Comparative Study on the Policy of Multiplicity Issues in Clinical Trials at Home and Abroad

Objective To study the content of China’s guiding principles on multiplicity issues in clinical trials,and to provide reference for the revision of China’s relevant guiding principles.Methods Based on ICH E9,the similarities and differences of the guiding principles of US Food and Drug Administration(FDA),European Medicines Agency(EMA),and National Medical Products Administration(NMPA)on the multiplicity issues in clinical trials were compared one by one.Results and Conclusion In general,NMPA guidelines are based on ICH E9,but in detail,the guidelines of FDA and EMA focus differently on the multiplicity issues.Therefore,NMPA guidelines need to be detailed and comprehensive.NMPA guidelines can be refined by referring to foreign guidelines to improve the practical guiding significance for clinical research and promote the level of domestic clinical trials in line with international standards.

Semi-analytical steady-state response prediction for multi-dimensional quasi-Hamiltonian systems

The majority of nonlinear stochastic systems can be expressed as the quasi-Hamiltonian systems in science and engineering. Moreover, the corresponding Hamiltonian system offers two concepts of integrability and resonance that can fully describe the global relationship among the degrees-of-freedom(DOFs) of the system. In this work, an effective and promising approximate semi-analytical method is proposed for the steady-state response of multi-dimensional quasi-Hamiltonian systems. To be specific, the trial solution of the reduced Fokker–Plank–Kolmogorov(FPK) equation is obtained by using radial basis function(RBF) neural networks. Then, the residual generated by substituting the trial solution into the reduced FPK equation is considered, and a loss function is constructed by combining random sampling technique. The unknown weight coefficients are optimized by minimizing the loss function through the Lagrange multiplier method. Moreover, an efficient sampling strategy is employed to promote the implementation of algorithms. Finally, two numerical examples are studied in detail, and all the semi-analytical solutions are compared with Monte Carlo simulations(MCS) results. The results indicate that the complex nonlinear dynamic features of the system response can be captured through the proposed scheme accurately.

Gut flora in multiple sclerosis:implications for pathogenesis and treatment

Multiple sclerosis is an inflammatory disorder chara cterized by inflammation,demyelination,and neurodegeneration in the central nervous system.Although current first-line therapies can help manage symptoms and slow down disease progression,there is no cure for multiple sclerosis.The gut-brain axis refers to complex communications between the gut flo ra and the immune,nervous,and endocrine systems,which bridges the functions of the gut and the brain.Disruptions in the gut flora,termed dys biosis,can lead to systemic inflammation,leaky gut syndrome,and increased susceptibility to infections.The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors,and gut flora may play a pivotal role in regulating immune responses related to multiple scle rosis.To develop more effective therapies for multiple scle rosis,we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis.This review provides an overview of the role of the gut flora in multiple scle rosis.

A Posteriori Stabilized Sixth-Order Finite Volume Scheme with Adaptive Stencil Construction:Basics for the 1D Steady-State Hyperbolic Equations

We propose an adaptive stencil construction for high-order accurate finite volume schemes a posteriori stabilized devoted to solve one-dimensional steady-state hyperbolic equations.High accuracy(up to the sixth-order presently)is achieved,thanks to polynomial recon-structions while stability is provided with an a posteriori MOOD method which controls the cell polynomial degree for eliminating non-physical oscillations in the vicinity of dis-continuities.We supplemented this scheme with a stencil construction allowing to reduce even further the numerical dissipation.The stencil is shifted away from troubles(shocks,discontinuities,etc.)leading to less oscillating polynomial reconstructions.Experimented on linear,Burgers',and Euler equations,we demonstrate that the adaptive stencil technique manages to retrieve smooth solutions with optimal order of accuracy but also irregular ones without spurious oscillations.Moreover,we numerically show that the approach allows to reduce the dissipation still maintaining the essentially non-oscillatory behavior.

