Accelerate vaccine development using seamless phase 2/3 trial designs.

BACKGROUND: Traditional vaccine development, often a lengthy and costly process of three separated phases. However, the swift development of COVID-19 vaccines highlighted the critical importance of accelerating the approval of vaccines. This article showcases a seamless phase 2/3 trial design to expedite the development process, particularly for multi-valent vaccines. RESEARCH DESIGN AND METHODS: This study utilizes simulation to compare the performance of seamless phase 2/3 design with that of conventional trial design, specifically by re-envisioning a 9-valent HPV vaccine trial. Across three cases, several key performance metrics are evaluated: overall power, type I error rate, average sample size, trial duration, the percentage of early stop, and the accuracy of dose selection. RESULTS: On average, when the experimental vaccine was assumed to be effective, the seamless design that performed interim analyses based solely on efficacy saved 555.73 subjects, shortened trials by 10.29 months, and increased power by 3.70%. When the experimental vaccine was less effective than control, it saved an average of 887.73 subjects while maintaining the type I error rate below 0.025. CONCLUSION: The seamless design proves to be a compelling strategy for vaccine development, given its versatility in early stopping, re-estimating sample sizes, and shortening trial durations.

Use of the alkaline comet assay for monitoring genotoxic effects of arsenic in human populations.

The alkaline comet assay has been widely used to determine genotoxicity in human populations exposed to arsenic. The sample sizes of earlier studies were usually small, and inconsistent results were found. Meta-analyses can merge the results of multiple studies of the same type and increase the credibility of the conclusion by increasing the sample size. Thus, to investigate the monitoring effect of alkaline comet assay on genotoxicity for arsenic exposed population, meta-analyses were performed. Thirteen studies were found to meet the inclusion criteria and were included in this study; of them, twelve articles were of medium quality (15-20 points), only one study was of high quality (21-27 points). Meta-analyses showed that the overall estimates of Mean Ratio (MR, defined as the mean value of the response in the exposed group divided by that in the reference group) were 2.81(95 % confidence interval (CI) 1.93-4.10); 2.37(95 % CI, 1.73-3.26), and 1.69(95 %CI, 1.29-2.20) for comet tail length, % tail DNA, and tail moment, respectively. This shows that the level of DNA damage in arsenic exposed population is significantly higher than that in control populations. A meta-analysis of the correlation coefficients showed that the overall estimate was 0.52 (95 %CI, 0.48∼0.56, P<0.05) with all correlation coefficients included, but it changed to 0.24 (95 %CI, 0.17∼0.28, P<0.05) when two abnormal correlation coefficients were excluded, suggesting there was a positive correlation between arsenic load in vivo and DNA damage, but the overall estimate value of coefficients was unstable. Therefore, we conclude that the alkaline comet assay can be used as an effective genotoxic biomonitoring tool for arsenic-exposed populations. However, more and higher-quality studies are still needed to verify its actual application value.

[Spatial variability of soil water content in field of Guanzhong Plain, Northwest China]. / å ³ä¸­å¹³åŽŸç”°é—´åœŸå£¤å«æ°´é‡çš„ç©ºé—´å˜å¼‚æ€§.

To clarify the spatial variability of soil water content at field scale, a reasonable sampling method was established to support precision irrigation in the field. Soil samples were collected from Caoxinzhuang experimental area in Yangling District, Shaanxi Province at seven different dates. The spatial variation of soil water content in different soil layers of 0-60 cm were analyzed with classical statistics and geostatistics methods. The results showed that spatial distribution of soil water content in field scale was weak and moderate. When soil water content was within the range of 11.7%-20.1%, soil water content was negatively correlated with spatial variability. Sampling interval signifi-cantly affected the calculation accuracy of the spatial variability of soil water content. The coefficient of variation of soil water content between the east-west direction spacing of 27 m and the north-south direction spacing of 9 m was about 3.3% higher than the east-west direction spacing of 9 m and the north-south direction spacing of 18 m. With increasing sampling density, the contour change of soil water content distribution increased, and the number of grids with the least spatial variability of soil water content at the field scale was 21 points. When the sampling spacing was 18 m in the east-west direction, 9 m in the north-south direction, soil water content at field scale had a high spatial distribution correlation with soil water content in the middle position being 3%-5% higher than the surrounding. Our results provided reference for reasonable sampling of soil water content in the Guanzhong Plain and could guide the precision irrigation in agriculture.

