Herein, we report a multiplex detection platform based on a suspension array with aggregation-induced emission luminogen (AIEgen) barcodes for simultaneous quantitative measurement of let-7b-5p, miR-16-5p and miR-19b-3p, which are associated with gastric cancer. A detection strategy by using a flow cytometer is proposed, which utilizes AIEgen-encoded microspheres to quantify the target miRNAs, and phycoerythrin as a fluorescence reporter on the detection probes to provide quantitative signals. This multiplex assay shows good specificity for recognizing single base mismatch, and possesses excellent sensitivity with limits of detection (LODs) ranging from 0.43 to 0.76 nM for the three miRNAs. The approach could be extended to the simultaneous detection of more target miRNAs by designing specific detection probes and increasing the number of fluorescence barcodes. We could foresee it holding great potential in future laboratory research and clinical applications due to its flexibility, strong multiplexed ability and good detection performance. A miRNA multiplex detection assay based on aggregation-induced emission luminogen encoded microspheres. Therefore, miRNA multiplex detection is beneficial to overcome the clinical sensitivity and specificity limitations. Although many miRNA detection technologies have been developed including northern blotting,14 microarrays,15 reverse-transcription polymerase chain reaction (RT-PCR),2,16,17 Isothermal amplification technology18,19 and next-generation sequencing technology,20 these methods have some drawbacks, such as requiring target amplification, being poorly flexible and reproducible, and not being easily multiplexed.21 In contrast, suspension array technology has been widely applied in multiplex detection with excellent flexibility and strong multiplex ability.22,23MicroRNAs (miRNAs) are small non-coding RNA molecules (18–25 nucleotides) that regulate gene expression by the degradation of target mRNAs or the inhibition of protein translation.24,25 A new kind of fluorescent material AIEgens has been reported in recent years, and has attracted considerable interests in constructing various novel chemosensors and biosensors due to their excellent optical properties, such as high brightness, excellent photobleaching resistance, low background interference and great biocompatibility except for unique AIE effect comparing with traditional organic dyes and QDs.26,27 Hence, AIEgens also will be ideal candidate for constructing optical encoded microspheres to establish miRNA multiplex detection platform.Suspension array technology commonly uses optically encoded microspheres as solid-supports and tracking codes to allow for the parallel detection of multiple targets. Traditional organic dyes and quantum dots (QDs) are the most popular fluorophores for constructing optically encoded microbead libraries because of their large encoding capacity and high-speed decoding of barcodes. However, both traditional organic dyes and QDs always exist aggregation-induced quenching phenomenon (ACQ) effect under high concentration during the preparation of encoded microbeads.co-maleic anhydride (PSMA) microspheres through facile Shirasu porous glass (SPG) membrane emulsification method.28,29 Based on the as-prepared AIEgens-encoded microspheres, a novel suspension array platform was established to achieve multiple detections of let-7b-5p, miR-16-5p and miR-19b-3p, which are associated with gastric cancer.13 Capture probes and chimeric probes for these three miRNAs were designed based on the general method proposed in this paper. To achieve higher detection sensitivity, several parameters were studied. The results of specificity tests showed that these multiplex assays could achieve excellent specificity even to recognize single base mismatch. Eventually, triplex detection assay was performed and showed high sensitivity with LOD ranging from 0.43 to 0.76 nM for the three miRNAs.Herein, AIEgens-encoded microspheres were firstly prepared by incorporating an AIEgen  into polystyrene-The hybridization reaction between target miRNAs and chimeric probes was performed in a thermal cycler . Oscillator  and shaker  were needed in the hybridization reaction between capture probes and chimeric probe-miRNAs at 37 °C as well as the RNase digestion at 30 °C. Filtration device  was used in the washing operations. Flow cytometer  was used for the barcoding and decoding of AIEgens-encoded microspheres, and analysis of samples after finishing hybridization.2C6 at the 5′ end and was purified by HPLC. Both capture probes and target miRNAs were dissolved in nuclease-free water. The chimeric probe included a DNA fragment and an RNA fragment from 5′ to 3′ end, and the 5′ end was biotinylated. Chimeric probes were dissolved in 1× Tris–EDTA (TE) buffer which was purchased from Sangon Biotech . Nuclease-free water, 0.5 M ethylenediaminetetraacetic acid , 3 M sodium acetate trihydrate , 1 M Tris(hydroxymethyl) aminomethane , Tween-20 and 10% sodium dodecyl sulfate (SDS) were purchased from Beyotime . 0.5 M EDTA (pH 8.0), 3 M NaAc (pH 5.2), 1 M Tris–HCl (pH 7.4) and Tween-20 were used to prepare the hybridization/wash buffer, which is a pH 7.7 buffer consisting of 10 mM Tris, 200 mM sodium acetate, 5 mM EDTA, and 0.05% Tween 20. Diethyl 2,5-di(thiophen-2-yl) terephthalate  was purchased from Yuanye Bio-Technology . 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) was purchased from SIGMA. Streptavidin and R-Phycoerythrin Conjugate  was purchased from Thermo Fisher. RNase ONE™ ribonuclease  was purchased from Promega.All chemicals were used as received, without further purification. Both capture probes and target miRNAs were synthesized by Sangon Biotech , and chimeric probes were synthesized by GENEWIZ . Specifically, the capture probe was modified NH22 Firstly, different amounts of HPS and 0.5 g of PSMA were dissolved in 8 mL of toluene to obtain dispersed phase. The amounts of HPS in dispersed phase for three barcodes are 0.05 mg, 0.25 mg and 1.25 mg, respectively. In the meantime, a continuous phase was prepared by dissolving 1 g of SDS into 200 mL of water. Then uniform oil-in-water droplets were continuously formed on the surface of SPG membrane by pressing dispersed phase into continuous phase under proper nitrogen pressure at room temperature. After toluene in oil-in-water emulsion was evaporated for 24 h, the solidified HPS-encoded microspheres (HPSMBs) were purified by centrifugation with water and ethanol separately three times to remove excess SDS. Finally, HPSMBs were resuspended in poly (PBST) buffer for later use.AIEgens-encoded microspheres were prepared through SPG membrane emulsification method using SPG membrane with the pore size of 5 μm.g for 4 min, and then the supernatants were removed. Such operations were repeated three times. After washing steps, 400 μL activation buffer MES was added to the dry microspheres followed by the centrifugation at 16 000 × g for 4 min. Appropriate amount of denatured capture probes and 10 μL of freshly prepared EDC solution (200 mg mL−1 in MES buffer) were quickly mixed with the acquired dry microspheres in 50 μL MES buffer. After 30 min incubation on a shaker at 600 rpm in the dark, the other 5 μL of freshly prepared EDC solution (10 mg mL−1 in MES buffer) was quickly added to the above mixture followed by a 30 min incubation on a shaker at 600 rpm in the dark. After that, excess EDC and capture probes were removed by the subsequent washing operations. 400 μL PBST buffer was added into the above regents and centrifugated at 14 000 × g for 4 min. Such washing steps were repeated twice followed by another wash by adding 400 μL 0.1% SDS to the prepared microspheres . Finally, the microspheres attached with capture probes were resuspended in a proper volume of 1× TE buffer and stored at 4 °C until further use.22To perform suspension assays for target miRNAs, capture probes were immobilized onto the carboxyl modified surface of the microspheres with chosen fluorescent barcodes. Before the coupling reaction, capture probes were firstly denatured at 95 °C for 10 min to remove the secondary structures and dimers, ensuring that capture probes could maintain the single-stranded structure before the hybridization reaction. Selected encoded microspheres were firstly washed and carboxyl activated. Specifically, microspheres storage solution (included one million microspheres) and 400 μL PBST buffer were mixed and centrifugated at 14 000 × 22,23,30Firstly, target miRNA solutions in different concentrations  were prepared with nuclease-free water, and chimeric probe solution was resuspended at 1 μM with 1× TE buffer firstly and diluted to some proper concentrations with hybridization buffer. Then the hybridization reaction between target miRNAs and chimeric probes was performed in mixtures containing 16.3 μL hybridization buffer, 2.5 μL miRNA solution in different concentrations and 1.25 μL chimeric probe solution with specific concentration. After quick vortex and spin, the hybridization samples were put in a thermal cycler. In brief, the hybridization was firstly performed at 90 °C for 3 