Structural basis of GABAB receptor-Gi protein coupling.

G-protein-coupled receptors (GPCRs) have central roles in intercellular communication1,2. Structural studies have revealed how GPCRs can activate G proteins. However, whether this mechanism is conserved among all classes of GPCR remains unknown. Here we report the structure of the class-C heterodimeric GABAB receptor, which is activated by the inhibitory transmitter GABA, in its active form complexed with Gi1 protein. We found that a single G protein interacts with the GB2 subunit of the GABAB receptor at a site that mainly involves intracellular loop 2 on the side of the transmembrane domain. This is in contrast to the G protein binding in a central cavity, as has been observed with other classes of GPCR. This binding mode results from the active form of the transmembrane domain of this GABAB receptor being different from that of other GPCRs, as it shows no outside movement of transmembrane helix 6. Our work also provides details of the inter- and intra-subunit changes that link agonist binding to G-protein activation in this heterodimeric complex.

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

Application Effect of Plan-do-check Action Cycle Nursing Protocol on Improving the Accuracy of Urine Specimen Collection in Newborn Female Infants.

Background: The effect of traditional disposable infant urine collectors is not ideal for female newborns. Due to the poor adhesion of the traditional urine collection bag, it does not meet the physiological and anatomical characteristics of female newborns. Therefore, it is necessary to adopt effective nursing in urine specimen collection in newborn female infants. Objective: To explore the effect of plan-do-check action cycle nursing protocol on improving the accuracy of urine specimen collection in newborn female infants. Design: This was a randomized controlled study. Setting: This study was carried out in the Department of Pediatrics, Strategic Support Force Medical Center. Participants: A total of 120 female newborns admitted to our hospital from January 2021 to June 2022 were selected and divided into a control group and a study group, with 60 cases in each group. Interventions: The control group collected urine samples by routine methods, which used the traditional disposable urine bag collection method. The study group collected urine samples using the plan-do-check action cycle nursing mode. Primary Outcome Measures: (1) success rate of urine collection, collection times, and sample contamination rate (2) cleanliness of the vaginal opening (3) satisfaction of urine collection (4) retention time of urine samples and (5) urine pondus hydrogenii values. Results: Compared to the control group, the success rate of urine collection in the study group was higher, the collection times and specimen contamination rate were significantly lower, the time for collecting urine samples in the study group was shorter, the cleanliness of female vaginal opening in the study group was significantly better, the proportion of female urine pondus hydrogenii 6-7 in the study group was significantly higher (all P < .05). Conclusion: The application of the plan-do-check action cycle management mode in the urine samples of newborn female infants can not only effectively improve the success rate of collection but also improve the cleanliness of the vaginal mouth and make the test results more accurate.

Subspace Identification of Bridge Frequencies Based on the Dimensionless Response of a Two-Axle Vehicle.

As an essential reference to bridge dynamic characteristics, the identification of bridge frequencies has far-reaching consequences for the health monitoring and damage evaluation of bridges. This study proposes a uniform scheme to identify bridge frequencies with two different subspace-based methodologies, i.e., an improved Short-Time Stochastic Subspace Identification (ST-SSI) method and an improved Multivariable Output Error State Space (MOESP) method, by simply adjusting the signal inputs. One of the key features of the proposed scheme is the dimensionless description of the vehicle-bridge interaction system and the employment of the dimensionless response of a two-axle vehicle as the state input, which enhances the robustness of the vehicle properties and speed. Additionally, it establishes the equation of the vehicle biaxial response difference considering the time shift between the front and the rear wheels, theoretically eliminating the road roughness information in the state equation and output signal effectively. The numerical examples discuss the effects of vehicle speeds, road roughness conditions, and ongoing traffic on the bridge identification. According to the dimensionless speed parameter Sv1 of the vehicle, the ST-SSI (Sv1 < 0.1) or MOESP (Sv1 ≥ 0.1) algorithm is applied to extract the frequencies of a simply supported bridge from the dimensionless response of a two-axle vehicle on a single passage. In addition, the proposed methodology is applied to two types of long-span complex bridges. The results show that the proposed approaches exhibit good performance in identifying multi-order frequencies of the bridges, even considering high vehicle speeds, high levels of road surface roughness, and random traffic flows.

