Study Duration Prediction for Clinical Trials with Time-to-Event Endpoints Using Mixture Distributions Accounting for Heterogeneous Population

In the era of precision medicine, more and more clinical trials are now driven or guided by biomarkers, which are patient characteristics objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. With the overarching objective to optimize and personalize disease management, biomarker-guided clinical trials increase the efficiency by appropriately utilizing prognostic or predictive biomarkers in the design. However, the efficiency gain is often not quantitatively compared to the traditional all-comers design, in which a faster enrollment rate is expected (e.g. due to no restriction to biomarker positive patients) potentially leading to a shorter duration. To accurately predict biomarker-guided trial duration, we propose a general framework using mixture distributions accounting for heterogeneous population. Extensive simulations are performed to evaluate the impact of heterogeneous population and the dynamics of biomarker characteristics and disease on the study duration. Several influential parameters including median survival time, enrollment rate, biomarker prevalence and effect size are identitied. Re-assessments of two publicly available trials are conducted to empirically validate the prediction accuracy and to demonstrate the practical utility. The R package \emph{detest} is developed to implement the proposed method and is publicly available on CRAN

Generative Design of Crystal Structures by Point Cloud Representations and Diffusion Model

Efficiently generating energetically stable crystal structures has long been a challenge in material design, primarily due to the immense arrangement of atoms in a crystal lattice. To facilitate the discovery of stable material, we present a framework for the generation of synthesizable materials, leveraging a point cloud representation to encode intricate structural information. At the heart of this framework lies the introduction of a diffusion model as its foundational pillar. To gauge the efficacy of our approach, we employ it to reconstruct input structures from our training datasets, rigorously validating its high reconstruction performance. Furthermore, we demonstrate the profound potential of Point Cloud-Based Crystal Diffusion (PCCD) by generating entirely new materials, emphasizing their synthesizability. Our research stands as a noteworthy contribution to the advancement of materials design and synthesis through the cutting-edge avenue of generative design instead of the conventional substitution or experience-based discovery.Comment: I have submitted to a journa

Dominância fiscal : uma investigação empírica sobre o caso brasileiro no período de 2003 a 2014

A estabilização econômica dos anos de 1990 e a adoção do tripé econômico, a partir de 1999, marcam o fim de um capítulo delicado da história brasileira; a partir de então, era necessária a existência de certa sintonia de políticas monetária e fiscal para a manutenção do controle dos diversos indicadores econômicos. Contudo, com essa reciprocidade na política econômica, são incitadas discussões sobre a orientação do governo na hora de definir suas prioridades nesse campo: as variáveis fiscais são priorizadas e, por conseguinte, determinadas, forçando as monetárias a se ajustarem – ou o contrário? A resposta para esse questionamento leva à discussão sobre a dominância fiscal. Assim, esse trabalho visa verificar empiricamente, usando das modelagens econométricas VAR e estudo de eventos, se há dominância fiscal ou monetária na economia brasileira e se a eficácia da política monetária mudou na transição do governo Lula para o governo Dilma. O resultado foi inconclusivo para o governo Lula e indicou dominância fiscal no governo Dilma. Ainda verificou-se não haver modificação na eficácia da política monetária.Economic stabilization, in the 1990s, and utilization of an economic tripod, after 1999, represents the end of a delicate chapter in Brazilian history. Ever since, it was necessary the existence of a certain agreement between monetary and fiscal politic, in order to maintain under control a variety of economic indicators. However, this reciprocity (in economic politic) starts discussions about the real government orientations when it comes to define its priority on this subject: are the fiscal variables priorized, and then, determined, forcing monetary variables to adjust themselves, or the opposite? The answer to these questions emerge from the fiscal dominance discussion. This paper intends to empiric verify, using econometric modeling VAR and event study, if there is fiscal dominance or monetary in Brazilian economy and whether the effectiveness of monetary politic has changed in the transition from Lula's government to the Dilma government. The result was inconclusive for the Lula government and indicated fiscal dominance in the Dilma government. There was still no change in the efficiency of the monetary politic.CAPE