min, and then incubated from 80 °C to 60 °C with the dropping rate at −1 °C per 6 min. When the temperature jumped to 37 °C, 4 μL microspheres solution coupled with capture probes was quickly added to the hybridization sample and incubated for 30 min at 37 °C on a shaker at 600 rpm. Then 2.5 μL RNase solution with specific concentration was added to the reaction sample. After 30 min of RNase digestion at 30 °C on a shaker at 600 rpm, samples were transferred to a PCR plate and washed three times with wash buffer to remove the excess probes, enzymatic residue and RNase. Then 100 μL SAPE solution with specific concentration was added to each well for staining, and the mixture was incubated at 25 °C on a shaker for 1 min at 1000 rpm and 29 min at 500 rpm. After that, each well was washed three times with wash buffer to remove the excessive SAPE. Finally, microspheres with probes hybridized on their surfaces were resuspended in 100 μL wash buffer and transferred to flow cytometer tubes for decoding. For each assay, about 1000 size-gated microbeads were read for analyzing and decoding by mapping the fluorescence profiles from 525/40 BP and 660/20 BP detection channels of the flow cytometry. The median fluorescence intensity value (MFI) of SAPE (PL peak at ∼580 nm) was positively correlated to the concentration of the corresponding target miRNA and was detected by the 585/42 BP detection channel.6 microspheres) and single chimeric probe  to ensure different miRNAs achieve better hybridization at the same time in the multiple assay.Let-7b-5p, miR-16-5p and miR-19b-3p were selected to demonstrate our miRNA multiplex assay model. The above miRNAs as plasma biomarkers are correlated with the development of human gastric cancer (proposed in our team's previous work).Tm was set to 35 to 45 °C and the length was set to 18 to 24 bp. Finally, 10 capture probes that were not easy to form either secondary structures or hairpin structures were screened out. After the preliminary screening, further screening of capture probes was performed. The Homology Analysis function in the software Oligo 7 was used to analyze the similarity among the 10 capture probes and the similarity between the 10 capture probes and the three target miRNAs. Eventually, three capture probes were selected by eliminating those which have more similarities with other probes and miRNAs  was diluted according to the ratios of 1 : 5, 1 : 10, 1 : 50 and 1 : 100 for miRNA detection. As expected, in all three assays, both the background noise and target signal went up as the dilution folds of RNase increased. However, it should be noted that the S/N slightly decreased as the dilution ratio increased in all three assays (To achieve higher detection sensitivity, several parameters were studied to obtain optimal conditions for detecting the target miRNAs, including the dilution ratio of RNase and SAPE, the dosage of capture probes and chimeric probes see . For eace assays . MoreoveOnce the RNase dilution ratio was determined, the dosage of chimeric probes was next to be optimized. Five concentrations ranging from 0.005, 0.01, 0.05 and 0.1 to 0.5 μM were studied. We found an interesting phenomenon that the background noise in all three assays increased firstly and then decreased with an increase in concentration of chimeric probes, reaching a peak at 0.05 μM. However, there was a slight difference in the target signal among the three assays. Like the background noise, the target signal increased firstly and then decreased as the concentration of chimeric probes increased, but the chimeric 2 and 3 reached a peak at 0.01 μM, while the chimeric 1 at 0.05 μM. For all three assays, the S/N ratio reached the maximum at 0.01 μM and minimum at 0.05 μM . When th6 microspheres were set. As expected, in the lower concentrations, both the background noise and target signal in the three assays were strengthened as the number of capture probes increased. However, in the higher concentrations, both the background noise and target signal tended to reach the plateau or even reduced. For all the three assays, the S/N ratios increased as the number of capture probes increased from 40 to 100 pmol/106 microspheres, but began to reduce once over 100 pmol/106 microspheres (6 microspheres were determined for all three assays.In this detection platform, the fluorescent signal read by the flow cytometer is the average of the fluorescent signals for all the encoded microspheres. In theory, the more capture probes coupled on the encoded microspheres, the higher the fluorescent signal will be. In order to investigate the actual effect of the number of capture probes on the microspheres, five values including 40, 60, 80, 100 and 120 pmol/10ospheres . This phBased on the fact that the fluorescent signal from emitter-conjugated chimeric probes is utilized to quantify the concentration of target miRNA, it is important to use proper amount of SAPE fluorescent dye. If the amount of SAPE is too excessive, the background noise may become too large, while if insufficient dye is used, not enough signals could be generated to mark the perfect hybridization structures. Five dilution ratios including 1 : 100, 1 : 200, 1 : 300, 1 : 400 and 1 : 500 were studied. Both the background noise and target signal reduced as the dilution ratio increased, and the declining tendency gradually slowed to a plateau since 1 : 200. As shown in Admittedly, there were S/N fluctuations during the optimization process. Especially, S/N values in In a multiplex assay for the detection of three miRNA targets mentioned above, cross-hybridization may occur among these different miRNAs and detection probes in the detection system. Therefore, before performing such assay the specificity of the proposed method needs to be evaluated. In order to simulate the interference of other miRNAs in the real sample, in addition to the existing three miRNAs, let-7a-5p with a single base mismatch and a random sequence miR-23a-3p see  were intR2 values were achieved between 0.993 and 0.998, showing good correlations of normalized MFI and target miRNA concentrations from 0.001 to 100 nM in all three miRNA assays. After that, triplex hybridization assay was performed by using mixed HPSMBs with three different fluorescent barcodes. As shown in Based on the optimized reaction parameters, single assay for the three plasma biomarkers of gastric cancer, named let-7b-5p, miR-16-5p and miR-19b-3p was performed. As shown in A novel suspension array platform based on AIEgens-encoded microspheres for miRNA multiplex detection was firstly constructed, wherein AIEgens-encoded microspheres were prepared by incorporating HPS into PSMA microspheres through using SPG membrane emulsification method. The as-prepared HPSMBs present high uniformity, bright fluorescent intensity and good distribution of HPS inside the microspheres resulting from the unique advantages of SPG membrane emulsification technique and excellent optical properties of HPS. Triplex detection assay based on suspension array platform with HPSMBs was performed for detecting let-7b-5p, miR-16-5p and miR-19b-3p as gastric cancer plasma biomarkers, demonstrating the feasibility of our miRNA multiplex assay platform. The results show that this multiplex assay has good specificity able to recognize single base mismatch, and high sensitivity with LODs ranging from 0.43 to 0.76 nM for the three miRNAs. Moreover, our method could be extended to the simultaneous detection of more other target miRNAs by designing specific capture probes and chimeric probes based on the developed method. With flexibility, strong multiplexed ability and good detection performance, it could hold good potential in further clinical diagnosis.Zou was responsible for the design of detection probes, experiments performing, data processing, and manuscript drafting. Wu mainly helped to design the experiment, prepared AIEgens microspheres and modified the manuscript. Zhang helped to discuss problems in the experiments and modify the manuscript. Qiang Ma collected clinical specimens and tested this method. Other authors helped to discuss the experiments and review the manuscript. All authors read and approved the final manuscript.There are no conflicts to declare.RA-009-C9RA07680H-s001


