Atmospheric pollution significantly impacts the regional economy and human health, and its prediction has been increasingly emphasized. The performance of traditional prediction methods is limited due to the lack of historical data support in new atmospheric monitoring sites. Therefore, this paper proposes a two-stage attention mechanism model based on transfer learning (TL-AdaBiGRU). First, the first stage of the model utilizes a temporal distribution characterization algorithm to segment the air pollutant sequences into periods. It introduces a temporal attention mechanism to assign self-learning weights to the period segments in order to filter out essential period features. Then, in the second stage of the model, a multi-head external attention mechanism is introduced to mine the network's hidden layer key features. Finally, the adequate knowledge learned by the model at the source domain site is migrated to the new site to improve the prediction capability of the new site. The results show that (1) the model is modeled from the data distribution perspective, and the critical information within the sequence of periodic segments is mined in depth. (2) The model employs a unique two-stage attention mechanism to capture complex nonlinear relationships in air pollutant data. (3) Compared with the existing models, the mean absolute error (MAE), root mean square error (RMSE), and mean absolute percentage error (MAPE) of the model decreased by 14%, 13%, and 4%, respectively, and the prediction accuracy was greatly improved.
BACKGROUND: Baijiu brewing adopts the solid-state fermentation method, using starchy raw materials, Jiuqu as saccharifying fermenting agent, and distilled spirits made by digestion, saccharification, fermentation and distillation. In the late stages of solid-state fermentation of Baijiu, the reduced activity of glucoamylase leads to higher residual starch content in the Jiupei, which affects the liquor yield. The direct addition of exogenous glucoamylase leads to problems such as the temperature of the fermentation environment rising too quickly, seriously affecting the growth of microorganisms. RESULTS: To solve the problem of reduced activity of glucoamylase in the late stage of solid-state fermentation of Baijiu, microcapsule beads (M-B) based on microcapsule emulsion were prepared and the effect of M-B on solid-state fermentation of Baijiu was investigated. The results showed that the release of M-B before and after drying was 53.27% and 25.77% in the liquid state (120 h) and 29.84% and 22.62% in the solid state (15 days), respectively. Adding M-B improved the alcohol by 0.33 %vol and reducing sugar content by 0.51%, reduced the residual starch content by 1.21% of the Jiupei, and had an insignificant effect on the moisture and acidity of the Jiupei. CONCLUSION: M-B have excellent sustained-release properties. The addition of M-B in solid-state fermentation significantly increased the alcohol content, reduced the residual starch content of Jiupei, ultimately improving the starch utilization rate and liquor yield of Baijiu brewing. The preparation of M-B provides methods and approaches for applying other active substances and microorganisms in the brewing of Baijiu. © 2023 Society of Chemical Industry.
Alcoholic Beverages , Glucan 1,4-alpha-Glucosidase , Fermentation , Capsules , Alcoholic Beverages/analysis , Starch/metabolism
CO2 foam injection has been shown to be effective under reservoir conditions for enhanced oil recovery. However, its application requires a certain stability and surfactant absorbability on rock surface, and it is also associated with borehole corrosion in the presence of water. Adding surfactants to CO2 can enhance the interaction between CO2 and crude oil and control the CO2 mobility, thereby improving the performance of CO2 flooding. This paper presents a review of the research of CO2-soluble surfactants and their applications. Molecular dynamics simulation is introduced as a tool for analyzing the behavior of the surfactants in supercritical CO2 (scCO2). The applications of CO2-soluble surfactants, including CO2 thickening, reducing miscibility pressure, and generating supercritical CO2 foam, are discussed in detail. Moreover, some opportunities for the research and development of CO2-soluble surfactants are proposed.
Rationale & Objective: In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD. Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was the time to first MACE. Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P = 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups. Limitations: Several analyses are exploratory. Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group. Funding: Akebia Therapeutics, Inc. Trial Registration: ClinicalTrials.gov identifier: NCT02680574.
Rationale & Objective: Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial. Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m2 and who may not have had access to dialysis. Limitations: Different regional treatment patterns of patients with NDD-CKD. Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.