Role of Electron Correlation along the Water Splitting Reaction

Electron correlation plays a crucial role in the energetics of reactions catalyzed by transition metal complexes, such as water splitting. In the present work we exploit the performance of various methods to describe the thermodynamics of a simple but representative model of water splitting reaction, based on a single cobalt ion as catalyst. Density Functional Theory (DFT) calculations show a significant dependence on the adopted functional, and not negligible differences with respect to CCSD(T) findings are found along the reaction cycle. We performed quantum Monte Carlo calculations using an unrestricted single Slater determinant wave function multiplied by a Jastrow factor using both DFT and fully optimized orbitals. Variational and Lattice Regularized Diffusion Monte Carlo results are in overall agreement with the CCSD(T) free-energy profile, even though differences in the description of the thermodynamics of the reaction cycle are found. NEVPT2 calculations reveal that the role of the static correlation of the different reaction steps is not large, and it is limited to only a few intermediate structures. Finally, the free-energy difference of the overall water splitting reaction computed at the quantum Monte Carlo level shows an excellent match with the experimental value of 4.92 eV, underlining the capability of these techniques to properly describe the dynamical correlation of such reactions

Analysis on the spatiotemporal evolutions of groundwater hydrochemistry and water quality caused by over-extraction and seawater intrusion in eastern coastal China

The over-extraction of groundwater has resulted in seawater intrusion and the southward migration of the saltwater interface, gradually deteriorating the groundwater quality in the Weibei Plain. In this research, groundwater samples were gathered from 46 monitoring wells for shallow groundwater during the years 2006, 2011, 2016, and 2021. The hydrochemical features of regional groundwater and the factors influencing the issue were subjected to statistical analysis. Additionally, the assessment of spatiotemporal variations in groundwater quality was conducted using the customized entropy-weighted water quality index (EWQI) method. The relationship between groundwater over-extraction and the southward intrusion of the saltwater interface was compared and analyzed. The results of this paper revealed that the Weibei Plain has been in a state of long-term over-extraction of groundwater from 2000 to 2021, with an average annual over-extraction of 118.49 million m3. The groundwater depression cone areas in the northern part of the study area increased from 3,247.37 to 4,581.34 km2 from 2006 to 2021, with the center of the cone experiencing a drop in groundwater level from −22 to −85 m. The saltwater interface shifted southward by 711.71 km2 from 2006 to 2021. In groundwater, the high concentrations of TH, TDS, and Cl− were primarily related to the seawater intrusion, while higher concentrations of NO3− were mainly determined by frequent agricultural production, industrial wastewater, and domestic sewage discharges. The groundwater hydrochemical types in the study area transitioned from predominantly HCO3·Ca-Mg type in 2006 to HCO3-Na type and SO4·Cl-Ca·Mg type in 2021 due to seawater intrusion. The results of PCA and HCA show the effects of seawater intrusion, human activities, and rock weathering on groundwater hydrochemistry. The evaluation results based on the EWQI revealed that the average value of the samples in 2021 was 101.36, which belonged to Class IV water quality standards, representing the poorest water quality among the 4 years. The southward migration of the saltwater interface led to the deterioration of groundwater quality in the groundwater depression cone areas, which gradually worsened from 2006 to 2021. The maximum increase in EWQI value was 174.68 during the period, shifting from Class III water quality to Class V water quality. Groundwater quality remained relatively better in the western and southern regions which were less affected or unaffected by seawater intrusion. The results of the study can provide a certain reference value for the sustainable management of groundwater resources and the management of groundwater pollution and seawater intrusion in the Weifang City area in the future

DataSheet1_Analysis on the spatiotemporal evolutions of groundwater hydrochemistry and water quality caused by over-extraction and seawater intrusion in eastern coastal China.xlsx

