Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

Relaxed Stability Criteria for Time-Delay Systems:A Novel Quadratic Function Convex Approximation Approach

This paper develops a quadratic function convex approximation approach to deal with the negative definite problem of the quadratic function induced by stability analysis of linear systems with time-varying delays.By introducing two adjustable parameters and two free variables,a novel convex function greater than or equal to the quadratic function is constructed,regardless of the sign of the coefficient in the quadratic term.The developed lemma can also be degenerated into the existing quadratic function negative-determination(QFND)lemma and relaxed QFND lemma respectively,by setting two adjustable parameters and two free variables as some particular values.Moreover,for a linear system with time-varying delays,a relaxed stability criterion is established via our developed lemma,together with the quivalent reciprocal combination technique and the Bessel-Legendre inequality.As a result,the conservatism can be reduced via the proposed approach in the context of constructing Lyapunov-Krasovskii functionals for the stability analysis of linear time-varying delay systems.Finally,the superiority of our results is illustrated through three numerical examples.

Evolutionary Safe Padé Approximation Scheme for Dynamical Study of Nonlinear Cervical Human Papilloma Virus Infection Model

This study proposes a structure-preserving evolutionary framework to find a semi-analytical approximate solution for a nonlinear cervical cancer epidemic(CCE)model.The underlying CCE model lacks a closed-form exact solution.Numerical solutions obtained through traditional finite difference schemes do not ensure the preservation of the model’s necessary properties,such as positivity,boundedness,and feasibility.Therefore,the development of structure-preserving semi-analytical approaches is always necessary.This research introduces an intelligently supervised computational paradigm to solve the underlying CCE model’s physical properties by formulating an equivalent unconstrained optimization problem.Singularity-free safe Padérational functions approximate the mathematical shape of state variables,while the model’s physical requirements are treated as problem constraints.The primary model of the governing differential equations is imposed to minimize the error between approximate solutions.An evolutionary algorithm,the Genetic Algorithm with Multi-Parent Crossover(GA-MPC),executes the optimization task.The resulting method is the Evolutionary Safe PadéApproximation(ESPA)scheme.The proof of unconditional convergence of the ESPA scheme on the CCE model is supported by numerical simulations.The performance of the ESPA scheme on the CCE model is thoroughly investigated by considering various orders of non-singular Padéapproximants.

Determining Hubbard U of VO_(2) by the quasi-harmonic approximation

Vanadium dioxide VO_(2) is a strongly correlated material that undergoes a metal-to-insulator transition around 340 K.In order to describe the electron correlation effects in VO_(2), the DFT+U method is commonly employed in calculations.However, the choice of the Hubbard U parameter has been a subject of debate and its value has been reported over a wide range. In this paper, taking focus on the phase transition behavior of VO_(2), the Hubbard U parameter for vanadium oxide is determined by using the quasi-harmonic approximation(QHA). First-principles calculations demonstrate that the phase transition temperature can be modulated by varying the U values. The phase transition temperature can be well reproduced by the calculations using the Perdew–Burke–Ernzerhof functional combined with the U parameter of 1.5eV. Additionally,the calculated band structure, insulating or metallic properties, and phonon dispersion with this U value are in line with experimental observations. By employing the QHA to determine the Hubbard U parameter, this study provides valuable insights into the phase transition behavior of VO_(2). The findings highlight the importance of electron correlation effects in accurately describing the properties of this material. The agreement between the calculated results and experimental observations further validates the chosen U value and supports the use of the DFT+U method in studying VO_(2).

