Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

Changes in Concentrations of Polyfluoroalkyl Substances in Human Milk Over Lactation Time and Effects of Maternal Exposure via Analysis of Matched Samples.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are potentially related to many adverse health outcomes and could be transferred from maternal blood to human milk, which is an important exposure source for infants during a long-term period. In this study, the maternal blood of 76 women after delivery and their matched human milk samples obtained at 0.5, 1, and 3 months were analyzed by solid-phase extraction method with metal-organic framework/polymer hybrid nanofibers as the sorbents and ultrahigh-performance liquid chromatography-negative electrospray ionization mass spectrometric for quantitative analysis of 31 PFAS. The perfluorooctanoic acid, perfluorooctane sulfonate, and N-methyl perfluorooctane sulfonamido acetic acid (N-MeFOSAA) contributed to more than approximately 50% of the total PFAS concentrations in blood and human milk, while N-MeFOSAA (median: 0.274 ng/mL) was the highest PFAS in human milk at 3 months. The transfer efficiencies for PFAS from maternal blood to human milk at 0.5 months were generally lower, with medians ranging from 0.20% to 16.9%. The number of PFAS species detected in human milk increased as the lactation time went on from 0.5 to 3 months, and the concentrations of 10 PFAS displayed an increasing trend as the prolongation of lactation time (p < 0.05).

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression.

BACKGROUND: Lactate accumulation leads to an acidic tumor microenvironment (TME), in turn promoting colorectal cancer (CRC) progression. Tumor-associated macrophages (TAMs) are the predominant cells in TME. This study aimed to reveal the regulation mechanism of CRC cell-derived lactate on TAMs and explore the mechanism underlying lactate accumulation-induced aggravation in CRC. METHODS: Cell growth and metastasis were evaluated by colony formation, Transwell, and wound healing assays. Western blot and RT-qPCR were applied to determine the protein and mRNA expression. Flow cytometry was used to analyze the polarization state and apoptotic rate of macrophages induced in THP-1 cells. The lactate in the cell supernatant was quantified using an ELISA kit. Immunofluorescence was performed to visualize the location of High Mobility Group Box 1 (HMGB1). H&E and Ki67 staining assays were used to assess tumorigenesis in nude mice bearing ectopic tumors. RESULTS: Cell growth and metastasis were promoted in the hypoxic CRC cells. The hypoxic cell supernatant stimulated the M2-type polarization of macrophages. The lactate level increased in hypoxic cancer cells. However, the inhibition of lactate using 3-hydroxy-butyrate (3-OBA) reversed the effects of hypoxia. Also, macrophages showed no promoting effect on cancer cell growth and migration in the presence of 3-OBA. HMGB1 was secreted into the extracellular space of lactate-induced macrophages, further enhancing the malignant behaviors of cancer cells. ERK, EMT, and Wnt signaling pathways were activated in cancer cells due to HMGB1 upregulation. CONCLUSIONS: The lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells.

Using a CT-based scale to evaluate disease extension and the resectability of locally advanced thyroid cancer.

OBJECTIVES: To establish a computed tomography (CT)-based scale to evaluate the resectability of locally advanced thyroid cancer. METHODS: This twin-centre retrospective study included 95 locally advanced thyroid cancer patients from the 1st centre as the training cohort and 31 patients from the 2nd centre as the testing cohort, who were categorised into the resectable and unresectable groups. Three radiologists scored the CT scans of each patient by evaluating the extension to the recurrent laryngeal nerve (RLN), trachea, oesophagus, artery, vein, soft tissue, and larynx. A 14-score scale (including all comprised structures) and a 12-score scale (excluding larynx) were developed. Receiver-operating characteristic (ROC) analysis was used to evaluate the performance of the scales. Stratified fivefold cross-validation and external verification were used to validate the scale. RESULTS: In the training cohort, compromised RLN (p < 0.001), trachea (p = 0.001), oesophagus (p = 0.002), artery (p < 0.001), vein (p = 0.005), and soft tissue (p < 0.001) were predictors for unresectability, while compromised larynx (p = 0.283) was not. The 12-score scale (AUC = 0.882, 95%CI: 0.812-0.952) was not inferior to the 14-score scale (AUC = 0.891, 95%CI: 0.823-0.960). In subgroup analysis, the AUCs of the 12-score scale were 0.826 for treatment-naïve patients and 0.976 for patients with prior surgery. The 12-score scale was further validated with a fivefold cross-validation analysis, with an overall accuracy of 78.9-89.4%. Finally, external validation using the testing cohort showed an AUC of 0.875. CONCLUSIONS: The researchers built a CT-based 12-score scale to evaluate the resectability of locally advanced thyroid cancer. Validation with a larger sample size is required to confirm the efficacy of the scale. CLINICAL RELEVANCE STATEMENT: This 12-score CT scale would help clinicians evaluate the resectability of locally advanced thyroid cancer. KEY POINTS: • The researchers built a 12-score CT scale (including recurrent laryngeal nerve, trachea, oesophagus, artery, vein, and soft tissue) to evaluate the resectability of locally advanced thyroid cancer. • This scale has the potential to help clinicians make treatment plans for locally advanced thyroid cancer.

