Permeable Bioelectronics toward Biointegrated Systems.

Bioelectronics integrates electronics with biological organs, sustaining the natural functions of the organs. Organs dynamically interact with the external environment, managing internal equilibrium and responding to external stimuli. These interactions are crucial for maintaining homeostasis. Additionally, biological organs possess a soft and stretchable nature; encountering objects with differing properties can disrupt their function. Therefore, when electronic devices come into contact with biological objects, the permeability of these devices, enabling interactions and substance exchanges with the external environment, and the mechanical compliance are crucial for maintaining the inherent functionality of biological organs. This review discusses recent advancements in soft and permeable bioelectronics, emphasizing materials, structures, and a wide range of applications. The review also addresses current challenges and potential solutions, providing insights into the integration of electronics with biological organs.

Antimicrobial second skin using copper nanomesh.

The functional support and advancement of our body while preserving inherent naturalness is one of the ultimate goals of bioengineering. Skin protection against infectious pathogens is an application that requires common and long-term wear without discomfort or distortion of the skin functions. However, no antimicrobial method has been introduced to prevent cross-infection while preserving intrinsic skin conditions. Here, we propose an antimicrobial skin protection platform copper nanomesh, which prevents cross-infectionmorphology, temperature change rate, and skin humidity. Copper nanomesh exhibited an inactivation rate of 99.99% for Escherichia coli bacteria and influenza virus A within 1 and 10 min, respectively. The thin and porous nanomesh allows for conformal coating on the fingertips, without significant interference with the rate of skin temperature change and humidity. Efficient cross-infection prevention and thermal transfer of copper nanomesh were demonstrated using direct on-hand experiments.

An organic transistor matrix for multipoint intracellular action potential recording.

Electrode arrays are widely used for multipoint recording of electrophysiological activities, and organic electronics have been utilized to achieve both high performance and biocompatibility. However, extracellular electrode arrays record the field potential instead of the membrane potential itself, resulting in the loss of information and signal amplitude. Although much effort has been dedicated to developing intracellular access methods, their three-dimensional structures and advanced protocols prohibited implementation with organic electronics. Here, we show an organic electrochemical transistor (OECT) matrix for the intracellular action potential recording. The driving voltage of sensor matrix simultaneously causes electroporation so that intracellular action potentials are recorded with simple equipment. The amplitude of the recorded peaks was larger than that of an extracellular field potential recording, and it was further enhanced by tuning the driving voltage and geometry of OECTs. The capability of miniaturization and multiplexed recording was demonstrated through a 4 × 4 action potential mapping using a matrix of 5- × 5-µm2 OECTs. Those features are realized using a mild fabrication process and a simple circuit without limiting the potential applications of functional organic electronics.

Robust, self-adhesive, reinforced polymeric nanofilms enabling gas-permeable dry electrodes for long-term application.

Robust polymeric nanofilms can be used to construct gas-permeable soft electronics that can directly adhere to soft biological tissue for continuous, long-term biosignal monitoring. However, it is challenging to fabricate gas-permeable dry electrodes that can self-adhere to the human skin and retain their functionality for long-term (>1 d) health monitoring. We have succeeded in developing an extraordinarily robust, self-adhesive, gas-permeable nanofilm with a thickness of only 95 nm. It exhibits an extremely high skin adhesion energy per unit area of 159 µJ/cm2 The nanofilm can self-adhere to the human skin by van der Waals forces alone, for 1 wk, without any adhesive materials or tapes. The nanofilm is ultradurable, and it can support liquids that are 79,000 times heavier than its own weight with a tensile stress of 7.82 MPa. The advantageous features of its thinness, self-adhesiveness, and robustness enable a gas-permeable dry electrode comprising of a nanofilm and an Au layer, resulting in a continuous monitoring of electrocardiogram signals with a high signal-to-noise ratio (34 dB) for 1 wk.

Effects of a hollow pontic design with various wall thicknesses on the axial internal fit and failure load of 3D printed three-unit resin prostheses.

