Psychometric properties of the Chinese version of the Quick Delay Questionnaire (C-QDQ) and ecological characteristics of reward-delay impulsivity of adults with ADHD.

BACKGROUND: The Quick Delay Questionnaire (QDQ) is a short questionnaire designed to assess delay-related difficulties in adults. This study aimed to examine the reliability and validity of the Chinese version of the QDQ (C-QDQ) in Chinese adults, and explore the ecological characteristics of delay-related impulsivity in Chinese adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Data was collected from 302 adults, including ADHD (n = 209) and healthy controls (HCs) (n = 93). All participants completed the C-QDQ. The convergent validity, internal consistency, retest reliability and confirmatory factor analysis (CFA) of the C-QDQ were analyzed. The correlations between C-QDQ and two laboratory measures of delay-related difficulties and Barratt Impulsiveness Scale-11 (BIS-11), the comparison of C-QDQ scores between ADHD subgroups and HCs were also analyzed. RESULTS: The Cronbach's α of C-QDQ was between 0.83 and 0.89. The intraclass correlation coefficient of C-QDQ was between 0.80 and 0.83. The results of CFA of C-QDQ favoured the original two-factor model (delay aversion and delay discounting). Significant positive associations were found between C-QDQ scores and BIS-11 total score and performance on the laboratory measure of delay-related difficulties. Participants with ADHD had higher C-QDQ scores than HCs, and female ADHD reported higher scores on delay discounting subscale than male. ADHD-combined type (ADHD-C) reported higher scores on delay aversion subscale than ADHD-inattention type (ADHD-I). CONCLUSION: The C-QDQ is a valid and reliable tool to measure delay-related responses that appears to have clinical utility. It can present the delay-related impulsivity of patients with ADHD. Compared to HCs, the level of reward-delay impulsivity was higher in ADHD.

Protective effects of oyster polypeptide from oyster (Crassostrea ariakensis) on cyclophosphamide induced immunosuppression rats based on 1H NMR metabolomics and 16S rRNA gene sequencing.

BACKGROUND: Oyster polypeptide (OP) is a mixture of oligopeptides extracted from oysters through enzyme lysis, separation and purification. OP is associated with immunomodulatory effects, but the underlying mechanisms are not known. Therefore, this study combined 1H-NMR urinary metabolomics and 16S rRNA gene sequencing of the gut microbiome to determine the immunoprotective mechanisms of OP in rats subjected to cyclophosphamide-induced immunosuppression. RESULTS: OP can restored the body weight and the structure of spleen and thymus in cyclophosphamide-induced immunosuppression rats. OP upregulated the levels of white blood cells (WBCs), hemoglobin (HGB), platelets (PLT), red blood cells (RBCs), immunoglobulin G (IgG), immunoglobulin M (IgM), cytokines such as IL-6 and TNF-α, and the numbers of CD3+ and CD4+ T cells in the immunosuppression rats. The 1H-NMR metabolomics results showed that OP significantly reversed the levels of ten metabolites in urinary, including 2-oxoglutarate, citrate, dimethylamine, taurine, N-phenylacetylglycine, alanine, betaine, creatinine, uracil, and benzoate. The 16S rRNA gene sequencing results showed that OP restored the gut microbiome homeostasis by increasing the abundance of beneficial bacteria and reducing the abundance of pathogenic bacteria. Finally combining metabolomics and microbiomics found that taurine an hypotaurine metabolism, also alanine, aspartate and glutamate metabolish were disturbed, but these metabolic pathways were restored by OP. CONCLUSION: This study demonstrated that OP had immunoprotective effects in cyclophosphamide-induced immunosuppression rats by restoring key metabolic pathways and the gut microbiome homeostasis. Our findings provides a framework for further research into the immunoregulatory mechanisms of OP and its potential use in drugs and nutritional supplements. This article is protected by copyright. All rights reserved.

Isoprenoid flavonoids isolated from Sophora davidii and their activities induces apoptosis and autophagy in HT29 cells.