A randomized superiority clinical trial: metronidazole improved the efficacy of high-dose dual therapy in Helicobacter pylori rescue treatment.

BACKGROUND AND OBJECTIVES: High-dose dual therapy [proton pump inhibitor (PPI) + amoxicillin] is recommended as a Helicobacter pylori rescue treatment. However, its efficacy is still controversial. The aim of this study was to evaluate the efficacy and safety of triple therapy containing high dose of PPI and amoxicillin plus metronidazole compared with dual therapy in rescue treatment. METHODS: Two hundred and sixty-eight patients who failed at least two courses of H. pylori treatment were recruited and randomly allocated into two 14-day groups: esomeprazole 40 mg twice daily and amoxicillin 1000 mg three times daily plus metronidazole 400 mg three times daily (EAM group); or esomeprazole 40 mg twice daily and amoxicillin 1000 mg three times daily (EA group). The agar-dilution method was performed as an antibiotic susceptibility test. The 13C urea breath test was used to assess H. pylori eradication at 6 weeks after the treatment. The study was registered at clinicaltrials.gov (NCT04024527). RESULTS: H. pylori eradication rates in the EAM group were 85.8% (115/134, 95% CI 79.9%-91.7%) in ITT analysis and 92.6% (113/122, 95% CI 87.9%-97.3%) in PP analysis, significantly higher than those of the EA group, which were 73.1% (98/134, 95% CI 65.6%-80.6%) and 83.1% (98/118, 95% CI 76.8%-89.8%) (P = 0.005, 0.011). Resistance rates of amoxicillin and metronidazole were 6.6% (13/196) and 89.8% (176/196). Metronidazole resistance did not affect the eradication rates in the EAM group. Both groups had similar moderate and severe adverse events and similar compliance. CONCLUSIONS: A triple therapy containing high dose of PPI and amoxicillin plus metronidazole could be a potential rescue therapy worldwide even in a high metronidazole-resistance region.

Identification of potential serum biomarkers for congenital heart disease children with pulmonary arterial hypertension by metabonomics.

BACKGROUND: Pulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD. METHODS: Samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography-tandem mass spectroscopy. RESULTS: Serum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455. CONCLUSION: We demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

Association between whole-grain intake and myopia in chinese children: a cross-sectional epidemiological study.

BACKGROUND: Nutritional status influences the growth and development of the eyes. However, there are few studies on the association between diet, especially whole grains (WG) consumption, and myopia. The study aimed to evaluate the association between WG intake and myopia prevalence among primary school-age children in China. METHODS: This cross-sectional epidemiological study conducted between November 2019 and December 2019 included 586 children, aged 6-12 years, attending primary school in Binhai district, Tianjin, China. Ophthalmologic examinations and optometric cycloplegic refraction measurements were conducted. Information was collected on known risks and protective factors for myopia and the consumption of WGs, vegetables, and fruits. This association between the probability of myopia and the proportion of WG consumption (WG proportion was calculated as the mean intake from WG sources divided by total grain intake), adjusted for protective and risk factors, was analysed using crude and multivariable logistic regression. RESULTS: Among the study participants, 226/586 (38.57%) children had myopia in at least one eye. WG intake was inversely correlated with the prevalence of myopia. Furthermore, in the multivariate analysis, WG intake of > 50% was identified as a protective factor against myopia after subsequent adjustment for children's age, sex, parental myopia, near-work activity, screen time, reading and writing habits, visual fatigue, outdoor time, and classroom light environment (all P < 0.05). CONCLUSION: WG intake (> 50%) was an independent protective factor against myopia. Modifying the form of grains consumed (whole versus refined) could be one of the targets of future public health measures.