STATEMENT OF PROBLEM: A 3-dimensionally (3D) printed 3-unit interim fixed dental prosthesis (FDP) undergoes inward polymerization shrinkage to the pontic region, leading to nonuniform internal fit and improper accuracy. Whether axial wall thickness influences accuracy is unclear. PURPOSE: The purpose of this in vitro study was to analyze the axial internal fit and failure load associated with a hollow pontic design of varying wall thicknesses in stereolithography (SLA) 3D printed 3-unit interim FDPs. MATERIAL AND METHODS: A master model for a 3-unit interim FDP with 2 implant abutments was designed. Two master models were produced by using milling and direct metal laser sintering (DMLS). Sixty SLA 3D printed specimens were produced with a hollow pontic design of 4 wall thicknesses (solid and 2.5, 2.0, and 1.5 mm). Fifteen milled specimens were produced with a solid pontic design. The axial internal fit in the coronal section was measured in terms of intaglio and cameo mid-axial wall areas relative to the abutments by using microcomputed tomography (µCT). The failure load was measured by using a universal testing machine at a loading rate of 1 mm/minute. For statistical analysis, parametric tests were performed (α=.05). Horizontal µCT sections were compared qualitatively, and failure patterns were categorized among groups. RESULTS: The hollow pontic designs with 2.0- and 1.5-mm wall thicknesses presented significantly lower mean intaglio mid-axial gaps than the solid pontic design (P<.001) and similar intaglio and cameo mid-axial gaps in the horizontal µCT sections. The hollow pontic design with the 2.0-mm wall thickness had a significantly higher mean failure load than that with the 1.5-mm wall thickness (P<.001) and a statistically similar mean failure load to that of the solid pontic design (P=.549). As the wall thickness of the hollow pontic decreased from 2.5 to 1.5 mm, the ratio of pontic fracture to complete fracture of the prosthesis increased. CONCLUSIONS: For SLA 3D printed 3-unit interim FDPs, axial internal fit was enhanced by the application of an appropriate hollow pontic design. Considering both the structural strength and fit, a hollow pontic design with a 2.0-mm wall thickness should be selected.

Cradle-to-Gate and Use-Phase Carbon Footprint of a Commercial Plug-in Hybrid Electric Vehicle Lithium-Ion Battery.

Increased use of vehicle electrification to reduce greenhouse gas (GHG) emissions has led to the need for an accurate and comprehensive assessment of the carbon footprint of traction batteries. Unfortunately, there are few lifecycle assessments (LCAs) of commercial lithium-ion batteries available in the literature, and those that are available focus on the cradle-to-gate stage, often with little or no consideration of the use phase. To address this shortfall, we report both cradle-to-gate and use-phase GHG emissions for the 2020 Model Year Ford Explorer plug-in hybrid electric vehicle (PHEV) NMC622 battery. Using primary industry data for battery design and manufacturing, cradle-to-gate emissions are estimated to be 1.38 t CO2e (101 kg CO2e/kWh), with 78% from materials and parts production and 22% from cell, module, and pack manufacturing. Using mass-induced energy consumptions of 0.6 and 1.6 kWh/(100 km 100 kg) for charge-depleting and -sustaining modes, respectively, the mass-induced use-phase emission of the battery is estimated to be 1.04 t CO2e. We show that battery emissions during the cradle-to-gate and use phases are comparable and that both phases need to be considered. A holistic and harmonized LCA approach that includes battery use is required to reduce carbon footprint uncertainties and guide future battery designs.

Improving the accuracy of noninvasive prenatal testing through size-selection between fetal and maternal cfDNA.