Four previously undescribed isoprenoid flavonoids (2-5) were isolated from Sophora davidii, along with five known analogues. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR, and absolute configurations determined by theoretical calculations, including ECD and NMR calculation. The cytotoxic effects of the isolated compounds on human HT29 colon cancer cells were evaluated using the MTT assay, compound 1 exhibited cytotoxicity against human HT29 colon cancer cells with an IC50 value of 8.39 ± 0.09 µM. Studies conducted with compound 1 in HT29 cells demonstrated that it may induce apoptosis and autophagy in HT29 by promoting the phosphorylation of P38 MAPK and inhibiting the phosphorylation of Erk MAPK.

Quality assessment of clinical practice guidelines for adult obstructive sleep apnea: A systematic review.

OBJECTIVE: Clinical Practice Guidelines (CPGs) are crucial in standardizing the management of obstructive sleep apnea (OSA) in adults. However, there has been insufficient evaluation of the overall quality of CPGs for adult OSA. This review aimed to comprehensively assess the overall quality of CPGs in the field of adult OSA. METHODS: A systematic search was conducted on various literature databases, guideline-related databases, and academic websites from January 2013 to December 2023 to select CPGs relevant to adult OSA. The methodological and reporting quality of the eligible CPGs were thoroughly appraised by three reviewers using the AGREE II instrument and RIGHT checklist, respectively. RESULTS: This review included 44 CPGs, consisting of 42 CPGs in English and 2 CPGs in Chinese. The assessment of methodological quality revealed that four domains attained an average standardized score above 60%. Among the domains, "clarity of presentation" received the highest standardized score of 85.10%, while the lowest standardized score was observed in the "rigor of development" domain with the value of 56.77%. The evaluation of reporting quality indicated an overall reporting rate of 51.30% for the eligible CPGs, with only three domains achieving an average reporting rate higher than 50%. The domain with the highest reporting rate was "basic information" at 60.61%, while the domain with the lowest reporting rate was "review and quality assurance" at 15.91%. Furthermore, a significantly positive correlation was found between the AGREE II standardized scores and the RIGHT reporting rates (r = 0.808, P < 0.001). CONCLUSIONS: The overall quality of the currently available guidelines for adult OSA demonstrated considerable variability. Researchers should prioritize the utilization of evidence-based methods and adhere to the items listed in the RIGHT checklist when developing CPGs to enhance efficient clinical decision-making and promote the translation of evidence into practice.

Radio frequency hyperthermia system for skin tightening effect by filled waveguide aperture antenna with compact metamaterials.

Radio frequency (RF) hyperthermia focuses on raising the target area temperature to a value exceeding 45°C. Collagen is stimulated when the temperature rises to 45°C at the dermal layer, resulting in skin tightening. However, most studies on RF hyperthermia have focused on tumor ablation or using electrodes to radiate an electromagnetic field, which is highly inefficient. This study proposed a non-invasive RF hyperthermia skin-tightening system with a compact metamaterial-filled waveguide aperture antenna. The proposed RF system increased the temperature by 11.6°C and 35.3°C with 20 and 80 W of 2.45 GHz RF power, respectively, within 60 s and exhibited a very focused effective area. Furthermore, a metamaterial was proposed to reduce the size of the waveguide aperture antenna and focus the electromagnetic field in the near-field region. The proposed metamaterial-filled waveguide aperture antenna was compact, measuring 10 mm × 17.4 mm, with a peak gain of 2.2 dB at 2.45 GHz. The measured hyperthermia performance indicated that the proposed RF system exhibited better power- and time-efficient hyperthermia performance than other RF hyperthermia systems in the cosmetic skin lifting commercial market. The proposed RF hyperthermia systems will be applied into a new generation of beauty cosmetic devices.

Ceftriaxone Pharmacokinetics and Pharmacodynamic Target Attainment for Three Pediatric Patients Receiving Continuous Kidney Replacement Therapy.

