Exosomes contain nucleic acids and proteins, which are transported from secretory cells to recipient cells. Molecules in exosomes are encapsulated in a lipid bilayer, which allows them to exist stably in body fluids without being affected by nuclease degradation enzymes. Therefore, the therapeutic use of exosomes as DDSs has been widely explored and is being used in clinical trials and other clinical settings. This review summarizes the current topics of EVs as DDSs in cardiac disease.Cardiac diseases such as myocardial infarction and heart failure have been the leading cause of death worldwide for more than 20 years, and new treatments continue to be investigated. Heart transplantation, a curative treatment for severe cardiac dysfunction, is available to only a small number of patients due to the rarity of donors and high costs. Cardiac regenerative medicine using embryonic stem cells and induced pluripotent stem cells is expected to be a new alternative to heart transplantation, but it has problems such as induction of immune response, tumor formation, and low survival rate of transplanted cells. On the other hand, there has been a focus on cell-free therapy using extracellular vesicles (EVs) due to their high biocompatibility and target specificity. Exosomes, one type of EV, play a role in the molecular transport system  Despite more rigorous management of risk factors such as smoking, dyslipidemia, and hypertension, cardiovascular diseases such as myocardial infarction (MI) and heart failure (HF) have been the leading cause of death worldwide for more than 20 years . Endovasin vivo, such as the blood‒brain barrier [EVs are vesicles composed of lipid bilayers budding out of almost all cells . EVs hav barrier , 21. EVs barrier –24.In this review, with hopes for EVs serving as DDSs in the field of cardiac disease treatment, we focus on the therapeutic effects of EVs in several cardiac diseases and recent results demonstrating EVs as DDSs.in vitro [EVs are a generic term for particles naturally released from almost all cells that are delimited by a lipid bilayer . Accordiin vitro . Specifiin vitro –42. ExosEVs have been found in body fluids such as blood , urine , saliva The most common method to remove extraneous substances in cell culture supernatants or blood samples is stepwise centrifugation . There aThis method uses polyethylene glycol (PEG) as a precipitant. EVs can be isolated by mixing the sample with PEG, allowing it to stand, and then centrifuging. The advantage of this method is that it does not require an ultracentrifuge or expensive special devices. The method is as simple as UC. However, the size range of the isolated products is wide, and there is a possibility of contamination by proteins or EVs larger than exosomes .The immunoprecipitation (IP) isolation method uses antibodies that recognize EV membrane proteins. Since the IP method is based on an antigen–antibody reaction, it is possible to isolate EVs with high purity and specificity . Howeverin vivo. At present, SEC and UC are not sufficient for clinical applications regarding EV recovery and purity. We think that, to advance the clinical application of EVs, new technological innovations in recovery methods will be essential. In fact, in the preclinical stage at the laboratory level, cultured cell-derived EVs are often used in research because they are relatively easy to handle and a stable supply of EVs of constant quality can be easily obtained, but the problem is that only a small number of EVs can be isolated. Currently, several strategies are being investigated to solve this quantitative problem of EV isolation [et al. used a hollow fiber culture system, which enabled continuous production of EVs and increased EV production by more than 40-fold compared to conventional cell culture techniques [et al. reported that exosome-like vesicles obtained from the plant acerola juice can be stably supplied at a low cost. Acerola-derived vesicles can be orally administered to mice, and the accumulation of EV inclusions in target organs has been confirmed [In addition to the above, there are several other purification methods for EVs. For example, there are size-exclusion chromatography (SEC) methods, tangential flow filtration, separation by biophysical properties such as surface charge or acoustic, and membrane-affinity columns. However, current investigations of EVs are focused on basic aspects such as the more convenient method for EV isolation (mainly SEC and UC) . Currentsolation . For exachniques . Others chniques . Althougonfirmed . IsolatiEVs affect receptor cells by delivering encapsulated nucleic acids and proteins, etc., and several methods have been developed to encapsulate pharmacologically active substances within EVs. These methods can be divided into two main categories. One is the preloading method, in which the EV-producing cells are modified before EVs are isolated, and the other is the postloading method, in which the isolated EVs are loaded with the drug by chemical or physical means.The preloading method is a method in which cells that are the source of EVs are genetically modified to strongly express a target protein or miRNA and encapsulate it in secreted EVs; alternatively, cells are cultured in a medium containing a compound to be delivered, the cells are allowed to take up the compound, and the EVs encapsulated in the compound are secreted –60. The A postloading method involves directly processing EVs and loading them with therapeutic molecules such as miRNA. This method is relatively easy to use compared to preloading and is widely used today.et al. successfully introduced siRNA into EVs and delivered nucleic acids to monocytes and lymphocytes, but it requires optimization of the voltage, capacitance, range between electrodes in the cuvette, and concentration of siRNA and EVs [In postloading, the most commonly used method at present is electroporation, among which there are many reports of siRNA internalization . Wahlgre and EVs . While t and EVs .et al. reported that exosomes loaded with siRNA targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein [Coincubation is used to efficiently load therapeutic molecules such as siRNA into EVs without altering vesicle size distribution or integrity , 70. Didet al. reported that EVs loaded with therapeutic siRNA via sonication were taken up by recipient cells and were capable of target mRNA knockdown, leading to reduced protein expression [et al. confirmed that EVs obtained by sonication were nonspherical EVs with structural changes [Sonication is a method of allowing drugs to permeate membranes by temporarily disrupting membrane integrity through sonication , 72. Lampression . However changes . It has  changes .et al. reported that the saponin-assisted method, in particular, allowed up to 11-fold higher drug loading of hydrophilic porphyrins compared to passive methods [in vivo hemolytic activity [Various other postloading methods have been proposed, including mechanical extrusion , 74, freactivity . Thus, det al. successfully expressed a protein called the RVG peptide on the membrane. This RVG peptide is a neuron-selective protein that binds to acetylcholine receptors, and its expression on the EV membrane enables specific delivery to neurons [et al. used crosslinkers to modify oligoarginine peptides against EV membrane proteins. The oligoarginine peptide modification allowed the active induction of macropinocytosis without cytotoxicity, thereby dramatically increasing the efficiency of EV uptake into target cells [EVs are expected to have a target specificity originally to their donor cells because they have many of the similar surface proteins of their donor cells. Thus EV surface proteins are specific ligands for recipient cell surface receptors, e.g., integrin family, etc. . In fact neurons . Nakase et cells . In thiset al. confirmed the prolonged therapeutic efficacy of EVs incorporated into alginate hydrogels in a mouse model of myocardial infarction [Magnetic, inorganic materials can be used for noninvasive treatment since their strength and direction can be easily controlled, enabling targeting to specific sites and improving delivery efficiency . In partfarction . Other rfarction –93.Generally, the biological functions of EVs depend on the state of the donor cells and can change during different microenvironments . For exaMI is a disease in which a coronary artery that nourishes the myocardium is blocked, resulting in necrosis of the myocardium due to lack of oxygen. The key to the treatment of MI is to rescue and protect myocardial cells, which once necrotic, will never regenerate. Once cardiomyocytes develop ischemia, inflammatory macrophages immediately accumulate and begin phagocytosis of the necrotic cells. Eventually, the spaces that once had cells are filled by fibrosis, which leads to lethal arrhythmias and reduced cardiac function. In addition, once occluded coronary arteries may recanalize, a large number of reactive oxygen species (ROS) flow into distal tissues, leading to necrosis of cardiomyocytes that could still be viable. This phenomenon, called ischemia/reperfusion injury (I/R injury), is also important in understanding myocardial damage caused by MI. Furthermore, as is generally observed in all tissues, the myocardium begins angiogenesis from the time it is exposed to ischemia to resist the lack of oxygen. EVs are involved in each of these processes: inflammation, fibrosis, I/R injury, and angiogenesis. In recent years, the efficacy of MSC-EVs has been widely reported, but there have been other reports of cardioprotective effects of EVs derived from various cell types.et al. reported that circulating EVs carrying IL-1α and IL-1β were increased and that the reduction of these inflammatory EVs improved cardiac function [Myocardial ischemia or inflammation causes myocardial cell loss, which in turn leads to replacement fibrosis in an attempt to maintain the myocardial tissue architecture. Following fibrosis, the electrophysiological integrity of myocardial tissue is also impaired, which is known to trigger arrhythmias and cause diastolic dysfunction due to increased stiffness. Using animal models of MI, Biemmi function . Inflammet al. reported that BM-MSC-derived EVs (BM-MSC-EVs) maintain anti-inflammatory macrophage phenotype polarity in a mouse MI model via miRNA-182 delivery, which has important effects on cardiac repair, inhibition of toll-like receptor 4 (TLR4) in recipient cells, and immune regulatory properties [Zhao operties . EVs deroperties . AD-MSC-operties . AD-MSC-operties , 100. InReports of EVs derived from MSCs are still the most common, with the second most common being reports of cardiosphere-derived cells (CDCs) serving as secretory cells. CDC-EVs have also been reported to have anti-inflammatory effects. In a rat MI model, treatment with CDC-EVs led to decreased expression of inflammatory genes such as Nos2 and Tnf. After 48 h of MI, CD68 + macrophages were reduced in the infarct border tissue. miRNA-181b in CDC-EVs is transferred to macrophages, reducing PKCδ transcript levels. This has been reported to alter the phenotype of macrophages and exert a cardioprotective effect . It has et al. reported that in a mouse model of chronic and acute MI, treatment with iPS-cardiac progenitor cell-extracellular vesicles (iPS-CPC-EVs) induced immune-related signaling pathways and promoted tissue repair in damaged hearts. In an acute model characterized by a strong inflammatory response, the number of neutrophils decreased, the expression of inflammatory cytokines such as IL-1α, IL-2, and IL-6 decreased, and anti-inflammatory IL-10 increased. In a chronic model, inflammatory monocytes and cytokines, namely, IL-1α, IL-1β, TNFα, and IFNγ, were decreased in the MI area [iPS cells have shown their efficacy in stem cell therapy, and cardioprotective effects have also been reported in EVs from iPS cells. Recently, Correa  MI area .Many reports on the anti-inflammatory effects of EVs after MI have focused on the regulation of inflammatory macrophage polarity, which is also an important target in other inflammatory diseases. EVs derived from ischemic tissue and cells induced anti-inflammatory macrophage polarity and decreased the expression of inflammatory cytokines such as IL-1α, IL-2, and IL-6, suggesting that they may have anti-inflammatory properties.To rapidly ameliorate the ischemic/hypoxic state of the infarcted myocardium, the