The research of fluid containing nanoparticles for the heat transport characteristics is very famous because of its variety of real-life applications in various thermal systems. Although the thermal efficiency of the nanofluid was effective but still the nano scientists were trying to introduce some new advance class of fluid. Therefore, an advance class of fluid is developed by the dispersion of two different nano sized particles in the conventional base fluid known as “Hybrid nanofluid” which is more effective compared to simple nanofluids in many engineering and industrial applications. Therefore, motivated from the hybrid type of nanofluids in the current research we have taken two-dimensional laminar and steady flow of second grade fluid passing through porous plate. The engine oil base fluid is widely used fluid in the engineering and industrial problems. Keeping these applications in mind the engine oil is considered and two different nanoparticles Copper and aluminum oxide are added in ordered to get the required thermal characteristics. In addition to this the thermal radiation, chemical reaction, activation energy, Brownian motion and thermophoresis are also addressed during the current research. The present proposed higher-order PDE’s is transformed to the non-linear system of ODE’s. For the solution of the proposed high non-linear model HAM method is employed. As the hybrid nanofluid are highlighted on the second-grade fluid flow over a horizontal porous flat plate. During the present analysis and experimental study, it has been proved that the performance of hybrid nanofluid is efficient in many situations compared to nanofluid and regular fluid. For physical interpretation all the flow parameters are discussed through graphs. The impact of volume fraction is also addressed through graphs. Moreover, the comparative analysis between hybrid and nanofluid is carried out and found that hybrid nanofluid performed well as compared to nanofluid and regular fluid. The engineering quantities obtained from the present research have been presented in tables. Afterwards, many researchers take interest in the research of nanofluid. Nanofluids have useful applications in different cooling systems, engineering, biology, medicine, nuclear power systems, heat generators, heat turbines, automobile engine and agriculture. Shahzad et al.2 explored a research by considering engine oil and found the efficient increase in the base fluid engine oil by taking molybdenum disulfide nanoparticles. Arif et al.3 where the authors inspected thermal transport features of different particles in engine oil and calculated that thermal characteristics can be improved by the addition of nanoparticles in the working fluid engine oil in different operating systems. Sepyani et al.4 examined an experiment and found that addition of ZnO nanoparticles in engine oil improve the thermal transport properties as well as lubricity. Patil et al.5 reported a review on collecting a data by suspending different nanoparticles in engine oil base fluid for long life span and increase the lubricity and working capability of engine oil. Krishna et al.6 investigated the impact of radiation on the flow of nanofluid for various thermal applications in different industrial problems. Similarly, Puneeth et al.7 explored the theoretical studies by highlighting the thermal features using the applications of nanofluid with the use of stretching sheet in many physical problems. In another paper Krishna and Chamkha8] developed nanofluid flow model and its applications using rotating boundary layer flow passes through vertical plate with various advance applications.Engine oil is widely used fluid for many engineering problems and has enormous applications in automobile, heat engine, cooling systems, transformer etc. The regular engine oil have low thermal properties in improve these properties initially, it was proved by Choi9, inspected engine oil performan ce by dissolving the mixture of MWCNT and Zno nanoparticles for improving the heat properties and lubrication performance. Sulgani et al.10 explained the improvement in the thermal transport efficiency of engine oil by taking the various temperature scales and adding the composite of Al2O3/Fe2O3 nanoparticles. In similar manner, Arif et al.11 explored in their studies the temperature enhances due to the dispersion of GO-MoS2 nanoparticles in engine oil making hybrid nanofluid and the fluid is assume to flow over an oscillating cylinder. Jamshed et al.12 discussed the entropy analysis using the mixture of nanoparticles in engine oil for advance applications. Krishna et al.13 carried a research by highlighting the flow of Casson fluid passes through exponentially accelerated surface with the fluid having two nanoparticles forming hybrid nanofluid using the applications in various cooling systems. Shah et al.14 where the authors inspected the hybrid nanofluid and its physical applications by highlighting the chemical reaction influence and motile microorganism using stretching sheet applications. Similarly, Kavya et al.15 investigated magnetic hybrid nanofluid and its useful applications in a variety of physical situations. In addition to this the authors studied the thermal features of MoS2 and copper hybrid nano composite fluid flow over stretching cylinder. Furthermore, Ghalambaz et al.16 and Mehryan et al.17 inspected some uniform thermal features of the hybrid nanofluid in a square cavity by highlighting various practical thermal applications in different circumstances. In another paper, Mehryan et al.18 where the authors decided to inspect the numerical study of the fluid containing the double nanoparticles at the same time for advance cooling applications and the fluid is assumed to flow inside a porous encloser.Although the performance of nanofluid in different operating systems was good and shows good thermal performance. But still the researchers need to advance cooling properties which cannot be obtained from the simple nanofluid. Recently, the idea developed by adding two particles forming mixture in a base fluid was studied and found the promising performance in the resultant fluid. When the composition of two or more nanoparticles added and mixed in base fluid then the obtained fluid is known as hybrid nanofluid become more efficient fluid in various circumstances. Recently, many researchers took interest in the research of hybrid nanofluid and use in different engineering and medical sciences, like heat exchangers, heat pumps, heat turbines, cooling of electrical circuits, etc. The study of engine oil-based hybrid nanofluid investigated by Asadi et al.19 inspected the dynamical behavior of second grade hybrid nanofluid with the radiation subject to Lorentz force. To describe the dynamics of such fluids, Roy and Pop20 examined the flow analysis of a second-grade hybrid nanofluid passes through stretching/shrinking sheet. Imran et al.21 developed the computational analysis of nanoparticles shaped on second grade hybrid nanofluid flow using the advance applications of solar collector. Alzahrani et al.22 explored the flow analysis of second hybrid nanofluid over a flat plate due to solar radiation. Mamaloukas et al.23 demonstrated the impact of second grade fluid with applications in various engineering problems. In addition to this motivated from the applications of non-Newtonian fluid recently Modather et al.24, Krishna et al.25 and VeeraKrishna26 explored some unique features of non-Newtonian fluid in different physical situations. Some other related studies of non-Newtonian fluids and its unique features can be found in31.The nature have two major classes of fluids i.e., Newtonian and non-Newtonian. Some practical situations where Newtonian fluid is used but many real-world problems exists which can’t be explained by the simple fluid. Therefore, the complex nature of the fluid can be highlighted by employing the non-Newtonian fluid models. In order to highlight these complex features of real phenomena non-Newtonian fluids play a vital rule in the investigation of such complex fluid flow problems. The non-Newtonian fluid have a attracted the attention because of novel applications in industries and engineering problems. The non-Newtonian fluids commonly applied in the food processing, polymeric material and have various applications in chemical processes petroleum engineering problems. The example of such fluids is paint, ketchup, honey, blood, starch, tooth paste, engine oil, etc. among the non-Newtonian fluid Second grade is famous fluid which have considerable attention in various physical situations. Motivated from the complex features of non-Newtonian fluids, Jawad et al.32. During the analysis they explains different applications of thermal radiation in physical problems. Similarly, Ali et al.33 investigated the impact of thermal radiation on the fluid flow profile with application of chemical reaction and non-uniform temperature at the boundary. Wang Ali et al.34 discussed the presence of thermal radiation phenomena and explained some useful features of the radiation in the dynamics of various fluid flow problems. Navarro et al.35 studied thermal radiation experimentally and explained the extreme kinds of unsteady flow (turbulent) in the presence of radiation using cavity fluid flow problems. Siegel et al.36 explored thermal effect in various physical applications like the authors calculated radiation and its applications in the engines turbine and discussed that turbine vanes and blades are important for temperature reduction in various situations. Bataller37 discusses some advance applications of thermal radiation effect in the Blasius type flow. In addition to this motivated from the advance applications of thermal radiation in different physical situation Chamkha41 inspected some real-life applications in various physical situations.The impact of thermal radiations has enormous applications in different fluid flow problems. The practical applications of thermal radiation are