Ceftriaxone is used commonly for sepsis, including in children requiring continuous kidney replacement therapy (CKRT). No reports exist of pharmacokinetic (PK) parameters for children receiving ceftriaxone on CKRT. We enrolled children admitted to our pediatric intensive care unit (PICU) who received CKRT for >24 hours and received >1 dose of ceftriaxone while on and off CKRT. We measured free ceftriaxone -concentrations from residual blood samples then used Bayesian estimation with PK modeling software to generate concentration-time profiles and determine PK parameters and the percentage of time free ceftriaxone concentrations were above 1× or 4× MIC (% fT >MIC). Three patients aged 2 to 17 years were included; all were anuric at CKRT initiation and received 50 mg/kg (max 2000 mg) ceftriaxone every 12 to 24 hours. Total ceftriaxone clearance (CL) was 0.50 to 3.67 L/hr while receiving CKRT and 0.29 to 2.71 L/hr while off, indicating CKRT provided 25% to 42% of total ceftriaxone CL. All achieved 100% fT >1× and 4× MIC using an estimated MIC (1 mg/L) for patients 1 to 2 (no culture data) and a measured MIC (0.016 mg/L) for patient 3. Therefore, CKRT contributed significantly to total ceftriaxone clearance in 3 children though the dosing strategies used in each patient attained PD targets.

European and US Guideline-Based Statin Eligibility, Genetically Predicted Coronary Artery Disease, and the Risk of Major Coronary Events.

BACKGROUND: A study was designed to investigate whether the coronary artery disease polygenic risk score (CAD-PRS) may guide lipid-lowering treatment initiation as well as deferral in primary prevention beyond established clinical risk scores. METHODS AND RESULTS: Participants were 311 799 individuals from the UK Biobank free of atherosclerotic cardiovascular disease, diabetes, chronic kidney disease, and lipid-lowering treatment at baseline. Participants were categorized as statin indicated, statin indication unclear, or statin not indicated as defined by the European and US guidelines on statin use. For a median of 11.9 (11.2-12.6) years, 8196 major coronary events developed. CAD-PRS added to European-Systematic Coronary Risk Evaluation 2 (European-SCORE2) and US-Pooled Cohort Equation (US-PCE) identified 18% and 12% of statin-indication-unclear individuals whose risk of major coronary events were the same as or higher than the average risk of statin-indicated individuals and 16% and 12% of statin-indicated individuals whose major coronary event risks were the same as or lower than the average risk of statin-indication-unclear individuals. For major coronary and atherosclerotic cardiovascular disease events, CAD-PRS improved C-statistics greater among statin-indicated or statin-indication-unclear than statin-not-indicated individuals. For atherosclerotic cardiovascular disease events, CAD-PRS added to the European evaluation and US equation resulted in a net reclassification improvement of 13.6% (95% CI, 11.8-15.5) and 14.7% (95% CI, 13.1-16.3) among statin-indicated, 10.8% (95% CI, 9.6-12.0) and 15.3% (95% CI, 13.2-17.5) among statin-indication-unclear, and 0.9% (95% CI, 0.6-1.3) and 3.6% (95% CI, 3.0-4.2) among statin-not-indicated individuals. CONCLUSIONS: CAD-PRS may guide statin initiation as well as deferral among statin-indication-unclear or statin-indicated individuals as defined by the European and US guidelines. CAD-PRS had little clinical utility among statin-not-indicated individuals.

Retrospective analysis on prognosis of oral cancer patients according to surgical approaches for effective cancer ablation: swing approach versus visor approach.