Kaempferol Protects Cell Damage in In Vitro Ischemia Reperfusion Model in Rat Neuronal PC12 Cells.

Ischemic cerebral stroke is a severe neurodegenerative disease with high mortality. Ischemia and reperfusion injury plays a fundamental role in ischemic cerebral stroke. To date, the strategy for ischemic cerebral stroke treatment is limited. In the present study, we aimed to investigate the effect of kaempferol (KFL), a natural flavonol, on cell injury induced by oxygen and glucose deprivation (OGD) and reoxygenation (OGD-reoxygenation) in PC12 cells. We found that KFL inhibited OGD-induced decrease of cell viability and the increase of lactate dehydrogenase (LDH) release. OGD-induced activation of mitochondrial dysfunction, mitochondrial apoptotic pathway, and apoptosis was inhibited by KFL. KFL also reduced OGD-induced oxidative stress in PC12 cells. P66shc expression and acetylation were increased by OGD and KFL inhibited these changes. Upregulation of P66shc suppressed KFL-induced decrease of apoptosis, the decrease of LDH release, and the increase of cell viability. Furthermore, KFL inhibited OGD-induced decrease of sirtuin 1 (SIRT1) expression and downregulation of SIRT1 blocked KFL-induced decrease of apoptosis, the decrease of LDH release, and the increase of cell viability. In summary, we identified that KFL exhibited a beneficial effect against OGD-induced cytotoxicity in an ischemia/reperfusion injury cell model. The findings suggest that KFL may be a promising choice for the intervention of ischemic stroke and highlighted the SIRT1/P66shc signaling.

Micronucleus assay for monitoring the genotoxic effects of arsenic in human populations: A systematic review of the literature and meta-analysis.

The micronucleus (MN) assay has been used to determine the potential genotoxic effects in human populations exposed to arsenic. Some of these studies found an increase in MN frequency among exposed individuals, but others found no increase or inconclusive results. Thus, the main purpose of this current study was to investigate whether MN can be used as a biomarker for the arsenic exposure, as well as whether or not the different cell types that have been used to monitor MN frequency differ in their sensitivity to upon arsenic exposure. A systematic literature review was conducted followed by a meta-analysis. The review identified 25 useful studies with data from 3232 exposed individuals (15 studies assaying lymphocytes, 16 assaying buccal cells, and 9 assaying urothelial cells), with 18 studies measuring drinking water exposure, 5 measuring occupational exposure, one measuring coal burning, and one measuring dietary exposure. The meta-analysis indicated that the overall estimates of Mean Ratio (MR, defined as the mean value of the response in the exposed group divided by the mean value of the response in the reference group) were 2.95 (95% confidence interval (CI): 2.00 to 4.35), 2.36 (95% CI: 1.77 to 3.15), and 2.82 (95% CI: 1.86 to 4.28) for MN assays conducted with lymphocytes, buccal cells, and urothelial cells in the MN assay, respectively. Subgroup analysis showed that when the exposure method was drinking water, the MN frequencies increased significantly in lymphocytes (MR = 3.59, 95% CI: 2.30 to 5.60), in buccal cells (MR = 2.35, 95% CI: 1.76 to 3.15), and in urothelial cells (MR = 3.16, 95% CI: 2.02 to 4.97). However, when the exposure method was the occupational setting or others, the MN detection using the three types of cells did not find significant differences between groups. Subgroup analysis also showed that lymphocyte MN frequencies increased significantly in both routine-culture MN assays (MR = 2.88, 95% CI: 1.15 to 7.24) and cytokinesis-block MN assays (MR = 2.89, 95% CI: 1.84 to 4.55). The performance of the MN assay with different types of cells was also compared, but no significant differences were found. Therefore, our analysis indicates that MN can be used as an effective biomarker for monitoring arsenic-exposed populations, and that MN assays conducted with lymphocytes, buccal cells, and urothelial cells do not differ in their ability to detect the genetic damage from arsenic.

[Spatial distribution of forest carbon storage in Maoershan region, Northeast China based on geographically weighted regression kriging model.] / åŸºäºŽåœ°ç†åŠ æƒå›žå½’å ‹é‡Œæ ¼æ¨¡åž‹çš„å¸½å„¿å±±åœ°åŒºæ£®æž—ç¢³å‚¨é‡ç©ºé—´åˆ†å¸ƒ.

