The combined application of stem cells and three-dimensional bioprinting scaffolds for the repair of spinal cord injury

Spinal cord injury is considered one of the most difficult injuries to repair and has one of the worst prognoses for injuries to the nervous system.Following surgery,the poor regenerative capacity of nerve cells and the generation of new scars can make it very difficult for the impaired nervous system to restore its neural functionality.Traditional treatments can only alleviate secondary injuries but cannot fundamentally repair the spinal cord.Consequently,there is a critical need to develop new treatments to promote functional repair after spinal cord injury.Over recent years,there have been seve ral developments in the use of stem cell therapy for the treatment of spinal cord injury.Alongside significant developments in the field of tissue engineering,three-dimensional bioprinting technology has become a hot research topic due to its ability to accurately print complex structures.This led to the loading of three-dimensional bioprinting scaffolds which provided precise cell localization.These three-dimensional bioprinting scaffolds co uld repair damaged neural circuits and had the potential to repair the damaged spinal cord.In this review,we discuss the mechanisms underlying simple stem cell therapy,the application of different types of stem cells for the treatment of spinal cord injury,and the different manufa cturing methods for three-dimensional bioprinting scaffolds.In particular,we focus on the development of three-dimensional bioprinting scaffolds for the treatment of spinal cord injury.

Phase II Clinical Study of Three-Dimensional Printed Coplanar Template Combined with CT-Guided Percutaneous Core Needle Biopsy of Pulmonary Nodules in Elderly Patients

Background: As the population age structure gradually ages, more and more elderly people were found to have pulmonary nodules during physical examinations. Most elderly people had underlying diseases such as heart, lung, brain and blood vessels and cannot tolerate surgery. Computed tomography (CT)-guided percutaneous core needle biopsy (CNB) was the first choice for pathological diagnosis and subsequent targeted drugs, immune drugs or ablation treatment. CT-guided percutaneous CNB requires clinicians with rich CNB experience to ensure high CNB accuracy, but it was easy to cause complications such as pneumothorax and hemorrhage. Three-dimensional (3D) printing coplanar template (PCT) combined with CT-guided percutaneous pulmonary CNB biopsy has been used in clinical practice, but there was no prospective, randomized controlled study. Methods: Elderly patients with lung nodules admitted to the Department of Oncology of our hospital from January 2019 to January 2023 were selected. A total of 225 elderly patients were screened, and 30 patients were included after screening. They were randomly divided into experimental group (Group A: 30 cases) and control group (Group B: 30 cases). Group A was given 3D-PCT combined with CT-guided percutaneous pulmonary CNB biopsy, Group B underwent CT-guided percutaneous pulmonary CNB. The primary outcome measure of this study was the accuracy of diagnostic CNB, and the secondary outcome measures were CNB time, number of CNB needles, number of pathological tissues and complications. Results: The diagnostic accuracy of group A and group B was 96.67% and 76.67%, respectively (P = 0.026). There were statistical differences between group A and group B in average CNB time (P = 0.001), number of CNB (1 vs more than 1, P = 0.029), and pathological tissue obtained by CNB (3 vs 1, P = 0.040). There was no statistical difference in the incidence of pneumothorax and hemorrhage between the two groups (P > 0.05). Conclusions: 3D-PCT combined with CT-guided percutaneous CNB can improve the puncture accuracy of elderly patients, shorten the puncture time, reduce the number of punctures, and increase the amount of puncture pathological tissue, without increasing pneumothorax and hemorrhage complications. We look forward to verifying this in a phase III randomized controlled clinical study. .

Evaluating the contribution of satellite measurements to the reconstruction of three-dimensional ocean temperature fields in combination with Argo profiles

Assimilation systems absorb both satellite measurements and Argo observations.This assimilation is essential to diagnose and evaluate the contribution from each type of data to the reconstructed analysis,allowing for better configuration of assimilation parameters.To achieve this,two comparative reconstruction schemes were designed under the optimal interpolation framework.Using a static scheme,an in situ-only field of ocean temperature was derived by correcting climatology with only Argo profiles.Through a dynamic scheme,a synthetic field was first derived from only satellite sea surface height and sea surface temperature measurements through vertical projection,and then a combined field was reconstructed by correcting the synthetic field with in situ profiles.For both schemes,a diagnostic iterative method was performed to optimize the background and observation error covariance statics.The root mean square difference(RMSD)of the in situ-only field,synthetic field and combined field were analyzed toward assimilated observations and independent observations,respectively.The rationale behind the distribution of RMSD was discussed using the following diagnostics:(1)The synthetic field has a smaller RMSD within the global mixed layer and extratropical deep waters,as in the Northwest Pacific Ocean;this is controlled by the explained variance of the vertical surface-underwater regression that reflects the ocean upper mixing and interior baroclinicity.(2)The in situ-only field has a smaller RMSD in the tropical upper layer and at midlatitudes;this is determined by the actual noise-to-signal ratio of ocean temperature.(3)The satellite observations make a more significant contribution to the analysis toward independent observations in the extratropics;this is determined by both the geographical feature of the synthetic field RMSD(smaller at depth in the extratropics)and that of the covariance correlation scales(smaller in the extratropics).