endocardial endothelium is induced, and angiogenesis is initiated by the action of vascular endothelial growth factor (VEGF) and other factors secreted by cardiomyocytes. This section describes EVs and angiogenesis with a focus on secretory cells, mainly MSCs, CPCs, and stem cells (iPS and ES cells).et al. observed that BM-MSC-EVs injected intravenously into mice with MI recovered cardiac function by increasing vascular density through downregulation of Efna3, a target gene of miRNA-210. Zhu et al. reported that this BM-MSC-EV-derived miRNA-210 was involved in the reduction of infarct size and apoptosis of cardiomyocytes, activation of resident progenitor cells, and ultimately in the improvement of cardiac function, in addition to its angiogenic effect [Wang c effect , 105.in vitro and have been used as a cardiac regeneration therapy by being transplanted into the infarcted heart [Cardiomyocyte progenitor cells (CPCs) are considered pluripotent stem cells that differentiate into cardiomyocyte-like cells and vascular cells ed heart –108. CPCed heart , and theed heart , 111.et al. The results showed that iPSC-EVs, as well as iPSCs, were enriched in miRNA associated with angiogenesis, adaptation to hypoxic stress, cell cycle regulation, and senescence processes. In particular, specific miRNA involved in cell proliferation, cell differentiation, apoptosis, and maintenance of self-renewal capacity and pluripotency, such as let-7, miRNA-145, the miRNA-17–92 cluster, and miRNA-302a-5p, were detected only in iPSC-EVs, not in iPSCs [Stem cell-derived EVs, such as those derived from iPS cells and ES cells, have been reported to have angiogenic effects similar to those of their parent cells, and several reports have suggested that they are superior to treatment with secretory cells themselves in several respects. Extensive transcriptomic and proteomic studies were performed on mouse FB-derived iPSC-EVs by Adamiak in iPSCs . On the in iPSCs . Thus, tPluripotent stem cells widely used for cardiomyocyte therapy also include ESCs . InjectiSimilar to inflammation after MI, ischemic tissues and cells promote angiogenesis to recover from hypoxia, and it was suggested that EVs were also involved in this process. EV therapy for angiogenesis may also be effective for ischemic heart disease such as angina pectoris, which is a preliminary stage of MI. It is expected that the effectiveness of EV therapy will be reported in the prevention of MI and the treatment of many ischemic diseases, not limited to MI.I/R injury occurs after an organ experiences an ischemic injury, and then blood flow is resumed. I/R injury is considered to be caused by ROS produced at various sites that disturb mitochondrial function and by hypercontractile zone necrosis due to excessive intracellular Ca2 + influx.et al. reported that in a rat MI model, treatment with BM-MSC-EVs pre-reperfusion reduced reperfusion injury by inducing increased autophagy in cardiomyocytes via the AMPK and Akt pathways, reducing cell apoptosis and infarct size [Liu rct size . In theirct size , 119.I/R injury is a common occurrence, especially during the catheterization of MI. The use of these EVs together with catheterization may minimize reperfusion injury.Cardiac fibrosis results from the activation of cardiac FBs and deposition of excess extracellular matrix, leading to increased stiffness and reduced flexibility of the myocardium, causing myocardial contractile or diastolic dysfunction . An impoet al. reported that CDC-EVs highly internalized miRNA-92a and attenuated myocardial fibrosis and improved survival in a mouse model of MI [There have been numerous reports of miRNA associated with fibrosis after MI –123. Forel of MI .Fibrosis is the result of an inflammatory response and is a state of burnout. Fibrosis is an irreversible phenomenon; it is important to suppress or reduce fibrosis, and the EVs described above were thought to have this effect. Currently, catheterization and bypass surgery are practiced as effective treatments for MI. In addition, an early combination of EV therapy with antifibrotic effects is expected to have a greater cardiac function preservation effect by preventing fibrosis.HF is a clinical syndrome caused by structural and functional abnormalities of the heart . The cliEVs from HF patients showed a decreased amount of miRNA-21-5p. Treatment with HF patient-derived EVs (HF-EVs) in a mouse myocardial infarction model resulted in reduced cardiac function and worsened left ventricular remodeling. More detailed analysis showed that HF-EV-derived miRNA-21-5p promotes angiogenesis and cardiomyocyte survival via the PTEN/Akt pathway and cardiac repair via EVs . In HF-EHypertrophic myocardium is often the cause of poor cardiac function, and there have been reports on cardiac hypertrophy and EVs. In cultured cardiomyocytes, MSC-EVs also inhibited hypertrophy of cells stimulated with angiotensin II. In addition, treatment of mice with induced HF (TAC mice) with BM-MSC-EVs showed significant protection of the myocardium against cardiac hypertrophy, antifibrotic effects by promoting premature aging of cardiac FBs, and maintenance of cardiac function under pressure overload. These results suggest that BM-MSC-EVs have an inhibitory effect on cardiac hypertrophy and may be an effective therapeutic tool against cardiac remodeling by promoting apoptosis and antifibrotic effects .In vitro, FBs stimulated with TNF-α also release EVs with high expression of miRNA-27a, miRNA-28-3p, and miRNA-34a, inducing dysregulation of the Nrf2 pathway. The resulting oxidative stress disorders have been shown to promote cardiac remodeling and dysfunction [In animal models of cardiac hypertrophy, EVs from hypertrophic cardiomyocytes were shown to activate macrophages by transferring miRNA-155 and induce adverse cardiac remodeling by releasing the inflammatory cytokines IL-6 and IL-8 , 136. Infunction . Cardiacfunction –140.HF is the result of various diseases, and many aspects of its pathogenesis remain unknown. EVs can influence the microscopic communication between cells, which will lead to the elucidation of the pathophysiology of cardiac diseases and new therapeutic agents.The few studies involving EVs and arrhythmias mainly focus on pathophysiology and diagnosis. Several studies have been reported on the diagnosis of atrial fibrillation and one of its causes, atrial fibrosis –145.et al. demonstrated that cardiomyocytes treated with MFB-derived EVs exhibit downregulation of the L-type calcium channel Cav1.2. They considered EV-mediated crosstalk between MFBs and cardiomyocytes, contributing to increased vulnerability to atrial fibrillation by reducing the expression of Cav1.2 in cardiomyocytes [et al. found that in beagles undergoing rapid atrial pacing for 7 days, the number of EVs in both the atria and plasma increased. Plasma EVs contained high levels of miRNA-21-5p, which was upregulated in the atria and was associated with decreased expression of its target, tissue inhibitor of metalloproteinase 3 (TIMP3), as well as increased expression of transforming growth factor-β1 (TGF-β1), collagen I/III, and matrix metalloproteinases. Furthermore, they reported that these effects in the atria were suppressed by inhibitors (GW4869) of EV generation, suggesting that miRNA in EVs is involved in part in the fibrosis progression process and that these EVs may be targets in the treatment of atrial fibrillation [As mentioned above, the most important step in fibrosis is the activation of cardiac FBs to MFBs. Paracrine factors released from MFBs modify ion channel expression in cardiomyocytes. Decreased expression of the L-type calcium channel Cav1.2 is a characteristic of atrial fibrillation-associated ion remodeling. Li myocytes . Yao et illation .EVs contain not only miRNA but also a wide variety of proteins and cytokines, and there have been numerous reports of their therapeutic effects in the field of cardiovascular medicine. The reports of cardioprotective EVs listed here are just a few. However, current EV therapies are far from clinical application, and most of them are at the level of animal experiments. A major reason for this is the difficulty in reaching and maintaining a sufficient amount of EVs in the heart to achieve an effect. The greatest challenge to clinical application is how to increase the cardiac specificity of EVs. Hence, attempts to improve target specificity and retention in the heart are discussed in the next section.As described above, EVs and EV-associated miRNA have been reported to demonstrate cardioprotective effects in cardiac diseases, and their high potential as a therapy for cardiac diseases has been recognized. However, it is also true that none of them are at the level of clinical application. The most important issues that need to be resolved are target specificity to the heart and local maintenance. To resolve this issue, creative efforts are being developed to further enhance the therapeutic effect on the heart, such as modifying EV inclusions, improving delivery to the myocardium, combining them with other tools, and investigating methods of administration, which are described below.et al. loaded BM-MSC-EVs with miRNA-132. miRNA-132 directly targets p120RasGap (RASA1) and regulates endothelial cell behavior during angiogenesis. Treatment of a mouse MI model with miRNA-132-loaded BM-MSC-EVs markedly enhanced peri-infarct angiogenesis and significantly increased the left ventricular ejection fraction [By the electroporation method described above, Ma fraction .et al. similarly demonstrated the electroporation method to load MSC-EVs with miRNA-101a, a major inhibitor of fibrosis. Surprisingly, even though only 4% of the injected EVs reached the ischemic myocardium, they reduced infarct size and fibrosis and improved cardiac function while inducing anti-inflammatory effects [Wang  effects .et al. found that BM-MSC-EVs overexpressing miRNA-148a had a significant reduction in SPARC-associated modular calcium-binding protein 2 (SMOC2), thereby inhibiting the onset of atrial fibrillation and reducing cardiomyocyte apoptosis [Zhang poptosis . Thus, mpoptosis –147.Cardioprotective additives within EVs are not limited to miRNA but also include a wide variety of natural compounds, transcription factors, cytokines, lncRNA, and many others. Curcumin, a natural compound, has both anti-inflammatory and antifibrotic effects –150. Mixet al. used an atrial fibrillation model and showed that treatment of rats with Nrf2 lentivirus-transduced BMSC-EVs significantly downregulated the Nrf2/HO-1 pathway and suppressed arrhythmias, myocardial fibrosis, apoptosis, and inflammation due to atrial fibrillation [Xu illation .et al. obtained IFN-γ-loaded MSC-EVs by coculturing IFN-γ with MSCs. Then, IFN-γ-loaded MSC-EVs were used to treat a mouse MI model in the infarction region, increasing the amount of miRNA-21 and causing decreased fibrosis, reduced apoptosis of cardiomyocytes, and improved cardiac function [Zhang function .In addition, X-inactive specific transcript (XIST), a type of lncRNA, was transfected into EVs derived from mouse adipose tissue-derived mesenchymal stem cells (AMSCs) and then injected into an atrial fibrillation mouse model. As a result, atrial fibrillation was suppressed. They suggested that XIST may blunt myocardial pyroptosis by absorbing miRNA-214-3p to promote Arl2 expression, providing encouraging insight into XIST-based targeted therapy for atrial fibrillation .In the following section, we discuss reports of EVs with improved cardiac targeting or cardiac retention to increase their therapeutic effect on the heart Table The next challenge is to effectively deliver and retain EVs, enhanced by the loading of therapeutic additives, to the site of cardiac damage. EVs are combined with hydrogels or sprays to increase EV retention in the local area of the heart. Additionally, directly administering them locally is expected to have the effect of prolonged local retention of EVs.et al. demonstrated that genetically engineered ISL1-MSC-EVs overexpressing islet-1 (ISL1) have endothelial-protective and angiogenesis-promoting effects. Furthermore, they found that the combined use of angiogenin-1 hydrogel significantly maintained ISL1-MSC-EVs in the ischemic region, improving endothelial cell survival and angiogenesis and enhancing MI recovery [et al. constructed an injectable ExoGel by embedding MSC-EVs in a hyaluronic acid hydrogel; injection of ExoGel into the