A Review on Vibration Control of Multiple Cylinders Subjected to FlowInduced Vibrations

The fatigue damage caused by flow-induced vibration(FIV)is one of the major concerns for multiple cylindrical structures in many engineering applications.The FIV suppression is of great importance for the security of many cylindrical structures.Many active and passive control methods have been employed for the vibration suppression of an isolated cylinder undergoing vortex-induced vibrations(VIV).The FIV suppression methods are mainly extended to the multiple cylinders from the vibration control of the isolated cylinder.Due to the mutual interference between the multiple cylinders,the FIV mechanism is more complex than the VIV mechanism,which makes a great challenge for the FIV suppression.Some efforts have been devoted to vibration suppression of multiple cylinder systems undergoing FIV over the past two decades.The control methods,such as helical strakes,splitter plates,control rods and flexible sheets,are not always effective,depending on many influence factors,such as the spacing ratio,the arrangement geometrical shape,the flow velocity and the parameters of the vibration control devices.The FIV response,hydrodynamic features and wake patterns of the multiple cylinders equipped with vibration control devices are reviewed and summarized.The FIV suppression efficiency of the vibration control methods are analyzed and compared considering different influence factors.Further research on the FIV suppression of multiple cylinders is suggested to provide insight for the development of FIV control methods and promote engineering applications of FIV control methods.

Cycle Multiplicity of Total Graph of Complete Bipartite Graph

Cycle multiplicity of a graph G is the maximum number of edge disjoint cycles in G. In this paper, we determine the cycle multiplicity of and then obtain the formula of cycle multiplicity of total graph of complete bipartite graph, this generalizes the result for, which is given by M.M. Akbar Ali in [1].

Secondary steady-state and time-periodic flows from a basic flow with square array of odd number of vortices

In a magnetohydrodynamic(MHD)driven fluid cell,a plane non-parallel flow in a square domain satisfying a free-slip boundary condition is examined.The energy dissipation of the flow is controlled by the viscosity and linear friction.The latter arises from the influence of the Hartmann bottom boundary layer in a three-dimensional(3D)MHD experiment in a square bottomed cell.The basic flow in this fluid system is a square eddy flow exhibiting a network of N~2 vortices rotating alternately in clockwise and anticlockwise directions.When N is odd,the instability of the flow gives rise to secondary steady-state flows and secondary time-periodic flows,exhibiting similar characteristics to those observed when N=3.For this reason,this study focuses on the instability of the square eddy flow of nine vortices.It is shown that there exist eight bi-critical values corresponding to the existence of eight neutral eigenfunction spaces.Especially,there exist non-real neutral eigenfunctions,which produce secondary time-periodic flows exhibiting vortices merging in an oscillatory manner.This Hopf bifurcation phenomenon has not been observed in earlier investigations.

THE EXISTENCE AND MULTIPLICITY OF k-CONVEX SOLUTIONS FOR A COUPLED k-HESSIAN SYSTEM

In this paper,we focus on the following coupled system of k-Hessian equations:{S_(k)(λ(D^(2)u))=f_(1)(|x|,-v)in B,S_(k)(λ(D^(2)v))=f2(|x|,-u)in B,u=v=0 on■B.Here B is a unit ball with center 0 and fi(i=1,2)are continuous and nonnegative functions.By introducing some new growth conditions on the nonlinearities f_(1) and f_(2),which are more flexible than the existing conditions for the k-Hessian systems(equations),several new existence and multiplicity results for k-convex solutions for this kind of problem are obtained.

High-Intensity Interval Training v/s Steady-State Cardio in Rehabilitation of Neurological Patients

Neuropathy is nerve damage that can cause chronic neuropathic pain, which is challenging to cure and has a significant financial burden. Exercise therapies, including High-Intensity Interval Training (HIIT) and steady-state cardio, are being explored as potential treatments for neuropathic pain. This systematic review compares the effectiveness of HIIT and steady-state cardio for improving function in neurological patients. This article provides an overview of the systematic review conducted on the effects of exercise on neuropathic patients, with a focus on high-intensity interval training (HIIT) and steady-state cardio. The authors conducted a comprehensive search of various databases, identified relevant studies based on predetermined inclusion criteria, and used the EPPI automation application to process the data. The final selection of studies was based on validity and relevance, with redundant articles removed. The article reviews four studies that compare high-intensity interval training (HIIT) to moderate-intensity continuous training (MICT) on various health outcomes. The studies found that HIIT can improve aerobic fitness, cerebral blood flow, and brain function in stroke patients;lower diastolic blood pressure more than MICT and improve insulin sensitivity and skeletal muscle mitochondrial content in obese individuals, potentially helping with the prevention and management of type 2 diabetes. In people with multiple sclerosis, acute exercise can decrease the plasma neurofilament light chain while increasing the flow of the kynurenine pathway. The available clinical and preclinical data suggest that further study on high-intensity interval training (HIIT) and its potential to alleviate neuropathic pain is justified. Randomized controlled trials are needed to investigate the type, intensity, frequency, and duration of exercise, which could lead to consensus and specific HIIT-based advice for patients with neuropathies.

