BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

OBJECTIVES: To investigate the ethnic origin of Chuanqing people, one of the largest unidentified ethnic groups in Guizhou, China, and analyze its genetic relationships with surrounding populations. METHODS: Based on a self-developed microhaplotype system, we conducted genotyping and analyzed the genetic distribution of microhaplotype loci and their forensic applicability in Chuanqing population in Guizhou Province. Using the microhaplotype data from different intercontinental populations and previously reported data from Han population living in Guizhou Province, we systematically investigated the genetic background of Chuanqing people through population genetic approaches, including genetic distance estimation, principal component analysis, and phylogenetic tree construction. RESULTS: Among the studied population, the number of haplotype per microhaplotype ranged from 6 to 25. The average expected heterozygosity (He), observed heterozygosity (Ho), power of discrimination (PD), and probability of exclusion (PE) were 0.8291, 0.8301, 0.9387, and 0.6593, respectively. The cumulative power of discrimination (CPD) and cumulative probability of exclusion (CPE) for these 33 loci were 1-2.62×10^-41 and 1-7.64×10^-17, respectively. Population genetic analyses revealed that the Chuanqing population had close genetic relationships with the East Asian populations, especially the local Guizhou Han population, Beijing Han population and the Han populations living in southern China. CONCLUSIONS The 33 microhaplotypes exhibit high levels of genetic diversity in the Guizhou Chuanqing population, highlighting their potentials for both forensic identification and parentage testing. The Han populations might have contributed a significant amount of genetic material to the Chuanqing population during the formation and development of the latter.
Humans ; China/ethnology* ; Ethnicity/genetics* ; Forensic Genetics/methods* ; Genetics, Population ; Genotype ; Haplotypes ; Phylogeny ; East Asian People/genetics*

OBJECTIVES: Root canal therapy is the most effective and common method for pulpitis and periapical periodontitis. During the root canal preparation, chemical irrigation plays a key role. However, sodium hypochlorite (NaOCl), the widely used irrigation fluid, may impact the bonding strength between dentin and restorative material meanwhile sterilization and dissolving. Therefore, it's important to explore the influence of NaOCl on the adhesion between dentin and restoration materials to ensure clinical efficacy. This study aims to explore the effect of NaOCl on dentine adhesion and evaluate the effect of dentine adhesion induced by sodium erythorbate (ERY), and to provide clinical guidance on dentin bonding after root canal therapy. METHODS: Seventy freshly complete extracted human third molars aged 18-33 years old, without caries and restorations were selected. A diamond saw was used under running water to achieve dentine fragments which were divided into 10 groups with 14 fragments in each group: 2 control [deionized water (DW)±10% ERY] and 8 experimental groups (0.5%, 1%, 2.5%, and 5.25% NaOCl±10% ERY). The dentine specimens in the control group (treated with DW) and the experimental groups (treated with 0.5% NaOCl, 1% NaOCl, 2.5% NaOCl, and 5.25% NaOCl) were immersed for 20 min using corresponding solutions which were renewed every 5 min. The other 5 groups were immersed in 10% ERY for 5 min after an initial washing with DW for 1 min. Then, we selected 4 dentine fragments from all 14 fragments in each group and the numbers and diameters of opening dentinal tubules were observed under scanning electron microscope (SEM). The other 10 dentine fragments from each group were used to make adhesive samples by using self-etch adhesive wand composite resin. All the above adhesive samples were sectioned perpendicular to the bonded interface into 20 slabs with a cross-sectional area of 1 mm×1 mm using a diamond saw under the cooling water, and then the morphology of 10 slabs in each group's bonding interface was observed from aspects of formation of resin tags, depth of tags in dentin, and formation of hybrid layer under SEM. The other 10 slabs of each group's microtensile bond strength and failure modes were also analyzed. RESULTS: Among the 0.5% NaOCl, 1% NaOCl, 2.5% NaOCl, and 5.25% NaOCl groups, the number and diameter of patent dentinal tubules gradually increased with the rise of concentration of NaOCl solution (all P<0.05). Among the DW, 0.5% NaOCl, 1% NaOCl, 2.5% NaOCl, and 5.25% NaOCl groups, the number and diameter of patent dentinal tubules increased after using ERY, but without significant difference (all P>0.05). Among the DW, 0.5% NaOCl, 1% NaOCl, and 2.5% NaOCl groups, the scores of formation of resin tags under SEM gradually increased with the increase of concentration of NaOCl solution, while the score in the 5.25% NaOCl group decreased significantly compared with the score of the 2.5% NaOCl group (P<0.05). There was no significant difference between using 10% ERY groups and without using 10% ERY groups (all P>0.05). The scores of length of the tags under SEM in the 5.25% NaOCl group was significantly higher than the scores of DW, 0.5% NaOCl, and 1% NaOCl groups (all P<0.05), and it was also higher than the score of the 2.5% NaOCl group, but without significant difference (P>0.05). There was no significant difference between using 10% ERY groups and without using 10% ERY groups (P>0.05). The scores of formation of hybrid layer under SEM in the 2.5% NaOCl and 5.25% NaOCl groups significantly decreased compared with the score of the DW group (all P<0.05). There were significant differences between the 2.5% NaOCl±10% ERY groups and between the 5.25% NaOCl±10% ERY groups (all P<0.05). Microtensile bond strength was greater in the 0.5% NaOCl, 1% NaOCl, and 2.5% NaOCl groups, but lower in the 5.25% NaOCl group than that in the DW group (all P<0.05). There were significant differences between the 2.5% NaOCl±10% ERY groups and between the 5.25% NaOCl±10% ERY groups (all P<0.05). The incidence of type "Adhesive" of failure modes in the 5.25% NaOCl group was significantly higher than that in other groups (all P<0.05), while the incidence of type "Adhesive" in the 5.25% NaOCl+10% ERY group was lower than that in the 5.25% NaOCl group (P<0.05). CONCLUSIONS The bonding strength to dentine increases with the increase of NaOCl concentration when the concentration lower than 2.5%; whereas it is decreased at a higher concentration (such as 5.25%). 10% ERY has a definite recovery effect on attenuated bonding strength to 5.25% NaOCl-treated dentine.
Adolescent ; Adult ; Ascorbic Acid ; Dental Bonding ; Dentin ; Dentin-Bonding Agents/pharmacology* ; Diamond/pharmacology* ; Humans ; Materials Testing ; Microscopy, Electron, Scanning ; Resin Cements/pharmacology* ; Sodium Hypochlorite/pharmacology* ; Tensile Strength ; Water/pharmacology* ; Young Adult