The primary cause of hazy weather is PM2.5, and forecasting PM2.5 concentrations can aid in managing and preventing hazy weather. This paper proposes a novel spatiotemporal prediction model called SpatioTemporal-Informer (ST-Informer) in response to the shortcomings of spatiotemporal prediction models commonly used in studies for long-input series prediction. The ST-Informer model implements parallel computation of long correlations and adds an independent spatiotemporal embedding layer to the original Informer model. The spatiotemporal embedding layer captures the complex dynamic spatiotemporal correlations among the input information. In addition, the ProbSpare Self-Attention mechanism in this model can focus on extracting important contextual information of spatiotemporal data. The ST-Informer model uses weather and air pollutant concentration data from numerous stations as its input data. The outcomes of the trials indicate that (1) The ST-Informer model can sharply capture the peaks and sudden changes in PM2.5 concentrations. (2) Compared to the current models, the ST-Informer model shows better prediction performance while maintaining high-efficiency prediction [Formula: see text]. (3) The ST-Informer model has universal applicability, and the model was applied to the concentration of other pollutants prediction with good results.
Air Pollutants , Air Pollution , Particulate Matter/analysis , Air Pollution/analysis , Models, Theoretical , Environmental Monitoring/methods , Air Pollutants/analysis
BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.
Anemia , Erythropoietin , Hematinics , Peritoneal Dialysis , Renal Insufficiency, Chronic , Humans , Darbepoetin alfa/therapeutic use , Renal Dialysis/adverse effects , Anemia/drug therapy , Anemia/etiology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy , Renal Insufficiency, Chronic/chemically induced , Peritoneal Dialysis/adverse effects , Hematinics/adverse effects , Hemoglobins/analysis , Erythropoietin/adverse effects
OBJECTIVE: To investigate the application of 3D printing percutaneous surgical guide plate in closed reduction and cannulated screw internal fixation of femoral neck fracture. METHODS: The clinical data of 12 patients with femoral neck fracture from March 2019 to March 2022 were retrospectively analyzed. Patients were divided into observation group and control group according to different operation plans, with 6 cases in each group. The observation group received percutaneous operation guide plate assisted closed reduction and hollow screw internal fixation, while the control group received closed reduction and hollow compression screw internal fixation. The operation time, intraoperative blood loss, fluoroscopy times, and Kirschner needle puncture times were compared between two groups. The location of screws were recordedon postoperative X-ray films, follow-up time, time of complete fracture healing, Harris score of hip joint and the incidence of complications were recorded on postoperative X-ray films. RESULTS: The operation time of observation group (32.17±6.18) min was shorter than that of control group (53.83±7.31) min (P<0.05). The amount of intraoperative bleeding in the observation group (18.33±2.94) ml was less than that in the control group (38.17±5.56) ml(P<0.05). The times of fluoroscopy in the observation group (7.50±1.05) were less than those in the control group (21.00±4.82) (P<0.05). The number of Kirschner needle punctures (8.00±0.63) in observation group was less than that in control group (32.67±3.08) (P<0.05). The follow-up time was(12.88±0.74) months in observation group and (12.83±0.72) months in control group, there was no significant difference between two groups (P>0.05). One year after operation, Harris score of hip joint in the observation group was(82.00±4.52) points, while that in the control group was(81.00±3.41) points, there was no significant difference between two groups(P>0.05). The time of complete fracture healing in the observation group was (7.50±1.05) months, while that in the control group was (7.67±1.21) months, there was no significant difference between two groups(P>0.05). The parallelism of the screws in the observation group was (0.50±0.11) ° and (0.76±0.15) °, which were lower than that in the control group (1.57±0.31) ° and (1.87±0.21) ° (P<0.05). The screw distribution area ratio (0.13±0.02) cm2 in the observation group was higher than that in the control group (0.08±0.01) cm2 (P<0.05). No complications such as necrosis of femoral head, nonunion of fracture, shortening of femoral neck and withdrawal of internal fixation occurred in both groups. CONCLUSION: The application of 3D printing percutaneous surgical guide plate improves the accuracy and safety of closed reduction and cannulated screw internal fixation for femoral neck fracture. It has the advantages of minimally invasive, reducing radiation exposure, fast and accurate, shortening the operation time and reducing intraoperative bleeding.