Saddlepoint Approximation Method in Reliability Analysis:A Review

The escalating need for reliability analysis(RA)and reliability-based design optimization(RBDO)within engineering challenges has prompted the advancement of saddlepoint approximationmethods(SAM)tailored for such problems.This article offers a detailed overview of the general SAM and summarizes the method characteristics first.Subsequently,recent enhancements in the SAM theoretical framework are assessed.Notably,the mean value first-order saddlepoint approximation(MVFOSA)bears resemblance to the conceptual framework of the mean value second-order saddlepoint approximation(MVSOSA);the latter serves as an auxiliary approach to the former.Their distinction is rooted in the varying expansion orders of the performance function as implemented through the Taylor method.Both the saddlepoint approximation and third-moment(SATM)and saddlepoint approximation and fourth-moment(SAFM)strategies model the cumulant generating function(CGF)by leveraging the initial random moments of the function.Although their optimal application domains diverge,each method consistently ensures superior relative precision,enhanced efficiency,and sustained stability.Every method elucidated is exemplified through pertinent RA or RBDO scenarios.By juxtaposing them against alternative strategies,the efficacy of these methods becomes evident.The outcomes proffered are subsequently employed as a foundation for contemplating prospective theoretical and practical research endeavors concerning SAMs.The main purpose and value of this article is to review the SAM and reliability-related issues,which can provide some reference and inspiration for future research scholars in this field.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy

Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.

Adaptive H_(∞)Filtering Algorithm for Train Positioning Based on Prior Combination Constraints

To solve the problem of data fusion for prior information such as track information and train status in train positioning,an adaptive H∞filtering algorithm with combination constraint is proposed,which fuses prior information with other sensor information in the form of constraints.Firstly,the train precise track constraint method of the train is proposed,and the plane position constraint and train motion state constraints are analysed.A model for combining prior information with constraints is established.Then an adaptive H∞filter with combination constraints is derived based on the adaptive adjustment method of the robustness factor.Finally,the positioning effect of the proposed algorithm is simulated and analysed under the conditions of a straight track and a curved track.The results show that the positioning accuracy of the algorithm with constrained filtering is significantly better than that of the algorithm without constrained filtering and that the algorithm with constrained filtering can achieve better performance when combined with track and condition information,which can significantly reduce the train positioning error.The effectiveness of the proposed algorithm is verified.

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells

The Myc gene is the essential oncogene in triple-negative breast cancer(TNBC).This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line.Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene.The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan(Chi-Se-DEC),which was then encapsulated in niosome-nanocarriers(NISM@Chi-Se-DEC).FT-IR,DLS,FESEM,and hemolysis tests were applied to confirm its characterization and physicochemical properties.Moreover,cellular uptake,cellular toxicity,apoptosis,cell cycle,and scratch repair assays were performed to evaluate its anticancer effects on cancer cells.All anticancer assessments were repeated under X-ray irradiation conditions(fractionated 2Gy).Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately.It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment.It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment,particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.

LociScan,a tool for screening genetic marker combinations for plant variety discrimination

To reduce the cost and increase the efficiency of plant genetic marker fingerprinting for variety discrimination,it is desirable to identify the optimal marker combinations.We describe a marker combination screening model based on the genetic algorithm(GA)and implemented in a software tool,Loci Scan.Ratio-based variety discrimination power provided the largest optimization space among multiple fitness functions.Among GA parameters,an increase in population size and generation number enlarged optimization depth but also calculation workload.Exhaustive algorithm afforded the same optimization depth as GA but vastly increased calculation time.In comparison with two other software tools,Loci Scan accommodated missing data,reduced calculation time,and offered more fitness functions.In large datasets,the sample size of training data exerted the strongest influence on calculation time,whereas the marker size of training data showed no effect,and target marker number had limited effect on analysis speed.

An Overview of Sequential Approximation in Topology Optimization of Continuum Structure

This paper offers an extensive overview of the utilization of sequential approximate optimization approaches in the context of numerically simulated large-scale continuum structures.These structures,commonly encountered in engineering applications,often involve complex objective and constraint functions that cannot be readily expressed as explicit functions of the design variables.As a result,sequential approximation techniques have emerged as the preferred strategy for addressing a wide array of topology optimization challenges.Over the past several decades,topology optimization methods have been advanced remarkably and successfully applied to solve engineering problems incorporating diverse physical backgrounds.In comparison to the large-scale equation solution,sensitivity analysis,graphics post-processing,etc.,the progress of the sequential approximation functions and their corresponding optimizersmake sluggish progress.Researchers,particularly novices,pay special attention to their difficulties with a particular problem.Thus,this paper provides an overview of sequential approximation functions,related literature on topology optimization methods,and their applications.Starting from optimality criteria and sequential linear programming,the other sequential approximate optimizations are introduced by employing Taylor expansion and intervening variables.In addition,recent advancements have led to the emergence of approaches such as Augmented Lagrange,sequential approximate integer,and non-gradient approximation are also introduced.By highlighting real-world applications and case studies,the paper not only demonstrates the practical relevance of these methods but also underscores the need for continued exploration in this area.Furthermore,to provide a comprehensive overview,this paper offers several novel developments that aim to illuminate potential directions for future research.