The Extended Hybrid Carrier-Based Multiple Access Technology for High Mobility Scenarios

The hybrid carrier(HC)system rooted in the carrier fusion concept is gradually garnering attention.In this paper,we study the extended hybrid carrier(EHC)multiple access scheme to ensure reliable wireless communication.By employing the EHC modulation,a power layered multiplexing framework is realized,which exhibits enhanced interference suppression capability owing to the more uniform energy distribution design.The implementation method and advantage mechanism are explicated respectively for the uplink and downlink,and the performance analysis under varying channel conditions is provided.In addition,considering the connectivity demand,we explore the non-orthogonal multiple access(NOMA)method of the EHC system and develop the EHC sparse code multiple access scheme.The proposed scheme melds the energy spread superiority of EHC with the access capacity of NOMA,facilitating superior support for massive connectivity in high mobility environments.Simulation results have verified the feasibility and advantages of the proposed scheme.Compared with existing HC multiple access schemes,the proposed scheme exhibits robust bit error rate performance and can better guarantee multiple access performance in complex scenarios of nextgeneration communications.

The Cumulative Method for Multiplication and Division

This paper provides a method of the process of computation called the cumulative method, it is based upon repeated cumulative process. The cumulative method is being adapted to the purposes of computation, particularly multiplication and division. The operations of multiplication and division are represented by algebraic formulas. An advantage of the method is that the cumulative process can be performed on decimal numbers. The present paper aims to establish a basic and useful formula valid for the two fundamental arithmetic operations of multiplication and division. The new cumulative method proved to be more flexible and made it possible to extend the multiplication and division based on repeated addition/subtraction to decimal numbers.

Multiple factors influencing high-purity indium electrolytic refining

The effects of various contaminants in the electrolytic refinement of indium were investigated using a glow discharge mass spectrometer(GDMS).The effects of several factors such as the indium ion(In3+)concentration,the sodium chloride(NaCl)concentration,the current density,the gelatin concentration,the pH,and the electrode distance,were examined.Significant variations in impurity levels concerning gelatin concentration were observed.Both the gelatin and In3+concentration were moderately positively correlated with the Pb content.The Sb concentration was associated positively with the NaCl concentration,while the Ti concentration had an adverse correlation with the NaCl concentration.The Bi element content was positively linked to the electrode distance.As the current density increased,Cu,Pb,and Bi impurities initially rose and then eventually declined.Notably,a critical current density of 45 A·m^(-2) was identified in this behavior.

Clinical features and possible pathogenesis of multiple evanescent white dot syndrome with different retinal diseases and events:a narrative review

●Multiple evanescent white dot syndrome(MEWDS)is a rare fundus disease,characterized by acute vision loss and visual field defects.Many previous studies have explained the possible pathogenesis and clinical features of primary MEWDS.However,as the number of reported cases increases,secondary MEWDS occurs in other related retinal diseases and injuries,exhibiting some special characteristics.The associated retinal diseases include multifocal choroiditis/punctate inner choroidopathy(MFC/PIC),acute zonal occult outer retinopathy,best vitelliform macular dystrophy,pseudoxanthoma elasticum,and ocular toxoplasmosis.The related retinal injury is laser photocoagulation,surgery,and trauma.Although primary MEWDS often have a self-limiting course,secondary MEWDS may require treatment in some cases,according to the severity of concomitant diseases and complications.Notably,MEWDS secondary to MFC/PIC that is prone to forming choroidal neovascularization and focal choroidal excavation,needs positive treatment with corticosteroids.The possible underlying pathogenesis of secondary MEWDS is the exposure of choroidal antigen after the disruption of Bruch’s membrane.The MEWDS-related features in secondary MEWDS are still evanescent under most circumstances.Its prognosis and treatment depend on the severity of complications.Current studies propose that the etiology is associated with immune factors,including viral infection,inflammation in choroid and Bruch’s membrane,and antigen exposure caused by retinal and/or choroidal insults.More pathogenic studies should be conducted in the future.Accurate diagnosis for secondary MEWDS could benefit patients in aspects of management and prognosis.