pericardial cavity of TAC mice reduced left ventricular chamber size and prevented thickening of the left ventricular wall thickness. The feasibility and safety of ExoGel injection were further confirmed in a porcine model [Regional infusion of miRNA-181a-overexpressing MSC-EVs for MI suppresses the inflammatory response, increases the Treg cell ratio through inhibition of c-Fos protein, and promotes recovery of the infarcted heart . Howeverrecovery . Cheng ene model .et al. constructed hUC-MSC-EVs binding an injectable conductive hydrogel (Gel@Exo). Gel@Exos effectively prolonged EV preservation in ischemic myocardium, increased l left ventricular ejection fraction, reduced fibrotic areas, and greatly improved cardiac function after being injected into the injured rat heart. Gel@Exos also promoted cell proliferation and angiogenesis and had a marked therapeutic effect on postmyocardial infarction I/R [Yang tion I/R .et al. combined cardiac patch formation with intrapericardial injection of biocompatible hydrogels containing EVs to achieve minimally invasive delivery of therapeutic agents into the pericardial cavity for cardiac repair. Cardiac patches based on intrapericardial injection showed strong cardiovascular repair performance and improved cardiac function in both mouse MI models and clinically relevant porcine models [Cheng e models , 159. Thet al. produced a minimally invasive exosome spray (EXOS) based on MSC-EVs and biomaterials. The treatment involves spraying a mixture of MSC-EVs, thrombin, and fibrinogen on the surface of the infarcted myocardium by injection into the epicardium. In a mouse model of acute MI, EXOS inhibited fibrosis, promoted endogenous vascular myogenesis in the injured heart, and improved cardiac function. Furthermore, EXOS has been shown to be a promising strategy to deliver therapeutic EVs for cardiac repair in a porcine model [Yao ne model .in vivo half-life and rapid clearance make the intravenous injection of EVs insufficient for the treatment of target lesions. Therefore, many homing peptides have been discovered that target diseased tissues and organs, and homing peptides that are decorated with EVs and promote targeting to damaged tissue areas have been proposed.Treatment with a hydrogel or spray in combination with EVs certainly increases the retention of EVs in the heart, but both require regional injection and are invasive, making them difficult to apply clinically. Intravenous injection of EVs, on the other hand, is a relatively minimally invasive method of treatment that can be easily applied clinically. Although EVs are said to have a certain degree of target specificity, their short et al. constructed CPCs overexpressing CXCR4, which binds to stromal cell-derived Factor 1 (SDF-1α). SDF-1α is overexpressed in ischemic tissue, including infarcted myocardium. Intravenous injection of CXCR4-overexpressing CPC-EVs into rat models of MI resulted in a reduction in infarct size and improved left ventricular ejection fraction compared to injection of unmodified EVs. This effect was attributed to the accumulation of CXCR4-overexpressing CPC-EVs in SDF-1-rich infarcted myocardium, and their contents were effectively taken up by the infarcted myocytes [et al. reported that MSC-EVs were modified with monocyte mimics through membrane fusion to improve the delivery efficiency of EVs to ischemia-injured myocardium. The monocyte membranes (Mons) were isolated from RAW 264.7 cells with commercial kits. MCS-EVs with Mons were cocultured and then passed through a polycarbonate membrane to obtain monocyte mimic-bioinspired MSC-EVs (Mon-Exos). Mon-Exos exhibited enhanced targeting efficiency to injured myocardium by mimicking the recruitment feature of monocytes after I/R. This strategy allowed Mon-Exos to promote endothelial maturation during angiogenesis and regulate macrophages after I/R, ultimately improving cardiac function in I/R model mice [et al. designed EV exosomes containing ischemic myocardial target peptides. To increase the accumulation of MSC-EVs carrying hsa-miRNA-590-3p, which promotes cardiomyocyte proliferation, at the MI region, cTnI-targeted EVs were created by expressing a cTnI-targeted short peptide on the surface of MSCs by transfection. These EVs were able to localize to the infarction region along the cTnI concentration gradient, and hsa-miRNA-590-3p-loaded MSC-EVs were endocytosed by cardiomyocytes, promoting peri-infarction myocyte proliferation and ultimately restoring cardiac function [Ciullo myocytes . Zhang edel mice . Focusinfunction . In addifunction . Other pfunction , 166.et al. developed a novel strategy using magnetic nanoparticles to accumulate EVs in the region of MI treatment. Two types of antibodies (GMNPECs) were designed on the surface of these magnetic nanoparticles, which can bind to both the CD63 antigen, an EV surface marker, and myosin light chain surface markers of injured cardiomyocytes. By applying a regional magnetic field, therapeutic EVs captured by GMNPECs actively accumulate in the infarcted heart region. In rabbit and rat models of MI, EVs accumulated in damaged cardiac tissue and induced a reduction in infarct size, enhanced angiogenesis, and improved cardiac function [Liu function .This article focuses on the latest findings on EVs as DDSs in the cardiac field. Although EVs tend to be focused on oncology, there are many reports of cardioprotective EVs as described above. Only a few effective drugs have been developed in recent years for the treatment of cardiovascular diseases, so one cannot help but have high expectations for EVs. Similarly, cell-based regenerative medicine has shown great promise for cardiac disease, but compared with cell-based therapy, EVs offer several potential advantages. The potential advantages of EVs over cell-based therapy include EV stability, relative non-immunogenicity, and capacity for pre- and post-isolation modification . Further


Background: Intracranial photoplethysmography (PPG) signals can be measured from extracranial sites using wearable sensors and may enable long-term non-invasive monitoring of intracranial pressure (ICP). However, it is still unknown if ICP changes can lead to waveform changes in intracranial PPG signals.Aim: To investigate the effect of ICP changes on the waveform of intracranial PPG signals of different cerebral perfusion territories.Methods: Based on lump-parameter Windkessel models, we developed a computational model consisting three interactive parts: cardiocerebral artery network, ICP model, and PPG model. We simulated ICP and PPG signals of three perfusion territories  in three ages  and four intracranial capacitance conditions . We calculated following PPG waveform features: maximum, minimum, mean, amplitude, min-to-max time, pulsatility index (PI), resistive index (RI), and max-to-mean ratio (MMR).Results: The simulated mean ICPs in normal condition were in the normal range (8.87–11.35 mm Hg), with larger PPG fluctuations in older subject and ACA/PCA territories. When intracranial capacitance decreased, the mean ICP increased above normal threshold (>20 mm Hg), with significant decreases in maximum, minimum, and mean; a minor decrease in amplitude; and no consistent change in min-to-max time, PI, RI, or MMR  for PPG signals of all perfusion territories. There were significant effects of age and territory on all waveform features except age on mean.Conclusion: ICP values could significantly change the value-relevant  waveform features of PPG signals measured from different cerebral perfusion territories, with negligible effect on shape-relevant features . Age and measurement site could also significantly influence intracranial PPG waveform. Intracranial pressure (ICP), defined as the pressure within the craniospinal compartment, is an important physiological parameter that reflects the biomechanical status of the brain. ICP is derived from cerebral blood and cerebrospinal fluid (CSF) circulatory dynamics. ICP can be significantly changed in many neurological diseases . For decThe photoplethysmography (PPG) technology has been applied in the daily monitoring of many physiological parameters and may enable non-invasive long-term ICP monitoring. The cyclic fluctuations of a PPG signal reflect volumetric changes in the microcirculation, which is regulated by many physiological factors, e.g., respiratory pattern, arterial stiffness, and the mechanical properties of surrounding tissues. Therefore, PPG signals derived from the distal area of intracranial arteries might reflect ICP-related changes in cerebral microcirculation. The infra-red PPG signals measured from extracranial skin surface could reflect the intracranial microcirculation in different cerebral perfusion territories . A recenComputational modelling and simulation based on biomechanical and hemodynamic theories have been widely applied in the investigation of intracranial blood flow and ICP . EspeciaTo fill this research gap, we aim to develop a computational model of intracranial PPG signals and investigate if the changes in ICP could lead to the changes in intracranial PPG signals of different cerebral perfusion territories .As shown in The cardiocerebral arterial network was based on the classic brain circulation model proposed by Regarding the outlets, the extracranial ones included thoracic aorta, brachial arteries (left and right), and external carotid arteries (left and right). These arteries were connected to a 3-element Windkessel model . The resTo simulate the artery blood flow in different age groups, we used age-dependent parameters in the Windkessel models of aorta and common carotid arteries.In the aorta model, we used the pressure-dependent Windkessel capacitance element proposed by The biomechanical relationship between the capacitance of common carotid artery and local blood pressure is described by a non-linear exponential function:ood flow .CCCAP=C studies . The age studies .The computational model for continuous ICP simulation was based on the classic model proposed by −6 m3, or 5 ml) was set marginally below the normal range (6.66–20 ml) derive from  is the transient value of simulated PPG signal, and To quantitatively investigate the ICP-induced changes of PPG waveform, we used five waveform features, as shown in servable .Based on the directly measured basic waveform features, we calculated three secondary waveform features which have been applied in hemodynamic research: pulsatility index (PI): velocity .The simulation was performed on MATLAB-Simulink . We simulated the ICP and PPG signals in male subjects of three ages: 20, 40, and 60 years old. The simulation was repeated in four pathophysiological conditions of intracranial capacitance decrease: 0 , 25%, 50%, and 75%. To verify the model, the ICP values simulated at normal condition were compared with the results of existing physiological measurement. Each simulation lasted 30 s. To avoid any initial effect, the features were measured in the first cardiac cycle after 10 s when the signal was stable. The PPG waveform features derived were quantitatively compared between different intracranial capacitance conditions to investigate if ICP changes could lead to the waveform changes of intracranial PPG signals.As shown in As to the PPG waveform, it can be observed that PPG signals of ACA, MCA, and PCA territories are similar in amplitude and baseline, but different in waveform . There iAs a more general case of all the simulations, Therefore, the model can reliably simulate the ICP values in subjects with different ages, and reflect the waveform features of human cerebral microcirculation in different perfusion territories.As shown in In On the other hand, we observed significant effects of age and cerebral perfusion territory on all the waveform features. When age increases, maximum, amplitude, PI, RI, and MMR are higher, while the minimum and min-to-max time are lower, with negligible changes of the mean. Compared with PCA and ACA territories, MCA territory has lower maximum, minimum, amplitude, PI, RI, and MMR, with lower age-relevant differences in min-to-max time .In this study, based on lump-parameter Windkessel models with age-dependent non-linear elements, we simulated the effect of ICP increase due to intracranial capacitance decrease on the waveform features of PPG signals of different cerebral perfusion territories in subjects of different ages. The simulation results showed that ICP changes could significantly influence the maximum, minimum, and amplitude of PPG signals, with limited effect on min-to-max time, PI, RI, and MMR. As far as we know, this is the first study that quantitatively investigates the effect of ICP on the waveform features of intracranial PPG signals using computational simulation.Recent years have witnessed the development of non-invasive ICP monitoring technologies, including transcranial Doppler measurement of cerebral blood flow, near-infrared spectroscopy (NIRS), tympanic membrane displacement (TMD) , ophthalCompared with existing techniques, PPG signals can be detected from different body sites using low-cost wearable sensors without any need for expertise or training. PPG technology has been widely used in healthcare monitoring and early detection of cardiovascular diseases . TranscrMeanwhile, the majority of existing studies on PPG-assisted ICP monitoring are based on the PPG signals of fingers, retina, or other extracranial sites. The transcranial brain PPG technology was developed to study the venules of cerebral cortex  but has We observed that ICP significantly influenced the value-related waveform features , with negligible effect on shape-related ones . Especially, the ICP changes did not generate any consistent differences in PI, which is in accordance with Fernando et al.