highlighted using the micropolar fluid passes through stretching sheet was investigated by Naveed et al.42 investigated the radiative fluid flow with the involvement of stretch surface and thermal effects. Gowda et al.43 examined in their research that the ferromagnetic nanofluid is allowed to pass through stretched surface with practical applications in the presence of magnetic dipole effect. Ziabakhsh et al.44 where the authors tried to develop an analytical solutions diffusion type flow with chemical effect and the fluid is allowed to pass through stretch sheet for advance engineering and industrial applications. Hayat et al.45 inspected the flow of second grade fluid using the stretching sheet surface with a detail explanation of a variety of daily life uses which include heat and mass transport phenomena. Dessie and Kishan46 carried research explaining the stretching sheet applications by highlighting the MHD effect in the presence of heat source variable viscosity and viscous dissipation. Layek et al.47 and Bhargava et al.48 considered the fluid flow through stretching porous surface using various physical phenomena in the presence of heat production effect and explain various daily life applications. The increasing interest of recent research shows that stretching sheet has a variety of applications in modern science and engineering problems. Motivated from these novel applications recently, Sreedevi et al.49 and Chamkha50 where the authors investigated some useful applications of stretching sheet phenomena and explain various physical situations where stretching sheet is applied.The phenomena of fluid flow on the stretching surfaces have unique industrial and engineering supplications especially, in electrochemistry and manufacturing of polymers. Stretching sheet applications in the flow dynamics can be used for the preparation of glass and paper. Cortell51 examined a thorough review by considering the presence of activation energy model and discussed its applications in the pyrolysis of lignocellulosic biomass. In next research paper, Cai and Liu52 use the same model for activation energy and focused to highlight some advance and novel applications of such energy models. Moreover, some polymeric properties of the activation energy were highlighted by Li et al.53 where the authors mentioned polymer pyrolysis properties of activation energy model. Further they discussed the activation energy mode selection, characteristics, validation of the model and its sensitive analysis. Henda et al.54 elevated the advance applications bioconvection assessment of the magnetized third grade nanofluid along with the applications of thermal radiation and exponential effect.In the last few decades, the research of activation energy and its applications in a variety of modern sciences like chemical engineering biological processes, fuels technology, and pyrolysis process has increased significantly. These novel applications become the main motivation of the researchers and scholars which are attracted to consider the impact of activation energy in various physical situations. Keeping these unique applications in mind recently, Cai et al.55 explored the chemical processes and its uses on the computational fluid dynamics in various physical situations. Similarly, the chemical processes was highlighted by Kuipers et al.56 by considering the mathematical modeling in computational fluid dynamics for evaluating different chemical processes. Lian et al.57 anticipated the impact of chemical processes and chemical reaction kinetics and Ozonation processes. Micale et al.58 scrutinized computational fluid dynamics CFD with chemically reacting fluid flows at surfaces for many physical applications. Keil et al.59 deliberated a scientific investigation computing in chemical engineering and its application in different physical situations using the computational fluid dynamics. Magyari and Chamkha60 explored a variety of industrial and engineering applications of chemical reactions using stretch surface.The research of computational fluid dynamics has widely used and become a versatile and powerful tool for investigating the chemical engineering problems. In modern era, many mathematical models have been used for chemical processes and its novel real-life applications in different circumstances. Raman et al.2O3 and copper Cu nanoparticles uniform dispersion in engine oil. The main motivation of mixing two particles at the same time is to calculate heat enhancement more effectively. Moreover, in the current study we also addressed the presence of radiation effect on the temperature profile, chemical process and activation energy is considered in the concentration of the fluid are also considered. The solutions of the present high order non-linear problem have been obtained by using the HAM method. All the flow parameters are highlighted through figures for explaining more physicals perspectives of the considered pertinent flow parameters. In addition, in the present analysis Al2O3 and Cu are mixed in engine oil for advance thermal characteristics. Finally, second grade fluid parameter is shown during the dynamics of the fluid through stretching sheet, the influence of volume friction is also addressed. The engineering quantities are calculated for mass, temperature and velocity equation and presented in tabular form.The present research work evaluated numerical analysis of incompressible, laminar steady second grade hybrid nanofluid flow over a horizontal stretching flat plate. To the best of our knowledge no work is reported to explain the thermal and concentration performance of second grade fluid model with the composition of aluminum oxide AlThe present analysis addressed non-Newtonian second grade fluid laminar flow through stretching porous surface. The second-grade fluid is assumed as laminar, steady, and incompressible two-dimensional flow. In the current research engine oil is used as base fluid by adding two kinds of nanoparticles to form a hybrid. Hybrid fluid is a new advance class of fluid have better thermal properties compared to nanofluid. Furthermore, the impact of radiative heat effect, viscous dissipation, activation energy and chemical reaction are also considered in the present analysis. The physical sketch is provided in Fig. 26, the stress tensor can be expressed as follows:The current research elevate second grade fluid using stretching sheet applications under the irregular extending rate which can be expressed as:Here The continuity equation for such flow can be expressed a:In the present study we assume two-dimensional steady and laminar flow, therefore velocity velocity can be expressed as follows:In the present study we have considered two-dimensional second grade hybrid nanofluid flow over a porous horizontal flat plate. The continuity equation to be satisfied given as under:The momentum equation in component form can be expressed as:The heat equation of the present flow in component form is given as:Finally, the concentration in the component form is given as:Here The radioactive heat flux for thermal radiation is given as:The BC’s to be satisfied are expressed as:11:The nanofluid expressions for The similarity transformation have been formed by suing the following variables:The transformed model can be expressed as:The physical BCs are to be satisfied:HereIn the current research we have the following non-dimensional parameters obtained which is defined in the nomenclature table.The Nusselt number , ca, ca\docuSimilarly, by putting the values of the Eqs. -29), be, be\docuBy employing the Taylor expansion in series form which is operated on the above equations.  and 37)37), we oIn the above Eqs. –40), pu, pu40), mth order form of the present proposed problem for the HAM numerical scheme can be written as follows:The In the above Eqs. –46), th, th46), The final general solution of the current proposed mode is obtained by using the particular solutions:Which are the final general solutions of the present proposed model by using the HAM numerical scheme.The current research inspects the incompressible, laminar and steady flow of second grade mentclass2pt{minimin Figs.  respectiin Figs. , 6, 7, 8in Figs. , 12, 13 in Figs. , 12, 13 In all the plots for energy, mass and momentum we have compared our obtained solutions for entclass1pt{minimaFigure The concentration of hybrid nanofluid for different values of volume fraction mentclasspt{minimaTable entclass1pt{minimaThe second-grade fluid parameter The higher values of volume fraction of hybrid nanofluid and mono nanofluid reduces the velocity of the fluid flow.The higher values of volume fraction of hybrid nanofluid and mono nanofluid reduces the fluid temperature.A comparison between Increasing the chemical reaction Increasing the activation energy The Nusselt number get higher for higher values of Sherwood number get lower for higher values of This section provides the impact of heat and mass transfer of incompressible second grade engine oil base hybrid nanofluid flow over a porous horizontal stretching porous flat plate. Furthermore, a comparison between


SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC infections, which are often severe and associated with substantial mortality. PPK, PTA, and clinical PK/PD analyses were conducted using all available PK and efficacy data to support SUL-DUR dose selection.PPK analyses were performed using PK data from 373 subjects, including 110 patients who received SUL-DUR and underwent PK sampling in the pivotal Phase 3 (ATTACK) trial. SUL-DUR concentrations in epithelial lining fluid (ELF) from healthy subjects were utilized to predict SUL-DUR ELF concentrations in Phase 3 patients. Covariate analyses evaluated the impact of demographic factors on PK exposures. The PPK model, non-clinical PK/PD data, and in vitro surveillance data were used to assess the PTA by MIC in simulated patients with ABC infections. Clinical PK/PD relationships were assessed using dichotomous and time-to-event efficacy endpoints from the ATTACK trial.10. No relationships were observed between PK/PD indices and efficacy endpoints, consistent with most patients achieving SUL and DUR exposures above nonclinical PK/PD targets for efficacy.Two-compartment models with linear kinetics best characterized SUL and DUR PK. Consistent with high renal clearance of SUL-DUR, dose adjustments are needed in patients with renal impairment or augmented renal function. Body weight, site of infection, and East Asian region  were statistically significant covariates in the PPK analysis but were not clinically relevant. No other statistical or clinically relevant covariates were identified. As shown in Figures A and B for plasma and ELF, respectively, the PTA was ≥ 90% for pathogens with an MIC ≤ 4 µg/mL across renal function categories in simulated patients, using PK/PD targets associated with a 1-log killPercent PTA by MIC on Day 1 based on the assessment of sulbactam %T>MIC ≥ 50% and durlobactam AUC:MIC ratio ≥ 10 targets and free-drug plasma (A) and total-drug ELF (B) exposures among simulated patients by CLcr group after administration of sulbactam 1 g/ durlobactam 1 g IV q6h and dosing regimens adjusted for renal impairment and augmented renal functionThe simulated plasma and ELF exposures yielded a high PTA, which when combined with the favorable efficacy and safety findings from ATTACK (abstract #1266378), support a dose of 1.0 g sulbactam/1.0 g durlobactam via a 3-hour infusion, every 6 hours in patients with normal renal function and renal function-based dose adjustments.Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Jeffrey P. Hammel, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Kajal Larson, PhD, Entasis Therapeutics: Employee Kathryn Liolios, MA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sarah McLeod, PhD, Entasis Therapeutics: Employee Alita Miller, PhD, Entasis Therapeutics: Employee Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. 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In the study of polymer flooding, researchers usually ignore the genetic stress properties of viscoelastic fluids. In this paper, we investigate the process of viscoelastic fluid flooding the remaining oil in the dead end. This work uses the fractional-order Maxwell in the traditional momentum equation. Furthermore, a semi-analytic solution of the flow control equation for fractional-order viscoelastic fluids is derived, and the oil-repelling process of viscoelastic fluids is simulated by a secondary development of OpenFOAM. The results show that velocity fractional-order derivative α significantly affects polymer solution characteristics, and increasing the elasticity of the fluid can significantly improve the oil repelling efficiency. Compared to the Newtonian fluid flow model, the fractional order derivative a and relaxation time b in the two-parameter instanton equation can accurately characterize the degree of elasticity of the fluid. The smaller the a, the more elastic the fluid is and the higher the oil-repelling efficiency. The larger the b, the less elastic the fluid is and the lower the cancellation efficiency. Moreover, the disturbance of the polymer solution to the dead end is divided into two elastic perturbation areas. The stronger the elasticity of the polymer solution, the higher the peak value of the area in the dead end and the higher the final oil displacement efficiency. In the structure of the global oil resources reserves, 40% is viscous oil and ultra-heavy oil. However, the major viscous oilfields enter the late stage of development in most countries. Long-term water injection makes the remaining oil distribution in the reservoir of these viscous oilfields very dispersed. Water flooding mining can no longer meet the demand for enhanced recovery from these waterflooded reservoirs ,2,3,4. TThe major factor for enhanced oil recovery from polymer flooding is changing the seepage characterization of water and enhanced volumetric sweep efficiency by using polymer ,8,9. ManThe law of viscoelastic polymer flooding is studied in two types of experiment and numerical simulation. In recent years, the grid model has mainly been used to study the fluid–fluid repulsion process in microporous channels; the advantage of this method is that it can establish a flow condition close to the real formation and the experimental results are more reliable ,21,22,23In recent years, with the development of fractional-order theory and computational methods, researchers have combined fractional-order theory with fluid mechanics to establish the fractional-order constitutive equations of fluids, such as the fractional-order Maxwell model, fractional-order Jeffreys model, and fractional-order O-B model ,28,29,30Research on fractional-order fluids has mainly focused on single-phase flow, and the problem of microscale multiphase flow in polymer flooding processes has not been solved. In this study, we developed a fractional-order semi-analytical transient model for calculating the velocity and pressure of polymer solution. The model divides the shear stress during the flow of polymer solution into two stress fields, Newtonian, and fractional-order non-Newtonian. The numerical solution is calculated for the Newtonian stress field, and the analytical solution for the fractional-order non-Newtonian stress field is obtained using the Laplace variation. We can predict the efficiency of polymer flood oil based on the model that performed a secondary development of the interFoam incompressible two-phase flow solver in OpenFOAM.In this paper, we investigated the dead-end capillary tube that is a representative residual oil capillary structure such as in When the above fluids are incompressible, the continuity equation isFor the incompatible polynomial system momentum equation, which considers gravity and source terms:When the two-phase fluid interface flow is in equilibrium, S method :(4)Ff=ΔPc denotes the controllable compression factor, when there is no compression effect. The larger the compression effect, the faster and more pronounced the compression effect.According to the treatment of the interfacial tension, the phase volume fraction of the two-phase fluid in the calculated region is unknown; therefore, the equation for the phase fraction is also needed. Applying the method proposed better for the phase volume fraction ,(5)∂α∂tThe relationship between the shear stress and shear rate is defined as the constitutive equation of fluid flow. When the fluid is considered a Newtonian fluid, the shear stress term The gamma Function in Equation (8) is defined asAbove governing and constitutive equations of polymer solution, the momentum equation is:The time-degenerate nature of fractional-order integrals leads to numerical discretization that cannot be adopted by a step-by-step method for integer-order solution derivatives. There are many numerical solution of fractional-order integral operators 0CDta ,38,39. TAfter replacing the intrinsic model with the fractional-order Maxwell model, the momentum equation is additionally increased with a fractional-order time and convection term. Equation (12) is the result of discretizing and dimensionless processing of Equation (11)As shown in (1)The fluid flow in a certain time interval can be regarded as a completely steady state. Therefore, under the physical model we developed in (2)Polymers are completely dissolved in water and uniformly distributed in the flow field;(3)The flow state of the polymer is exactly the same as that of water; i.e., the velocity distribution of both is exactly the same.Based on the physical problem investigated in this paper, we proposed an approximate method to solve the computational problem of fractional order momentum equations in complex flows. The Reynolds number of the polymer solution in the capillary during the flooding processing is generally on the order of Therefore, by Laplace transformation, Equation (7) becomesRectification to obtain relaxation modulus H-Fox function, which is defined as:Using Laplace inverse transformation in Equation (14),Converting Equation (15) into an M-L function:Under the assumptions of this paper, the analytical solution Equation (7) is: OpenFOAM , EquatioThe The pressure correction