Three-dimensional magnetic reconnection in complex multiple X-point configurations in an ancient solar-lunar terrestrial system

Magnetic reconnection processes in three-dimensional(3D)complex field configurations have been investigated in different magneto-plasma systems in space,laboratory,and astrophysical systems.Two-dimensional(2D)features of magnetic reconnection have been well developed and applied successfully to systems with symmetrical property,such as toroidal fusion plasmas and laboratory experiments with an axial symmetry.But in asymmetric systems,the 3D features are inevitably different from those in the 2D case.Magnetic reconnection structures in multiple celestial body systems,particularly star-planet-Moon systems,bring fresh insights to the understanding of the 3D geometry of reconnection.Thus,we take magnetic reconnection in an ancient solar-lunar terrestrial magneto-plasma system as an example by using its crucial parameters approximately estimated already and also some specific applications in pathways for energy and matter transports among Earth,ancient Moon,and the interplanetary magnetic field(IMF).Then,magnetic reconnection of the ancient lunar-terrestrial magnetospheres with the IMF is investigated numerically in this work.In a 3D simulation for the Earth-Moon-IMF system,topological features of complex magnetic reconnection configurations and dynamical characteristics of magnetic reconnection processes are studied.It is found that a coupled lunar-terrestrial magnetosphere is formed,and under various IMF orientations,multiple X-points emerge at distinct locations,showing three typical magnetic reconnection structures in such a geometry,i.e.,the X-line,the triple current sheets,and the A-B null pairs.The results can conduce to further understanding of reconnection physics in 3D for plasmas in complex magnetic configurations,and also a possible mechanism for energy and matters transport in evolutions of similar astrophysical systems.

Infection in Multiple Myeloma: Microbiological Profile and Prognosis in Senegalese Patients

Introduction: Infections are additional factors of morbidity and mortality in multiple myeloma (MM), and the current recommendation is antibiotic prophylaxis. In sub-Saharan Africa, few data on infectious complications of MM are available. We aim to describe the microbiological features of infections in MM, and their impact on survival in Senegalese patients. Methods: A retrospective (January 2005-January 2022), analytic, multicenter study on infections in patients followed for MM (IMWG criteria) in Senegalese clinical hematology services. The socio-epidemiological, diagnostic, microbiological, evolutionary and survival aspects were analyzed. Results: The study included 106 patients with multiple myeloma who had an infection at admission or during the treatment. Ten patients have the comorbidity (hypertension, lupus, type 2 diabetes). These patients had 136 infectious events identified at diagnosis (79.2%) or during chemotherapy (20.8%). The sites of infection are lung (42.6%), urinary (29.4%), dermatological (6.6%), digestive (5.2%), osteoarticular (4.4%), ear, nose and throat (3.7%), central nervous system (1.5%), or without site. We recorded 26.4% of patients with multi-site infections. The causal pathogens are bacteria (Gram-negative bacilli: 22.1%;Gram positive bacilli: 9.5%, Mycobacterium tuberculosis: 13.3%), parasitique (plasmodium falciparum 6.6%), viruses (SARS-COV2: 2.9%, VZV: 2.2%) and fungal (2.9%). Survival was reduced in patients who had an infection at the time of multiple myeloma diagnosis (p: 0.189) and those who had multiple infectious foci (p: 0.011). Conclusion: Infections in multiple myeloma are more frequent at diagnosis. The germs are varied and mostly bacteria, particularly gram-negative bacteria, and Kochs bacillus. Our study reveals that multiple infectious foci are a poor prognosis factor. It is necessary to evaluate the infectious risk early, and to adopt an antibiotic prophylaxis based on our tropical environment.