Adjuvant chemotherapy decision-making in stage II colon adenocarcinoma associated with patients' age and high-risk factors.

PURPOSE: To clarify whether the combination of age and high-risk factors (HRFs) was preferable for adjuvant chemotherapy (AC) decision-making in patients with stage II colon adenocarcinoma. METHODS: We conducted a retrospective study analyzing eligible colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. A nomogram was used to predict patient prognosis. Decision curve analysis (DCA) predicted model clinical benefit. Restricted cubic spline calculated the optimal cut-off value. RESULTS: A total of 8570 patients with stage II colon adenocarcinoma were included in this study; 25.2% received AC. A nomogram predicting the prognosis of patients with stage II colon adenocarcinoma was constructed with age and HRFs, and scores were assigned to the relevant variables. DCA showed that age combined with HRFs was superior to treatment decision-making based on HRFs alone. Patients were grouped according to their total score with the cut-off value of 100. AC did not significantly improve overall survival (OS) in low-score group (hazard ratios (HRs) 1.01, 95% confidence intervals (CIs) 0.86-1.18, p = 0.918). In high-score group, AC improved 5-year OS by about 7.6% (HR 0.73, 95% CI 0.61-0.88, p = 0.001). And high-score group mainly included patients aged < 50 years with two or more HRFs and patients aged ≥ 50 years with at least one HRF. CONCLUSION: Age and HRFs could be preferable for determining the group of stage II colon adenocarcinoma patients who would benefit from AC. Patients aged < 50 years with two or more HRFs might be a potential benefit population for AC.

Comparison of the prophylactic antithrombotic effect of indobufen and warfarin in patients with nephrotic syndrome: a randomized controlled trial.

PURPOSE: The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. MATERIALS AND METHODS: This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. RESULTS: No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p < .05). Finally, adverse events were more frequent in warfarin-treated patients. CONCLUSIONS: This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013428.

[Isolation and quantification of a 17-epi-dammarane triterpenoid rhuslactone from roots of Rhus chinensis and its preventive effects on coronary heart disease and thrombosis in zebrafish].

Based on mass spectrometry(MS)-guided separation strategy, compound 1 was obtained from the roots of Rhus chinensis. By comprehensive analysis of high resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR) data, and quantum chemical calculation of NMR(qcc-NMR) parameters, compound 1 was elucidated as rhuslactone, a 17-epi-dammarane triterpenoid with a rare 17α-side chain. An HPLC-ELSD method for its quantification in R. chinensis was established and adopted for the quantification of rhuslactone in different batches of R. chinensis. Rhuslactone displayed a good linear relationship within the range of 0.021 3-1.07 µmol·mL~(-1 )(r=0.997 6), and the average recovery was 99.34% [relative standard deviation(RSD) 2.9%). Moreover, the results of the evaluation test of the preventive effects of rhusalctone on coronary heart disease(CHD) and thrombosis showed that rhuslactone(0.11 nmol·mL~(-1)) significantly alleviated heart enlargement and venous congestion and increased cardiac output(CO), blood flow velocity(BFV), and heart rate, thereby reducing thrombus formation in zebrafish with CHD. The effects of rhuslactone on CO and BFV were superior to that of digoxin(1.02 nmol·mL~(-1)), and its effect on improving heart rate was comparable to that of digoxin. This study provides experimental references for the isolation, identification, quality control, and application of rhuslactone from R. chinensis against CHD. It is worth mentioning that this study has discussed some omissions in the determination of the stereochemistry of C-17 in dammarane triterpenoids in the present coursebook Chemistry of Chinese Medicine and some research papers, that is, the compound may be 17-epi-dammarane triterpenoid. This paper has also proposed steps for the establishment of C-17 stereochemistry.

Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting.

Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.

Association of novel rare coding variants with juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape. METHODS: We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway. RESULTS: By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes. CONCLUSION: This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.

Timing of do-not-resuscitate orders and health care utilization near the end of life in cancer patients: a retrospective cohort study.

PURPOSE: The objectives are to explore the prevalence of DNR orders, the factors influencing them, and the association between DNR signing and health care utilization among advanced cancer patients. METHODS: This was a retrospective cohort study. Data from cancer decedents in three hospitals in China from January 2016 to December 2017 during their last hospitalization before death were obtained from the electronic medical records system. RESULTS: In total, 427 cancer patients were included; 59.0% had a DNR order. Patients who had solid tumors, lived in urban areas, had more than one comorbidity, and had more than five symptoms were more likely to have DNR orders. The cut-off of the timing of obtaining a DNR order was 3 days, as determined by the median number of days from the signing of a DNR order to patient death. Patients with early DNR orders (more than 3 days before death) were less likely to be transferred to the intensive care unit and undergo cardiopulmonary resuscitation, tracheal intubation, and ventilation, while they were more likely to be given morphine and psychological support compared with those with late (within 3 days before death) and no orders. CONCLUSIONS: Advanced cancer patients with solid tumors living in urban areas with more symptoms and comorbidities are relatively more likely to have DNR orders. Early DNR orders are associated with less aggressive procedures and more comfort measures. However, these orders are always signed late. Future studies are needed to better understand the timing of DNR orders.

Iron Sucrose as MRI Contrast Agent in Ischemic Stroke Model.

BACKGROUND: Despite the growing concern about the safety of gadolinium-based contrast agents (GBCAs), they are still the most commonly used. Ferumoxytol, as an off-label alternative MRI contrast agent, cannot be administered by a rapid bolus for dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI). PURPOSE: To assess the feasibility of iron sucrose (IS) as a contrast agent for MR angiography (MRA) and DSC-PWI. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Thirty-six normal rats (16 for MRA, 20 for biocompability tests) and 36 occlusion of the middle cerebral artery (MCAO) model rats. FIELD STRENGTH/SEQUENCE: 3.0T; head and neck angiography, using a fast spoiled gradient-recalled-echo (FSPGR) sequence and DSC-MRI using echo planar imaging(EPI) sequence. ASSESSMENT: MRA was performed on normal rats to examine the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of different doses of IS. DSC-PWI was performed on MCAO rats at 0, 24, 48, and 72 hours postreperfusion to investigate the lesion detectability of IS. Arterial spin labeling (ASL) and DSC-PWI enhanced by GBCAs were conducted on MCAO rats as controls. STATISTICAL TESTS: Kruskal-Wallis test was used to compare qualitative assessment. One-way analysis of variance (ANOVA) was used to compare the parametric data. Pearson's r values were evaluated between relative cerebral blood flow(rCBF)-ASL, rCBF-DSCIS , and rCBF obtained from DSC-PWI enhanced by GBCA. RESULTS: The mean SNR and CNR of the common carotid artery at doses of 10 mg Fe/kg of IS were comparable with the standard dose of GBCAs (SNR: 68.04 ± 12.55 vs. 67.72 ± 14.66; CNR: 23.78 ± 7.21vs. 21.63 ± 6.83). In MCAO rat models, rCBF and relative cerebral blood volume (rCBV) of ipsilateral striatum declined (0.72 ± 0.14, 0.86 ± 0.11) with prolonged relative mean transit time (rMTT) and relative time-to-peak (rTTP) (1.27 ± 0.24, 1.07 ± 0.03) following occlusion. Hyperperfusion was observed in all rats at 48 and 72 hours postreperfusion, in 4/6 rats at 24 hours postreperfusion for IS-mediated DSC-PWI. DATA CONCLUSION: IS may be an effective contrast agent for both MRA and DSC-PWI in ischemic stroke models. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:836-849.