equation is:Without loss of generality, the involved variable parameters are given as follows: the fractional-order The first normal stress differences can indicate the elastic behavior of the fluid during the flow, which is one of the main differences between a viscoelastic fluid and a Newtonian fluid. We extracted the first normal stress difference at the oil-water interface in the dead end at t = 1 s. As illustrated in Relaxation time The viscoelastic fluid is significantly more effective in displacing the remaining oil in the dead end than the Newtonian fluid;The perturbed region of viscoelastic fluid within the blind end can be divided into two, which gradually invade deeper into the dead end through the elastic wave transmission between the two areas;The smaller the fractional order derivative a, the greater the fluid viscoelasticity and the higher the oil displacement efficiency;The smaller the fractional order derivative a, the larger the first normal stress difference peak in the elastic perturbation region 1, the greater the fluid viscoelasticity, and the higher the oil displacement efficiency;The relaxation time of the fluid has a significant effect on the viscoelasticity of the fluid, and when the relaxation time is close to 1 s, the flow characteristics of the fluid gradually change from viscoelastic to pure viscous fluid.This paper studies the unsteady process of the viscoelastic fluid flooding oil in the dead end. The fractional derivative is introduced in Maxwell’s constitutive model. Analytic solutions of the fractional order Maxwell model were computed and implanted into the N-S equations by showing the forces. The analytical solution of the fractional-order Maxwell model is calculated, and a semi-analytical solution model for viscoelastic fluid flow is developed by making the viscoelastic stresses explicit. The process of polymer flooding is simulated by performing a secondary development of the interFoam incompressible two-phase flow solver in OpenFOAM. Some useful conclusions are drawn from the simulation results:


Intraoperative diffusion MRI could provide a means of visualising brain fibre tracts near a neurosurgical target after preoperative images have been invalidated by brain shift. We propose an atlas-based intraoperative tract segmentation method, as the standard preoperative method, streamline tractography, is unsuitable for intraoperative implementation.A tract-specific voxel-wise fibre orientation atlas is constructed from healthy training data. After registration with a target image, a radial tumour deformation model is applied to the orientation atlas to account for displacement caused by lesions. The final tract map is obtained from the inner product of the atlas and target image fibre orientation data derived from intraoperative diffusion MRI.The simple tumour model takes only seconds to effectively deform the atlas into alignment with the target image. With minimal processing time and operator effort, maps of surgically relevant tracts can be achieved that are visually and qualitatively comparable with results obtained from streamline tractography.Preliminary results demonstrate feasibility of intraoperative streamline-free tract segmentation in challenging neurosurgical cases. Demonstrated results in a small number of representative sample subjects are realistic despite the simplicity of the tumour deformation model employed. Following this proof of concept, future studies will focus on achieving robustness in a wide range of tumour types and clinical scenarios, as well as quantitative validation of segmentations. Neurosurgery carries risks to healthy brain structures, including neuron fibre bundles called white matter tracts, injury to which can cause disruption to such important functions as movement, vision and speech. The spatial relationship between neurosurgical targets and adjacent white matter tracts can be determined preoperatively from diffusion magnetic resonance imaging (dMRI). However, the information in preoperative images becomes inaccurate as the spatial relationships change over the course of surgery (brain shift).Intraoperative dMRI offers a means for imaging fibre tracts after brain shift has invalidated preoperative imaging. However, the unique challenges of intraoperative imaging, which include strict time constraints on image acquisition and post-processing , and on the availability of specialist operators and computing equipment, mean that standard preoperative image processing techniques do not translate easily to the intraoperative environment.The current clinical standard for reconstructing tracts from dMRI data preoperatively is streamline tractography , 2, in wOne difficulty of using atlas-based segmentation methods in clinical subjects is that of anatomical non-correspondence between subject and template images caused by space-occupying lesions. Deformable registration alone is often insufficient for handling this mismatch , and so Given the time constraints of intraoperative imaging and the practical constraints of the computing capacity which can reasonably be assumed to be available in an operating room, our aim is to achieve an estimate of tract displacement with low computational complexity. The first component of tractfinder, the tract orientation atlas, provides a degree of spatial tolerance that alleviates the need for voxel-perfect registration and deformation, allowing the implementation of a minimal deformation algorithm. We then derive a tract segmentation from the overlap between the deformed atlas and fibre orientation information in the target image.The novel contributions of this work are explicit handling of large-scale deformations and an automated pipeline that can produce results within 15 minutes. The pipeline can be run fully automatically with no minimal to no user input, depending on the particularities of an individual case (such as lesion mass effect and extent of resection). Tractfinder has been developed specifically for intraoperative imaging, but is equally applicable to any diffusion MRI data.The tractfinder pipeline consists of three main components. The first component, the tract atlas, acts as a prior on a tract’s spatial location and orientation. It incorporates known knowledge about tracts in a way similar to the use of regions of interest in tractography. Next, tumour deformation modelling of the atlas corrects for the displacement of tracts by space-occupying lesions. Minimal adjustment to precomputed deformations can account for intraoperative brain shift. Finally, the deformed tract atlas and target dMRI fibre orientation data are combined to compute a likelihood map for the tract.Since the focus of this communication is on tumour deformation modelling, the other components will only be briefly summarised for completeness. Throughout this section, wherever there is talk of an orientation distribution, all such distributions are represented in spherical harmonic (SH) basis . In thisA separate atlas is created for each tract of interest to capture its typical orientation and location. To date, bilateral atlases have been constructed for the optic radiation and corticospinal tract. First, the tract is reconstructed in each of a series of healthy training dMRI datasets (n=16)  using muNext, tract orientation distribution (TOD) mapping  is used The resulting tract atlas is an average map of the tract over all training subjects, which contains both a spatial and orientational components. For use in unseen target subjects, the tract atlas is linearly registered to the target image for subsequent calculations.The tract orientation atlas represents the expected orientation and location of the tract for a typical healthy subject. In order to correct for displacement of white matter tracts due to space occupying lesions, a simple radial tumour expansion model is employed.P to the tumour centre of mass, S. Along S to the brain surface and S to the tumour surface   2) descrmentclass2pt{minimP within the lesion boundary is displaced to a new position P.If the lesion is not invading the surrounding tissue but instead fully displacing it (non-infiltrative), then under the simplified assumption that no original, healthy tissue is destroyed, k is strictly decreasing and P.Given that the gradient of equation , where \s, as appropriate for a given tumour) take less than 10 seconds, as long as the tumour and brain segmentations remain unchanged.The tumour deformation model is implemented in Python, and full execution takes on average 1 min for a 208 x 256 x 256 voxel image. If lookup tables for The final step, after registering and deforming the orientation atlas to approximately match the anatomy of the target image, is to compare the expectation represented in the atlas with the observed dMRI data of the target image. Our objective is to obtain a measure per voxel of how closely the predicted tract orientation distribution overlaps with the observed fibre orientation distribution (FOD), which is modelled from the target dMRI data using multi-shell multi-tissue constrained spherical deconvolution (CSD) , 27 Fig.This can be achieved by taking