Objective:To determine the oxygen concentration threshold for explosion induced by high-frequency electric knife or argon knife at different energies.Methods:① In vivo experiment The smooth muscle tissue or adipose-rich tissue in 10 pairs of isolated porcine lungs and trachea was electrocauterized at 30 and 50 W with high-frequency electroknife or argon knife at different oxygen concentrations.The initial oxygen concentration was 20%, the oxygen concentration was gradually increased in increments of 5% until the oxygen concentration reached 80%.Each sample was electrocauterized 10 times at each concentration, and the number of explosion was recorded.As long as one explosion occurred, it could be considered that the concentration could induce explosion, and the minimum oxygen concentration inducing explosion was considered as the threshold.② Measurement of oxygen concentration in the airway of patients received bronchoscopic intervention Thirty patients scheduled for elective bronchoscopy with cryotherapy were selected, the oxygen concentration inhaled was reduced from 100% until 50% in decrements of 10%, and the oxygen concentration in airway was measured with the AIRVO 2 transnasal high-flow oxygen inhalation device.ICC consistency analysis was performed between the oxygen concentration in airway and oxygen concentration inhaled. Results:In adipose-rich tissues, the threshold of the oxygen concentration for explosion was 70% at 30 W and 65% at 50 W when using the high-frequency electric knife; the threshold of the oxygen concentration for explosion was 35% at 30 W and 30% at 50 W when using the high-frequency argon knife.In smooth muscle tissues, no explosion occurred at each oxygen concentration when using the high-frequency electric knife and argon knife at 30 or 50 W, and the threshold value was above 80%.There was moderate consistency (ICC value 0.722, 95% CI 0.537-0.850, P<0.001) between the oxygen concentration in airway and oxygen concentration inhaled. Conclusions:In smooth muscle tissues, explosion is not easy to occur at oxygen concentrations below 80% when using the high-frequency electric knife or argon knife.In adipose-rich tissues, explosion is not easy to occur at oxygen concentrations less than 70% at 30 W and at oxygen concentrations less than 65% at 50 W when using the high-frequency electric knife; explosion is not easy to occur at oxygen concentrations less than 35% at 30 W and at oxygen concentrations less than 30% at 50 W when using the high-frequency argon knife.The threshold of oxygen concentrations in airway can be determined using the oxygen concentration inhaled.