BACKGROUND: For the surgical treatment of oral cancer, it is sometimes necessary to expand intraoral access within the oral cavity. The "swing approach" that involves lip splitting of the mandible and temporary mandibular osteotomy and the "visor approach" that does not split the lower lip and mandible are mainly used. This study analyzed postoperative outcomes such as complications, recurrence rate, and survival rate by these two approaches. The goal of this study is to evaluate the surgical outcomes of patients using these two approaches, to propose effective perioperative management for oral cancer surgery, and to compare the prognosis of oral cancer patients. MATERIALS AND METHODS: From 2005 to 2020, 29 patients who underwent surgery at the Department of Oral and Maxillofacial Surgery of Pusan National University Dental Hospital for oral cancer lesions occurred in the mandible, floor of mouth, and tongue were selected for the study. Based on the surgical approach used, a chart review was conducted on various prognostic clinical factors such as the patients' sex and age, primary site, TNM stage, histopathologic grade, recurrence and metastasis, postoperative survival rate, adjuvant chemo-radiation therapy, satisfaction with aesthetics/function/swallowing, length of hospital stay, tracheostomy and its duration, and neck dissection and its type. Statistical analysis was conducted using SPSS 25.0 (SPSS Inc., Chicago, IL) through Fisher's exact t-test. RESULT: There was no statistically significant difference between two groups in terms of clinical and pathological findings, such as survival rate, the need for adjuvant therapies, and the local recurrence rate. Although better outcomes were observed in terms of function, aesthetics, and postoperative complications in the group with visor approach, there was still no statistically significant difference between two groups. However, the duration of hospital stay was shorter in the visor approach group. CONCLUSION: There was no statistically significant difference in clinical prognostic factors between the swing approach and the visor approach. Therefore, when choosing between the two approaches for the ablation of oral cancer, it is considered to select the surgical priority approach that can be easy access based on the size and location of the lesion. The visor approach had advantages of aesthetics and healing period.

Development of a formula for estimated glomerular filtration rate in pregnant women from physiological hyperfiltration of serum creatinine.

Increased body fluids during pregnancy complicates the application of estimated glomerular filtration rate (eGFR) formulas that are based on body surface area. Furthermore, gestational renal dysfunction cannot be identified if the serum creatinine (SCr) concentration is within the non-pregnant reference interval (RI) despite inadequate pregnancy-related renal hyperfiltration. 1484 SCr measurements from 957 healthy pregnant women were collected. The average SCr value of gestational week (GW) 0-3 was the representative SCr value of non-pregnant status. While the distribution of SCr measurements varied across GWs, it was transformed into a normal distribution using the bootstrap resampling method. A polynomial linear regression method was applied to achieve a continuous and smooth transformation of values. The normally distributed SCr values of each GW were compared to the non-pregnant status, leading to the calculation of SCr hyperfiltration. The final equation, (2 - SCr (µmol/L) / 55.25) × 103.1 × 55.25/(56.7 - 0.223 × GW - 0.113 × GW2 + 0.00545 × GW3 - 0.0000653 × GW4), and reference intervals for both SCr and eGFR for each GW were obtained. These RIs and novel equations can be effectively used to monitor renal dysfunction in pregnant women.

Meta-analysis of the human gut microbiome uncovers shared and distinct microbial signatures between diseases.

Microbiome studies have revealed gut microbiota's potential impact on complex diseases. However, many studies often focus on one disease per cohort. We developed a meta-analysis workflow for gut microbiome profiles and analyzed shotgun metagenomic data covering 11 diseases. Using interpretable machine learning and differential abundance analysis, our findings reinforce the generalization of binary classifiers for Crohn's disease (CD) and colorectal cancer (CRC) to hold-out cohorts and highlight the key microbes driving these classifications. We identified high microbial similarity in disease pairs like CD vs ulcerative colitis (UC), CD vs CRC, Parkinson's disease vs type 2 diabetes (T2D), and schizophrenia vs T2D. We also found strong inverse correlations in Alzheimer's disease vs CD and UC. These findings detected by our pipeline provide valuable insights into these diseases.

One-year follow-up of the effectiveness and mediators of cognitive behavioural therapy among adults with attention-deficit/hyperactivity disorder: secondary outcomes of a randomised controlled trial.