Femoral Neck Fractures , Humans , Retrospective Studies , Treatment Outcome , Femoral Neck Fractures/surgery , Fracture Fixation, Internal , Bone Screws , Printing, Three-Dimensional
INTRODUCTION: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. METHODS: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. RESULTS: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. DISCUSSION/CONCLUSION: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
Anemia , Erythropoietin , Hematinics , Renal Insufficiency, Chronic , Humans , Darbepoetin alfa/adverse effects , Quality of Life , Anemia/drug therapy , Anemia/etiology , Erythropoietin/therapeutic use , Renal Insufficiency, Chronic/drug therapy , Hematinics/adverse effects , Renal Dialysis/adverse effects , Hemoglobins/analysis
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
Anemia , Erythropoietin , Hematinics , Renal Insufficiency, Chronic , Anemia/drug therapy , Anemia/etiology , Clinical Trials, Phase III as Topic , Darbepoetin alfa/therapeutic use , Erythropoiesis , Erythropoietin/therapeutic use , Ferritins , Glycine/analogs & derivatives , Hematinics/therapeutic use , Hemoglobins/metabolism , Hepcidins , Humans , Iron/therapeutic use , Picolinic Acids , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Transferrins/therapeutic use
INTRODUCTION: Ferric citrate (FC) is indicated as an oral iron replacement for iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis. The recommended starting dose is one 1-g tablet three times daily (TID). This study investigated long-term efficacy and safety of different FC dosing regimens for treating anemia in nondialysis-dependent CKD (NDD-CKD). METHODS: In this phase 4, randomized, open-label, multicenter study, patients with anemia with NDD-CKD (estimated glomerular filtration rate, ≥20 mL/min and <60 mL/min) were randomized 1:1 to one FC tablet (1-g equivalent to 210 mg ferric iron) TID (3 g/day) or 2 tablets twice daily (BID; 4 g/day). At week 12, dosage was increased to 2 tablets TID (6 g/day) or 3 tablets BID (6 g/day) in patients whose hemoglobin (Hb) levels increased <0.5 g/dL or were <10 g/dL. Primary endpoint was mean change in Hb from baseline to week 24. RESULTS: Of 484 patients screened, 206 were randomized and 205 received FC. Mean (standard deviation) changes from baseline in Hb at week 24 were 0.77 (0.84) g/dL with FC TID 3 g/day and 0.70 (0.98) g/dL with FC BID 4 g/day. DISCUSSION/CONCLUSIONS: FC administered BID and TID for 48 weeks was safe and effective for treating anemia in this population, supporting potentially increased dosing flexibility.
Anemia, Iron-Deficiency/drug therapy , Ferric Compounds/administration & dosage , Hemoglobins/metabolism , Renal Insufficiency, Chronic/complications , Adult , Aged , Aged, 80 and over , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/etiology , Female , Ferric Compounds/adverse effects , Fibroblast Growth Factor-23/blood , Glomerular Filtration Rate , Humans , Male , Middle Aged , Phosphates/blood , Time Factors
The cytotoxicity of docosahexaenoic acid (DHA) on normal cells is still unclear. This study investigated the effects of DHA on the cytotoxicity and possible mechanism in the BRL-3A cell. The cultured rat liver BRL-3A cell line was treated with 50, 100 and 200 µM DHA for 24 h. The cell viability was increased in the 50 and 100 µM DHA treatments, but decreased in the 200 µM DHA treatment. The 50, 100 and 200 µM DHA treatments increased the proportion of the apoptotic cells, the levels of lactate dehydrogenase (LDH), alkaline phosphatase (AKP) and IL-6 in the supernatant, and the ratio of the phosphonated p38MAPK to the p38MAPK (p-p38/p38) protein in the cells. The expression of TGF beta-activated kinase 1 (TAK1), nuclear transcription factor-κB p65 (NF-κB p65) and the inhibitor of NF-κB alpha (IκBα) mRNA, and the ratio of the phosphonated IκBα (p-IκBα) to IκBα protein were increased in the 200 µM DHA treatment, while the ratio of phosphonated extracellular regulated protein kinases (p-ERK) to ERK protein was decreased in the 200 µM DHA treatment. These results indicate that DHA-treated (50, 100 and 200 µM) BRL-3A cells for 24 h promotes cell apoptosis and inflammatory response, and the p38 MAPK, ERK and NF-κB signal pathways were involved in mediating the apoptosis and inflammatory response.