Forest carbon storage has important impacts on climate change. The previous models do not take into consideration of the inherent spatial correlation structure of residual and non-stationary of forest carbon storage which limits the prediction accuracy. Based on ETM+ remotely sensed imagery and 193 fixed plots of Maoershan Experimental Forest Farm of Northeast Forestry University, we established the geographically weighted regression kriging (GWRK) model between forest carbon storage and extracted factors from remotely sensed imagery and topographic factors. The prediction accuracy of GWRK, ordinary least square (OLS) model and geographically weighted regression (GWR) were compared. The results showed that the mean absolute error (MAE) and root mean square error (RMSE) of GWRK were lower than those of OLS and GWR models, while the mean error (ME) of GWRK model was lower than that of GWR model and was close to that of OLS model. The prediction accuracy of GWRK model was 83.2%, which was 6% and 10% higher than that of OLS model (73.7%) and GWR model (77.3%). Therefore, the GWRK model was more effective in estimating forest carbon storage than the others. The mean value of forest carbon storage predicted by GWRK model was 70.31 t·hm-2. The relatively high values presented in high altitude area, indicating that altitude had a great impact on forest carbon storage.

Field implementation of long-distance quantum key distribution over aerial fiber with fast polarization feedback.

Quantum key distribution with polarized qubits has not yet been realized over the aerial fiber, due to rapid polarization changes. Here, we report our recent work towards quantum communication through an aerial fiber channel. We designed a fast polarization feedback module featuring high efficiency, fast speed, and good stability. With this module, we implemented long-distance quantum key distribution over different types of aerial fiber links based on polarization encoding. Our work takes a significant step towards the application of quantum communications in complex environments.

Identification of novel biomarker and therapeutic target candidates for acute intracerebral hemorrhage by quantitative plasma proteomics.

BACKGROUND: The systematic mechanisms of acute intracerebral hemorrhage are still unknown and unverified, although many recent researches have indicated the secondary insults. This study was aimed to disclose the pathological mechanism and identify novel biomarker and therapeutic target candidates by plasma proteome. METHODS: Patients with AICH (n = 8) who demographically matched healthy controls (n = 4) were prospectively enrolled, and their plasma samples were obtained. The TMT-LC-MS/MS-based proteomics approach was used to quantify the differential proteome across plasma samples, and the results were analyzed by Ingenuity Pathway Analysis to explore canonical pathways and the relationship involved in the uploaded data. RESULTS: Compared with healthy controls, there were 31 differentially expressed proteins in the ICH group (P < 0.05), of which 21 proteins increased while 10 proteins decreased in abundance. These proteins are involved in 21 canonical pathways. One network with high confidence level was selected by the function network analysis, in which 23 proteins, P38MAPK and NFκB signaling pathways participated. Upstream regulator analysis found two regulators, IL6 and TNF, with an activation z-score. Seven biomarker candidates: APCS, FGB, LBP, MGMT, IGFBP2, LYZ, and APOA4 were found. Six candidate proteins were selected to assess the validity of the results by subsequent Western blotting analysis. CONCLUSION: Our analysis provided several intriguing pathways involved in ICH, like LXR/RXR activation, acute phase response signaling, and production of NO and ROS in macrophages pathways. The three upstream regulators: IL-6, TNF, LPS, and seven biomarker candidates: APCS, APOA4, FGB, IGFBP2, LBP, LYZ, and MGMT were uncovered. LPS, APOA4, IGFBP2, LBP, LYZ, and MGMT are novel potential biomarkers in ICH development. The identified proteins and pathways provide new perspectives to the potential pathological mechanism and therapeutic targets underlying ICH.

[Spatial point pattern analysis of main trees and flowering Fargesia qinlingensis in Abies fargesii forests in Mt Taibai of the Qinling Mountains, China]. / å¤ªç™½å±±å·´å±±å†·æ‰æž—ä¸»è¦æ ‘ç§ä¸Žå¼€èŠ±ç§¦å²­ç®­ç«¹çš„ç©ºé—´ç‚¹æ ¼å±€åˆ†æž.