BACKGROUND: The long-term effectiveness of cognitive behavioural therapy (CBT) in medicated attention-deficit/hyperactivity disorder (ADHD) adults with residual symptoms needs to be verified across multiple dimensions, especially with respect to maladaptive cognitions and psychological quality of life (QoL). An exploration of the mechanisms underlying the additive benefits of CBT on QoL in clinical samples may be helpful for a better understanding of the CBT conceptual model and how CBT works in medicated ADHD. METHODS: We conducted a secondary analysis of a randomised controlled trial including 98 medicated ADHD adults with residual symptoms who were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M)-only group. Outcomes included ADHD-core symptoms (ADHD Rating Scale), depression symptoms (Self-rating Depression Scale), maladaptive cognitions (Automatic Thoughts Questionnaire and Dysfunctional Attitude Scale), and psychological QoL (World Health Organization Quality of Life-Brief Version-psychological domain). Mixed linear models (MLMs) were used to analyse the long-term effectiveness at one-year follow-up, and structural equation modeling (SEM) was performed to explore the potential mechanisms of CBT on psychological QoL. RESULTS: ADHD patients in the CBT + M group outperformed the M-only group in reduction of ADHD core symptoms (d = 0.491), depression symptoms (d = 0.570), a trend of reduction of maladaptive cognitions (d = 0.387 and 0.395, respectively), and improvement of psychological QoL (d = - 0.433). The changes in above dimensions correlated with each other (r = 0.201 ~ 0.636). The influence of CBT on QoL was mediated through the following four pathways: 1) changes in ADHD core symptoms; 2) changes in depressive symptoms; 3) changes in depressive symptoms and then maladaptive cognitions; and 4) changes firstly in depressive symptoms, maladaptive cognitions, and then ADHD core symptoms. CONCLUSIONS: The long-term effectiveness of CBT in medicated ADHD adults with residual symptoms was further confirmed. The CBT conceptual model was verified in clinical samples, which would be helpful for a deeper understanding of how CBT works for a better psychological QoL outcome. TRIAL REGISTRATION: ChiCTR1900021705 (2019-03-05).

Chaenomelin, a New Phenolic Glycoside, and Anti-Helicobacter pylori Phenolic Compounds from the Leaves of Salix chaenomeloides.

Salix chaenomeloides Kimura, commonly known as pussy willow, is a deciduous shrub and tree belonging to the Salicaceae family. The genus Salix spp. has been known as a healing herb for the treatment of fever, inflammation, and pain relief. The current study aimed to investigate the potential bioactive natural products from S. chaenomeloides leaves and evaluate their antibacterial activity against Helicobacter pylori. A phytochemical investigation of the ethanol (EtOH) extract of S. chaenomeloides leaves led to the isolation of 13 phenolic compounds (1-13) from the ethyl acetate (EtOAc) fraction, which showed antibacterial activity against H. pylori strain 51. The chemical structure of a new phenolic glycoside, chaenomelin (1), was established by a detailed analysis of 1D and 2D (1H-1H correlation spectroscopy (COSY), heteronuclear single-quantum coherence (HSQC), and heteronuclear multiple-bond correlation (HMBC)) nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectroscopy (HR-ESIMS), and chemical reactions. The other known compounds were identified as 5-O-trans-p-coumaroyl quinic acid methyl ester (2), tremulacin (3), citrusin C (4), benzyl 3-O-ß-d-glucopyranosyl-7-hydroxybenzoate (5), tremuloidin (6), 1-[O-ß-d-glucopyranosyl(1→2)-ß-d-glucopyranosyl]oxy-2-phenol (7), arbutin cinnamate (8), tremulacinol (9), catechol (10), 4-hydroxybenzaldehyde (11), kaempferol 3-rutinoside (12), and narcissin (13), based on the comparison of their NMR spectra with the reported data and liquid chromatography/mass spectrometry (LC/MS) analysis. The isolated compounds were evaluated for antibacterial activity against H. pylori strain 51. Among the isolates, 1-[O-ß-d-glucopyranosyl(1→2)-ß-d-glucopyranosyl]oxy-2-phenol (7) and arbutin cinnamate (8) exhibited antibacterial activity against H. pylori strain 51, with inhibitions of 31.4% and 33.9%, respectively, at a final concentration of 100 µM. These results were comparable to that of quercetin (38.4% inhibition), which served as a positive control. Generally, these findings highlight the potential of the active compounds 7 and 8 as antibacterial agents against H. pylori.