Metabolomics strategy of Pikang oral liquid in the treatment of psoriasis.

This study aimed to investigate the effect of Pikang oral liquid (PK) on psoriasis and analyze its possible mechanism from the perspective of metabolism. A psoriasis-form mouse model established using imiquimod (IMQ) was used to evaluate the anti-psoriatic effects of PK. The serum samples were analyzed by high-resolution nuclear magnetic resonance (1 H NMR)-based metabonomics. Nine amino acids were further quantitatively analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). This study suggested that PK treatment markedly attenuated IMQ-induced psoriasis in a dose-dependent manner. 1 H NMR-based multivariate trajectory analysis revealed that PK had a certain regression effect on eight differential metabolites. The quantitative results showed that PK could significantly regulate the serum levels of alanine, histidine and arginine to healthy control levels. The anti-psoriasis mechanism of PK may be associated with the restoration of the disturbance in the amino acid metabolism, energy metabolism and lipid metabolism and so on. Quantitative results further confirmed that amino acid metabolism play an key role in the pathogenesis of psoriasis. Our investigation provided a holistic view of PK for intervention psoriasis and provided the scientific information in vivo about a clinical value of PK for psoriasis.

One-dimensional consolidation of highly saturated abandoned-soil under time-dependent stress: An analytical study.

A thorough knowledge of the consolidation behavior of highly saturated soil under time-dependent stress is essential for the design and construction of abandoned-soil dump sites in the soft soil regions of China. In this study, one-dimensional consolidation analytical solutions are derived for such soil under one-way and two-way drainage conditions, accommodating the time-dependent stress created by various dumping protocols. Representative soil samples are obtained, and consolidation tests are conducted with various saturation degrees (one-way drainage) and loading protocols (two-way drainage), to verify the consolidation equation and determine its range of applicability to various saturation degrees. The effects of layer thickness, dumping type, and compaction degree on the consolidation behaviors of highly saturated abandoned-soil dumps are investigated. The one-dimensional consolidation equation is applicable to soil with saturation degree not lower than 75% under instantaneous stress, stepped stress, and linear stress. The pore pressure distribution with depth is not symmetrical; the eccentric distance of consolidation degree increases with increasing layer thickness in the stress application stage and is approximately zero in the stress keeping stage. The pore pressure at middle of the soil layer increases with increasing layer thickness and decreases with increasing dumping rate from the completion of soil dumping. With increasing compaction degree, the middle pore pressure increases, while the surface settlement decreases. In the premise of the stability of an abandoned-soil dump, where the goals are to reduce post-construction settlement and to shorten the consolidation process of the entire soil layer, the important factors are smaller layer thickness, higher dumping rate, and larger compaction degree.

Kindlin-2 protects pancreatic ß cells through inhibiting NLRP3 inflammasome activation in diabetic mice.

Diabetes mellitus has been a major public health problem worldwide, characterized by insulin resistance and dysfunction of ß-cells. A previous study showed that Kindlin-2 loss in ß-cells dramatically reduces insulin secretion and decreases ß-cell mass, resulting in severe diabetes-like phenotypes. It suggests that Kindlin-2 in ß-cells play an important role in regulating glucose homeostasis. However, the effect of Kindlin-2 on the function of ß-cells under chronic hyperglycemia in diabetes has not been explored. Here we report that Kindlin-2 overexpression ameliorates diabetes and improves insulin secretion in mice induced by streptozocin. In contrast, Kindlin-2 insufficiency exacerbates diabetes and promotes ß-cells dysfunction and inflammation in ß-cells induced by a high-fat diet (HFD). In vitro, Kindlin-2 overexpression prevented high-glucose (HG)-induced dysfunction in ß-cells. Kindlin-2 overexpression also decreased the expression of pro-inflammatory cytokines and NLRP3 inflammasome expression in ß-cells exposed to HG. Furthermore, the loss of Kindlin-2 aggravates the expression of inflammatory cytokines and NLRP3 induced by HG in ß-cells. Collectively, we demonstrate that Kindlin-2 protects against diabetes by inhibiting NLRP3 inflammasome activation.

