm (p = 0.68); LA-L:0.36 ± 0.26 mm, LA-A:0.36 ± 0.27 mm (p = 0.85); EA-E:0.34 ± 0.27 mm, EA-A:0.41 ± 0.28 mm (p = 0.63)). Regarding treatment zone, Lucid showed the largest HMDTZ and VMDTZ (both p < 0.05). Regarding the WHCZ, none of the pairs showed significant differences. For the ADV and ADA, Lucid had more ADV and ADA than Euclid (ADV: LE-L:0.73 ± 0.44 mm, LE-E:0.55 ± 0.45 mm, p < 0.05; ADA: LE-L:0.80 ± 0.41 mm, LE-E:0.63 ± 0.44 mm, p < 0.05), and the remaining pairs showed no significant difference. For the overall cohort with 113 eyes, the change in AL was weakly correlated with both ADV and ADA (both p < 0.05). Regarding the ADV/ADA, all pairs showed no significant differences, indicating equal lens position stability. Conclusion: After OK, there were no significant differences between the different pairs of the three brands in AL growth, WHCZ, or lens position stability, although Lucid had a larger treatment zone than Euclid and Alpha, and Lucid had more decentration than Euclid. A larger lens decentration were weakly related to less AL growth.

Biomarkers of preschool children with autism spectrum disorder: quantitative analysis of whole-brain tissue component volumes, intelligence scores, ADOS-CSS, and ages of first-word production and walking onset.

BACKGROUND: Preschooling is a critical time for intervention in children with autism spectrum disorder (ASD); thus, we analyzed brain tissue component volumes (BTCVs) and clinical indicators in preschool children with ASD to identify new biomarkers for early screening. METHODS: Eighty preschool children (3-6 years) with ASD were retrospectively included. The whole-brain myelin content (MyC), white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), and non-WM/GM/MyC/CSF brain component volumes were obtained using synthetic magnetic resonance imaging (SyMRI). Clinical data, such as intelligence scores, autism diagnostic observation schedule-calibrated severity scores, age at first production of single words (AFSW), age at first production of phrases (AFP), and age at walking onset (AWO), were also collected. The correlation between the BTCV and clinical data was evaluated, and the effect of BTCVs on clinical data was assessed by a regression model. RESULTS: WM and GM volumes were positively correlated with intelligence scores (both P < 0.001), but WM and GM did not affect intelligence scores (P = 0.116, P = 0.290). AWO was positively correlated with AFSW and AFP (both P < 0.001). The multivariate linear regression analysis revealed that MyC, AFSW, AFP, and AWO were significantly different (P = 0.005, P < 0.001, P < 0.001). CONCLUSIONS: This study revealed positive correlations between WM and GM volumes and intelligence scores. Whole-brain MyC affected AFSW, AFP, and AWO in preschool children with ASD. Noninvasive quantification of BTCVs via SyMRI revealed a new visualizable and quantifiable biomarker (abnormal MyC) for early ASD screening in preschool children.