Proteolytic enzymes, also known as peptidases, are critical in all living organisms. Peptidases control the cleavage, activation, turnover, and synthesis of proteins and regulate many biochemical and physiological processes. They are also involved in several pathophysiological processes. Among peptidases, aminopeptidases catalyze the cleavage of the N-terminal amino acids of proteins or peptide substrates. They are distributed in many phyla and play critical roles in physiology and pathophysiology. Many of them are metallopeptidases belonging to the M1 and M17 families, among others. Some, such as M1 aminopeptidases N and A, thyrotropin-releasing hormone-degrading ectoenzyme, and M17 leucyl aminopeptidase, are targets for the development of therapeutic agents for human diseases, including cancer, hypertension, central nervous system disorders, inflammation, immune system disorders, skin pathologies, and infectious diseases, such as malaria. The relevance of aminopeptidases has driven the search and identification of potent and selective inhibitors as major tools to control proteolysis with an impact in biochemistry, biotechnology, and biomedicine. The present contribution focuses on marine invertebrate biodiversity as an important and promising source of inhibitors of metalloaminopeptidases from M1 and M17 families, with foreseen biomedical applications in human diseases. The results reviewed in the present contribution support and encourage further studies with inhibitors isolated from marine invertebrates in different biomedical models associated with the activity of these families of exopeptidases. Proteolytic enzymes, known as peptidases or proteases, are critical in all living organisms . ProteasPeptidases are one of the most abundant groups of enzymes in living organisms. Thus, in mammals, more than six hundred genes have been assigned to them. They control the activation, synthesis, and turnover of proteins and regulate most biochemical and physiological processes, such as digestion, fertilization, growth, differentiation, cell signaling/migration, immunological defense, wound healing, and apoptosis ,2,3. TheAmong peptidases, aminopeptidases catalyze the cleavage of the N-terminal amino acids of proteins or peptide substrates. They are distributed in many phyla and play critical roles in physiology and pathophysiology ,8,9,15. Marine habitats are an extraordinary source of structurally complex bioactive metabolites, characterized by unique functions with marked biological activities and polished through evolution. These features can be attributed to varied environmental conditions, such as access to/lack of light, high pressure, aqueous environment, ionic concentration, pH and temperature changes, scarcity of nutrients, and restricted living spaces. Marine organisms are an abundant source of bioactive molecules , such as toxins ,21, antiMetallopeptidases constitute the most diverse catalytic type within proteases, since they include both endopeptidases and exopeptidases, cytosolic enzymes, and others that are secreted to the outside of cells, as well as enzymes associated with the plasma membrane and cell organelles. They are widely distributed in all forms of life such as viruses, bacteria, fungi, and plant and animal cells, indicating the important role they play in biological processes.2+) but can sometimes be cobalt (Co2+) or manganese (Mn2+). The metal ion is held in the protein structure by amino acids that act as ligands.Metalloproteases are included among the hydrolases in which the nucleophilic attack on the peptide bond is mediated by a water molecule. This is a feature they share with aspartic-type peptidases, but in metallopeptidases, a divalent metal cation activates the water molecule . This di2+; however, there is another group of families in which two cocatalytically acting metal ions are required. Within this group, there are families that have two Zn2+ ions and all the families in which Co2+ or Mn2+ are essential for catalysis. In families where only one metal ion acts, three amino acid residues are required to act as metal ligand coordinators, and in families with cocatalytic ions, only five amino acids are required since one of them acts as a ligand coordinator for both metal ions. All metallopeptidases with cocatalytic ions are exopeptidases, while metallopeptidases with a single metal ion can be both exo- and endopeptidases.Metallopeptidases can be divided into two large groups based on the number of metal ions required for catalysis. In many metallopeptidases, only one metal ion