[Effect evaluation of health education intervention on nutrition label for community residents in Shanghai].

OBJECTIVE: To understand the knowledge, attitude and practice(KAP) of nutrition label for community residents in Shanghai and the effects of health education interventions, and to explore the factors affecting the knowledge, attitude and practice(KAP), and to provide theoretical bases for relevant policies. METHODS: Using stratified random sampling to randomly select at least 20 residents before and after the intervention in each community in Shanghai. A baseline survey was carried out in early March 2016. The survey included basic information and the knowledge、attitude and practice of nutrition label. Using a combination of online and offline method such as issuing posters, folding pages, conducting lectures on knowledge, tweeting on WeChat public accounts, etc. , for a 4-month intervention, and an assessment survey was conducted in June. The same questionnaire was used before and after the intervention. RESULTS: The awareness rate of nutrition labels among community residents in Shanghai increased from 63. 0% before the intervention to 87. 4% after the intervention. The proportion of those who felt it necessary to label nutrition labels increased from 77. 7% before the intervention to 88. 3%. When purchasing prepackaged food, the proportion of people who often read nutrition labels increased from 32. 2% before intervention to 51. 8%, and the above differences were statistically significant(P<0. 05). After the intervention, the mastery of nutrition labeling knowledge, attitudes and behaviors of men were positively changed(P<0. 05). After the intervention, residents in the suburban areas have significantly improved their knowledge, attitudes and behaviors related to nutrition labeling(P<0. 05). The improvement effects of residents in the suburbs was lower than that in the other two types of areas(P<0. 05). Logistic regression analysis showed that intervention, female, high education, living in the central city, knowing the nutrition label, and thinking that it is necessary to label the nutrition label are the protective factors of looking at the nutrition label when buying foods. CONCLUSION: Health education can effectively improve the awareness rate of prepackaged food nutrition labels, relevant attitudes and behavior changes of residents in Shanghai communities. After intervention, the knowledge and behavior of nutrition labels in Shanghai communities are at a high level. Men, low-education low-income and residents in remote areas are the key population for future health education related to nutrition labels.

MR textural analysis on T2 FLAIR images for the prediction of true oligodendroglioma by the 2016 WHO genetic classification.

BACKGROUND: The genetic status of 1p/19q is important for differentiating oligodendroglioma, isocitrate-dehydrogenase (IDH)-mutant, and 1p/19q-codeleted from diffuse astrocytoma, IDH-mutant according to the 2016 World Health Organization (WHO) criteria. PURPOSE: To assess the value of magnetic resonance textural analysis (MRTA) on T2 fluid-attenuated inversion recovery (FLAIR) images for making a genetically integrated diagnosis of true oligodendroglioma by WHO guidelines. STUDY TYPE: Retrospective case control. SUBJECTS: In all, there were 54 patients with a histopathological diagnosis of diffuse glioma (grade II). All were tested for IDH and 1p/19q. FIELD STRENGTH/SEQUENCE: 3.0T, including T2 FLAIR sequence, axial T1 -weighted, and T2 -weighted sequence. ASSESSMENT: MRTA on a representative tumor region of interest (ROI) was made on preoperative T2 FLAIR images around the area that had the largest diameter of solid tumor using Omni Kinetics software. STATISTICAL TESTS: Differences between IDH-mutant and 1p/19q-codeleted and IDH-mutant and 1p/19q-intact gliomas were analyzed by the Mann-Whitney rank sum test. Receiver operating characteristic curves (ROC) were created to assess MRTA diagnostic performance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with a cutoff value according to the Youden Index. RESULTS: Comparisons demonstrated significant differences in kurtosis (P = 0.007), energy (0.008), entropy (0.008), mean deviation (MD) (<0.001), and high gray-level run emphasis (HGLRE) (0.002), cluster shade (0.025), and sum average (0.002). First-order features comprising entropy (area under the curve [AUC] = 0.718, sensitivity = 97.1%) and energy (0.719, 94.1%) had the highest sensitivity but lower specificity (both 45%). Second-order features such as HGLRE (AUC = 0.750, sensitivity = 73.5%, specificity = 80.0%) and sum average (0.751, 70.6%, 80.0%) had relatively higher specificity, and all had AUC >0.7. MD had the highest diagnostic performance, with AUC = 0.878, sensitivity = 94.1%, specificity = 75.0%, PPV = 86.5%, and NPV = 88.2%. DATA CONCLUSION: MRTA on T2 FLAIR images may be helpful in identifying oligodendroglioma, IDH-mutant, and 1p/19q-codeleted. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Evaluation of an activated carbon-based deactivation system for the disposal of highly abused opioid medications.