MULTIPLE INTERSECTIONS OF SPACE-TIME ANISOTROPIC GAUSSIAN FIELDS

Let X={X(t)∈R^(d),t∈R^(N)}be a centered space-time anisotropic Gaussian field with indices H=(H_(1),…,H_(N))∈(0,1)~N,where the components X_(i)(i=1,…,d)of X are independent,and the canonical metric√(E(X_(i)(t)-X_(i)(s))^(2))^(1/2)(i=1,…,d)is commensurate with■for s=(s_(1),…,s_(N)),t=(t_(1),…,t_(N))∈R~N,α_(i)∈(0,1],and with the continuous functionγ(·)satisfying certain conditions.First,the upper and lower bounds of the hitting probabilities of X can be derived from the corresponding generalized Hausdorff measure and capacity,which are based on the kernel functions depending explicitly onγ(·).Furthermore,the multiple intersections of the sample paths of two independent centered space-time anisotropic Gaussian fields with different distributions are considered.Our results extend the corresponding results for anisotropic Gaussian fields to a large class of space-time anisotropic Gaussian fields.

Development of a cell adhesion-based prognostic model for multiple myeloma:Insights into chemotherapy response and potential reversal of adhesion effects

Multiple myeloma(MM)is a hematologic malignancy notorious for its high relapse rate and development of drug resistance,in which cell adhesion-mediated drug resistance plays a critical role.This study integrated four RNA sequencing datasets(CoMMpass,GSE136337,GSE9782,and GSE2658)and focused on analyzing 1706 adhesionrelated genes.Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes,including KIF14,TROAP,FLNA,MSN,LGALS1,PECAM1,and ALCAM,which demonstrated the strongest associations with poor overall survival(OS)in MM patients.To comprehensively evaluate the impact of cell adhesion on MM prognosis,an adhesion-related risk score(ARRS)model was constructed using Lasso Cox regression analysis.The ARRS model emerged as an independent prognostic factor for predicting OS.Furthermore,our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs,protein kinase inhibitors,and drugs targeting the PI3K/Akt/mTOR signaling pathway.Nevertheless,we identified promising drug candidates,such as tirofiban,pirenzepine,erlotinib,and bosutinib,which exhibit potential in reversing this resistance.In vitro,experiments employing NCIH929,RPMI8226,and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs.By employing siRNA-mediated knockdown of the key ARRS model gene KIF14,we observed suppressed proliferation of NCIH929 cells,along with decreased adhesion to BMSCs and fibronectin.This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM.Additionally,potential molecular mechanisms underlying adhesion-related resistance are proposed,along with viable strategies to overcome such resistance.These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

Multiple Matching Attenuation Based on Curvelet Domain Extended Filtering

The paper develops a multiple matching attenuation method based on extended filtering in the curvelet domain,which combines the traditional Wiener filtering method with the matching attenuation method in curvelet domain.Firstly,the method uses the predicted multiple data to generate the Hilbert transform records,time derivative records and time derivative records of Hilbert transform.Then,the above records are transformed into the curvelet domain and multiple matching attenuation based on least squares extended filtering is performed.Finally,the attenuation results are transformed back into the time-space domain.Tests on the model data and field data show that the method proposed in the paper effectively suppress the multiples while preserving the primaries well.Furthermore,it has higher accuracy in eliminating multiple reflections,which is more suitable for the multiple attenuation tasks in the areas with complex structures compared to the time-space domain extended filtering method and the conventional curvelet transform method.

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Linear paired electrolysis of furfural to furoic acid at both anode and cathode in a multiple redox mediated system

Implementing a new energy-saving electrochemical synthesis system with high commercial value is a strategy of the sustainable development for upgrading the bulk chemicals preparation technology in the future.Here,we report a multiple redox-mediated linear paired electrolysis system,combining the hydrogen peroxide mediated cathode process with the I2 mediated anode process,and realize the conversion of furfural to furoic acid in both side of the dividedflow cell simultaneously.By reasonably controlling the cathode potential,the undesired water splitting reaction and furfural reduction side reactions are avoided.Under the galvanostatic electrolysis,the two-mediated electrode processes have good compatibility,which reduce the energy consumption by about 22%while improving the electronic efficiency by about 125%.This system provides a green electrochemical synthesis route with commercial prospects.