Photoredox-Cobaloxime Catalysis for Selective Oxidative Dehydrogenative [4+2] Annulation of Imidazo-Fused Heterocycles with Alkenes.

A selective oxidative [4+2] annulation of alkenes with imidazo-fused heterocycles has been developed by using the synergistic combination of photoredox and cobaloxime catalysts. It allows facile access to various imidazole-fused polyaromatic scaffolds accompanied by H2 evolution. This protocol features high regioselectivity as well as a broad substrate scope. Detailed mechanistic studies indicate that twice the electron/H transfer processes facilitated by this catalytic system achieve the annulation π-extension of imidazo-fused heterocycles with alkenes.

Association of Increased Lateral Femoral Condylar Ratio With Lateral Meniscus Posterior Root Tear in Noncontact ACL Injury.

Background: In the setting of anterior cruciate ligament (ACL) injury, lateral meniscus posterior root tears (LMPRTs) are less readily diagnosed on preoperative magnetic resonance imaging (MRI). Therefore, to predict LMPRTs in ACL injuries, it is necessary to understand the risk factors associated with them. Purpose/Hypothesis: The purpose of this study was to investigate the association of lateral femoral condylar ratio (LFCR) with LMPRTs in ACL injuries. It was hypothesized that an increased LFCR would be associated with LMPRTs in noncontact ACL injuries. Study Design: Cohort study; Level of evidence, 3. Methods: Enrolled were consecutive patients who underwent primary acute (<6 weeks from injury) ACL reconstruction after noncontact injury and had LMPRT confirmed on preoperative MRI and arthroscopically (combined group; n = 62) as well as patients who underwent isolated acute ACL reconstruction (isolated group; n = 80) who were matched to the combined group by age, height, and body mass index (BMI). All patients underwent surgery between January 1999 and November 2021. LFCR and posterior tibial slope (PTS) were measured and compared between the isolated and combined groups. The area under the receiver operating characteristic curve (AUC) was calculated to determine the cutoff for detecting increased risk of LMPRTs. Results: The demographic characteristics of the 2 groups did not differ significantly, nor did the PTS. The LFCR was a significant factor (odds ratio [OR], 1.23; P = .001) associated with LMPRT. Patient age, height, BMI, and PTS were not associated with LMPRT. The AUC (0.66; 95% CI, 0.57-0.75) for LFCR had a sensitivity of 39% and specificity of 90% to predict LMPRT. The calculated cutoff associated with an increased risk for LMPRT when compared with the isolated group was 67.0% (OR, 4.98; 95% CI, 2.10-11.79). Conclusion: Increased LFCR was associated with the presence of LMPRTs in patients with acute ACL injuries. The LFCR may provide surgeons with additional information regarding the risk of having a concomitant LMPRT when planning ACL reconstructions.

Research on an evaluation rubric for promoting user's continuous usage intention: a case study of serious games for Chinese cultural heritage.

The sustainable development of serious games dedicated to Chinese cultural heritage faces challenges due to the lack of prolonged user engagement and iterative optimization based on long-term user feedback. This situation not only hinders the sustainable growth of these games but also limits the transmission of Chinese cultural heritage, a problem that demands urgent attention yet remains under-acknowledged. This study synthesizes literature to unearth user needs from three dimensions: motivational use, quality requirements of games, and continuous usage intention. It identifies 14 influential factors, including cognitive satisfaction, immersion satisfaction, and achievement satisfaction. Drawing from the User Experience Rubric for Educational Games-CH (UEREG-CH) evaluation rubric and the Delphi method, these factors are expanded into an evaluation system model comprising six primary indicators, 14 secondary indicators, and 38 tertiary indicators. The analytic hierarchy process (AHP) is utilized for expert scoring to assign weights to each indicator. This is combined with the fuzzy comprehensive evaluation method to arrive at a final user score of Z = 3.4228, indicating that the evaluation rubric is close to 'good' and has received positive user feedback. Ultimately, this generates an evaluation rubric tailored to the specific context of serious games for cultural heritage. By integrating qualitative and quantitative methods, this paper confirms the scientific and rational nature of the evaluation rubric. The study aims to establish a user-approved rubric that encourages continuous usage intention, thereby providing effective guidance for game developers and assisting users in selecting appropriate games, while also addressing the theoretical gap in the field of evaluation for serious games related to cultural heritage.