‘s observation in a recent systematic review that PI derived from TCD signal (TCD-PI) has poor accuracy in estimating ICP (range of area under the receiver operating characteristic curve: .550–.718) . Here weWe observed strong effects of age and measurement site  on intracranial PPG waveform features. The PPG waveform depends on many physiological features including age, measurement site, blood pressure, respiratory pattern, and neural activities . The bioPPG waveform also strongly depends on the blood pressure value and can be used for blood pressure estimation . The comThe proposed model consists of 33 artery segments from aorta to the Circle of Willis. To generate reliable simulation results for clinical application, the biomechanical properties of the arteries need to be evaluated individually in different subjects. In this model, the biomechanical and anatomic properties of the arteries were derived from some earlier physiological measurement results  where thin vivo ICP often has three peaks in a cardiac cycle: P1 (percussion wave), P2 , and P3 (dicrotic wave)  . This miic wave) . In the ic wave) . Some adic wave) . Howeveric wave) . A compuetc., which can significantly deform the PPG signals  especially in cerebral venous system , adding ICP values could significantly change the value-relevant  waveform features of PPG signals measured from different cerebral perfusion territories, with negligible effect on shape-relevant features . In addition, age and measurement site significantly influence all PPG waveform features except the mean.


Endometrial cancer (EC) is the most common gynecological malignancy in women, with increasing incidence in the last decades. Surgical therapy is the mainstay of the initial management. The present study analyzed the evolving trends of surgical therapy in Germany in patients diagnosed with EC recorded in a nationwide registry.All patients with the diagnosis of EC undergoing open surgery, laparoscopic surgery, and robotic-assisted laparoscopic surgery between 2007 and 2018 were identified by international classification of diseases (ICD) or specific operational codes (OPS) within the database of the German federal bureau of statistics.p < 0.001), of prolonged mechanical ventilation , and of prolonged hospital stay  compared to laparoscopic surgery. A total of 1551 (0.04%) patients undergoing laparoscopic surgery were converted to laparotomy. Procedure costs were highest for laparotomy, followed by robotic-assisted laparoscopy and laparoscopy .A total of 85,204 patients underwent surgical therapy for EC. Beginning with 2013, minimal-invasive surgical therapy was the leading approach for patients with EC. Open surgery was associated with a higher risk of in-hospital mortality (1.3% vs. 0.2%, The present study revealed that minimal-invasive surgery has increasingly become the standard surgical procedure for patients with EC in Germany. Furthermore, minimal-invasive surgery had superior in-hospital outcomes compared to laparotomy. Moreover, the use of robotic-assisted laparoscopic surgery is increasing, with a comparable in-hospital safety profile to conventional laparoscopy. Endometrial cancer (EC) is the most common gynecological malignancy in Europe and continues to be a major cause of morbidity and mortality . The estA survey conducted by the German Gynecologic Laparoscopy Working Group highlighted the fact that more than 50% of the surgical procedures for EC in Germany in 2012 were carried out by laparoscopy . LaparosThe main aim of this study was to analyze and describe the evolving trends in the surgical treatment of EC in Germany from 2007 and 2018, with special emphasis on the surgical technique and perioperative outcomes.Since 2005, data on all hospitalizations in Germany are available for scientific use via the Diagnosis-Related Groups statistics collected by the Research Data Center of the Federal Bureau of Statistics (DESTATIS). These hospitalization data, including diagnoses and procedures, are a valuable source of representative nationwide data on the in-hospital treatment of patients. This database represents a virtually complete collection of all hospitalizations in German hospitals that are reimbursed according to the Diagnosis-Related Groups system. From this database, we extracted data on patients with EC [ICD-10  C54*] who underwent surgical therapy  by laparotomy, laparoscopy, or by robotic-assisted laparoscopy (OPS 5–987). Finally, three groups of patients who underwent surgery for EC were compared: patients who underwent laparotomy, patients who underwent laparoscopy, and patients who underwent robotic-assisted laparoscopy.Our study did not involve direct access by the investigators to data on individual patients, the Research Data Center solely provided access to summary results. Therefore, approval by an ethics committee and informed consent were not applicable, in accordance with German law. All summary results were anonymized by DESTATIS. In practice, this means that any information allowing the drawing of conclusions about a single patient or a specific hospital was censored by DESTATIS in order to guarantee data protection. Moreover, in order to prevent the possibility to draw conclusions to a specific hospital, the data are verified and situationally censored by DESTATIS.In-hospital mortality, length of mechanical ventilation during operation and postoperative discharge destination, length of hospital stay, and reimbursement were part of DESTATIS’ main set of variables. Hence, our analysis focused on six different endpoints: in-hospital mortality, mechanical ventilation, discharge destination , length of hospital stay, and reimbursement. The baseline characteristics were used to calculate the Charlson Comorbidity Index (CCI) in order to assess general patients health status .No imputation for missing values could be conducted due to the absence of codes indicating that data were missing. If the patients electronic health record did not include information on a clinical characteristic, it was assumed that that characteristic was not present. Time trends were calculated using linear regression models. Between-group differences of patient characteristics and in-hospital outcomes were calculated using unpaired t-test and Fisher’s exact test without adjustment for multiple testing. Thus, p-values may not be interpreted as confirmatory but are descriptive in nature. All statistical analyses were performed with Stata 16 .p < 0.001), the annual number of laparotomies decreased from 5412 in 2007 to 2497 in 2018 (p < 0.001), with the number of minimal-invasive surgical procedures increasing from 1087 in 2007 to 5364 in 2018 (p < 0.001)  and were at lower risk of severe outcome and death according to the Charlson Comorbidity Index (CCI) (p < 0.001). Among the patients undergoing minimal-invasive surgery, patients undergoing robotic-assisted laparoscopy were significantly younger (p < 0.001) and at higher risk of severe outcome and death according to the CCI (p < 0.001) . The share of postoperative prolonged mechanical ventilation was higher in the group of patients who underwent laparotomy compared to the group of patients who underwent laparoscopy . A total of 1551 patients (0.04%) undergoing laparoscopy were converted to laparotomy. Patients who underwent laparotomy had a longer hospital stay  and were more likely to be discharged toward another hospital or rehabilitation facility (p < 0.001) compared to patients who underwent laparoscopy  (Table p = 0.84). Patients undergoing robotic-assisted laparoscopy were more likely to be discharged home compared to patients undergoing laparoscopy (p = 0.01) (Table p < 0.001) (Table None of the patients with EC staged by robotic-assisted laparoscopy died since the first recorded procedure in 2011 (Table The present study analyzed the trends in surgical therapy and in-hospital outcomes of patients undergoing surgery for EC in Germany. Analysis of a nationwide dataset, including all cases who underwent surgery for EC between 2007 and 2018, revealed that minimal-invasive surgical procedures have increasingly become the standard surgical procedure for patients with EC. Furthermore, minimal-invasive staging surgery had superior in-hospital outcomes compared to laparotomy. Moreover, the use of robotic-assisted laparoscopy is increasing with comparable in-hospital safety profile to laparoscopy. This evidence is in line with data from other European countries .EC is a major cause of morbidity and mortality, since it is a common cancer in women with rising incidence , 19. AccAlthough we found increasing use of robotic-assisted laparoscopy from 2011 until 2018, the share of robotic-assisted laparoscopies in all patients with EC in Germany was 3.2%. Compared to other countries, in Germany there is a long-lasting tradition in minimal-invasive techniques in gynecological surgery, especially in laparoscopic surgery [Two randomized trials showed the superiority of laparoscopic surgery with respect to in-hospital complications and quality of life compared to laparotomy for EC , 22. TheAlthough robotic-assisted laparoscopy was less frequently used in the current study, in-hospital outcomes are comparable with conventional laparoscopic surgery for patients with EC. Until 2018 no reported death among patients with EC undergoing robotic-assisted surgery in Germany was recorded. Furthermore, no conversion from robotic-assisted laparoscopy to open surgery was necessary in accordance with available evidence , 24.The nationwide introduction of robotic-assisted surgical staging in Denmark changed the surgical approach for early-stage EC from open surgery to minimal-invasive surgery . This chThe cost-effectiveness of robotic-assisted surgery is controversial and varies greatly in different surgical fields . Our stuThe strengths of this study include the analysis of a large nationwide dataset, with over 85 000 patients with EC, over a time span of 12 years. The dataset is well controlled by independent supervision. Therefore, it is reliable in respect to clinical characteristics and outcome risk analyses according to the three treatment groups. Several limitations need to be considered. Analyses were performed in a registry study setting from a national database according to ICD and OPS codes. Important clinical factors of patients with EC, e.g., tumor stage, initial extent of the disease, and subsequent adjuvant therapies, are missing in the present dataset precluding a balancing of the groups. Thus, the direct comparison between the three groups of patients has limitations, since higher tumor stage and disease extent at initial diagnosis determine the surgical technique. Furthermore, there was no follow-up available in order to evaluate long-term oncological outcomes of the three treatment groups.The present analysis shows that minimal-invasive surgery has increasingly become the standard surgical technique for patients with EC in Germany, with excellent in-hospital outcomes in clinical practice. Robotic-assisted laparoscopy is an emerging surgical procedure in Germany with promising results compared to conventional laparoscopy.