A Clinical Study to Assess the Effectiveness of Oral Combination Kit Therapy in Syndromic Management of Abnormal Vaginal Discharge (FEMINE Study) in Kinshasa, Democratic Republic of Congo

Background: Vaginal discharge is one of most common and nagging problems that women face. About 20% - 25% of women who visit gynecology department complain of vaginal discharge and leucorrhoea. An orally administered combination kit, containing 2 g secnidazole, 1 g azithromycin and 150 mg fluconazole (Azimyn FS Kit), has been successfully evaluated in clinical trials and used in several countries for management syndromic vaginal discharge due to infections. Methods: This is a longitudinal study which aimed to verify the clinical efficacy of the combined oral kit containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in the syndromic treatment of abnormal vaginal discharge in patients received in outpatient consultations in Kinshasa/DR Congo from March to September 2023. Results: Majority of patients had whitish vaginal discharge (51.6%) of average abundance (56.2%), accompanied by pruritus in 72.1% of cases, and dyspareunia in 23.5% of cases and hypogastralgia in 40.2% of cases. One week after treatment with the Azimyn FS® combined kit, at the greatest majority of patients (97.3%), abnormal vaginal discharge had decreased by more than 50% (84.1%). Two weeks after treatment with the Azimyn FS® combined kit, almost all patients (97.3%) no longer had abnormal vaginal discharge which had completely disappeared. Conclusion: A single dose of secnidazole, azithromycin and fluconazole in the form of an oral combi-kit (Azimyn FS Kit) has shown excellent therapeutic effectiveness in the syndromic treatment of abnormal vaginal discharge wherein patients were treated without diagnostic confirmation.

Nonlinear Filtering With Sample-Based Approximation Under Constrained Communication:Progress, Insights and Trends

The nonlinear filtering problem has enduringly been an active research topic in both academia and industry due to its ever-growing theoretical importance and practical significance.The main objective of nonlinear filtering is to infer the states of a nonlinear dynamical system of interest based on the available noisy measurements. In recent years, the advance of network communication technology has not only popularized the networked systems with apparent advantages in terms of installation,cost and maintenance, but also brought about a series of challenges to the design of nonlinear filtering algorithms, among which the communication constraint has been recognized as a dominating concern. In this context, a great number of investigations have been launched towards the networked nonlinear filtering problem with communication constraints, and many samplebased nonlinear filters have been developed to deal with the highly nonlinear and/or non-Gaussian scenarios. The aim of this paper is to provide a timely survey about the recent advances on the sample-based networked nonlinear filtering problem from the perspective of communication constraints. More specifically, we first review three important families of sample-based filtering methods known as the unscented Kalman filter, particle filter,and maximum correntropy filter. Then, the latest developments are surveyed with stress on the topics regarding incomplete/imperfect information, limited resources and cyber security.Finally, several challenges and open problems are highlighted to shed some lights on the possible trends of future research in this realm.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Heterogeneous information phase space reconstruction and stability prediction of filling body–surrounding rock combination

Traditional research believes that the filling body can effectively control stress concentration while ignoring the problems of unknown stability and the complex and changeable stress distribution of the filling body–surrounding rock combination under high-stress conditions.Current monitoring data processing methods cannot fully consider the complexity of monitoring objects,the diversity of monitoring methods,and the dynamics of monitoring data.To solve this problem,this paper proposes a phase space reconstruction and stability prediction method to process heterogeneous information of backfill–surrounding rock combinations.The three-dimensional monitoring system of a large-area filling body–surrounding rock combination in Longshou Mine was constructed by using drilling stress,multipoint displacement meter,and inclinometer.Varied information,such as the stress and displacement of the filling body–surrounding rock combination,was continuously obtained.Combined with the average mutual information method and the false nearest neighbor point method,the phase space of the heterogeneous information of the filling body–surrounding rock combination was then constructed.In this paper,the distance between the phase point and its nearest point was used as the index evaluation distance to evaluate the stability of the filling body–surrounding rock combination.The evaluated distances(ED)revealed a high sensitivity to the stability of the filling body–surrounding rock combination.The new method was then applied to calculate the time series of historically ED for 12 measuring points located at Longshou Mine.The moments of mutation in these time series were at least 3 months ahead of the roadway return dates.In the ED prediction experiments,the autoregressive integrated moving average model showed a higher prediction accuracy than the deep learning models(long short-term memory and Transformer).Furthermore,the root-mean-square error distribution of the prediction results peaked at 0.26,thus outperforming the no-prediction method in 70%of the cases.