OBJECTIVES: In general, fetal cfDNA is shorter than maternal cfDNA, and accuracy of noninvasive prenatal testing (NIPT) results can be improved by selecting shorter cfDNA fragments to enrich fetal-derived cfDNA. This study investigated potential improvements in the accuracy of NIPT by performing classification and analysis based on differences in cfDNA size. METHODS: We performed paired-end sequencing to identify size ranges of fetal and maternal cfDNA from 62,374 pregnant women. We then developed a size-selection method to isolate and analyze both fetal and maternal cfDNA, defining fetal-derived cfDNA as less than 150 bp and maternal-derived cfDNA as greater than 180 bp. RESULTS: By implementing size-selection method, the accuracy of NIPT was improved, resulting in an increase in the overall positive predictive value for all aneuploidies from 89.57% to 97.1%. This was achieved by enriching both fetal and maternal-derived cfDNA, which increased fetal DNA fraction while the number of false positives for all aneuploidies was reduced by more than 70%. CONCLUSIONS: We identified the differences in read length between fetal and maternal-derived cfDNA, and selectively enriched both shorter and longer cfDNA fragments for subsequent analysis. Our approach can increase the detection accuracy of NIPT for detecting fetal aneuploidies and reduce the number of false positives caused by maternal chromosomal abnormalities.

All-nanofiber-based, ultrasensitive, gas-permeable mechanoacoustic sensors for continuous long-term heart monitoring.

The prolonged and continuous monitoring of mechanoacoustic heart signals is essential for the early diagnosis of cardiovascular diseases. These bodily acoustics have low intensity and low frequency, and measuring them continuously for long periods requires ultrasensitive, lightweight, gas-permeable mechanoacoustic sensors. Here, we present an all-nanofiber mechanoacoustic sensor, which exhibits a sensitivity as high as 10,050.6 mV Pa-1 in the low-frequency region (<500 Hz). The high sensitivity is achieved by the use of durable and ultrathin (2.5 µm) nanofiber electrode layers enabling a large vibration of the sensor during the application of sound waves. The sensor is ultralightweight, and the overall weight is as small as 5 mg or less. The devices are mechanically robust against bending, and show no degradation in performance even after 1,000-cycle bending. Finally, we demonstrate a continuous long-term (10 h) measurement of heart signals with a signal-to-noise ratio as high as 40.9 decibels (dB).

Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.

Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.

Skin bioelectronics towards long-term, continuous health monitoring.

Skin bioelectronics are considered as an ideal platform for personalised healthcare because of their unique characteristics, such as thinness, light weight, good biocompatibility, excellent mechanical robustness, and great skin conformability. Recent advances in skin-interfaced bioelectronics have promoted various applications in healthcare and precision medicine. Particularly, skin bioelectronics for long-term, continuous health monitoring offer powerful analysis of a broad spectrum of health statuses, providing a route to early disease diagnosis and treatment. In this review, we discuss (1) representative healthcare sensing devices, (2) material and structure selection, device properties, and wireless technologies of skin bioelectronics towards long-term, continuous health monitoring, (3) healthcare applications: acquisition and analysis of electrophysiological, biophysical, and biochemical signals, and comprehensive monitoring, and (4) rational guidelines for the design of future skin bioelectronics for long-term, continuous health monitoring. Long-term, continuous health monitoring of advanced skin bioelectronics will open unprecedented opportunities for timely disease prevention, screening, diagnosis, and treatment, demonstrating great promise to revolutionise traditional medical practices.

Decomposition of Reaching Movements Enables Detection and Measurement of Ataxia.

Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for objectively quantifying motor characteristics of ataxia. Participants with ataxia (N=88), participants with parkinsonism (N=44), and healthy controls (N=34) performed a computer tablet version of the finger-to-nose test while wearing inertial sensors on their wrists. Data features designed to capture signs of ataxia were extracted from participants' decomposed wrist velocity time-series. A machine learning regression model was trained to estimate overall ataxia severity, as measured by the Brief Ataxia Rating Scale (BARS). Classification models were trained to distinguish between ataxia participants and controls and between ataxia and parkinsonism phenotypes. Movement decomposition revealed expected and novel characteristics of the ataxia phenotype. The distance, speed, duration, morphology, and temporal relationships of decomposed movements exhibited strong relationships with disease severity. The regression model estimated BARS with a root mean square error of 3.6 points, r2 = 0.69, and moderate-to-excellent reliability. Classification models distinguished between ataxia participants and controls and ataxia and parkinsonism phenotypes with areas under the receiver-operating curve of 0.96 and 0.89, respectively. Movement decomposition captures core features of ataxia and may be useful for objective, precise, and frequent assessment of ataxia in home and clinic environments.