Fructobacillus apis sp. nov., isolated from the gut of honeybee (Apis mellifera).

A Gram-positive, facultatively anaerobic, catalase-negative, fructose-dependent strain (W13T) was isolated from the gut of honeybee (Apis mellifera). Phylogenetic analysis based on 16S rRNA gene sequencing indicated that strain W13T represents a distinct line of descent within the genus Fructobacillus, with the closest neighbours being Fructobacillus broussonetiae BCRC 81240T (98.9 % sequence similarity) and Fructobacillus durionis DSM 19113T (96.8 % sequence similarity). Comparative sequencing of the additional phylogenetic markers rpoC and recA confirmed the 16S rRNA gene tree topology. The complete genome of strain W13T consisted of 1 292 712 bp with a G+C content of 48.3 mol%. Pairwise comparisons of the average nucleotide identity values and digital DNA-DNA hybridization values between the genomes of W13T and its close phylogenetic neighbours, F. broussonetiae BCRC 81240T and F. durionis DSM 19113T, resulted in 76.2-84.1 % and 20.2-27.6 %, respectively. The main cellular fatty acids of strain W13T were C16 : 0, C18 : 1 ω9c and C18 : 1 ω7c. Thus, we propose a novel species within the genus Fructobacillus, with the name Fructobacillus apis sp. nov. and the type strain is W13T (= NBRC 115637T=BCRC 81365T).

Evaluation of antityrosinase activity and mechanism, antioxidation, and UV filter properties of theaflavin.

Tyrosinase is a key metalloenzyme for the biosynthesis of melanin that plays a critical role in the prevention of skin damage caused by ultraviolet (UV) radiation. However, the overproduction of melanin may cause a variety of skin diseases. Due to the toxicity and inefficiency of existing tyrosinase inhibitors, it is urgent to identify safe and potent alternatives from natural sources. Theaflavin, a single-component extracted from black tea, has been found to possess a variety of pharmacological activities. Herein, the inhibition kinetics of theaflavin on tyrosinase and inhibitory mechanism were determined using spectroscopy, molecular docking, and zebrafish model. The results showed that theaflavin inhibited the diphenolase activity of tyrosinase in a reversible mixed type manner with IC50 of 229.75 µmol/L and hindered the synthesis of melanin in zebrafish. This may be due to the formation of eight hydrogen bonds and hydrophobic effects between theaflavin and tyrosinase according to the results of molecular docking. To study the possible effects on the prevention of free radical-mediated skin cancer and photoaging caused by UV radiation, the antioxidation and UV filter properties of theaflavin were further verified. This study demonstrates that theaflavin is a potential multifunctional compound that can be used in cosmetic and medicinal products.

A high-throughput microfluidic diploid yeast long-term culturing (DYLC) chip capable of bud reorientation and concerted daughter dissection for replicative lifespan determination.