Background: Midline exploratory laparotomy is essential in emergency surgery, and effective closure of the abdominal wall is crucial for optimal healing and reduced complications. The far-near-near-far technique for rectus sheath closure has gained attention due to potential advantages over conventional closure due to the fact that even if one suture gives way it does not affect the nearby suture and the rectus sheath is still held in place. This study aims to compare these techniques in emergency exploratory laparotomy.Methods: This single-center prospective observational study included all patients undergoing emergency exploratory laparotomy at a tertiary care hospital. Patients were categorized into two groups based on the closure technique used: conventional closure or far-near-near-far technique. Sociodemographic data and comorbidities were collected. Operative time, closure time, and postoperative complications were assessed. Statistical analysis was performed using IBM SPSS Statistics 22.0 .Results: The study included patients with a mean age of 42.14 years. Operative and closure times did not significantly differ between the groups. There was no significant difference in comorbidities between the two techniques. The incidence of wound infection, dehiscence, burst abdomen, incisional hernia, and sinus formation did not significantly differ between the groups. Late complications were also similar.Conclusion: The far-near-near-far technique for rectus sheath closure in emergency exploratory laparotomy showed comparable outcomes to conventional closure methods. No significant differences were found in operative time, closure time, or postoperative complications. This study contributes to the understanding of different closure techniques, allowing surgeons to make informed decisions In emergency surgery, midline exploratory laparotomy is crucial in diagnosing and treating a wide range of life-threatening abdominal conditions . The sucConventionally, abdominal wall closure involves a continuous suture technique or interrupted sutures placed in a layered fashion. However, concerns have been raised regarding these closures' strength, integrity, and durability, particularly in emergencies where the abdominal wall is often under increased tension due to trauma or infection. In contrast, the far-near-near-far technique offers an innovative approach that incorporates multiple sutures and distributes the tension more evenly, potentially minimizing the risk of wound dehiscence and incisional hernias . A meta-This clinical comparison study aims to evaluate the outcomes associated with the far-near-near-far technique in comparison to conventional closure methods. Parameters such as time taken to operate, post-operative abdominal wall complications such as wound infection, dehiscence, burst abdomen, incisional hernia rates, and sinus formation were examined to assess the effectiveness of the far-near-near-far technique in an emergency exploratory laparotomy. Understanding the nuances of different closure techniques is vital for surgeons, enabling them to make informed decisions and employ the most appropriate method for each patient . By shedStudy designIt is a single-center prospective observational study conducted at a tertiary care hospital, AIIMS Bhopal.Study settingThis study was conducted in the surgery and emergency department at All India Institute of Medical Sciences, Bhopal a tertiary care teaching hospital in Central India. The study was conducted from March 11, 2020 to December 2021.Study populationAll patients over 18 years of age undergoing emergency exploratory laparotomy procedures at AIIMS Bhopal between March 2020 to December 2021 were included in the study. Patients who underwent elective laparotomy, pre-operative proven malignancy, previous laparotomy for any condition , discharge against medical advice or death before the 10th post-operative day, any requirement of a re-laparotomy within 10 days for a cause not attributable to a complication of wound closure and lack of adequate post-operative follow-up were excluded from the study.Sample sizeThis study incorporated universal sampling and included all the patients who underwent emergency exploratory laparotomy surgery in the surgery and emergency department at AIIMS Bhopal.Ethical statementPermission from the Institutional Human Ethics Committee- Post Graduate Research (IHEC-PGR) (LOP No: IHECPGRMD047) was taken before the commencement of the study. The subjects were informed about the research and procedures through a participant information sheet. Data collection was not done without written informed consent. Confidentiality of information has been maintained. Only the research team has access to personal information. Personal identifiers were removed during data analysis and reporting.Data collectionPatients undergoing emergency exploratory laparotomy surgery from March 2020 to December 2021 who fulfilled the inclusion criteria were approached and informed consent was taken. Patients were included in two groups according to the surgeon's closure method, i.e., conventional closure or “far-near-near-far” technique of abdominal wall closure. An instrument was developed to obtain the demographic and clinical data of the subjects in the study. The instrument consisted of two parts: Demographic and Clinical data. The demographic data included the following information: age, sex, date of admission, date of operation, date of discharge, number of post-operative outpatient visits, and period of postoperative follow-up in the hospital. Clinical data included information about the patients’ health status: the presence of comorbid illness, lifestyle factors, the diagnosis of the patient, the focus of insult, the operation done, the stoma formed, admission in the surgical intensive care unit for monitoring/mechanical ventilation, postoperative complications and the period of follow-up in the out-patient department. The follow-up was for twenty-one months and outcomes included wound infection, wound dehiscence, burst abdomen, and late complications .Operational definitionsContinuous/Conventional ClosureConventional closure included closure of rectus fascia in a continuous fashion. The sutures were placed 1 cm from the edge of the Linea alba on both sides and a 1-cm distance was maintained between two adjacent sutures.Far-Near-Near-Far/Interrupted ClosureThis technique included suture approximation of the rectus sheath, in an interrupted fashion. The entry and exit of Polypropylene was 2 cm from the wound edges and 1 cm from the edge of Linea Alba on either side. The distance between two adjacent sutures was 1 cm.Statistical analysisStatistical analysis was carried out using statistical packages for IBM SPSS Statistics 22.0 for Windows . Continuous and categorical variables were expressed as frequencies, means, and percentages, respectively. The chi-square test was used to compare categorical variables. Two-sided p-values were considered statistically significant at p<0.05. Logistic regression was done to assess the association of demographic variables, comorbidities, and lifestyle factors with wound infection and wound dehiscence.The flow of the study is depicted in Figure The study revealed that the mean age of the subjects enrolled was 42.14 ± 15.12 years. The majority of subjects in the study were obese and males comprised 68.25% of the study population. Table The mean total operating time in the continuous group was 177.25 ± 45.88 minutes which was longer than that in the far-near-near-far group was 160.80 ± 45.27 minutes (p=0.157). The mean total time to close the wound in the continuous group was 16.34 ± 3.219 minutes which was slightly lesser than that in the far-near-near-far group 17.94 ± 3.54 minutes (p=0.067). The two groups matched in terms of comorbidities and lifestyle factors. 18.8% patients in the continuous group had a stoma made and required post-operative ICU admission in contrast to 41.9% patients in the far-near-near-far group (Table Table Table The closure of the rectus sheath is critical in exploratory laparotomy, particularly in emergencies where the abdominal wall is under increased tension. The choice of closure technique can significantly impact patient outcomes, including the incidence of postoperative complications . In thisOne of the far-near-far technique's key advantages is its ability to distribute tension more evenly across the abdominal wall, potentially reducing the risk of wound dehiscence and incisional hernias. The far-near-near-far technique of abdominal wall closure is advantageous because it prevents the simultaneous involvement of the entire sheath and the sutures due to interruptions. This means that if one suture is infected and loosens, it does not spread to the nearby suture, and because the tension is equally distributed amongst all the sutures, the rectus sheath is still in place. Interestingly, a vent is inadvertently created, allowing the collected from the affected site to drain through, helping other sutures stay intact. This benefits us, as easy closure can be planned later without planning a significant operation when the patient stabilizes. This has a substantial advantage over the continuous technique because if any of the bites of continuous suture give way, it weakens the entire fascial closure and makes early closures difficult . HoweverWhile the study provides valuable information on the clinical comparison between the far-near-near-far technique and conventional closure methods, several limitations should be acknowledged. Firstly, the study design is observational, which may introduce bias and confounding factors, and the relatively small sample size limits the findings' generalizability. A randomized controlled trial with a larger sample size would provide more substantial evidence for comparing the two closure techniques. Secondly, the study was conducted at a single center, which may limit the generalizability of the findings. Multi-center studies involving diverse populations would enhance the external validity of the results. Additionally, the surgeon's discretion in selecting the closure technique introduces potential bias, and a randomized controlled trial would mitigate this bias. Finally, the far-near-near-far group exhibited a shorter mean follow-up period than the continuous group, which may have implications for assessing long-term complications.In conclusion, this study contributes to the existing knowledge on rectus sheath closure techniques in emergency exploratory laparotomy. Our study provides initial insights into the clinical comparison between conventional rectus sheath closure and the far-near-near-far process in an emergency exploratory laparotomy. While we did not observe significant differences in postoperative abdominal wall complications between the two approaches, further research with larger sample sizes is warranted. The far-near-near-far technique may offer potential advantages in terms of tension distribution and is balanced in terms of operative time in contrast to popular belief. Still, additional studies are needed to confirm these findings. Surgeons should consider individual patient characteristics and optimize perioperative care to minimize complications in emergency abdominal surgeries. This study adds valuable insights to the surgical community, highlighting the need for comprehensive assessment when selecting abdominal closure techniques in emergency abdominal surgery.