Integrin α5ß1 activates the NLRP3 inflammasome by direct interaction with a bacterial surface protein.

Integrins are cell-surface heterodimeric glycoproteins composed of alpha and beta subunits that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. In this study, we report a specific role of integrin α5ß1 in NLRP3 inflammasome activation in macrophages stimulated by Td92, a surface protein of the periodontopathogen, Treponema denticola. The direct interaction of Td92 with the cell membrane integrin α5ß1 resulted in ATP release and K(+) efflux, which are the main events in NLRP3 activation. This interaction was arginine-glycine-aspartate (RGD)-independent, and Td92 internalization was not required for the activity. An integrin α5ß1 antibody and oxATP, an ATP receptor antagonist, inhibited NLRP3 expression, caspase-1 activation, interleukin-1ß (IL-1ß) secretion, and proIL-1ß synthesis, all of which were regulated by NF-κB activation. Therefore, our data has identified the integrin α5ß1 as a principal cell membrane receptor for both NLRP3 inflammasome activation and IL-1ß transcription by a bacterial protein, which could exaggerate inflammation, a characteristic of periodontitis.

Continuous measurement of surface electrical potentials from transplanted cardiomyocyte tissue derived from human-induced pluripotent stem cells under physiological conditions in vivo.

Recording the electrical potentials of bioengineered cardiac tissue after transplantation would help to monitor the maturation of the tissue and detect adverse events such as arrhythmia. However, a few studies have reported the measurement of myocardial tissue potentials in vivo under physiological conditions. In this study, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSCM) sheets were stacked and ectopically transplanted into the subcutaneous tissue of rats for culture in vivo. Three months after transplantation, a flexible nanomesh sensor was implanted onto the hiPSCM tissue to record its surface electrical potentials under physiological conditions, i.e., without the need for anesthetic agents that might adversely affect cardiomyocyte function. The nanomesh sensor was able to record electrical potentials in non-sedated, ambulating animals for up to 48 h. When compared with recordings made with conventional needle electrodes in anesthetized animals, the waveforms obtained with the nanomesh sensor showed less dispersion of waveform interval and waveform duration. However, waveform amplitude tended to show greater dispersion for the nanomesh sensor than for the needle electrodes, possibly due to motion artifacts produced by movements of the animal or local tissue changes in response to surgical implantation of the sensor. The implantable nanomesh sensor utilized in this study potentially could be used for long-term monitoring of bioengineered myocardial tissue in vivo under physiological conditions.

Dynamic Remodeling of Membranes and Their Lipids during Acute Hormone-Induced Steroidogenesis in MA-10 Mouse Leydig Tumor Cells.

Lipids play essential roles in numerous cellular processes, including membrane remodeling, signal transduction, the modulation of hormone activity, and steroidogenesis. We chose steroidogenic MA-10 mouse tumor Leydig cells to investigate subcellular lipid localization during steroidogenesis. Electron microscopy showed that cAMP stimulation increased associations between the plasma membrane (PM) and the endoplasmic reticulum (ER) and between the ER and mitochondria. cAMP stimulation also increased the movement of cholesterol from the PM compared to untreated cells, which was partially inhibited when ATPase family AAA-domain containing protein 3 A (ATAD3A), which functions in ER and mitochondria interactions, was knocked down. Mitochondria, ER, cytoplasm, PM, PM-associated membranes (PAMs), and mitochondria-associated membranes (MAMs) were isolated from control and hormone-stimulated cells. Lipidomic analyses revealed that each isolated compartment had a unique lipid composition, and the induction of steroidogenesis caused the significant remodeling of its lipidome. cAMP-induced changes in lipid composition included an increase in phosphatidylserine and cardiolipin levels in PAM and PM compartments, respectively; an increase in phosphatidylinositol in the ER, mitochondria, and MAMs; and a reorganization of phosphatidic acid, cholesterol ester, ceramide, and phosphatidylethanolamine. Abundant lipids, such as phosphatidylcholine, were not affected by hormone treatment. Our data suggested that PM-ER-mitochondria tethering may be involved in lipid trafficking between organelles and indicated that hormone-induced acute steroid production involves extensive organelle remodeling.