is required, which frequently is Znhttps://www.ebi.ac.uk/merops/, accessed on 9 January 2023) . Ot. Ot50 ofNeutral aminopeptidases are enzymes that catalyze the cleavage of neutral amino acids from the N-terminus of protein or peptide substrates. They have been classified in several metallopeptidase families, such M1 and M17 ,9. TheseNatural inhibitors of human and mammalian APN in general are scarce and have mainly been described from microorganisms ,96, planPoecillastra sp. and Jaspis sp. . S. S122]. Hermodice carunculata in aqueous extracts from Cuban marine invertebrates, our group extended the screening to porcine and human APN as targets. As part of a first study carried out in 2011–2015 in aqueous extracts from marine invertebrates belonging to the phyla   and that of Bryiozoo sp2. The active extracts were submitted to clarification treatments (such as 2.5% trichloroacetic acid and heat treatments) to eliminate contaminants (mainly proteins) and to promote dissociation from endogenous inhibitor–target complexes. Clarification increases the specific inhibitory activity of the extracts, suggesting that the procedure should be useful in future works dealing with the isolation of the inhibitory molecules ..50 value50 values below 100 µg/mL, are observed for the species showing the strongest hAPN inhibition. An IC50 value under 5 µg/mL for L. isodictyalis extract vs. both cancer cells lines, similar to the effect displayed by bestatin, indicates that this species is promissory for the isolation of hAPN inhibitors. In this work, the IC50 values for cell viability are in good agreement with the IC50 values for hAPN inhibition, including the bestatin results. To the best of our knowledge, this work was the first to show concomitantly natural inhibitor potency on hAPN and indications of activity on hAPN-expressing cells [Taking into account that the effect of the inhibition of hAPN was corroborated, the effect of each treated extract on the viability of two APN+ cancer cell lines PC3 and 3LL was evaluated . All treng cells .Membrane glutamyl aminopeptidase, also known as acidic aminopeptidase , is a type II membrane protein of the M1 family, MA subclade (E), of metallopeptidases  Figure B. This eNerita peloronta, Nerita versicolor, Lissodendoryx (Lissodendoryx) isodictyalis, Tripneustes ventricosus, Echinaster (Othilia) echinophorus, Isostichopus badionotus, and Stichodactyla helianthus displayed dose-dependent inhibition of porcine APA activity, with IC50 values in the range of 11.00–1005.00 µg/mL . We observed that extracts from the species 00 µg/mL , showingClan MF contains aminopeptidases that require cocatalytic metal ions for activity. The clan contains only the single family M17, a family of leucyl aminopeptidases . The proPlasmodium falciparum, the main agent of malaria in humans. The most important clinical stage of the complex P. falciparum life cycle [Leucyl aminopeptidases are also distributed in Apicomplexan protist parasites such as fe cycle , which hfe cycle . PfA-M17fe cycle  and is cfe cycle ,140,141.from Bos taurus, leucyl aminopeptidase (plant-type) from Solanum lycopersicum, PepA aminopeptidasa from Escherichia coli and other bacteria, and PfA-M17 from Plasmodium falciparum among others, being PfA-M17, joint with the mammalian enzyme, the more representative in tridimensional structure available at PDB, supporting the relevance of the search for new inhibitors as potential new antimalarial chemotherapy agents  isodyctialis, Isostichopus badionotus, and Stichodactyla helianthus. Inhibitory activity against rPfA-M17 was detected in the species Cenchritis muricatus, Echinaster (Othilia) echinophorus, Isostichopus badionotus, Physalia physalis, Stichodactyla helianthus, and Bunodosoma granuliferum  isodictyalis, Tripneustes ventricosus, Isostichopus badionotus, and Stichodactyla helianthus). Comparing the inhibitions on rPfA-M17 and hLAP, in all cases, the plasmodial enzyme was more susceptible than its human counterpart, with ratios of selectivity between 1.87 and 60 times. The most selective extract was from Nerita versicolor, an attractive result even if its IC50 value for the malarial enzyme is moderate. All of the treated extracts displayed a dose-dependent effect on a chloroquine-resistant Plasmodium falciparum strain (FcB1) cell’s viability, with the exception of Cenchritis muricatus, Stichodactyla helianthus, and Bunodosoma granuliferum. The best effects were obtained for Tripneustes ventricosus and Lissodendoryx (Lissodendoryx) isodictyalis. Particularly attractive were the T. ventricosus