Despite its ability to summarise thousands of measurements into semantically interpretable components, GSA often results in hundreds of significantly enriched gene-sets. However, summarisation and effective visualisation of GSA results to facilitate hypothesis generation is still lacking. While some webservers provide gene-set visualization tools, there is still a need for tools that can effectively summarize and guide exploration of GSA results. To enable versatility, webservers accept gene lists as input, however, none provide end-to-end solutions for emerging data types such as single-cell and spatial omics. Here, we present vissE.Cloud, a webserver for end-to-end gene-set analysis, offering gene-set summarisation and highly interactive visualisation. vissE.Cloud uses algorithms from our earlier R package vissE to summarise GSA results by identifying biological themes. We maintain versatility by allowing analysis of gene lists, as well as, analysis of raw single-cell and spatial omics data, including CosMx and Xenium data, making vissE.Cloud the first webserver to provide end-to-end gene-set analysis of sub-cellular localised spatial data. Structuring the results hierarchically allows swift interactive investigations of results at the gene, gene-set, and clusters level. vissE.Cloud is freely available at   High throughput molecular technologies, such as RNA-seq, single-cell RNA-seq, spatial transcriptomics and proteomics, have unlocked new avenues of modelling and understanding the complexity of biological systems. However, this empowerment is dependent on appropriate analysis and interpretation of large high-dimensional data. Many statistical and computational approaches have been developed to address the challenge of genes/proteins prioritisation based on some statistics ; howeverThough GSA can summarise thousands of measurements into semantically interpretable components, it still presents experimental researchers with two major challenges. First, GSA often results in hundreds of significantly enriched gene-sets, primarily due to redundancy within and between knowledgebases . Since nExisting popular GSA web servers attempted to partially address the issues of result summarisation and broad applicability Table  16–25)..16–25). https://www.vissE.Cloud.We have previously addressed the issue of result summarisation of GSA results in our R/Bioconductor package, vissE , where wThe vissE.Clould workflow consists of three main steps Figure : (i) inpTo maintain versatility, vissE.Cloud accepts a wide range of inputs allowing the integration of the workflow with differential analysis of bulk transcriptomics, proteomics, single-cell and spatial transcriptomics data.P-value. vissE.Cloud supports seven different gene ID types, including UniProt, that are then mapped to their corresponding gene-sets. To facilitate proteomics analysis, vissE.Cloud can handle protein groups commonly produced from proteomics search tools such as MaxQuant  a list of genes of interest, such as those found to be significant in a differential analysis and (ii) genes with their associated statistics, commonly log-fold change or MaxQuant  and DIA-MaxQuant .Orchestrating Single-Cell Analysis (OSCA) workflow  ,36, whicP-value threshold, or filter gene-set by their size. In factor analysis, gene loadings for each factor are used as gene weights that are subsequently used to score gene-sets using the singscore R package  is computed for all words within the gene-set cluster. These results are then presented as word clouds with the TF-IDF score determining the size of the word. To link gene-set clusters to their member genes, gene-level statistics are projected on a protein-protein interaction network  and are The overall architecture for vissE.Cloud is shown in Figure vissE.Cloud presents analysis results using three main views that the user can access from the side panel Figure –C: (i) GIn this view, important GSA summary statistics associated with genes, gene-sets and clusters are displayed to allow users to validate and identify any issues that may occur in the GSA step. For example, vissE.Cloud shows the number of genes that were mapped to gene-sets in the database used, and that subsequently contributed to the GSA results. This information can reveal mismatching gene identifiers as a useful quality control step. At the gene-set level, distribution of their sizes and categories can uncover potential analysis bias. Additionally, these results can also inform the feasibility of theme identification: if the number of significant gene-sets is very small (in the 10s), any further result summarisation may not be necessary and may not reveal much more that a classic GSA analysis. Collectively, these summary statistics can guide users to understand the overall known functional information content of their data and the status of the GSA analysis performed.Here, users can investigate GSA results holistically by visualising the relationships between all significant gene-sets as a gene-set network, potentially uncovering consistent yet previously unknown patterns across the experiment. Different gene-set statistics and annotations such as (sub-)category, false discovery rate (FDR), gene-set size, enrichment score and node degree (a statistic to represent the connectivity of a gene-set) can be used to annotate the colour and size of nodes interactively. Users can change the colour scheme, choosing from 47 different palettes to use for visualisation. To enhance the user experience, site-wide preferred palettes can be specified for categorical, sequential, and diverging data types. Furthermore, this view offers agile network-based navigation between clusters. Interacting with the network by hover over gene-sets (nodes) highlights the gene-set cluster, shows the corresponding word cloud, and displays gene-level statistics and gene-gene interactions inferred from known protein-protein interaction networks .Since gene-set clusters are composed of numerous gene-sets, vissE.Cloud semantically describe them as word cloud to facilitate user exploration. Interactively, the ‘WordCloud Gallery’ panel renders word clouds progressively as a continuous feed, allowing optimised visualisation of even hundreds of clusters. The biological terms presented by the word clouds augment the user's domain knowledge of the biological systems of interest, relating the identified terms to the biology. As such, the relatively loose semantic definitions afforded by word clouds can be combined with expert domain knowledge to come up with a more complete semantic interpretation. The ‘WordCloud Gallery’ panel provides users entry into more detailed cluster exploration views provided by vissE.Cloud.This view allows thorough investigation of the composition and semantics of a gene-set cluster. Focusing on a selected cluster, vissE.Cloud displays four panels encompassing information across the three hierarchical levels. These panels are: (i) cluster-level word cloud description, (ii) gene-set level similarity network, (iii) gene-level statistics scatter plot and (iv) protein–protein interaction (PPI) network for the genes in the cluster. Collectively, presenting this multiple hierarchical information as a single inter-linked view greatly enhances the interpretation of results in the context of the biological system being studied.The results of the factor analysis of single-cell and spatial transcriptomics data performed using PCA are displayed in the ‘Factors Summary’ view. This view presents the top factors as word cloud panels, showing four genes-set clusters of each factor. This word cloud panelled view is coupled with the corresponding dimension reduction plots visualising the selected factor of interest. In the case of single-cell transcriptomics data, uniform manifold approximation and projection (UMAP) , t-stochTo generate biological hypotheses from ‘omics data, should researchers focus on a handful of important genes or on overall trends and hallmarks? This dilemma of determining the appropriate scale and scope of bioinformatics analysis has been a challenging issue preventing researchers from fully unleashing the potential of high-dimensional and high-resolution molecular data. On the one hand, gene function is dependent on molecular contexts and interactions that are often omitted if hypotheses are solely developed from focusing on a few important genes. On the other hand, it is also important to select a distinct subset of genes that represent observed trends to generate more specific testable hypothesis (e.g. using perturbation models).The solution presented in vissE.Cloud enables researchers to toggle between very broad trends represented in biological themes or gene-set clusters, and narrower contexts at the gene level. Empowered by highly interactive visualisations, researchers can generate hypotheses using both top-down and bottom-up approaches. In the top-down approach, users start with a biological theme of interest and investigate changes in their member gene-sets and genes. Alternatively, users can start with genes of interest and explore how their expression contribute to observed overall trends.By having an analysis core based on the R framework ensures vissE.Cloud remains versatile and abreast with newly developed methods. Supporting different input types including proteomics, single-cell, and spatial data, vissE.Cloud offers no-code access to methods that would otherwise require high technical expertise. The software engineering challenges of performing R-based long-running analyses while maintaining interactivity were addressed by coupling the backend server with a job queueing service and resolving the architectural complexity with container orchestration. This modular architectural design not only enables rolling out new methods and algorithms for emerging data types but can also be adapted to deploy a wide range of R-based bioinformatics pipelines beyond the scope of vissE.Cloud.This no-code access and intuitive interactive interface via the cloud will enable a widespread uptake of vissE.Cloud by researchers, even those users with limited bioinformatics experience. The ability to quickly deploy new methods and algorithms will enable high quality research with quality GSA results and visualisations.https://github.com/ahmohamed/vissEServerRpkg and on Zenodo at https://doi.org/10.5281/zenodo.7841244. The docker-compose setup for the full architecture is available upon request.The analysis core for the web server including example data is available as a R package on GitHub at