A combination of digital design and three-dimensional printing to assist treatment of thoracolumbar compression fractures using percutaneous kyphoplasty

Objective:To evaluate the clinical efficacy of the preoperative digita1 design combined with three dimensional(3D)printing models to assist percutaneous kyphoplasty(PKP)treatment for thoracolumbar compression frac tures.Methods:From January 2018 to August 2020,we obtained data of 99 patients diagnosed thoracolumbar compression fractures.These patients were divided into control group(n=50)underwent traditional PKP surgery,and observation group(n=49)underwent preoperative digital design combined with 3D printing model assisted PKP treatment.The clinical efficacy was evaluated with five parameters,including operation time,number of intraoperative radiographs,visual analogue scale(VAS)score,Cobb Angle change,and high compression rate of injured vertebrae.Results:There were statistically significant differences of operation time and number of intraoperative radio graphs between the two groups(P<0.05).For VAS score,Cobb Angle change and vertebral height compression rate,all of these three parameters were significantly improved when the patients accepted surgery teatment in two groups(P<0.05).However,there were no significant differences between control group and observation group for these three parameters either before or after surgery(P>0.05).Conclusions:Through the design of preoperative surgical guide plate and the application of 3D printing model to guide the operation,the precise design of preoperative surgical puncture site and puncture Angle of the injured vertebra was realized,the number of intraoperative radiographs was reduced,the operation time was shortened and the operation efficiency was improved.

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.

A theory for three-dimensional response of micropolar plates

Through combined applications of the transfer-matrix method and asymptotic expansion technique,we formulate a theory to predict the three-dimensional response of micropolar plates.No ad hoc assumptions regarding through-thickness assumptions of the field variables are made,and the governing equations are two-dimensional,with the displacements and microrotations of the mid-plane as the unknowns.Once the deformation of the mid-plane is solved,a three-dimensional micropolar elastic field within the plate is generated,which is exact up to the second order except in the boundary region close to the plate edge.As an illustrative example,the bending of a clamped infinitely long plate caused by a uniformly distributed transverse force is analyzed and discussed in detail.

Oxygen tension modulates cell function in an in vitro three-dimensional glioblastoma tumor model

Hypoxia is a typical feature of the tumor microenvironment,one of the most critical factors affecting cell behavior and tumor progression.However,the lack of tumor models able to precisely emulate natural brain tumor tissue has impeded the study of the effects of hypoxia on the progression and growth of tumor cells.This study reports a three-dimensional(3D)brain tumor model obtained by encapsulating U87MG(U87)cells in a hydrogel containing type I collagen.It also documents the effect of various oxygen concentrations(1%,7%,and 21%)in the culture environment on U87 cell morphology,proliferation,viability,cell cycle,apoptosis rate,and migration.Finally,it compares two-dimensional(2D)and 3D cultures.For comparison purposes,cells cultured in flat culture dishes were used as the control(2D model).Cells cultured in the 3D model proliferated more slowly but had a higher apoptosis rate and proportion of cells in the resting phase(G0 phase)/gap I phase(G1 phase)than those cultured in the 2D model.Besides,the two models yielded significantly different cell morphologies.Finally,hypoxia(e.g.,1%O2)affected cell morphology,slowed cell growth,reduced cell viability,and increased the apoptosis rate in the 3D model.These results indicate that the constructed 3D model is effective for investigating the effects of biological and chemical factors on cell morphology and function,and can be more representative of the tumor microenvironment than 2D culture systems.The developed 3D glioblastoma tumor model is equally applicable to other studies in pharmacology and pathology.

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.

Three-dimensional cell-based strategies for liver regeneration

Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient 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.

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.