extracts that displayed a 300 times more potent effect on the FcB1 strain of P. falciparum than the human cancer cells, indicating parasite effect specificity. Additionally, this effect of the T. ventricosus extract on the FcB1 strain was stronger than the effect of bestatin (a pure compound). Due to the fact that IC50 for L. isodyctialis and T. ventricosus were lower on the FcB1 strain of P. falciparum than on the PfA-M17 recombinant enzyme, it is very likely that these extracts may contain not only PfA-M17 inhibitors but also other compounds active on other malarial targets. For example, for L. isodyctialis, inhibition of subtilisin from Bacillus licheniformes with an IC50 value of 3 µg/mL was described by Gonzalez et al. [Nerita versicolor extract showing effects on parasite growth with IC50 in the same order of enzyme inhibition, indicating that this species is also attractive. These results are the first and still only report of inhibition of M17 enzymes  by marine invertebrate species aqueous extracts and supports that sponges as well as marine invertebrates from other phyla such as mollusks, echinoderms, and cnidarians are a good and still underexplored source of potential anticancer and antimalarials associated with the inhibition of neutral aminopeptidases from the M1 and M17 families involved in these human pathologies.All the clarified extracts showed inhibitory activity against both peptidases: malarial rPfA-M17 and native human LAP . These as tested . Inhibitz et al. . AnotherEscherichia coli, Aeromonas proteolytica, Streptomyces lividans, and Pseudomonas aeruginosa, among others) are important virulence factors [5 was stronger than that of compound 6). It is well established that LAP3 plays an important role in the metastasis of breast cancer; hence LAP3 inhibitors may have a remarkable effect on the treatment of breast cancer [M17 enzymes are not only a very well established target for malaria and other parasitic diseases but also for bacterial infections and chronic pathologies such as cancer. Bacterial LAPs (from gram-negative or -positive bacteria such as  factors . Leucine factors . Recentl factors  identifit cancer .Marine biodiversity is an important and promising source of inhibitors of metalloexopeptidases from different families, in particular M1 and M17 enzymes with biomedical applications in human diseases. The results reviewed in the present contribution support and encourage further fundamental applicative studies with inhibitors isolated from marine species in different biomedical models associated with the activity of these families of exopeptidases.


To determine urea accurately in clinical samples, food samples, dairy products, and agricultural samples, a new analytical method is required, and non-enzymatic methods are preferred due to their low cost and ease of use. In this study, bitter gourd peel biomass waste is utilized to modify and structurally transform nickel oxide (NiO) nanostructures during the low-temperature aqueous chemical growth method. As a result of the high concentration of phytochemicals, the surface was highly sensitive to urea oxidation under alkaline conditions of 0.1 M NaOH. We investigated the structure and shape of NiO nanostructures using powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). In spite of their flake-like morphology and excellent crystal quality, NiO nanostructures exhibited cubic phases. An investigation of the effects of bitter gourd juice demonstrated that a large volume of juice produced thin flakes measuring 100 to 200 nanometers in diameter. We are able to detect urea concentrations between 1–9 mM with a detection limit of 0.02 mM using our urea sensor. Additionally, the stability, reproducibility, repeatability, and selectivity of the sensor were examined. A variety of real samples, including milk, blood, urine, wheat flour, and curd, were used to test the non-enzymatic urea sensors. These real samples demonstrated the potential of the electrode device for measuring urea in a routine manner. It is noteworthy that bitter gourd contains phytochemicals that are capable of altering surfaces and activating catalytic reactions. In this way, new materials can be developed for a wide range of applications, including biomedicine, energy production, and environmental protection. Urea is a major component of nitrogen sources used in fertilizers and chemical industry applications . VariousSince NiO nanostructures were green synthesized for nonenzymatic urea determination, no studies have been conducted to assess their catalytic