Objective To investigate the influence of prepubertal exposure to estradiol benzoate (EB)in the male reproductive system of the rats and the natural process of tissue repair,and to clarify the possible mechanism of the reproductive toxicity of exogenous estrogen.Methods Ninety 2 1-day-old male Wistar rats were randomly divided into 2 experimental groups (low dose of EB group and high dose of EB group,n=30)and control group (n=30). The rats in the experimental groups were injected with EB dissolved in peanut oil at 15(low dose of EB group)and 15 000μg·kg-1 (high dose of EB group)respectively,the rats in control group received equal vehicle injection only,once every other day for two weeks from postnatal day(PND)21 to 34.All of them were normally fed after the drug usage was stopped.The testes were harvested at the stages of PND 60 and PND 125(n=15 at each stage).The serum levels testosterone of (T),follicle-stimulating hormone(FSH),luteinizing hormone(LH),prolactin (PRL)and estradiol(E2)of the rats in various groups were detected with radioimmunology method and the weights of the rats in various groups were recorded;the histological changes of the testes tissue were observed with light microscope.Results On PND60,compared with control group,the T levels in low dose of EB group and high dose of EB group were decreased(P<0.05 or P<0.01);the FSH,LH and E2 levels were increased (P<0.05 or P<0.01),and the PRL levels had no change(P>0.05);the weights of testes were decreased(P<0.01);the histological changes of the testes of the rats in experimental groups included seminiferous tubules maldevelopment, decreased cell number of seminiferous epithelia.Compared with low dose of EB group,the T and FSH levels in high dose of EB group were decreased (P<0.05 or P<0.01),the E2 and LH levels were increased(P<0.01),the PRL level had no change (P>0.05 ), and the weight of testes was decreased (P<0.01 );the diameters of seminiferous tubules were smaller,there was no sperm in high dose of EB group while there were a few sperms in low dose of EB group.On PND125,compared with control group,the T,FSH and PRL levels in low dose of EB group and high dose of EB group were decreased(P<0.01),the E2 levels were increased (P<0.01);the LH level in low dose of EB group was increased(P<0.05),the LH level in high dose of EB group was decreased(P<0.01), and the weights of testes in high dose of EB group were decreased(P<0.01);the diameters of seminiferous tubules and the cell number of seminiferous epithelia were increased but not apparent change.Compared with low dose of EB group,the T,LH levels in high dose of EB group were decreased (P<0.01),the E2 and FSH levels were increased(P<0.01),the PRL level had no change(P>0.05),and the weight of testes was decreased(P<0.01);there was still no sperm in high dose of EB group, the number of sperms was increased in low dose of EB group, but it was still lower than that in control group.Conclusion EB is harmful to the reproductive system and can change the normal serum sex hormone levels,even induces the irreversible injury.

ated acute peritonitis induced by LPS in rats.

Objective To explore the two-dimensional images features and color flow characteristics of scrofula, as well as their application in the localization of scrofula. Methods A total of 110 cases of the scrofula confirmed by operation were retrospectively analyzed. Two-dimensional images and color flow characteristics, the relationship with vascular traveling and the invasion site were recorded. Results Lymph nodes of the lateral neck region along with large vessels were most commonly involved, then followed the submaxillary lymph nodes and the lymph nodes anterior neck longitudinally. There might be multiple lesions behaving differently on two-dimensional images and with different color flow characteristics. Conclusion Most of scrofula can be diagnosed clearly according to the two-dimensional images and color flow characteristics. The description of relationship between involved lymph nodes with vascular, the depth and position of scrofula make the operation safety.

Human interleukin-15 (hIL-15) is an important cytokine to activate endothelial cells and can be regulated by many other cytokines. The aim of this study is to examine the ability of interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) to induce the production of human interleukin-15 (hIL-15) and IL-15 receptor (IL-15Ralpha) by human umbilical vein endothelial cells (HUVECs). The data are summarized as follows: 1. Northern blot revealed that IL-15 mRNA was up-regulated by IFN-gamma and TNF-alpha. 2. Intracellular IL-15 protein was visualized by fluorescence microscopy, whereas the expression of IL-15 on the surface of HUVECs was detected by fluorescence activated cell sorting (FACS), and no detectable IL-15 in the medium was verified by ELISA. 3. IL-15Ralpha was detected on the surface of HUVECs by FACS after IFN-gamma and TNF-alpha stimulation, whereas Western blotting revealed that the elevated expression on surface IL-15Ralpha was not due to the increased protein expression. The conclusion demonstrated from our results is that IFN-gamma and TNF-alpha play an important role in regulating the expression of IL-15 and IL-15Ralpha on the surface of HUVECs.