Edible insects in food.

Edible insects, with their high protein and lipid content, offer a safe and cost-effective alternative to traditional protein sources. They are environmentally friendly, emitting fewer greenhouse gases and requiring less water than livestock farming. Their rapid reproduction, efficiency, and labor-saving qualities make them attractive for industry. However, the unappealing appearance of edible insects hinders consumer acceptance. To overcome this, materialization technologies should be developed, and negative perceptions addressed with objective data. Promoting the nutritional value, safe rearing, disease prevention, and cost-efficiency of edible insects can boost consumer interest. Commercializing various insect products is crucial to revitalize their integration into the food industry.

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease.

We evaluated the pharmacokinetics (PK) of oral ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) (age <12 years) and chronic GVHD (cGVHD) (age ≤18 years) using our published pediatric dosing. PK sampling was performed before and 2 hours after ruxolitinib administration in patients with established cGVHD. More extensive PK analyses were performed in patients with newly diagnosed aGVHD or cGVHD before and .5, 1, 2, 4, and 6 hours after ruxolitinib administration in patients weighing >10 kg and before, 3+, and 6+ hours in children weighing <10 kg. pSTAT1, pSTAT3, and pSTAT5 expression levels were measured on CD4+ and CD8+ T cells before and 2 hours after ruxolitinib administration as a pharmacodynamic marker of JAK/STAT inhibition. Thirteen patients were prospectively enrolled, including 8 with existing cGVHD (age 0 to ≤18 years), 4 with new-onset steroid-refractory aGVHD (age 0 to <12 years) and 1 with newly diagnosed steroid-refractory cGVHD. Great variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (range, 3.1 to 15.3 L/h). The average elimination half-life was 2.32 ± 1.0 hours. Mean ruxolitinib clearance was higher in children age <2 years versus those age >2 years (12.1 ± 3.0 L/h versus 5.7 ± 2.8 L/h; P = .005) and was reduced with concurrent treatment with azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T cells at time of peak ruxolitinib absorption (2 hours after dosing). Children <10 kg had lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variability in dosing methods, leading to decreased drug absorption.

Expression and clinical significance of hypoxia-induced long non-coding RNA TCONS_I2_00001955 in breast cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been found to play important roles in occurrence, development, and metastasis of various tumors. We aimed to screen long non-coding RNAs (lncRNAs) that promote invasion and metastasis of breast cancer cells under hypoxia, and investigate the relationship between lncRNA expression and clinicopathological features and prognosis in invasive breast cancer. METHODS: LncRNA microarray was used to screen the differentially expressed lncRNAs in MCF7, MDA-MB-231, and SKBR3 breast cancer cell lines cultured under normoxia and hypoxia, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to verify the microarray results. CCK8 and Transwell experiments were performed to identify the lncRNA that promote proliferation, migration, and invasion of breast cancer cells. Expression of the lncRNA and HIF-1α in invasive breast cancer was detected by RNAscope and immunohistochemistry, respectively. Correlation between the lncRNA expression and baseline characteristics was analyzed. Prognostic value of the lncRNA was evaluated using univariate and multivariate Cox regression. RESULTS: Expression of lncRNA TCONS_I2_00001955 in all the three breast cancer cells was increased under hypoxia. Overexpression of TCONS_I2_00001955 significantly enhanced proliferation, migration, and invasion of SKBR3 cells. Positive expression of TCONS_I2_00001955 was associated with recurrence, metastasis, and high expression of HIF-1α (P < 0.05), and it was an independent risk factor for poor disease-free survival of breast cancer. CONCLUSION: Hypoxia-induced lncRNA TCONS_I2_00001955 was associated with aggressive feature and poor prognosis of breast cancer.

Structural and functional insight into the interaction of Clostridioides difficile toxin B and FZD7.

The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD1,2,7, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD7, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD7. The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.