effect, their dimensions, and their shapes, or the nonenzymatic determination of urea, particularly for large samples and real samples, where the matrix effect should be considered as a significant indicator. In our research on practical non-enzymatic urea sensors made of NiO materials, as well as a green chemical approach to NiO nanostructure synthesis, we examined various phytochemicals found in bitter gourd peel extract that are capable of acting as reduction and capping agents for surface modification ,46,47,48All chemicals were purchased from Sigma-Aldrich Karachi, Sindh Pakistan. These samples were all of high analytical quality and were used as received. Nickel chloride hexahydrate, sodium hydroxide, ammonia (33%), urea, Nafion (5%), magnesium chloride, ascorbic acid, glucose, and uric acid. Prior to the experiment, the glassware was cleaned and rinsed with deionized water. All of the glassware was dried in an oven at 60 °C for 30 min. A 0.1 M sodium hydroxide solution was used as a supporting electrolyte. All the solutions for electrochemical measurements were completed in aqueous 0.1 M sodium hydroxide. Deionized water was used as a solvent.NiO nanostructures were prepared by low-temperature aqueous chemical growth method followed by thermal annealing in the air. A pristine NiO sample was prepared by dissolving nickel chloride hexahydrate (0.1 M) in 200 mL of deionized water. Following this, 10 mL of an aqueous solution of ammonia at a concentration of 33% was added. In addition, 10 and 15 mL of bitter gourd peel extract were added separately to two other beakers containing nickel chloride hexahydrate and aqueous ammonia. There were two samples, referred to as sample 1 and sample 2. During low-temperature aqueous chemical growth method at 95 °C for five hours, growth solutions were tightly covered with aluminum sheets. It resulted in the formation of a light green nickel hydroxide product on the filter paper, after which it was washed several times with deionized water and allowed to dry overnight. Air calcination at 500 °C was then carried out for five hours. Similarly, pristine NiO was synthesized without the use of bitter gourd peel extract. A schematic illustration of the phytochemical synthesis is provided in For analyzing the crystal quality of NiO nanostructures, powder X-ray diffraction was used at 45 kV, 45 mA, with X-rays emitted from a Cu anode as the source of diffraction patterns. The X-rays were scanned at an angle of 10–85° two-theta. We investigated the shape and orientation of nanostructured NiO, by depositing a few amounts of NiO sample on the conducting carbon tape, using low-resolution scanning electron microscopy at an accelerating potential of 20 kV.We prepared a suspension of NiO nanostructures by dispersing 10 mg of each sample in 3 mL of deionized water. In a subsequent step, 30 μL of 5% Nafion was poured into NiO suspension in an ultrasonic bath and stirred for 20 min. Prior to the modification of GCE, the surface was cleaned with silicon paper and alumina paste, followed by washing with deionized water and drying at room temperature with air. A suspension of 10 µL with a loading mass of (0.2 mg) was then applied to the surface of GCE and dried at 50 °C in an electric oven for five minutes. In the electrochemical cell system, NiO-modified GCE served as the working electrode, silver–silver chloride (Ag/AgCl) filled with (3.0 M KCl) served as the reference electrode, and platinum wire served as the counter electrode. The working of GCE was exhibiting an area of 3 mm and it was used to deposit the catalytic material. The urea stock solution was prepared using a solution of 0.1 M NaOH. Various electrochemical methods were used to analyze the results, including cyclic voltammetry, electrochemical impedance spectroscopy, and chronoamperometry. As part of the scan rate study, CVs were measured at various scan rates. The purpose of this study was to examine electrochemical impedance spectroscopy (EIS) at 100 kHz to 0.1 Hz, a sinusoidal potential of 10 mV, and a biasing potential of 0.5 V. The raw EIS data were simulated using Z-view software, and well-fitting results were obtained. In order to determine the interference pattern and stability of the modified electrode, chronoamperometry was used. We conducted all measurements at room temperature. In order to determine the urea concentration in the real samples, 1:10 dilutions of the real samples into 0.1 M NaOH were made before the spiking for direct measurement of urea in curd, milk, wheat flour, blood, and urine. Blood and urine samples