CONTEXT: The improper disposal of unused prescription opioids has a potential for abuse as well as environmental contamination. Consequently, there is an imperative need for an environmentally safe, convenient, and effective drug disposal system. OBJECTIVE: The objective of this study is to analyze the deactivation efficiency of the disposal system employing four model opioid drugs of high abuse potential. METHODS: The deactivation system used in this investigation is an activated granular carbon based disposal system in the form of a pouch, which can be used to safely and effectively deactivate unused or expired medications. HPLC method validation for each drug was performed prior to analyzing drug content in the deactivation study. Opioid drugs in different dosage forms were added to individual pouches in the presence of warm water. Pouches were shaken and sealed, then stored at room temperature. The deactivation efficiency of the system was tested by collecting samples at different time points up to 28 d. RESULTS: An average of 98.72% of medications were adsorbed by activated carbon within 8 h and continued to do so over time. At the end of the 28-d study, more than 99.99% of all drugs were deactivated. In the desorption study, almost no drug leached out from the activated carbon in larger volume of water and less than 1.3% leached out on extraction with ethanol. CONCLUSION: This unique drug disposal system successfully adsorbed and deactivated the model opioid medications by the end of 28 d, offering a safe and convenient route of disposal of unused or residual opioid drugs.

Enhancement in the Transdermal and Localized Delivery of Honokiol Through Breast Tissue.

Honokiol is a natural phenolic anti-cancer compound isolated from an extract of seed cones from Magnolia grandiflora. This study investigated the transdermal delivery of honokiol using various enhancement methods and to explore the potential of honokiol to treat breast cancer directly via delivery through mammary papilla. Poration of dermatomed human skin with microneedles significantly increased the delivery of honokiol by nearly 3-fold (97.81 ± 18.96 µg/cm2) compared with passive delivery (32.56 ± 5.67 µg/cm2). Oleic acid was found to be the best chemical penetration enhancer, increasing the delivery almost 27-fold (868.06 ± 100.91 µg/cm2). Addition of oleic acid also resulted in better retention of drug in the porcine mammary papilla (965.41 ± 80.26 µg/cm2) compared with breast skin (294.16 ± 8.49 µg/cm2). Anti-cancer effect of honokiol was demonstrated with the decrease in the release of cytokine IL-6 and further suppression of Ki-67 proliferative protein. In addition, the topical honokiol formulation investigated was found to be safe and non-irritant. In summary, both microneedles and chemical enhancers can improve the absorption of honokiol through skin. Directly applying honokiol on mammary papilla is a potential administration route which can increase localized delivery into breast tissue.

Permeability Surface of Deep Middle Cerebral Artery Territory on Computed Tomographic Perfusion Predicts Hemorrhagic Transformation After Stroke.