BACKGROUND: Budding yeast, Saccharomyces cerevisiae, has been extensively favored as a model organism in aging and age-related studies, thanks to versatile microfluidic chips for cell dynamics assay and replicative lifespan (RLS) determination at single-cell resolution. However, previous microfluidic structures aiming to immobilize haploid yeast may impose excessive spatial constraint and mechanical stress on cells, especially for larger diploid cells that sprout in a bipolar pattern. RESULTS: We developed a high-throughput microfluidic chip for diploid yeast long-term culturing (DYLC), optical inspection and cell-aging analysis. The DYLC chip features 1100 "leaky bowl"-shaped traps formatted in an array to dock single cells under laminar-perfused medium and effectively remove daughter cells by hydraulic shear forces. The delicate microstructures of cell traps enable hydrodynamic rotation of newborn buds, so as to ensure bud reorientation towards downstream and concerted daughter dissection thereafter. The traps provide sufficient space for cell-volume enlargement during aging, and thus properly alleviate structural compression and external stress on budding yeast. Trapping efficiency and long-term maintenance of single cells were optimized according to computational fluid dynamics simulations and experimental characterization in terms of critical parameters of the trap and array geometries. Owing to the self-filling of daughter cells dissected from traps upstream, an initial trapping efficiency of about 70% can rapidly reach a high value of over 92% after 4-hour cell culturing. During yeast proliferation and aging, cellular processes of growth, budding and daughter dissection were continuously tracked for over 60 h by time-lapse imaging. Yeast RLS and budding time interval (BTI) were directly calculated by the sequential two-digit codes indicating the budding status in images. With the employed diploid yeast strain, we obtained an RLS of 24.29 ± 3.65 generations, and verified the extension of BTI in the first couple of generations after birth and the last several generations approaching death, as well as cell de-synchronization along diploid yeast aging. CONCLUSIONS: The DYLC chip offers a promising platform for reliable capture and culturing of diploid yeast cells and for life-long tracking of cell dynamics and replicative aging processes so that grasping comprehensive insights of aging mechanism in complex eukaryotic cells.

Development pattern of ocular biometric parameters and refractive error in young Chinese adults: a longitudinal study of first-year university students.

BACKGROUND: The increase in the prevalence of myopia has become a matter of serious public health concern, and few studies to date have examined the ocular biometric parameters of myopia in young Chinese adults. This study aimed to investigate the longitudinal ocular biometric and refractive development of first-year university students and the influence of near work. METHODS: This study included 526 first-year university students from Tianjin Medical University (mean age, 18.34 years; 313 females and 213 males). From 2016 to 2018, participants underwent ocular biometry measurements and subjective refraction annually. Near-work activities such as the use of electronic devices, online games, reading, and writing as well as demographic data were recorded by questionnaires. RESULTS: The prevalence of myopia in this population from 2016 to 2018 was 92.40%, 92.59%, and 92.97%, respectively. Importantly, the prevalence of high myopia increased significantly from 20.91% to 28.33% (P < .001). The spherical equivalent refraction was significantly more myopic by approximately - 0.38 D (from - 4.18 ± 2.44 to - 4.56 ± 2.57 D; P < .001) during the period. The axial length, central corneal thickness, and lens thickness became significantly different (all P < .05), and the axial length significantly increased by 0.12 mm during 2 years (P < .001). Using binary logistic regression analysis, the data indicated that spending more time on online games (odds ratio, 2.09; 95% confidence interval, 1.33-3.29) could speed up the progression of myopia (P < .05). CONCLUSIONS: This study showed that the prevalence of high myopia continued to increase in undergraduate students over 2 years. Baseline myopia correlated with myopic shift, the time spent on online games, and parental myopia were significantly associated with an increase in myopia in these young adult populations.

Prevalence of myopia and influencing factors among high school students in Nantong, China: A cross-sectional study.

INTRODUCTION: Myopia is an increasingly serious health problem in China. The aim of this study was to investigate the prevalence of myopia and the factors associated with it among students in Nantong, China, to show the current status of myopia prevention. METHODS: This school-based, cross-sectional study examined students from all high schools in an urban area of Nantong, China. At least two classes were randomly selected from each grade of each school. A self-reported questionnaire was used to collect the required information.Univariate analyses were performed to identify associations between myopia and various parameters.Non-cycloplegic autorefraction and visual acuity were assessed for each student. Factors that were statistically significant in univariate analyses were selected for multivariate analyses. Myopia was defined as a spherical equivalent refraction of ≤ -0.5 diopters. RESULTS: The completion percentage of students out of the whole high school was 6.5%.The overall prevalence of myopia was 94%. The response percentage of the number of validated questionnaires was 90.2%, of which 50.2% (n = 1,466) were from male participants, and 49.8% (n = 1,452) were from female participants. The mean (SD) of age was 15.22±1.75 years, ranging from 12-18 years. Factors such as female sex, older age, parental myopia, sitting in the back of the classroom, increased homework time, and minimal outdoor activity were significantly associated with a higher risk of myopia (P < 0.05). In the myopic population, most students (67.9%) did not take measures to prevent further progression of myopia. CONCLUSION: The prevalence of myopia among high school students was 94%. Female sex, older age, parental myopia, sitting in the back of the classroom, increased homework time, and minimal outdoor activity were significantly associated with a higher risk of myopia. Most students with myopia (67.9%) did not take measures to prevent further progression of myopia.