were collected from human subjects represented by laboratory personnel with their consent for use in our research.As shown in As shown in The catalytic activity of NiO nanostructures was further decreased by the addition of bitter gourd. The adverse effects are due to the presence of a high concentration of phytochemicals in 15 mL of bitter gourd juice. The increased oxidation peak current in sample 1 indicates better electron transfer in the recently designed architecture with tailored surface properties. In In light of the CV studies, it is evident that bitter gourd phytochemicals are highly effective for surface modification of nanostructured materials for a specific application. Consequently, bitter gourd could be used for surface modification of other materials for catalytic applications. In addition to these preliminary electrochemical tests, we have also performed comprehensive measurements of the non-enzymatic urea sensor in terms of kinetics, linear range, repeatability, reproducibility, selectivity, charge transfer kinetics, and real sample analysis using a variety of electrochemical methods.For the study of diffusion-controlled behavior of modified electrodes, a variety of scan rates ranging from 10–390 mV/s were used to assess the behavior of sample 1 of NiO electrodes during the electrochemical process in 0.1 mM urea. An illustration of this can be found in Furthermore, we have added a table describing the peak current ratio and peak separation potential for better understanding as given in The working range of the presented non-enzymatic urea sensor was determined by measuring CV curves at a scan rate of 50 mV/s for various urea concentrations as shown in Under the given equations ,61,62, t2 = 0.96, which suggests doubts about the performance of the sensor. Our case, however, demonstrates excellent analytical features and well-described performance. Additionally, the presented urea sensor offered real-time urea quantification from a variety of real samples. It is evident that NiO nanostructures are economical, facile, and environmentally friendly with a linear range of 1.0 mM to 9 mM and a low limit of detection of 0.02 mM. Therefore, the proposed method is a potential and alternative method for quantifying urea in real biological fluids. We have measured the chronoamperometric response for various urea concentrations ranging from 0.1 mM to 5 mM and have observed that the current increases linearly with increasing urea concentration, as shown in Herein, M shows the slope and S is the standard deviation. The measured LOD and LOQ were about 0.02 mM and 0.09 mM, respectively. The results presented in ct) for bare GCE, pristine NiO, and 10 and 15 mL of bitter gourd-assisted NiO nanostructure was 650 kΩ, 78 Ω, and 324 Ω, respectively. Due to its high conductivity and favorable charge transfer during urea oxidation, sample 1 displayed low charge transfer resistance and demonstrated rapid kinetics.Chronoamperometry was used to further investigate the stability of sample 1 in 0.1 mM urea during the time period of 300 s. The results indicated that NiO nanostructures displayed a high degree of compatibility with GCE. It is because they were able to detect the presence of urea without any fluctuation in current for the time period of 300 s, as shown in We also examined the repeatability, reproducibility, and stability of sample 1 in 1 mM urea solution by means of cyclic voltammetry at a scan rate of 50 mV/s. The repeatability was studied for the concentration range of 1 mM to 9 mM using sample 1 for three alternative days as given in In order to obtain a deeper understanding of the performance evaluation, the electrochemically active surface areas of each sample were also evaluated with curves in the non-Faradic region at various scan rates as displayed in The practical aspects of the non-enzymatic urea sensor were studied using various real-life samples, such as blood, urine, dairy milk, curd, and wheat leaves. The results are presented in To summarize, we have used green chemistry to synthesize NiO nanostructures using bitter gourd peel extract by low-temperature aqueous chemical growth method. An investigation of NiO nanostructures revealed the presence of a thin, flake-shaped cubic phase using bitter gourd extract. The XRD study has revealed a cubic phase and high purity of prepared NiO samples with bitter gourd extract. The electrochemical properties of different NiO samples prepared with 10 mL and 15 mL of bitter extract and pure NiO were studied for the non-enzymatic quantification of urea in the