Origin of the Insulating Phase and First-Order Metal-Insulator Transition in 1T-TaS_{2}.

Using density functional theory calculations, we investigate the origin of the insulating phase and metal-insulator transition (MIT) in octahedral tantalum disulfide (1T-TaS_{2}), a layered van der Waals material with a prominent two-dimensional (2D) charge density wave (CDW) order. We show that the MIT is driven not by the 2D order itself, but by the vertical ordering of the 2D CDWs or the 3D CDW order. We identify two exceptionally stable 3D CDW configurations; one is insulating and the other is metallic. The competition and mixing of the two CDW configurations account for many mysterious features of the MIT in 1T-TaS_{2}, including the pressure- and doping-induced transitions and the hysteresis behavior. The present results emphasize that interlayer electronic ordering can play an important role in electronic phase transitions in layered materials.

Preparation and characterization of adefovir dipivoxil-stearic acid cocrystal with enhanced physicochemical properties.

The objectives of this study were to prepare cocrystal composed of adefovir dipivoxil (AD) and stearic acid (SA) and to investigate the enhanced properties of the cocrystal. The cocrystal was prepared by antisolvent precipitation and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). The enhanced properties were evaluated by dissolution testing, permeability studies, and powder rheology analysis. The AD raw material has a cuboid-like crystal and the cocrystal has a needle shape. In the FT-IR study, there were bathochromic shifts caused by the hydrogen bonding. The melting point of the cocrystal was 52.9 °C, which was lower than that of AD. The XRPD pattern also had distinct differences, supporting the formation of a new crystalline form. The cocrystal showed changes in the lattice energy and the solvation strength, which caused an enhanced dissolution. The permeability was increased due to the SA, which acts as a P-gp inhibitor. The tabletability was enhanced due to the altered crystal habit. In conclusion, cocrystal containing AD and SA was successfully prepared, presenting advantages such as enhanced solubility, tabletability, and permeability. The use of the cocrystal is a desirable approach for the improved physicochemical properties.

Slim coherent backlight unit for holographic display using full color holographic optical elements.

The coherent backlight unit (BLU) using a holographic optical element (HOE) for full-color flat-panel holographic display is proposed. The HOE BLU consists of two reflection type HOEs that change the optical beam path and shape by diffraction. The illumination area of backlight is 150 mm x 90 mm and the thickness is 10 mm, which is slim compared to other conventional coherent backlight units for holographic display systems. This backlight unit exhibits a total efficiency of 8.0% at red (660 nm), 7.7% at green (532 nm), and 3.2% at blue (460 nm) using optimized recording conditions for each wavelength. As a result, we could get a bright full color hologram image.

Integrated profiling of global metabolomic and transcriptomic responses to viral hemorrhagic septicemia virus infection in olive flounder.

Viral hemorrhagic septicemia virus (VHSV) is one of the most serious viral pathogen that infects farmed fish. In this study, we measured the replication of VHSV increased steadily at 9, 24, 72, and 120 h after infection and progression of necrosis was observed at 72 hpi. We performed transcriptomic and metabolomics profiling of kidney tissues collected at each infection time using Illumina HiSeq2000 and ultra-performance liquid chromatography/quadrupole time-of-flight mass spectroscopy to investigate the mechanisms of VHSV infection in the kidneys of olive flounder. A total of 13,862 mRNA molecules and 72 metabolites were selected to identify the mechanisms of infection and they were integrated using KEGG pathway database. Six KEGG metabolic pathways, including carbohydrate metabolism, amino acid metabolism, lipid metabolism, transport and catabolism, metabolism of cofactors and vitamins, and energy metabolism, were significantly suppressed, whereas the immune system was activated by VHSV infection. A decrease in levels of amino acids such as valine, leucine, and isoleucine, as well as in their derivative carnitines, was observed after VHSV infection. In addition, an increase in arachidonic acid level was noted. Integrated analysis of transcriptome and metabolome using KEGG pathway database revealed four types of responses in the kidneys of olive flounder to VHSV infection. Among these, the mechanisms related to the immune system and protein synthesis were activated, whereas ATP synthesis and the antioxidant system activity were suppressed. This is the first study describing the mechanisms of metabolic responses to VHSV infection in olive flounder. The results suggest that the suppression of ATP synthesis and antioxidant systems, such as glutathione and peroxisome signaling, could be the cause of necrosis, whereas the activation of the immune system could result in the inflammation of kidney tissue in VHSV-infected olive flounder.