Human interleukin-15 (hlL-15) is an important cytokine to activate endothelial cells and can be regulated by many other cytokines. The aim of this study is to examine the ability of interferon-γ,(IFN-γ), and tumor necrosis factor-ct (TNF-α) to induce the production of human interleukin-15 (hlL-15)and IL-15 receptor (IL-15Rα) by human umbilical vein endothelial cells (HUVECs). The data are summarized as follows: 1. Northern blot revealed that IL-15 mRNA was up-regulated by IFN-γ and TNF-α. 2. lntracellular IL-15 protein was visualized by fluorescence microscopy, whereas the expres-sion of IL-15 on the surface of HUVECs was detected by fluorescence activated cell sorting (FACS),and no detectable IL-15 in the medium was verified by ELISA. 3. IL-15Rα was detected on the surface of HUVECs by FACS after IFN-γ and TNF-α stimulation, whereas Western blotting revealed that the elevated expression on surface IL-15Rα was not due to the increased protein expression. The conclusion demonstrated from our results is that IFN-γ and TNF-α play an important role in regulating the expres-sion of IL-15 and IL-15Rα on the surface of HUVECs.

Objective To explore the effects of peroxisome proliferator-activated receptorγ (PPARγ) agonist rosiglitazone and 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) on the expression of PPARγ, toll-like receptor 4 (TLR4) and the activation of STAT1 as well as the local inflammation reaction of abdominal cavity in sprague dawley (SD) rats with peritoneal dialysis- related acute peritonitis induced by lipopolysaccharide (LPS). Methods Twenty-four male SD rats were equally randomized to four groups(n=6 each): control group, injected with 4.25% dextrose peritoneal dialysate (PDF) via abdominal cavity(90 ml/kg); LPS group, injected with LPS(1 mg/kg) via abdominal cavity 4 hours later follewed by PDF injection; rosiglitazone plus LPS group (Rosi group), preconditioned with rosiglitazone (20 mg·kg-1·d-1) by intragastric way for 3 days, then injected with LPS and PDF via abdominal cavity; 15d-PGJ2 plus LPS group (15d-PGJ2 group), preconditioned with 15d-PGJ2 (0.3 mg·kg-1·d-1)via abdominal cavity injection for 3 days, then injected with LPS and PDF via abdominal cavity. The rats were killed 4 hours after PDF injection, IL-6 level in abdominal dropsy was determined by ELISA. Peritoneum tissue was stained by Masson. Leucocyte count in abdominal dropsy was performed. The mRNA expression of PPARγ and TLR4 in peritoneum tissue was determined by RT-PCR; the protein expression of PPARγ, TLR4, p-STAT1 and STAT1 in peritoneum tissue was analyzed by Western blot. Results IL-6 level of abdominal dropsy in LPS group [median 268.53 (range 201.87-335.19) ng/L] was significantly higher than that of control group [median 147.62 (range 130.60-164.64) ng/L] (P<0.01). The IL-6 level of abdominal dropsy in Rosi group [median 110.20 (range 77.60-142.80) ng/L] was significantly lower than that of LPS group (P<0.05). Compared to that of control group, the edematous degree of peritoneum in LPS group was significantly severer, meanwhile, mRNA and proteins expression of PPARγ and TLR4 in rat peritoneum were also significantly higher (P<0.05, P<0.01). Compared to that of LPS group, the edematous degree of peritoneum in Rosi group was lighter, the expression of PPARγ and TLR4 mRNA was significantly up-regulated (P<0.05), meanwhile their proteins expression was down-regulated (P<0.05); and in 15d-PGJ2 group, the edematous degree of peritoneum, the expression of PPARγ mRNA and protein was also decreased (P<0.05), but TLR4 mRNA expression was up-regulated (P<0.01), however, its protein expression was down-regulated (P<0.05). There were no significant differences in leucocyte count of abdominal dropsy among the four groups. The p-STAT1 expression in the rats peritoneum induced by LPS was markedly increased by both rosiglitazone and 15d-PGJ2 (P<0.01). Conclusions Both rosiglitazone and 15d-PGJ2 can down-regnlate the inflammatory reaction in rat peritonitis induced by LIPS, which may be involved in modulating the expression of associated functional protein during LPS signal pathway.