alkaline 0.1 M NaOH aqueous solution. We observed that the NiO sample 1 prepared with 10 mL of bitter gourd extract was found highly active for the oxidation of urea. The non-enzymatic urea sensor based on sample 1 was capable of detecting urea concentrations over a wide range of 1 to 9 mM with a detection limit of 0.02 mM when using CV mode. Chronoamperometric measurements have shown a linear range of 0.1 to 5 mM. The wide linear range and low limit of detection of urea on the surface of sample 1 were supported by the high amount of active surface area and the fast charge transfer rate. Our newly developed urea sensor has also demonstrated a high degree of sensitivity, selectivity, stability, and repeatability. The proposed non-enzymatic sensor configuration has been successfully applied to the determination of urea from various real samples, such as agricultural, clinical, dairy, and food samples and the obtained performance was found highly satisfactory. Compared with conventional methods for urea quantification, the fabricated sensor is low-cost, simple, highly sensitive, and selective. Biomass waste from bitter gourds could potentially be utilized for a new class of materials for tuning the catalytic properties and obtaining favorable surfaces for a wide range of applications such as energy conversion and storage systems.


Inflammatory bowel disease (IBD) has been referred to as the “green cancer,” and its progression to colorectal cancer (CRC) poses a significant challenge for the medical community. A common factor in their development is glycolysis, a crucial metabolic mechanism of living organisms, which is also involved in other diseases. In IBD, glycolysis affects gastrointestinal components such as the intestinal microbiota, mucosal barrier function, and the immune system, including macrophages, dendritic cells, T cells, and neutrophils, while in CRC, it is linked to various pathways, such as phosphatidylinositol-3-kinase (PI3K)/AKT, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and transcription factors such as p53, Hypoxia-inducible factor (HIF), and c-Myc. Thus, a comprehensive study of glycolysis is essential for a better understanding of the pathogenesis and therapeutic targets of both IBD and CRC. This paper reviews the role of glycolysis in diseases, particularly IBD and CRC, via its effects on the intestinal microbiota, immunity, barrier integrity, signaling pathways, transcription factors and some therapeutic strategies targeting glycolytic enzymes. The two main types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD) . IBD is The regulation of the glycolytic pathway, an important mechanism in both intestinal inflammation and tumors, is one of the therapeutic targets in IBD and CRC . We revi22.1Sugar metabolism in organisms involves several processes, such as glycolysis, aerobic oxidation, pentose phosphate pathway, and glycogen synthesis and catabolism. Glycolysis, in particular, is the process of breaking down glucose or glycogen to produce lactate and energy under relatively anoxic conditions. This process can be divided into two stages: the first stage converts glucose or glycogen into pyruvate through the action of various enzymes, and the second stage reduces pyruvate to lactate via lactate dehydrogenase (LDH) activity. Through this process, one molecule of glucose can produce two molecules of ATP . Three k2.2Glycolysis has an important impact on the physiological functions and disease processes of living organisms. The glycolytic process provides the energy required by organisms and is the basis for their survival and activity. However, in some diseases, abnormalities in the glycolytic process may lead to the disruption of physiological functions and adversely affect the organism. Changes in glycolysis in some representative diseases are shown in 2.2.1As a metabolic process, glycolysis is of great importance in metabolic diseases. A typical example of a metabolic disorder is Diabetes mellitus, which is characterized by hyperglycemia caused by multiple factors. Diabetes can be divided into two main types, type 1 and type 2 diabetes, and 90% of patients are diagnosed with type 2 diabetes . Type 2 2.2.2Glycolysis is also implicated in neurological disorders. Alzheimer’s disease (AD) is a progressive neurological disorder characterized by memory loss and cognitive dysfunction. In the early stages of AD, reduced glycolysis is commonly observed, and impaired glycolytic metabolism due to reduced glycolytic flux may be inherent to the pathogenesis of AD . Glial c2.2.3Glycolysis is