the inner product of the two functions, i.e. multiplying them and integrating the product over all spherical angles. The FOD and TOD atlas are both represented by their spherical harmonic (SH) distribution functions as follows:ribed in . The sphThe methodology described above was initially developed and tested in preoperative tumour images. However, the target application is in intraoperative imaging. The main difference therein is the need to account for brain shift, which is unpredictable: differing effects stem from drainage of fluid, pressure changes, tumour debulking and gravitational sag. Nevertheless, we aim to achieve intraoperative tract segmentation while avoiding the need to perform additional tumour and/or resection cavity segmentation intraoperatively.s to simulate a reduction in tumour volume.As the atlas is designed to be spatially inclusive, with the inner product acting to correct small spatial inaccuracies, it is possible in some cases where brain shift is minimal to reuse the preoperative tumour deformation field. In cases of significant tumour debulking, the deformation field can be recomputed from the preoperative tumour segmentation by adjusting the value of s and reusing preoperatively computed values of This scenario is demonstrated in Fig. in vivo dMRI images, especially in neurosurgical cases, a quantitative validation of this method is not currently possible. However, comparison with the current clinical standard, streamline tractography, illustrates the effectiveness of tractfinder. Targeted probabilistic streamline tractography reconstructions were produced by an experienced operator utilising ROI placement strategies routinely utilised in clinical practice at our institution. The clinical reliability and biological accuracy of tractography is difficult to determine in vivo. While some consider the “gold standard” to be validation against intraoperative direct electrical stimulation and post-surgical outcomes [Due to the lack of ground truth information for white matter tract segmentation in outcomes , which ik(P).The tumour deformation model successfully captures large-scale tract displacements in seconds, where much longer timescales  are typical for more complex tumour growth modelling algorithms and nonlinear registration. The short computational time further makes it trivial to recompute the deformation with small adjustments if necessary. The model presents a simplified prediction of tumour deformation: No distinctions are made between the highly deformable ventricles and stiffer brain tissues, and the tumour is “grown” isotropically from a single point outward with no regard for the surrounding topology (except for the brain boundary) or peri-tumoural tissue effects. Nevertheless, the objective of the deformation step, which is to bring the tract orientation atlas into approximate alignment with the actual target tract, is achieved despite these simplifications. Improvement is needed in cases involving infiltrative tumours, where tracts are not entirely displaced and tumour cells mix with surrounding functional structures, as the current model only supports single tumours with defined boundaries. Modelling this scenario will require a modified deformation model, using a different expression for b-values, on segmentation quality. So far, there has been limited validation of applying tractfinder to intraoperative cases, and this will be the subject of future research. One example of such a case is shown in Fig. The inner product between the orientation atlas and target FOD image provides an intuitive map of tract location and is computationally straightforward Figs.  and 5. Ss are necessary; however, this nevertheless amounts to far less operator input than advanced streamline tractography as described in the introduction. A final critical practical aspect of intraoperative implementation will be the integration of segmentation results with neuronavigation tools for display during surgery, including the appropriate data conversions. Tools to enable such interfacing have been developed by others [If implemented clinically, intraoperative processing steps would be limited to minimal preprocessing including de-noising , 35, 36 y others , 43 and In conclusion, a white matter mapping method is presented that is shown to produce plausible tract reconstructions in cases with space occupying lesions, using an atlas in conjunction with tumour deformation modelling. Producing results requiring minimal user input and on intraoperatively feasible timescales, the method thus has the potential to bring effective white matter mapping into the intraoperative domain.


Introduction The Burch procedure (1961) was considered the gold standard treatment for stress urinary incontinence (SUI) before the midurethral slings (MUSs) were introduced, in 2001.Objective This historical perspective of the Burch's timeline can encourage urogynecological surgeons to master the Burch technique as one of the options for surgical treatment of SUI.Search Strategy and Selection Criteria A bibliographic search was performed in the PubMed and National Library of Medicine (NIH) databases with the termsBurch colposuspensionANDhistoryANDstress urinary incontinencein the last 20 years. The original article by Burch (1961) was included. The references were read by three authors. The exclusion criterion was studies in non-English languages. Biomedical Library Special Collections were included as historical relevant search.Data Collection, Analysis and Main Results Some modifications of the technique have been made since the Burch procedure was first described. The interest in this technique has been increasing due to the negative publicity associated with vaginal synthetic mesh products. Twenty-nine relevant articles were included in the present review article, and numerous trials have compared Burch colposuspension with MUS.Conclusion This historical perspective enables the scientific community to review a standardized technique for SUI. Burch colposuspension should be considered an appropriate surgical treatment for women with SUI, and an option in urogynecological training programs worldwide. Stress urinary incontinence (SUI) is a prevalent condition that interferes with women's health-related quality of life. It is generally attributable to urethral hypermobility as a result of diminished urethral support, although there can also be a component of urethral sphincter weakness. In women with incontinence secondary to urethral hypermobility, retropubic colposuspension surgery (or urethropexy) is a traditional repair that surgically elevates and reinforces the periurethral tissue.stcentury, following the introduction of the MUS.There are several colposuspension techniques, although none is as commonly performed as the Burch procedure. The Burch procedure was first described by Dr John Chistopher Burch in 1961.Notwithstanding, in 2011, the Food and Drug Administration (FDA) issued a notification on the serious complications associated with transvaginal mesh for the surgical treatment for pelvic organ prolapse (POP).Given this scenario, the present historical perspective aims to write a narrative review, a systematic search on the history of the Burch procedure. This review can encourage urogynecological surgeons to master the Burch technique as one of the options for the surgical treatment of SUI.Burch colposuspensionANDhistoryANDstress urinary incontinencein the last 20 years (2001–2021), since the advent of mid-urethral slings. The last date of search was included due to the original Burch's article .To compose the timeline of Burch's surgery, a bibliographic search was performed in the PubMed and National Library of Medicine (NLM) databases with the termsJohn Christopher Burch, eldest son of Dr. Lucius E. Burch and Sarah Polk (Cooper) Burch, was born on July 21, 1900, in Nashville, TN. He attended Vanderbilt University from 1917 to 1919 and then entered medical school, graduating in 1923 as Founder's medalist. After completing residence programs in Boston and New York and studying in Europe, he returned to Nashville in 1926 to begin his practice at the Burch Clinic and to begin his long career of teaching at Vanderbilt Medical School.Dr. Burch is remembered for his service as Dean of the Vanderbilt Medical School from 1914 to 1925 and chairman of the department of obstetrics and gynecology until 1945. He served as professor not only in the field of urogynecology, but also obstetrics and gynecology. In 1965, as shown inHysterectomyis considered a classic. During World War II, he served as chief of the surgical service at Brooke General Hospital in Fort Sam Houston, Texas. Over his long career at Vanderbilt, John Burch taught some 2,000 medical students and trained more than 300 interns and residents.During his career, Dr. Burch authored more than 150 articles. His bookCurrently, The Vanderbilt University is considered one of the top 15 universities in the United States and one of the top 50 in the world.In 1961, John C. BurchThe following steps describe the original Burch procedure (1961).