In Abies fargesii forests of the giant panda's habitats in Mt. Taibai, the spatial distribution patterns and interspecific associations of main tree species and their spatial associations with the understory flowering Fargesia qinlingensis were analyzed at multiple scales by univariate and bivaria-te O-ring function in point pattern analysis. The results showed that in the A. fargesii forest, the number of A. fargesii was largest but its population structure was in decline. The population of Betula platyphylla was relatively young, with a stable population structure, while the population of B. albo-sinensis declined. The three populations showed aggregated distributions at small scales and gradually showed random distributions with increasing spatial scales. Spatial associations among tree species were mainly showed at small scales and gradually became not spatially associated with increasing scale. A. fargesii and B. platyphylla were positively associated with flowering F. qinlingensis at large and medium scales, whereas B. albo-sinensis showed negatively associated with flowering F. qinlingensis at large and medium scales. The interaction between trees and F. qinlingensis in the habitats of giant panda promoted the dynamic succession and development of forests, which changed the environment of giant panda's habitats in Qinling.

[The Real World Study on Evaluating the Effect of Chinese Medicine Combined Western Medicine in Treating Rheumatoid Arthritis].

Objective To observe the curative effect of Chinese medicine (CM) combined West- ern medicine (WM) in treating rheumatoid arthritis (RA) patients. Methods Totally 351 RA patients were allocated into two groups by their willingness, 52 cases in the control group and 299 cases in the combination group. Treatment of WM mainly included non-steroidal anti-inflammatory drugs, glucocorti- coids, and anti-rheumatic drugs. And treatment based on syndrome differentiation of CM was adopted. Four diagnostic information of CM, joint pain, tenderness, swelling index, laboratory indices, and treat- ment expenses were observed. Disease activity score 28 (DAS28) , quality of life score [health assessment questionnaire (HAQ) ] , and efficacy of disease were assessed. Results After 2-3 months of treatment, the total effective rate was higher in the combination group than in the control group (P < 0. 05). After 6-12 months of treatment, the total effective rate, DAS28, and HAQ score were better in the combination group than in the control group (P <0. 05). There was no statistical difference in use of Western drugs, total expenses of hospitalization, total expenses of outpatient service between the two groups (P >0. 05). Patients who were treated by combined treatment, or having higher DAS obtained better effects after 2-3 months of treatment (P <0. 05). Patients who were treated by combined treatment, or having lower DAS obtained better effects after 6-12 months of treatment (P <0. 05). Conclusions Real world study (RWS) observed that combined CM and WM could get more significant effect. It also could effectively reduce disease activity, improve patients' QOL, with no economic burdens added.

[The effective parts of liangxue tongyu prescription on cooling-blood and activating-blood and analysis of chemical constituents by HPLC-MS and GC-MS].

In order to clarify material basis of effective parts of liangxue tongyu prescription, blood-heat and blood-stasis rat model induced by dry yeast was established. The changes of rectal temperature, blood viscosity and plasma viscosity were used to evaluate the cooling-blood and activating-blood effects of liangxue tongyu prescription and its parts. Compared with the model group, the extract from liangxue tongyu prescription, its volatile oil and n-butanol part could significantly reduce rectal temperature (P<0.01), and also reduce blood viscosity and plasma viscosity to various degrees (P<0.01 or P<0.05). So volatile oil and n-butanol part were primarily identified as effective parts of liangxue tongyu prescription. By using GC-MS with normalization method of area to analyze volatile oil of liangxue tongyu prescription, 70 compounds were identified, accounting for about 92.54%, mainly as ß-asarone, paeonol, α-asarone and shyobunone. 42 compounds such as peony glycosides, tannins, and iridoid glycosides were identified by HPLC-MS techniques and standard comparison. The study determined the effective parts of liangxue tongyu prescription and clarified the chemical composition providing the foundation for further studies on material basis of liangxue tongyu prescription.

[Experiences of Professor Zhou Zhong-ying in diagnosing and treating rheumatoid arthritis by data mining].

OBJECTIVE: To summarize Professor ZHOU Zhong-ying's academic ideas and clinical experiences in diagnosing and treating rheumatoid arthritis (RA). METHODS: Totally 153 clinical case reports were recruited. Data mining techniques like frequencies, factor analysis, and association analysis were used in order to find out laws of syndrome, pathogenesis, treatment methods, formulae and medication. RESULTS: By statistical analyses, we found 14 main symptoms, 76 commonly used clinical drugs, 8 core prescriptions for RA, and the correlation between main pathogeneses and related drugs. CONCLUSION: Results analyzed and summarized from mining his experiences in RA treatment were in line with clinical practice.

Systematic review and meta-analysis of randomized controlled trials comparing botulinum toxin injection with lateral internal sphincterotomy for chronic anal fissure.