also relevant in the study of various vascular diseases. Atherosclerosis (AS) is a common vascular disease, and among many causative factors, endothelial cell injury in arteries is considered a major trigger for its development . Endothe2.2.4Glycolysis is a major focus of research in various tumors and a popular subject of study. The effect of glycolysis on tumors is complex. On one hand, the metabolism of tumor cells is characterized by a high growth rate and high metabolism, requiring a large amount of energy, making glycolysis an important process in tumors. On the other hand, the glycolytic pathway of tumor cells is usually abnormal, leading to an increased demand for sugar in tumor cells, while the metabolism of normal cells is suppressed , 44. Wan2.2.5Digestive system diseases are a major threat to human health. According to relevant epidemiological statistics, digestive system diseases exist in more than one-third of epidemic cases . The rel3Glycolysis plays a vital role in supporting the growth and metabolism of intestinal microbiota by producing energy and metabolites. However, the composition of the intestinal microbiota in patients with IBD differs in structure from that of healthy individuals, which can negatively affect the balance of intestinal homeostasis. For instance, alteration in the intestinal microbiota impacts the synthesis of short-chain fatty acids (SCFAs), which play an essential role in maintaining intestinal health. Moreover, glycolysis has a crucial role in regulating immune system functions. The glycolytic metabolic pathway can regulate the polarization of macrophages, which affects their activation status and cellular function. Glycolysis is also involved in the regulation of neutrophil, dendritic cell, and T cell populations and their cellular functions. Additionally, glycolysis has a unique mechanism for intestinal barrier function Figure 23.1Faecalibacterium), Bacteroides (Bacteroides), and Fusobacteria, and increases in Proteobacteria (adherent invasive E. coli), Actinobacteria, and Verrucomicrobia  is a crucial glycolysis-related enzyme and mediator of the inflammatory process. Serum PKM2 levels are six-fold higher in patients with IBD than in healthy population controls . PKM2 up3.2The glycolytic pathway has an important impact on the activation and regulation of the immune system, especially in the context of IBD. As a metabolic process, glycolysis has the potential to regulate the immune system and changes in glycolysis can cause alterations in the immune system response. This may lead to the development of IBD, which is characterized by chronic inflammation of the intestine. Glycolysis affects important immune cells, such as macrophages, neutrophils, dendritic cells, and regulatory T cells.3.2.1Macrophages are an important class of immune cells, and their role in IBD is significant. They are distributed in the submucosal tissues of the intestine and play a key role in the immune response of the intestinal mucosa . In the GLUT1), enolase 1 (ENO1), pyruvate kinase (PKM), pyruvate dehydrogenase kinase 1 (PDK1), aldolase, lactate dehydrogenase A (LDHA), phosphoglycerate mutase (PGAM), phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GhAPDH) were significantly elevated, indicating that glycolysis in macrophages is significantly elevated in the IBD state. Further studies revealed that the HIF-1α/glycolytic axis was responsible for inhibiting macrophage M1 polarization and thus repair of IBD (In vitro experiments have shown that glycolysis in apoptotic cells promotes sustained efferocytosis through lactate-mediated upregulation of macrophage c-mer tyrosine kinase (MerTK) and lipoprotein receptor-related protein 1 (LRP1). Therefore, macrophage efferocytosis-induced glycolysis is a unique metabolic process and a promising therapeutic idea for IBD  inflammasome mediates macrophage polarization in innate immunity. NLRP3 activation requires glycolytic downstream metabolism, including lactate fermentation and pyruvate oxidation . In one r of IBD . Among tr of IBD . Meanwhir of IBD . In addi for IBD .3.2.2White blood cells in the blood are neutrophils, possessing great importance. However, in inflammatory diseases, neutrophils are a double-edged sword, properly wielded as a powerful weapon to protect the body, but when they are not strictly regulated, they become a destructive force. In IBD, the accumulation of neutrophils in epithelial crypts and the intestinal lumen is directly related to epithelial damage, so neutrophil migration across the mucosal epithelium can be a hallmark