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
Anemia/drug therapy , Darbepoetin alfa/therapeutic use , Glycine/analogs & derivatives , Hematinics/therapeutic use , Picolinic Acids/therapeutic use , Prolyl-Hydroxylase Inhibitors/therapeutic use , Renal Dialysis/adverse effects , Renal Insufficiency, Chronic/complications , Aged , Anemia/blood , Anemia/etiology , Cardiovascular Diseases/chemically induced , Darbepoetin alfa/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Hematinics/adverse effects , Hemoglobins/analysis , Humans , Male , Middle Aged , Picolinic Acids/adverse effects , Prolyl-Hydroxylase Inhibitors/adverse effects , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/therapy
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
Anemia/drug therapy , Darbepoetin alfa/therapeutic use , Glycine/analogs & derivatives , Hematinics/therapeutic use , Picolinic Acids/therapeutic use , Prolyl-Hydroxylase Inhibitors/therapeutic use , Renal Insufficiency, Chronic/complications , Administration, Oral , Aged , Anemia/blood , Anemia/etiology , Cardiovascular Diseases/chemically induced , Darbepoetin alfa/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Hematinics/adverse effects , Hemoglobins/analysis , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Picolinic Acids/adverse effects , Prolyl-Hydroxylase Inhibitors/adverse effects , Renal Insufficiency, Chronic/mortality
This study aimed to investigate the effect of the fermented soybean meal on the reproductive performance, oxidative stress and colostrum composition of sows, and the growth performance of their progeny. A total of 44 sows were allotted to four dietary groups (n = 11/group). The dietary groups included the basal diet group (control) and the treatment groups in which soybean meal in the basal diet was replaced with 2%, 4%, and 6% fermented soybean meal, respectively. The experimental diets were fed to the sows from the 78th day of gestation to the 21st day of lactation. Replacing soybean meal in the basal maternal diet with the fermented soybean meal decreased the levels of malondialdehyde, cortisol, and 8-iso-prostaglandinF2α in the serum of sows and increased the average weight of piglets on the 14th day and the 21st day after birth. The activity of superoxide dismutase in the serum of sows was increased in the group with 4% fermented soybean meal on the 17th day of lactation. The levels of estrogen and growth factors in the serum of sows were enhanced in the group with 6% fermented soybean meal. In the colostrum, the levels of the protein and the immunoglobulin G were enhanced in the group with 4% fermented soybean meal. In conclusion, replacing the soybean meal in the basal maternal diet with the fermented soybean meal attenuates the oxidative stress status of the gestational and lactational sows, and enhances the average weight of their offspring.
OBJECTIVES: To explore the efficacy of glucosamine sulfate (GS) combined with loxoprofen sodium (LS) in rats with knee osteoarthritis (KOA) and its effect on chondrocytes. METHODS: We randomly assigned 40 SPF SD rats to normal group (NG), control group (CG), treatment group (TG), and model group (MG). CG and TG were processed with continuous irrigation of LS and GS. NG and MG were given normal saline. We collected 3 mL of venous blood from the rat's lower limb for the detection of serum IL-1ß, IL-6, IL-8, and TNF-α by ELISA. Four weeks after irrigation, 5 rats in each group were randomly selected for anesthesia. The water content was detected, and the chondrocytes were collected. MTT assay was used to detect apoptosis, and Western blot (WB) to measure concentrations of Bax, Bcl-2, Caspase3, Caspase9, TLR4, and NF-kB. RESULTS: The levels of IL-1 ß, IL-6, IL-8, and TNF-α decreased in CG and TG, but increased in MG (P<0.05). After treatment, the expression of inflammatory factors was highest in MG (P<0.05). CONCLUSIONS: GS combined with LS showed good efficacy in rats with knee osteoarthritis, which may be achieved by inhibiting the expression of inflammatory factors and knee chondrocyte apoptosis via the TLR4-NF-kB pathway.