Glycyrrhizic acid assists anti-psoriatic efficacy of a self-deformable curcumin loaded transdermal gel.

The aim of this study was to explore the function of glycyrrhizic acid (GA) in an anti-psoriatic dermal delivery, whereby GA is originally designed as the matrix agent, with curcumin (Cur) as the active agent and silica as the drug carrier. Formulations with different GA proportions were prepared and named W-GA (without GA), L-GA (13% w/w GA) and H-GA (26% w/w GA). The results showed that GA had no significant effect on the physical characteristics, such as particle size and amorphous state, as exhibited by scanning electron microscopy and x-ray diffractograms, respectively. Compared with W-GA and L-GA, H-GA resulted in 10% less photodegradation of Cur after storage for one month, 0.45 µg more penetrated Cur in the epidermis, 2-fold higher viscosity, fewer signals of imiquimod-induced psoriasiform skin lesions and less histological morphological changes. The findings showed that H-GA significantly inhibited expression of interleukin 17 A in the dermis, and interleukin IL-23 in the epidermis, compared with Cur raw drug powder (RDP), whereas L-GA had no significant effect on the expression. These results indicated that a high GA proportion results in superior anti-psoriatic efficacy. Therefore, Cur-loaded silicas with approximately 26% GA are recommended as the superior formulation for the treatment of psoriasis.

Neo-adjuvant radiation therapy provides a survival advantage in T3-T4 nodal positive gastric and gastroesophageal junction adenocarcinoma: a SEER database analysis.

BACKGROUND: Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. METHODS: We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1-2N-, T1-2N+, T3-4N-, and T3-4N+). RESULTS: Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3-4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P <  0.001), but not in diffuse type (P = 0.11) for T3-4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3-4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. CONCLUSIONS: NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

Prognostic value of CAD-RADS classification by coronary CTA in patients with suspected CAD.

BACKGROUND: The study sought to compare Coronary Artery Disease Reporting and Data System (CAD-RADS) classification with traditional coronary artery disease (CAD) classifications and Duke Prognostic CAD Index for predicting the risk of all-cause mortality in patients with suspected CAD. METHODS: 9625 consecutive suspected CAD patients were assessed by coronary CTA for CAD-RADS classification, traditional CAD classifications and Duke Prognostic CAD Index. Kaplan-Meier and multivariable Cox models were used to estimate all-cause mortality. Discriminatory ability of classifications was assessed using time dependent receiver-operating characteristic (ROC) curves and The Hosmer-Lemeshow goodness-of-fit test was employed to evaluate calibration. RESULTS: A total of 540 patients died from all causes with a median follow-up of 4.3 ± 2.1 years. Kaplan-Meier survival curves showed the cumulative events increased significantly associated with CAD-RADS, three traditional CAD classifications and Duke Prognostic CAD Index. In multivariate Cox regressions, the risk for the all-cause death increased from HR 0.861 (95% CI 0.420-1.764) for CAD-RADS 1 to HR 2.761 (95% CI 1.961-3.887) for CAD-RADS 4B&5, using CAD-RADS 0 as the reference group. The relative HRs for all-cause death increased proportionally with the grades of the three traditional CAD classifications and Duke Prognostic CAD Index. The area under the time dependent ROC curve for prediction of all-cause death was 0.7917, 0.7805, 0.7991for CAD-RADS in 1 year, 3 year, 5 year, respectively, which was non-inferior to the traditional CAD classifications and Duke Prognostic CAD Index. CONCLUSIONS: The CAD-RADS classification provided important prognostic information for patients with suspected CAD with noninvasive evaluation, which was non-inferior than Duke Prognostic CAD Index and traditional stenosis-based grading schemes in prognostic value of all-cause mortality. Traditional and simplest CAD classification should be preferable, given the more number of groups and complexity of CAD-RADS and Duke prognostic index, without using more time consuming classification.