A Study on the Effects of Different Interaction Combinations and Language Levels on Continuous Writing in Online Environments

This study was conducted with non-English sophomore students,aiming to explore the effects of different interaction combinations and language levels on continuous writing in an online environment,and compare the differences in lexical alignments and composition quality of learners with different interaction combinations and language levels in the same continuous writing task through experiments.The results show that the mean values of the word-phrase alignment of the paired group were higher than those of the individual group in different interaction combinations,and the two groups showed significant differences;in terms of composition quality,the individual group was better than the paired group,but there was no significant difference between the two groups in terms of task continuation.Secondly,the word-phrase alignment and composition scores of the different language-level groups were higher than those of the same language-level groups,and there was a significant difference between the two groups in terms of word-phrase alignments,but not in terms of composition scores.The results of this study can be useful and informative for second language teachers in future continuous teaching in online environments.

Anlotinib in combination with Envolizumab plus Etoposide for the treatment of EX-SCLC:a case report

Background:Small cell lung cancer(SCLC)is an aggressive malignant tumor with strong immunosuppressive effects,characterized by rapid doubling time and poor prognosis.Currently,effective therapeutic options are urgently needed for Extensive-stage small-cell lung Cancer.Case description:In the present case,a combination therapy of anlotinib,envolizumab,and etoposide was administered to treat an 80-year-old female patient with extensive-stage SCLC accompanied by mediastinal lymph node and bone metastasis.After two cycles of treatment,the tumor lesions in the right lungs decreased from 5.04*3.44 cm to 1.65*1.42 cm.As of now,no significant mass is seen there and no serious adverse reactions in this patient.Until September 2023,she has survived for 18 months with no disease progression.Conclusions:Research shows that Alectinib,in combination with evolocumab plus etoposide,could be an original,viable therapeutic option for the treatment option of patients with extensive-stage SCLC.

The Research on the Logic and Value of“Two Combinations”

Through the comprehensive analysis of the connotation and logic,inheritance and innovation and the value of social governance,and the dialectical relationship of“two combination”,the inheritance of the idea of Marxism,the inheritance of excellent traditional culture and the governance of contemporary society.

A Case Report on Treating Progressive Supranuclear Palsy with a Combination of Chinese and Western Medicine

A case of progressive supranuclear palsy in a 66-year-old woman is presented.The patient complained of“progressive stiffness of both lower limbs for five years,accompanied by choking and coughing for more than 1 year,”and was diagnosed with paralysis in traditional Chinese medicine(TCM),which was characterized by a deficiency of liver and kidney,and phlegm and blood stasis blocking the collaterals.Western medicine diagnosed it as progressive supranuclear palsy.The patient was diagnosed with“Parkinson’s disease”several times in the past and was given“polybasic hydrazide”and“amantadine hydrochloride tablets,”etc.The patient did not have significant symptomatic relief,so she sought further treatment with a combination of traditional Chinese and Western medicine.Based on the concept of deficiency and excess,this disease is categorized as a paralytic disease in Chinese medicine,and the onset of the disease is closely related to the deficiency of the body after a long period of illness,with wind,phlegm,blood stasis,and deficiency as the main pathogenetic mechanism.The treatment is based on the combination of disease and evidence,with traditional Chinese medicine and acupuncture as the main treatments,supplemented by intermediate-frequency pulsed electrical stimulation,transcranial repetitive magnetic stimulation,medicated canisters,wax therapy,traditional Chinese medicine guasha,and acupoint injections.Western medicine is based on symptomatic treatment,and the patient’s symptoms were relieved significantly after the combination of Chinese and Western medicine.