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Apoptosis/drug effects , Chondrocytes/drug effects , Glucosamine/administration & dosage , Osteoarthritis, Knee/drug therapy , Phenylpropionates/administration & dosage , Animals , Apoptosis/physiology , Cells, Cultured , Chondrocytes/pathology , Drug Therapy, Combination , Female , Male , Osteoarthritis, Knee/pathology , Rats , Rats, Sprague-Dawley
Current clinical practice guidelines for anemia management in non-dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (Nâ¯=â¯1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (Nâ¯=â¯1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.
Anemia/drug therapy , Glycine/analogs & derivatives , Picolinic Acids/administration & dosage , Renal Insufficiency, Chronic/complications , Administration, Oral , Aged , Anemia/etiology , Female , Follow-Up Studies , Glycine/administration & dosage , Humans , Male , Middle Aged , Renal Dialysis , Treatment Outcome
Anemia , Erythropoietin , Prolyl-Hydroxylase Inhibitors , Renal Insufficiency, Chronic , Anemia/drug therapy , Epoetin Alfa , Erythropoietin/therapeutic use , Humans , Network Meta-Analysis , Prolyl-Hydroxylase Inhibitors/therapeutic use , Renal Dialysis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy
BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. METHODS: Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36). RESULTS: A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. CONCLUSIONS: The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.
Anemia , Glycine/therapeutic use , Hematinics , Picolinic Acids/therapeutic use , Renal Insufficiency, Chronic , Adult , Anemia/drug therapy , Anemia/etiology , Erythropoietin , Glycine/analogs & derivatives , Hematinics/therapeutic use , Hemoglobins/analysis , Humans , Renal Dialysis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy
The aim of this study is to investigate the effect of the maternal diet with fish oil on the oxidative stress and inflammatory response in sows, and the protective effect on the piglets suckling the sows fed the diet with fish oil in the context of inflammatory stimulation. Twelve sows were divided into two groups. Sows were fed soybean oil diet (SD) or soybean oil + fish oil diet (FD) from gestation to lactation period. The blood samples of sows were collected from the auricular vein at the 16th day of lactation. One piglet was selected from each litter on the 14th day after birth. Lipopolysaccharide (LPS) was injected into the neck muscle after pre-treatment blood samples were collected from the anterior vena cava of piglets. The blood samples of piglets were collected at 5 h and 48 h post-LPS injection from the front cavity vein. Liver samples were collected at 48 h post-LPS injection. The FD diet significantly increased the level of high-density lipoprotein cholesterol (HDL-C) in the plasma of lactating sow, decreased the levels of alkaline phosphatase(AKP) and tumor necrosis factor alpha(TNF-α) in the plasma of lactating sows, and increased the level of immunoglobulin G(IgG) in the colostrum and interleukin-10(IL-10) in the milk (p < 0.05). In the FD group, the levels of glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) significantly increased in the plasma of piglets at 48 h post-LPS injection (p < 0.05). Meanwhile, the relative expression of GSH-Px mRNA was decreased in the FD group (p < 0.05). However, the levels of interleukin-1 beta (IL-1ß) and interleukin-6(IL-6) in the plasma of piglets were significantly higher in the FD group pre- and post-LPS injection (p < 0.05). The ratio of the phosphonated extracellular regulated protein kinases to the extracellular regulated protein kinases (p-ERK/ERK) protein in the livers of piglets was decreased (p < 0.05), but the expression of nuclear transcription factor-κB (NF-κB) mRNA and the ratio of the phosphonated inhibitor of NF-κB to the inhibitor of NF-κB (p-IκB-α/IκB-α) protein was increased in the livers of piglets (p < 0.05). These results indicate that a maternal diet with fish oil might decrease the oxidative stress and inflammatory response in sows, and enhance the antioxidative ability but increase the susceptibility to inflammatory stimulation in their progenies.