Efficacy and tolerability of preservative-free 0.0015% tafluprost in glaucoma patients: a prospective crossover study.

BACKGROUND: The aim of this work is to evaluate efficacy and tolerability of preservative containing 0.0015% tafluprost and preservative-free 0.0015% tafluprost using a prospective crossover study. METHODS: Primary open angle glaucoma (POAG) and normotensive glaucoma (NTG) patients were randomized enrolled. Group 1 ("NPT to PT") patients used preservative-free 0.0015% tafluprost (NPT) for 6 months and then changed to preservative containing 0.0015% tafluprost(PT) for 6 months. Group 2 ("PT to NPT") patients used preservative containing 0.0015% tafluprost for 6 months and changed to preservative-free 0.0015% tafluprost for 6 months. At 1, 3, 6, 7, 9, and 12 months, we measured intraocular pressure for efficacy and graded corneal erosion, tear break-up time (TBUT), and subjective discomfort. RESULTS: A total of 20 patients and 20 eyes were enrolled. In Group 1 and 2, intraocular pressure was well controlled to approximately 14 mmHg (9.38-18.46% decrease). Generally, subjective satisfaction was improved after changing from PT to NPT (p = 0.03) and TBUT using PT was numerically inferior to that using NPT (p = 0.06) but not when changing from NPT to PT. CONCLUSION: Both preservative containing and preservative-free 0.0015% tafluprost reduced intraocular pressure significantly. In addition, changing medication from PT to NPT might improve subjective satisfaction and tear break up time. TRIAL REGISTRATION: The trial registration number is NCT 03104621 (Apr/1/2017). Retrospectively registered.

Identifying predictors for postoperative clinical outcome in lumbar spinal stenosis patients using smart-shoe technology.

BACKGROUND: Approximately 33% of the patients with lumbar spinal stenosis (LSS) who undergo surgery are not satisfied with their postoperative clinical outcomes. Therefore, identifying predictors for postoperative outcome and groups of patients who will benefit from the surgical intervention is of significant clinical benefit. However, many of the studied predictors to date suffer from subjective recall bias, lack fine digital measures, and yield poor correlation to outcomes. METHODS: This study utilized smart-shoes to capture gait parameters extracted preoperatively during a 10 m self-paced walking test, which was hypothesized to provide objective, digital measurements regarding the level of gait impairment caused by LSS symptoms, with the goal of predicting postoperative outcomes in a cohort of LSS patients who received lumbar decompression and/or fusion surgery. The Oswestry Disability Index (ODI) and predominant pain level measured via the Visual Analogue Scale (VAS) were used as the postoperative clinical outcome variables. RESULTS: The gait parameters extracted from the smart-shoes made statistically significant predictions of the postoperative improvement in ODI (RMSE =0.13, r=0.93, and p<3.92×10-7) and predominant pain level (RMSE =0.19, r=0.83, and p<1.28×10-4). Additionally, the gait parameters produced greater prediction accuracy compared to the clinical variables that had been previously investigated. CONCLUSIONS: The reported results herein support the hypothesis that the measurement of gait characteristics by our smart-shoe system can provide accurate predictions of the surgical outcomes, assisting clinicians in identifying which LSS patient population can benefit from the surgical intervention and optimize treatment strategies.