OBJECTIVE: The aim of this review is to systematically analyze the prospective randomized controlled trials on the efficacy of botulinum toxin injection (Botox) vs. lateral internal sphincterotomy (LIS) for the treatment of chronic anal fissure (CAF). MATERIALS AND METHODS: A systematic review of the literature was undertaken. The prospective randomized controlled trials on the effectiveness of Botox vs. LIS for the management of CAF were selected according to specific criteria and analyzed to generate pooling data. RESULTS: Four studies encompassing 279 patients were qualified for the meta-analysis. There was a statistically significant higher healing in LIS group compared with Botox group (RR 1.31[1.57, 1.50] 95% CI, z = 4.11, p < 0.0001). Absolute benefit increase rate (ABI) is 23% for LIS group compared with Botox group. The recurrence rate was statistically significantly higher in Botox groups than in LIS groups (RR 5.83[2.96, 11.49] 95% CI, z = 5.09, p < 0.00001).LIS was associated with a high rate of minor anal incontinence as compared to Botox (RR 0.08[0.01, 0.59] 95% CI, z = 2.47, p = 0.01). CONCLUSION: Botulinum toxin injection was associated with a higher rate of recurrent disease. LIS was more effective in healing chronic anal fissure.

Randomized and controlled clinical study of modified prescriptions of Simiao Pill in the treatment of acute gouty arthritis.

OBJECTIVE: To investigate the compatibility of a modified prescription of Simiao Pill in the treatment of acute gouty arthritis and to verify the clinical efficacy and safety of the drug through a clinical trial. METHODS: A randomized and controlled clinical trial was designed based on clinical epidemiological principles. A total of 107 patients with acute gouty arthritis were enrolled and randomly assigned to four groups. The first group (Group I) included 27 patients taking gout prescription I; the second group (Group II) included 27 patients taking gout prescription II; the third group (Group III) included 28 patients taking gout prescription III; and the fourth group (control group) included 25 patients taking indomethacin and Benzobromarone as a control group. The duration of the treatment in all 4 groups was two weeks. After the treatment, the index of blood uric acid, blood leukocyte count, score of clinical symptoms, etc. were observed and measured. RESULTS: The total clinical effective rate of the three different modified prescriptions of the Simiao Pill was above 96%, significantly superior to that of the control group (68%, P<0.05). In terms of the improvement of main symptoms, the scores of four symptoms in all TCM treatment and control groups decreased after treatment, with statistically significant differences (P<0.05). Moreover, the scores markedly fell more so in the three Chinese herb groups than in the control group, and especially in Group III (P<0.05). There was a statistically significant difference in blood uric acid values before and after the treatment in the same group but no significant inter-group difference was seen. CONCLUSION: The modified prescriptions, based on the clinical research, clinical experience and traditional Chinese medicine theory, did show a better effect than Western medicine in this clinical study. Moreover, the prescriptions were precise, with the herbs inexpensive and readily available. The patients had good compliance with less adverse reactions noted. The modified prescription has a favorable prospect for future development and is worthy of further blind trials with larger samples.

The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent.

Hypoxia (low-oxygen tension) is an important physiological stress that influences responses to a wide range of pathologies, including stroke, infarction, and tumorigenesis. Prolonged or chronic hypoxia stimulates expression of the stress-inducible transcription factor gene c-jun and transient activation of protein kinase and phosphatase activities that regulate c-Jun/AP-1 activity. Here we describe evidence obtained by using wild-type and HIF-1 alpha nullizygous mouse embryonic fibroblasts (mEFs) that the induction of c-jun mRNA expression and c-Jun phosphorylation by prolonged hypoxia are completely dependent on the presence of the oxygen-regulated transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha). In contrast, transient hypoxia induced c-jun expression in both types of mEFs, showing that the early or rapid induction of this gene is independent of HIF-1 alpha. These findings indicate that the c-jun gene has a biphasic response to hypoxia consisting of inductions that depend on the degree or duration of exposure. To more completely define the relationship between prolonged hypoxia and c-Jun phosphorylation, we used mEFs from mice containing inactivating mutations of critical phosphorylation sites in the c-Jun N-terminal region (serines 63 and 73 or threonines 91 and 93). Exposure of these mEFs to prolonged hypoxia demonstrated an absolute requirement for N-terminal sites for HIF-1 alpha-dependent phosphorylation of c-Jun. Taken together, these findings suggest that c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in pathophysiological microenvironments.