Study on Failure Mechanism and Bearing Capacity of Three-Dimensional Rectangular Footing Subjected to Combined Loading

This paper presents two kinematic failure mechanisms of threc-dimensional rectangular footing resting on homogeneous undrained clay foundation under uniaxial vertical loading and uniaxial moment loading. The failure mechanism under vertical loading comprises a plane strain Prandti-type mechanism over the central part of the longer side, and the size of the mechanism gradually reduces at the ends of the longer side and over the shorter side as the corner of rectangular footing is being approached where the direction of soil motion remains normal to each corresponding side respectively. The failure mechanism under moment loading comprises a plane strain scoop sliding mechanism over the central part of the longer side, and the radius of scoop sliding mechanism increases linearly at the ends of the longer side. On the basis of the kinematic failure mechanisms mentioned above, the vertical ultimate bearing capacity and the ultimate bearing capacity against moment or moment ultimate bearing capacity are obtained by use of upper bound limit analysis theory. At the same time, numerical analysis results, Skempton＇ s results and Salgado et al. ＇s results are compared with this upper bound solution. It shows that the presented failure mechanisms and plastic limit analysis predictions are validated. In order to investigate the behaviors of undrained clay foundation beneath the rectangular footing subjected to the combined loadings, numerical analysis is adopted by virtue of the general-purpose FEM software ABAQUS, where the clay is assumed to obey the Mohr-Coulomb yielding criterion. The failure envelope and the ultimate bearing capacity are achieved by the numerical analysis results with the varying aspect ratios from length L to breadth B of the rectangular footing. The failure mechanisms of rectangular footing which are subjected to the combined vertical loading V and horizontal loading H （Vertical loading V and moment loading M, and horizontal loading H and moment loading M respectively are observed in the finite element analysis. ） is explained by use of the upper bound plasticity limit analysis theory. Finally, the reason of eccentricity of failure envelope in H-M loading space is given in this study, which can not be explained by use of the traditional ＇ swipe test＇.

Isolation and Identification of Cancer Stem Cells from Human Osteosarcom by Serum-free Three-dimensional Culture Combined with Anticancer Drugs

The cancer stem cells(CSCs)from human osteosarcoma by serum-free three-dimensional culture combined with anticancer drugs were isolated and identified.The primary cells derived from human osteosarcoma were digested by trypsin to prepare a single-cell suspension,and mixed homogeneously into 1.2% alginate gel.Single-cell alginate gel was cultured with serum-free DMEM/F12 medium.Epirubicin(0.8μg/mL)was added to the medium to enrich CSCs.After cultured conventionally for 7 to 10 days,most of cells suspended in ...

Development of a toroidal soft x-ray imaging system and application for investigating three-dimensional plasma on J-TEXT

A toroidal soft x-ray imaging(T-SXRI)system has been developed to investigate threedimensional(3D)plasma physics on J-TEXT.This T-SXRI system consists of three sets of SXR arrays.Two sets are newly developed and located on the vacuum chamber wall at toroidal positionsφof 126.4°and 272.6°,respectively,while one set was established previously atφ=65.50.Each set of SXR arrays consists of three arrays viewing the plasma poloidally,and hence can be used separately to obtain SXR images via the tomographic method.The sawtooth precursor oscillations are measured by T-SXRI,and the corresponding images of perturbative SXR signals are successfully reconstructed at these three toroidal positions,hence providing measurement of the 3D structure of precursor oscillations.The observed 3D structure is consistent with the helical structure of the m/n=1/1 mode.The experimental observation confirms that the T-SXRI system is able to observe 3D structures in the J-TEXT plasma.

Intraoperative application of three-dimensional printed guides in total hip arthroplasty: A systematic review

BACKGROUND Acetabular component positioning in total hip arthroplasty(THA)is of key importance to ensure satisfactory post-operative outcomes and to minimize the risk of complications.The majority of acetabular components are aligned freehand,without the use of navigation methods.Patient specific instruments(PSI)and three-dimensional(3D)printing of THA placement guides are increasingly used in primary THA to ensure optimal positioning.AIM To summarize the literature on 3D printing in THA and how they improve acetabular component alignment.METHODS PubMed was used to identify and access scientific studies reporting on different 3D printing methods used in THA.Eight studies with 236 hips in 228 patients were included.The studies could be divided into two main categories;3D printed models and 3D printed guides.RESULTS 3D printing in THA helped improve preoperative cup size planning and post-operative Harris hip scores between intervention and control groups(P=0.019,P=0.009).Otherwise,outcome measures were heterogeneous and thus difficult to compare.The overarching consensus between the studies is that the use of 3D guidance tools can assist in improving THA cup positioning and reduce the need for revision THA and the associated costs.CONCLUSION The implementation of 3D printing and PSI for primary THA can significantly improve the positioning accuracy of the acetabular cup component and reduce the number of complications caused by malpositioning.