The over-extraction of groundwater has resulted in seawater intrusion and the southward migration of the saltwater interface, gradually deteriorating the groundwater quality in the Weibei Plain. In this research, groundwater samples were gathered from 46 monitoring wells for shallow groundwater during the years 2006, 2011, 2016, and 2021. The hydrochemical features of regional groundwater and the factors influencing the issue were subjected to statistical analysis. Additionally, the assessment of spatiotemporal variations in groundwater quality was conducted using the customized entropy-weighted water quality index (EWQI) method. The relationship between groundwater over-extraction and the southward intrusion of the saltwater interface was compared and analyzed. The results of this paper revealed that the Weibei Plain has been in a state of long-term over-extraction of groundwater from 2000 to 2021, with an average annual over-extraction of 118.49 million m3. The groundwater depression cone areas in the northern part of the study area increased from 3,247.37 to 4,581.34 km2 from 2006 to 2021, with the center of the cone experiencing a drop in groundwater level from −22 to −85 m. The saltwater interface shifted southward by 711.71 km2 from 2006 to 2021. In groundwater, the high concentrations of TH, TDS, and Cl− were primarily related to the seawater intrusion, while higher concentrations of NO3− were mainly determined by frequent agricultural production, industrial wastewater, and domestic sewage discharges. The groundwater hydrochemical types in the study area transitioned from predominantly HCO3·Ca-Mg type in 2006 to HCO3-Na type and SO4·Cl-Ca·Mg type in 2021 due to seawater intrusion. The results of PCA and HCA show the effects of seawater intrusion, human activities, and rock weathering on groundwater hydrochemistry. The evaluation results based on the EWQI revealed that the average value of the samples in 2021 was 101.36, which belonged to Class IV water quality standards, representing the poorest water quality among the 4 years. The southward migration of the saltwater interface led to the deterioration of groundwater quality in the groundwater depression cone areas, which gradually worsened from 2006 to 2021. The maximum increase in EWQI value was 174.68 during the period, shifting from Class III water quality to Class V water quality. Groundwater quality remained relatively better in the western and southern regions which were less affected or unaffected by seawater intrusion. The results of the study can provide a certain reference value for the sustainable management of groundwater resources and the management of groundwater pollution and seawater intrusion in the Weifang City area in the future.</p

Algorithm Research on Detail and Contrast Enhancement of High Dynamic Infrared Images

Infrared images have the advantages of being employed in all weather conditions and exhibiting strong anti-interference abilities and are widely used in many fields. However, there are also problems of low contrast, high noise and blurred details, for which a high dynamic infrared image enhancement method based on wavelet transform is proposed. First, multi-resolution analysis is performed using wavelet transform, and the image is decomposed into a low-frequency information layer and high-frequency information layer, which are processed separately. The low-frequency information layer is subjected to contrast-constrained adaptive histogram equalisation to improve the contrast. The high-frequency information layer is enhanced with adaptive coefficients, and the gain coefficients are determined using gamma transform, which is designed to increase the applicability. Wavelet inverse transform is performed on the processed image to meet the desired requirements. It is shown that the algorithm can effectively enhance the high dynamic image contrast and improve the image detail information

Transcriptional Regulation of Frizzled-1 in Human Osteoblasts by Sp1.

The wingless pathway has a powerful influence on bone metabolism and is a therapeutic target in skeletal disorders. Wingless signaling is mediated in part through the Frizzled (FZD) receptor family. FZD transcriptional regulation is poorly understood. Herein we tested the hypothesis that Sp1 plays an important role in the transcriptional regulation of FZD1 expression in osteoblasts and osteoblast mineralization. To test this hypothesis, we conducted FZD1 promoter assays in Saos2 cells with and without Sp1 overexpression. We found that Sp1 significantly up-regulates FZD1 promoter activity in Saos2 cells. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift (EMSA) assays identified a novel and functional Sp1 binding site at -44 to -40 from the translation start site in the FZD1 promoter. The Sp1-dependent activation of the FZD1 promoter was abolished by mithramycin A (MMA), an antibiotic affecting both Sp1 binding and Sp1 protein levels in Saos2 cells. Similarly, down-regulation of Sp1 in hFOB cells resulted in less FZD1 expression and lower alkaline phosphatase activity. Moreover, over-expression of Sp1 increased FZD1 expression and Saos2 cell mineralization while MMA decreased Sp1 and FZD1 expression and Saos2 cell mineralization. Knockdown of FZD1 prior to Sp1 overexpression partially abolished Sp1 stimulation of osteoblast differentiation markers. Taken together, our results suggest that Sp1 plays a role in human osteoblast differentiation and mineralization, which is at least partially mediated by Sp1-dependent transactivation of FZD1