“The dissection to expose Cooper's ligament and the fascia surrounding the vagina begins by breaking through the endoabdominal fascia, which descends from the anterior abdominal wall onto the symphysis and superior ramus of the pubic bone. The most convenient breakthrough site is at the lower angle of the abdominal wound and, when the fascia is broken through, the fingers rest on the bare bone of the symphysis. Now with the left index finger in the vagina and continuing· in this plane, the endoabdominal fascia is stripped from Cooper's ligament and the side wall of the pelvis by the right hand. This plane is relatively avascular and keeping in it avoids the rupture of many small vessels and prevents a most troublesome ooze. In working downward to the fascia surrounding the vagina, the right hand sweeps the endoabdominal fascia from the lateral structures with a lateral and superior motion. When the lateral edge of the vagina becomes apparent, further medial dissection will usually outline to some degree the edge of the bladder.The distinctness of the bladder edge is not always sharp, especially in the obese, and in passing the suture into the perivaginal fascia, one can easily penetrate the bladder.For suture material, number 2 chromic catgut has so far proved satisfactory. Perhaps stainless-steel wire or even fascia may be the eventual choice. The point on the vagina through which the needle and suture have been passed is now matched to Cooper's ligament, and the needle is passed through this ligament and tied by the assistant as the operator pushes up with the intravaginal finger. Three such sutures are passed on each side. The abdomen is closed, the legs retracted and perineorrhaphy and posterior colporrhaphy done if indicated.”The relevant step in the development of the operation was the utilization of the Cooper ligament as a point of fixation. This strong thick band of fibrous tissue runs along the superior surface of the superior ramus of the pubic bone and is ideal from the standpoint of both passing and holding a suture.Variations of the description of the classic Burch technique can be explained in didatic stepsEither a Pfannenstiel or straight midline subumbilical incision is made (at least 5 cm).The retropubic space is exposed, and the peritoneum is swept superiorly. The periurethral fat is removed for adequate visualization of the anterolateral vaginal wall.A Foley catheter is inserted per the urethra, and the balloon is inflated. With an index finger in the vagina and gentle traction on the catheter, the bladder neck with the Foley balloon is palpable. With an assistant providing exposure by retracting the bladder medially and superiorly, the endopelvic and vaginal fascia are visible.Two (or 3) absorbable stitches are then placed through the endopelvic and vaginal fascial complex, using the index finger to determine the appropriate depth . The most cephalad suture is usually placed at the level of the bladder neck , and sutures are placed about 1 cm apart caudally.The vaginal sutures are then placed through the Cooper ligament and tied loosely (2- to 4-cm suture bridge between the vagina and the Cooper ligament) in a tension-free manner.According to Burch,The critical aspects of the Burch procedure, regardless of surgical approach, are to obtain adequate exposure and to avoid reapproximating tissue under undue tension. The surgical goal is to loosely approximate the Cooper ligament to the periurethral tissue in order to allow postoperative adhesion formation that provides broad support for the urethra and bladder neck. To date, there are no randomized trials to suggest superiority of one suture type over another; however, most surgeons use absorbable suture. In addition, reviews have shown no difference in outcomes whether placing 2, 3, or 4 sutures per side, although, as mentioned above, it has been demonstrated that one suture per side is insufficient.Over the years, several authors and surgeons have presented numerous modifications of the original operation described by Burch.The wealth of data from comparative and observational studies assessing the outcome of Burch colposuspension has been reported in numerous textbooks and structured summary publications.Numerous trials have compared Burch colposuspension with MUS. Several observational and randomized studies have showed similar eficacy and lower morbidity for MUS procedures compared to Burch colposuspension.In general, bladder injury, voiding dysfunction, and hematoma can be reported equally with Burch colposuspension or midurethral tapes. Midurethral slings may exhibit a much higher risk of intraoperative complications, such as bladder perforation and urinary retention, than the Burch procedure.Basically, data on long-term effectiveness and adverse events are, however, limited, especially around the comparative adverse events profiles of MUS and non-MUS procedures. A better understanding of complications after surgery for SUI is imperative.Although mesh slings remain a strong option to surgical treatment for SUI, there has been renewed interest in autologous fascial slings (AFSs) for the treatment of SUI, because of the investigations of mesh safety for POP.Currently, regulations surrounding the use of mesh implants for POP differ depending on the country and can influence the number of procedures of synthetic slings for SUI. Although in the United States of America (USA), the United Kingdom (UK), Canada, Australia, New Zealand, and France, transvaginal mesh implants for POP have been removed from the market, in most mainland European countries, Asia, and South America, they are still available as a surgical option for POP correction.Then, it is expected that in the USA, the UK, Australia, New Zealand, Canada, and France, with the removal or the restriction of transvaginal mesh implants as a surgical option for POP, the spectrum of urogynecological operations, including surgeries for SUI, might be greatly affected. Conventional transvaginal native tissue repair and abdominal  surgical procedures, as well as Burch colposuspension or non-synthetic mesh procedures are expected to be increasingly performed. This requires appropriate training of younger physicians.According to this scenario, a strong point in the study is the heterogeneous source of historical research current overview of Burch's surgery. Encouraging the study of this established technique can rescue an effective surgical option for SUI in a setting of valorization of individualized conducts.A limitation of the present study is the non-systematic methodology. The search for a historical description of Burch's surgery overlooked classic articles without a systematic review. However, these documents deserve to be part of the knowledge of the urogynecological surgeon due to the scientific contribution in the development of surgical techniques throughout the century in urogynecology.The authors believe that the limitation of the non-systematized methodology does not detract from the study because the objective was to demonstrate, through a collection of its history, a surgical treatment option for urinary incontinence. A technique that has survived for more than 50 years, still recommended today, carries its scientific value.The Burch colposuspension has a 50-plus year history demonstrating strong long-term outcomes with minimal complications. Iterations of the procedure, including laparoscopic, robotic, and mini-incisional approaches, appear to have equal efficacy to the open procedure. Although the current use of the Burch colposuspension has waned with the growing shift toward sling surgery, it continues to have a role in the treatment of SUI.Specifically, given satisfactory long-term outcomes over the course of the last half-century, it seems that the Burch colposuspension should be considered an appropriate surgical treatment for any woman with SUI, especially in settings where vaginal access is limited, where intra-abdominal surgery is already planned, or if mesh is contraindicated.On the other side, the National Institute for Care and Health Excellence (NICE) guidelines include amongst their recommendations that laparoscopic Burch colposuspension should not be used as a routine procedure for the treatment of SUI in women. It was highlighted, that the procedure should be performed only by surgeons with appropriate training as well as expertise working in a multidisciplinary team, and women should be advised about the limited evidence.Finally, the Burch procedure has an ongoing role in the surgical repair of female SUI and should remain in the surgical repertoire of female pelvic medicine and reconstructive surgeons. The authors suggest new long-term follow-up studies for the association of the Burch colposuspension technique in the setting of laparoscopic, robotic, or minimally invasive urogynecological surgery. The science has no answer, so far, whether urogynecology has started a journey back to the future by revitalizing the Burch procedure. However, in light of such a development, training in both open and laparoscopic Burch colposuspension should nowadays be provided in urogynecological fellowship and training programs worldwide.