Artificial intelligence (AI) based on deep neural networks (DNNs) has demonstrated great performance in computer vision. However, their clinical application in the diagnosis and prognosis of cancer using medical imaging has been limited. Not knowing the AI’s decision-making process (interpretability) presents a major obstacle in AI medical applications. To this end, we studied and propose the integration of DNN-derived biomarkers and expert-derived radiomics in interpretable ConRad models. ConRad models achieved great performance for malignancy classification while maintaining inherent interpretability. Without interpretability, a black box classifier such as end-to-end DNNs may harbor critical failure modes that are unknown and unknowable.Despite the unprecedented performance of deep neural networks (DNNs) in computer vision, their clinical application in the diagnosis and prognosis of cancer using medical imaging has been limited. One of the critical challenges for integrating diagnostic DNNs into radiological and oncological applications is their lack of interpretability, preventing clinicians from understanding the model predictions. Therefore, we studied and propose the integration of expert-derived radiomics and DNN-predicted biomarkers in interpretable classifiers, which we refer to as ConRad, for computerized tomography (CT) scans of lung cancer. Importantly, the tumor biomarkers can be predicted from a concept bottleneck model (CBM) such that once trained, our ConRad models do not require labor-intensive and time-consuming biomarkers. In our evaluation and practical application, the only input to ConRad is a segmented CT scan. The proposed model was compared to convolutional neural networks (CNNs) which act as a black box classifier. We further investigated and evaluated all combinations of radiomics, predicted biomarkers and CNN features in five different classifiers. We found the ConRad models using nonlinear SVM and the logistic regression with the Lasso outperformed the others in five-fold cross-validation, with the interpretability of ConRad being its primary advantage. The Lasso is used for feature selection, which substantially reduces the number of nonzero weights while increasing the accuracy. Overall, the proposed ConRad model combines CBM-derived biomarkers and radiomics features in an interpretable ML model which demonstrates excellent performance for lung nodule malignancy classification. Cancer kills about 10 million people annually and is a leading cause of death worldwide. Lung cancer is the most prevalent type of cancer in the world . IndividTo overcome this challenge in the context of lung nodule malignancy classification, we have developed and investigated an interpretable machine learning model called ConRad that combines concept bottleneck models (CBMs), which predict tumor biomarkers, and radiomics features, which are based on expert-derived characterization of medical images . Both ofImportantly, instead of using the annotated biomarkers directly in the malignancy prediction, we followed the concept bottleneck model (CBM) architecture  and traiWe have performed a comprehensive evaluation of various machine learning (ML) algorithms in ConRad models. Through five-fold cross-validation, the performances were measured in terms of model accuracy, receiver operating characteristic (ROC) curves, and other metrics. For a baseline comparison, we also built an end-to-end convolutional neural network (CNN), which directly predicts malignancy. From the end-to-end CNN, the CNN features are extracted and used in independent ML classifiers for further comparison. Both the end-to-end CNN and the usage of CNN features represent uninterpretable black-box models since radiologists do not gain any understanding of how the model is making its prediction. Our interpretable models perform comparably or better than the CNN. There is an inherent trade-off between interpretability and accuracy in machine learning, including DNNs . InsteadIn the next While the comprehensive review of DNNs applied on the lung nodule classification is beyond the scope of this paper, we note a few related analyses of the LIDC-IDRI dataset ; see TabOur model shares similarities with the methods employed in ,19,20, wRadiomics extracts high-dimensional expert-derived features from medical images, some of them being clinically validated and interpretable by clinicians . There hThe proposed ConRad model was designed to extract different aspects of cancer images, leveraging well-established statistical properties and clinical variables of tumors. Particularly, our final model uses biomarkers predicted from a concept bottleneck model (CBM)  and radiWe particularly focus on CT images of lung tumors from the LIDC-IDRI (Lung Image Database Consortium and Image Database Resource Initiative) dataset . The datInput samples were created by first isotropically resampling the CT scans to 1 mm spacing and then extracting First, we conduct the radiomics feature extraction from LIDC-IDRI samples using the PyRadiomics package . Particuhttps://www.pytorchlightning.ai/, accessed on 15 April 2023) and an Nvidia V100 GPU.Second, a ResNet-50  model prNote, that the degree to which the described features are interpretable, as well as in which way they are interpretable, varies. Radiomics features are all interpretable in the sense that they follow from an explicit and simple mathematical definition. Since many of them represent rather abstract statistical features, their meaning may nonetheless be not intuitive for clinicians. The predicted biomarkers, on the other hand, are computed by an opaque algorithm (the DNN), but their meaning can be immediately understood.To match the input dimensions of the ResNet-50 model, input samples are upscaled to Third, we also extracted features from training a convolutional neural network (CNN) to directly predict the tumor status. For a fair comparison, the same ResNet-50 architecture used in CBM was used to build the CNNs. The preprocessing and training procedure is identical to the CBM described above. This end-to-end classifier gives us a baseline to be compared with our proposed interpretable ConRad model. Furthermore, we extracted 512 features from the global average pooling layer of the fine-tuned ResNet-50, which are also fused with the radiomics features and CBM-derived biomarkers for downstream classification. We investigated whether a black box DNN model may have superior performance for classifying lung cancer images, and if so, what trade-off between interpretability and accuracy may exist and be acceptable for radiological applications.Biomarkers + radiomics (ConRad models);Radiomics features;Biomarkers (predicted by CBM);CNN features;CNN + radiomics;CNN + biomarkers;CNN + radiomics + biomarkers .There are three types of features available for training a model to classify the malignancy of nodules. Using each type of feature and their combinations, we constructed a total of 7 datasets for the final classifier:Note that the nodule diameter appears in both the biomarker and radiomics feature sets. Having two features that are closely related would cause instability. Thus, when necessary we removed the diameter from the biomarkers. All datasets were z-score normalized on the training set, and identical normalization was applied on the test set.https://scikit-learn.org, accessed on 15 April 2023) implementation of these classifiers. The SVM and Lasso regularization parameters C and As final-layer classifiers , we applfeatures . For eacOverall, we built five classifiers using the seven aforementioned datasets, combing three types of features. We applied an independent 5-fold cross-validation, where each classifier was trained on four folds, and performance was evaluated on the hold-out fold. The performance metrics  were calculated and averaged across 5-fold cross-validation. A receiver operating characteristic (ROC) curve was constructed by measuring the false-positive rates (FPRs) and true-positive rates (TPRs) at a wide range of thresholds.Our proposed model can be contrasted with popular end-to-end DNN algorithms which are considered to be uninterpretable “black box” models. We are interested in creating an interpretable method, where the final prediction is explainable by statistically and clinically relevant features. Furthermore, we leverage and expose oncological knowledge by directly utilizing radiomics features. Importantly, ML classifiers competitively use multiple types of features (radiomics and biomarkers) which helps to highlight their interplay.ConRad models combine tumor biomarkers predicted by DNNs and radiomics features defined by radiological experts. LIDC-IDRI contains 8 biomarkers, which were used to construct a concept bottleneck model (CBM) using the pre-trained ResNet-50. We ran each of the CT scans through PyRadiomics to obtain first-order statistics (18 features), 3D shapes (14 features), and higher- order statistics (75 features). We trained and evaluated five different ML classifiers based on a total of 115 features.The model accuracy, recall, and precision were averaged over five-fold cross-validation, where the test set was not used in training. When the Lasso (least absolute shrinkage and selection operator) was additionally applied on logistic regression, only 12 out of 114 features . The five considered ML classifiers were trained on this feature set, and performances were measured over five-fold cross-validation  for predicting biomarkers was used. When applied, the proposed ConRad model does not need annotated biomarkers as they are usually not readily available in real world applications. In total, we investigated 35 classifiers, utilizing seven combinations of features and five ML algorithms. Additionally, an end-to-end CNN classifier was evaluated as a baseline. ConRad classifiers based on biomarkers and radiomics features showed excellent performance on par with the end-to-end CNN model, which inherently acts as a black box. Nonlinear SVM and logistic regression with the Lasso showed the best performance generally.The intermediate features that feed into the final classifier are interpretable and clinically meaningful by design. The biomarkers represent properties of nodules that have an intuitive meaning for clinicians, who can therefore gain an understanding of the decision-making process of the model. This can nurture trust in the ML model since the users do not have to blindly believe the model’s classifications. Instead, the users can comprehend, and even interact with, how the model reaches its decisions. For example, if a truly small nodule has been incorrectly predicted to have a large diameter, the clinician may recognize this by visually inspecting the CT scan . This may allow the clinician to make informed decisions with the support of ML. Furthermore, in the ConRad model, the diameter prediction can be corrected by the clinician, directly resulting in an updated prediction. Our ConRad model, therefore, lends itself to a human-in-the-loop (HITL) approach, that may help gain a deeper understanding and trust of the model’s operating characteristics.Besides using independent training steps to create an interpretable classifier, we also consider feature selection in malignancy classification. When combining biomarkers and radiomics features, the number of selected features was drastically reduced with the Lasso . Many biThe combination of biomarkers and radiomics features outperforms all other considered combinations, although the biomarkers demonstrated the most predictive power for the LIDC-IDRI data . Some ofOverall, the proposed ConRad model combines concept bottleneck models and radiomics to create an interpretable model. The model’s performance is on par with an end-to-end DNN classifier, despite the additional interpretability constraints. The increased transparency of our model can help radiologists and oncologists to understand its predictions, better allowing them to perform well-informed diagnoses. Without this critical interpretability component, a black box classifier such as an end-to-end DNN may harbor critical failure modes that are unknown and difficult to discover. Therefore, instead of focusing solely on model performance for medical applications, more investigations that consider interpretability are warranted to realize the broader incorporation of explainable AI into radiology and oncology.