Poorly differentiated is more significant than signet ring cell component for lymph node metastasis in mixed-type early gastric cancer: a retrospective study from a large-volume hospital.

OBJECTIVE: The purpose of this study was to explore the role of different undifferentiated components in the lymph node metastasis (LNM) of early mixed gastric cancer. METHODS: A total of 1596 patients with EGC who underwent gastrectomy were divided into four types: pure differentiated (PD), pure poorly differentiated (Poorly D), pure signet ring cell carcinoma (SRC), and mixed. Mixed type was classified into four subtypes: differentiated-predominant type mixed with poorly differentiated component (MD-P), poorly differentiated-predominant type mixed with differentiated component (MP-D), differentiated-predominant type mixed with SRC component (MD-S), and poorly differentiated-predominant type mixed with SRC component (MP-S). We analyzed the clinicopathological differences between all types and the rates of LNM of patients fulfilling endoscopic submucosal dissection (ESD) criteria. RESULTS: LNM was more common in mixed (21.9%) than in PD (7.5%, P < 0.001) or SRC (11.3%, P < 0.001). When analyzed the subgroups of mixed type, LNM was more frequent in MD-P (15.4%) than in PD (7.5%, P = 0.003). LNM in MD-S (7.4%, P = 1.000) was not higher than in PD. MP-S (24.5%) showed a higher rate of LNM than SRC (11.3%, P < 0.001) rather than Poorly-D (22.7%, P = 0.681). For lesions satisfying ESD criteria, MD-S (0%, P = 1.000), and MD-P (5.9%, P = 0.12) did not have higher rates of LNM than PD (1.4%). CONCLUSION: The presence of poorly differentiated component but not SRC increases the LNM rate of mixed type. ESD is recommended for the treatment of MD-S and MD-P consistent with ESD criteria.

Fabrication and characterization of dissolving microneedles for transdermal drug delivery of allopurinol.

Allopurinol (AP) is the first line drug in treating hyperuricemia and gout in clinical by oral drug delivery, which is associated with severe adverse effects and the hepatic first-pass effect. Herein, we first proposed AP encapsulated dissolving microneedles (DMNs) for transdermal drug delivery to realize the sustained drug release and avoid the hepatic first-pass effect, which will help to reduce the adverse effects and improve the bioavailability of AP. DMNs were fabricated by a suspension solution casting method with precisely controlled dose. They had sufficient mechanical strength to penetrate through the skin and resulted in the formation of hundreds of micropores in skin. The results of in vitro and ex vivo release experiments demonstrated that the release profile of DMNs was independent with the dose of AP, and they indeed had much higher drug delivery efficiency (DDE) than the equal amount of AP in solutions. In vivo DDE reached to 38.9% within 1 h, and the drug residual can be served as a drug reservoir for sustained drug release. The result of pharmacodynamic study further confirmed that the sustained release and the anti-hyperuricemia effect of DMNs encapsulating AP were achieved. Moreover, transepidermal water loss significantly increased to 49.50 ± 3.82 g/m2·h after the application of DMNs and returned to normal levels (12.25 ± 0.21 g/m2·h) after 8 h, indicating that the DMNs were well tolerated. These results suggest that transdermal drug delivery of AP by using DMNs is an efficient and safe alternative to currently available routes of administration.