BACKGROUND AND PURPOSE: Permeability surface (PS) on computed tomographic perfusion reflects blood-brain barrier permeability and is related to hemorrhagic transformation (HT). HT of deep middle cerebral artery (MCA) territory can occur after recanalization of proximal large-vessel occlusion. We aimed to determine the relationship between HT and PS of deep MCA territory. METHODS: We retrospectively reviewed 70 consecutive acute ischemic stroke patients presenting with occlusion of the distal internal carotid artery or M1 segment of the MCA. All patients underwent computed tomographic perfusion within 6 hours after symptom onset. Computed tomographic perfusion data were postprocessed to generate maps of different perfusion parameters. Risk factors were identified for increased deep MCA territory PS. Receiver operating characteristic curve analysis was performed to calculate the optimal PS threshold to predict HT of deep MCA territory. RESULTS: Increased PS was associated with HT of deep MCA territory. After adjustments for age, sex, onset time to computed tomographic perfusion, and baseline National Institutes of Health Stroke Scale, poor collateral status (odds ratio, 7.8; 95% confidence interval, 1.67-37.14; P=0.009) and proximal MCA-M1 occlusion (odds ratio, 4.12; 95% confidence interval, 1.03-16.52; P=0.045) were independently associated with increased deep MCA territory PS. Relative PS most accurately predicted HT of deep MCA territory (area under curve, 0.94; optimal threshold, 2.89). CONCLUSIONS: Increased PS can predict HT of deep MCA territory after recanalization therapy for cerebral proximal large-vessel occlusion. Proximal MCA-M1 complete occlusion and distal internal carotid artery occlusion in conjunction with poor collaterals elevate deep MCA territory PS.

Proactive green innovation and firm climate resilience: the nonlinear interaction effect of climate risk.

Based on empirical analysis of 113 climate disasters affecting 3563 listed firms across 31 provinces in China from 2010 to 2022, as documented in the Emergency Events Database (EM-DAT), this study employs event study and multiple regression to explore the impact of proactive green innovation on firm climate resilience. By categorizing proactive green innovation into process and product innovation and climate resilience into short-term and long-term resilience, a proactive green innovation-firm climate resilience 2 × 2 matrix is constructed to provide innovative insights. This study reveals that proactive green innovation enhances firm climate resilience. Specifically, proactive green process innovation both enhances short-term and long-term climate resilience, while proactive green product innovation only enhances long-term rather than short-term climate resilience. Furthermore, climate disaster has inverted U-shaped interaction effect on the relationship between proactive green innovation and short-term climate resilience and U-shaped interaction effect on the relationship between proactive green innovation and long-term climate resilience. Additionally, this study also investigates the heterogeneous mechanisms of proactive green innovation enhancing short-term and long-term climate resilience based on network embeddedness theory and legitimacy theory.

Treatment Strategies for Asymptomatic Carotid Stenosis: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND AND OBJECTIVES: To compare the safety and efficacy of carotid endarterectomy (CEA), carotid stenting (CAS), and optimal medical therapy (OMT) in patients with asymptomatic carotid stenosis. METHODS: Relevant randomized controlled trials were researched with PubMed, Web of Science, and the Cochrane Library databases. Fixed-effects model and random-effects model were used to estimate the relative risks and the hazard ratios (HRs). The results of the probabilistic analysis were reported as surfaces under the cumulative ranking curve. RESULTS: Eight randomized controlled trials were included. Data from 10 348 patients (CEA: n = 4758; CAS: n = 3919; OMT: n = 1673) were evaluated. Compared with the previous OMT, CEA, CAS, and the current OMT (c-OMT) were all effective in reducing the risk of stroke (CEA: HR, 0.52; CI, 0.40-0.66; CAS: HR, 0.58; CI, 0.42-0.81; c-OMT: HR, 0.40; CI, 0.15-0.94); CEA and CAS reduced the risk of ipsilateral stroke (CEA: HR, 0.41; CI, 0.28-0.59; CAS: HR, 0.51; CI, 0.31-0.84), and the risk of fatal or disabling stroke (CEA: HR, 0.59; CI, 0.43-0.81; CAS: HR, 0.57; CI, 0.34-0.95). Regarding reducing the risk of stroke, only CEA was statistically significant in patients with any degree of stenosis compared with the previous medical treatment (<80%: HR, 0.48; CI, 0.33%-0.70%; 80%-99%: HR, 0.53; CI, 0.38-0.73). CONCLUSION: In the treatment of asymptomatic carotid stenosis, the perioperative outcomes of CAS were similar to that of CEA; CEA, CAS, and c-OMT shared similar long-term outcomes; and CEA and CAS may be more effective in patients with high levels of asymptomatic stenosis.