Currently, decentralized redactable blockchains have been widely applied in IoT systems for secure and controllable data management. Unfortunately, existing works ignore policy privacy , causing severe privacy leakage threats to users since users’ policies usually contain large amounts of private information  and limiting the applications in IoT systems. To bridge this research gap, we propose PFRB, a policy-hidden fine-grained redactable blockchain in decentralized blockchain-based IoT systems. PFRB follows the decentralized settings and fine-grained chameleon hash-based redaction in existing redactable blockchains. In addition, PFRB hides users’ policies during policy matching such that apart from successful policy matching, users’ policy contents cannot be inferred and valid redactions cannot be executed. Some main technical challenges include determining how to hide policy contents and support policy matching. Inspired by Newton’s interpolation formula-based secret sharing, PFRB converts policy contents into polynomial parameters and utilizes multi-authority attribute-based encryption to further hide these parameters. Theoretical analysis proves the correctness and security against the chosen-plaintext attack. Extensive experiments on the FISCO blockchain platform and IoT devices show that PFRB achieves competitive efficiency over current redactable blockchains. The Internet of Things (IoT) is defined as connecting all objects through information-sensing devices such as radio frequency identification to the Internet, enabling intelligent recognition and management. The concept of IoT entails integrating sensors into various objects, including power grids and railways, enabling data collection and communication for seamless connectivity and interaction with the physical world ,2,3. Howhttps://www.mordorintelligence.com/industry-reports/blockchain-iot (accessed on 31 July 2023)), the market size of blockchain-based IoT systems is expected to grow from USD 568.51 million in 2023 to USD 3436.54 million by 2028. Despite these benefits, immutable blockchains present two limitations in current blockchain-based IoT systems. Firstly, the immutability of blockchain violates the right to be forgotten in the General Data Protection Regulation (GDPR) (https://gdpr-info.eu/art-17-gdpr/ (accessed on 31 July 2023)), severely limiting the development and implementation of blockchain-based IoT systems. GDPR mandates that users should be able to erase their personal data  from data management systems. However, with immutable blockchains, once data are appended to the blockchain, no modifications can be made [To address these challenges, blockchain has been widely applied in IoT systems as a decentralized data management platform, providing traceability and integrity to secure IoT systems ,7,8. Acc be made . This co be made ,11,12.To address these limitations, some redactable blockchains have been proposed, adopting chameleon hashes ,16,17,18We propose a policy-hidden fine-grained redactable blockchain scheme (named PFRB) for blockchain-based IoT systems. With decentralized settings, PFRB enables users to achieve fine-grained data redaction without compromising policy privacy.PFRB leverages multi-authorized attribute-based encryption and Newton’s interpolation formula-based secret sharing to construct a decentralized secret sharing for policy hiding. Then, based on the constructed secret sharing, PFRB further enriches chameleon hashes to achieve decentralized policy-hidden fine-grained redactable blockchains.Security analysis proves the security of PFRB under the chosen-plaintext attack in the random oracle model. Experimental results show that PFRB has competitive efficiency over recent fine-grained redactable blockchain schemes.To solve the above problem, we propose a policy-hidden fine-grained redactable blockchain scheme (named PFRB) in decentralized blockchain-based IoT systems. In PFRB, users can enjoy blockchain services while hiding their policies. A technical challenge in designing PFRB is how to hide policy contents and support policy matching. PFRB draws inspiration from Newton’s interpolation formula-based secret sharing and gracefully converts policy contents into polynomial parameters. Particularly, we summarize the main contributions as follows:Organization. The remainder of this paper is structured as follows. In the next section, we review existing works on redactable blockchains to introduce the research gap. In This section provides a systematic review of the current literature on redactable blockchain techniques and introduces the research gap.In 2017, Ateniese et al.  introducTo address the above limitation, Derler et al.  proposedHowever, redaction policies in the above redactable blockchains are open to all participants, which is infeasible in practical blockchain-based IoT systems since policies in IoT systems usually contain users’ private information. For instance, in IoT-based smart healthcare applications, patients use their smart swatches to collect their health conditions  and specify policies to allow their private doctors to edit. Evidently, these policies usually contain sensitive information regarding patients’ health conditions and geographical locations. Once this private information is leaked, adversaries can launch attacks on these patients such as robbery and discrimination. Thus, the protection of policy privacy in decentralized redactable blockchains represents an urgent matter.In this section, we introduce the building blocks of PFRB, i.e., multi-authority attribute-based encryption, Newton’s interpolation formula-based secret sharing, and chameleon hash.A multi-authority attribute-based encryption (MA-ABE)  system cGlobal Setup : A multi-authority attribute-based encryption In this paper, Newton’s interpolation formula is primarily used for key recovery. Also, due to the introduction of polynomial-oriented secret sharing, PFRB achieves higher efficiency than traditional linear secret sharing matrix-based works. The transaction issuer hides the key within the zeroth term of a polynomial, ensuring that only users who meet the policy requirements can reconstruct the polynomial and access the hidden key.Secret Generation: Assume that there are Based on Specifically, based on i-th order divided difference, respectively. For more details, the reader can refer to previous literature.Thus, Secret Construction: We can reconstruct the secret with Newton’s parameters as follows:m, hash value h, and randomness value r as input. It then determines whether the tuple h, and randomness value r as input. It then generates an adapted randomness value A chameleon hash In this section, we present the system model, brief definition, and security model of PFRB.Authorities: The authorities are all trusted. One of them initializes the system, and they can all generate attribute-value pairs.Transaction Owner: The transaction owner is also trusted and wants to place a deal or some data on the blockchain. They hash the data and attempt to add the transaction to the blockchain.Transaction Modifier: The transaction modifier is a user who wants to modify a transaction in the blockchain. They retrieve the attribute-value pairs and try to match the transaction to modify it.Blockchain Participants: The blockchain participants are users of the redactable blockchain. They verify each transaction published by the transaction owners or the transaction modifiers.As shown in We next provide a brief definition of PFRB and summarize the notations in Setup  if any probabilistic polynomial-time adversary We say that the adversary In this section, we present detailed construction of PFRB. The workflow of PFRB is shown in Setup   while inIn the Hash part, we have Similarly, In the Adapt part, we have: Transform these two parts as follows:Similarly, we have z from V as follows: When assuming that the two instances of z, thereby reducing the correctness of this paper’s scheme to the correctness of RBDS22. As RBDS22 is known to be correct, it follows that this paper’s scheme is also correct.From the above, it is evident that when the calculations of Theorem 1.PFRB is secure against the chosen-plaintext attack.Proof. To prove the security of the encryption method against the chosen-plaintext attack, we need to demonstrate that the adversary cannot distinguish the generated ciphertext, even if it can choose a set of plaintexts and observe their encryption forms.m, the challenger first generates a randomness z = Considering the message need to be encrypted g, m are values chosen by Recall the above encryption process, we know that Also, PFRB can resist user collusion attacks if the soundness of Newton’s interpolation formula-based secret sharing is hard. As shown in the detailed construction, PFRB relies on Newton’s interpolation formula-based secret sharing to achieve controllable redaction. Specifically, Newton’s interpolation formula-based secret sharing is used to specify policies and generate secret keys. namely, the user collusion resistance of PFRB can be reduced to the soundness of Newton’s interpolation formula-based secret sharing. As proven in prior works, Newton’s interpolation formula-based secret sharing holds soundness. Thus, PFRB is secure against the user collusion attack.The emergence of decentralized policy-hidden fine-grained redactable blockchain (PFRB) technology has opened new avenues for secure data management and privacy preservation. In this section, we explore the potential benefits of integrating PFRB with smart healthcare, smart industry, and artificial intelligence (AI) systems.Currently, with policy privacy, PFRB can be widely applied in smart healthcare applications to collect and manage medical data. For instance, PFRB ensures that nobody can infer users’ private information from users’ redaction policies. This benefit can impel users’ enthusiasm for using portable devices  to collect data associated with their health condition, such as heart rate and temperature . ClearlyIn the industry environment, due to the harsh environment and heavy data collection tasks, IoT devices have been deployed to replace humans’ work and securely transmit their data through blockchains . In thisRecently, some cases have been proposed to prove the practical feasibility of combining the advantages of blockchains, AI, and IoT systems, such as swarm learning and machine/deep-learning-based IoT systems . SpecifiIn this section, we conduct experiments on the FISCO blockchain platform to evaluate the practical efficiency of PFRB.Configuration: The experiment was conducted on a personal computer running Windows 10 (x64) with an Intel i7 8550U processor clocked at 1.80GHz and 8GB of memory. The implementation was done using the JPBC library in Java 8, and the MNT224 curve, known for its type-III properties and offering a 96-bit security level, was selected for pairing operations. Additionally, a 2048-bit RSA group was used for the Chameleon hash, providing a security level of 112 bits. Our scheme was deployed on the FISCO BCOS platform, which is an open-source platform customized for the financial industry. It is built upon the BCOS platform and incorporates module upgrades and functionality customization. The “Arbitration Chain” in FISCO leverages blockchain decentralization, tamper resistance, and trustworthiness. Real-time preserved data are securely stored on the blockchain using distributed data storage and encryption algorithms, ensuring the authenticity, legality, and relevance of the evidence.Parameter design: The data owner randomly selects a news headline and uploads it to the service node as a transaction. In our experiment, we assume that each user can choose up to 100 attributes, such as gender, age, region, education level, occupation, etc., for access permissions. The access control policies for transactions are determined based on information such as the time and location of the news, and up to 100 policies can be set. It is important to note that the traditional scheme lacks policy protection and is vulnerable to security issues such as privacy leaks. This paper presents the experimental performance of key generation, hashing, and adaptation and chooses recent related works ,18 as coDataset: The implementation of our proposed solution utilizes the MNH9 dataset, which is derived from a real-world open dataset provided by the Australian Broadcasting Corporation. The MNH9 dataset consists of millions of news headlines.In this paper, we present a superior solution that excels in key generation, hashing, verification, and adaptation compared to traditional methods.Moving on to In this paper, we propose a policy-hidden fine-grained redactable blockchain (named PFRB) in decentralized blockchain-based IoT systems. Considering existing redactable blockchains, PFRB supports decentralized settings and fine-grained chameleon hash-based redaction. In addition, PFRB ensures that apart from successful policy matching, anyone cannot infer users’ policy contents and execute any valid redaction. PFRB draws inspiration from Newton’s interpolation formula-based secret sharing to convert policy contents into polynomial parameters. PFRB then utilizes multi-authority attribute-based encryption to hide these parameters further. Theoretical analysis proves that PRFB is secure against the chosen-plaintext attack. Extensive experiments on the FISCO blockchain platform and IoT devices show that PFRB achieves competitive efficiency over current redactable blockchains. For future work, we will focus on providing more comprehensive privacy protection  and richer functionalities (such as accountability and revocation) in decentralized IoT systems. In addition, we will also focus on achieving richer data analytic mechanisms by combining various machine learning schemes.