Computer-assisted three-dimensional individualized extreme liver resection for hepatoblastoma in proximity to the major liver vasculature

BACKGROUND The management of hepatoblastoma(HB)becomes challenging when the tumor remains in close proximity to the major liver vasculature(PMV)even after a full course of neoadjuvant chemotherapy(NAC).In such cases,extreme liver resection can be considered a potential option.AIM To explore whether computer-assisted three-dimensional individualized extreme liver resection is safe and feasible for children with HB who still have PMV after a full course of NAC.METHODS We retrospectively collected data from children with HB who underwent surgical resection at our center from June 2013 to June 2023.We then analyzed the detailed clinical and three-dimensional characteristics of children with HB who still had PMV after a full course of NAC.RESULTS Sixty-seven children diagnosed with HB underwent surgical resection.The age at diagnosis was 21.4±18.8 months,and 40 boys and 27 girls were included.Fifty-nine(88.1%)patients had a single tumor,39(58.2%)of which was located in the right lobe of the liver.A total of 47 patients(70.1%)had PRE-TEXT III or IV.Thirty-nine patients(58.2%)underwent delayed resection.After a full course of NAC,16 patients still had close PMV(within 1 cm in two patients,touching in 11 patients,compressing in four patients,and showing tumor thrombus in three patients).There were 6 patients of tumors in the middle lobe of the liver,and four of those patients exhibited liver anatomy variations.These 16 children underwent extreme liver resection after comprehensive preoperative evaluation.Intraoperative procedures were performed according to the preoperative plan,and the operations were successfully performed.Currently,the 3-year event-free survival of 67 children with HB is 88%.Among the 16 children who underwent extreme liver resection,three experienced recurrence,and one died due to multiple metastases.CONCLUSION Extreme liver resection for HB that is still in close PMV after a full course of NAC is both safe and feasible.This approach not only reduces the necessity for liver transplantation but also results in a favorable prognosis.Individualized three-dimensional surgical planning is beneficial for accurate and complete resection of HB,particularly for assessing vascular involvement,remnant liver volume and anatomical variations.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

Three-dimensional numerical analysis of plant-soil hydraulic interactions on pore water pressure of vegetated slope under different rainfall patterns

Understanding the pore water pressure distribution in unsaturated soil is crucial in predicting shallow landslides triggered by rainfall,mainly when dealing with different temporal patterns of rainfall intensity.However,the hydrological response of vegetated slopes,especially three-dimensional(3D)slopes covered with shrubs,under different rainfall patterns remains unclear and requires further investigation.To address this issue,this study adopts a novel 3D numerical model for simulating hydraulic interactions between the root system of the shrub and the surrounding soil.Three series of numerical parametric studies are conducted to investigate the influences of slope inclination,rainfall pattern and rainfall duration.Four rainfall patterns(advanced,bimodal,delayed,and uniform)and two rainfall durations(4-h intense and 168-h mild rainfall)are considered to study the hydrological response of the slope.The computed results show that 17%higher transpiration-induced suction is found for a steeper slope,which remains even after a short,intense rainfall with a 100-year return period.The extreme rainfalls with advanced(PA),bimodal(PB)and uniform(PU)rainfall patterns need to be considered for the short rainfall duration(4 h),while the delayed(PD)and uniform(PU)rainfall patterns are highly recommended for long rainfall durations(168 h).The presence of plants can improve slope stability markedly under extreme rainfall with a short duration(4 h).For the long duration(168 h),the benefit of the plant in preserving pore-water pressure(PWP)and slope stability may not be sufficient.

A Bioequivalence Study of Empagliflozin/Metformin Fixed-Dose Combination in Healthy Subjects under Fasting Conditions

Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.

Influence of sampling on three-dimensional surface shape measurement

In order to accurately measure an object’s three-dimensional surface shape,the influence of sampling on it was studied.First,on the basis of deriving spectra expressions through the Fourier transform,the generation of CCD pixels was analyzed,and its expression was given.Then,based on the discrete expression of deformation fringes obtained after sampling,its Fourier spectrum expression was derived,resulting in an infinitely repeated"spectra island"in the frequency domain.Finally,on the basis of using a low-pass filter to remove high-order harmonic components and retaining only one fundamental frequency component,the inverse Fourier transform was used to reconstruct the signal strength.A method of reducing the sampling interval,i.e.,reducing the number of sampling points per fringe,was proposed to increase the ratio between the sampling frequency and the fundamental frequency of the grating.This was done to reconstruct the object’s surface shape more accurately under the condition of m>4.The basic principle was verified through simulation and experiment.In the simulation,the sampling intervals were 8 pixels,4 pixels,2 pixels,and 1 pixel,the maximum absolute error values obtained in the last three situations were 88.80%,38.38%,and 31.50%in the first situation,respectively,and the corresponding average absolute error values are 71.84%,43.27%,and 32.26%.It is demonstrated that the smaller the sampling interval,the better the recovery effect.Taking the same four sampling intervals in the experiment as in the simulation can also lead to the same conclusions.The simulated and experimental results show that reducing the sampling interval can improve the accuracy of object surface shape measurement and achieve better reconstruction results.