of inflammatory diseases such as UC and CD , 71. At Neutrophils are traditionally considered short-lived cells with high protein synthesis activity, and polymorphonuclear neutrophils (PMN) have a low number of mitochondria. Most of their required ATP is produced by glycolysis . Therefo3.2.3Dendritic cells (DCs) are a crucial type of antigen-presenting cells that play a vital role in the immune response of the body. In addition, they are also involved in the pathogenesis of IBD, as patients with IBD have a higher number of DCs in their intestinal tissues compared to healthy individuals . DCs relDifferent DC subtypes have diverse metabolic requirements, and metabolic profiles play a critical role in their function. Similar to macrophages, mTORC1, HIF-1α, and mitochondrial fitness play important roles in DC differentiation and polarization. In the resting state, DCs rely primarily on oxidative phosphorylation and AMPK signaling to maintain their quiescent metabolic state. However, in the activated state, they turn to glycolysis to increase the production of biosynthetic precursors, thereby promoting cell growth and function . The rap3.2.4As cells responsible for recognition and attack in abnormal situations such as infection, cancer, and autoimmunity, T cells have a major responsibility. T cells can be activated and differentiated into various subtypes, such as helper T cells  and regulatory T cells (Treg), which further regulate and control the extent and type of immune response . In IBD,Activated Treg cells need to migrate to the site of inflammatory tissues to perform their immunomodulatory functions, and this migration process is closely related to glycolysis . Kishore3.3Gut Barrier function refers to the ability of the intestinal epithelium to act as a barrier between the external and internal environment. Its crucial role in human health has been widely recognized for a long time . The los4Colorectal cancer (CRC) is one of the leading causes of cancer incidence and mortality . As the 4.14.1.1The PI3K/AKT pathway is a crucial regulator of cell proliferation, survival, and metabolism, and is activated by several growth factors and cytokines. Dysregulation of this pathway is often observed in cancer, making it an important event in colorectal carcinogenesis. In particular, it plays a key role in drug resistance and metastasis in CRC . AcquireCCND1). It was found that circIL4R activates the PI3K/AKT signaling pathway in CRC cells, and the knockdown of circIL4R inhibits the proliferation, migration, and invasion abilities of CRC cells  has been observed in CRC and shown to promote disease progression , 110. KnRC cells . In reseRC cells . Long etRC cells  have rep4.1.2SOD2 gene in cells results in significant decreases in glycolytic markers, including L-lactate and MCT4. Moreover, inhibiting the AMPK pathway leads to a decrease in glycolytic activity and the migratory capacity of CRC cells. Elena et al.  in CRC treatment  and mTOR complex 2 (mTORC2)  pathway is a central regulator of cell growth and metabolism, involved in a variety of cellular processes, including protein synthesis, autophagy, and energy metabolism. It integrates signals from various upstream pathways such as the PI3K/AKT pathway. mTOR is encoded by the (mTORC2) . mTORC1 ed genes , while med genes . Karl eted genes  found thed genes . Moreoveed genes . Therefo4.24.2.1GLUT1, GLUT3, and GLUT4 genes, thus reducing the uptake of glycolytic raw materials to achieve glycolysis inhibition  can enhance the immunosuppressive function of myeloid-derived suppressor cells (MDSC) to promote the development of CRC. C. tropicalis stimulation significantly enhanced glycolysis by increasing the level of glucose uptake by MDSCs, along with the production of more lactate and the appearance of elevated levels of extracellular acidification rate (ECAR). The immunosuppressive capacity of MDSCs was effectively attenuated by treatment with the glycolysis inhibitor 2DG, demonstrating that glycolysis mediates the effect of MDSCs. It was further found that C. tropicalis treatment of MDSCs increased the interaction between the glycolytic enzyme PKM2 and HIF-1α, which increased the stability of HIF-1α and thus glycolysis (HIF is a transcription factor that regulates cellular responses to hypoxic levels. HIF-1 is a heterodimer composed of the constitutively expressed subunit HIF-1β and the oxygen-regulated subunit HIF-1α . Among tycolysis . Wei (13ycolysis  et al. rycolysis . Althougycolysis , indicat4.2.3HK2, PKM2, GLUT1, and LDHA, is severely suppressed after treatment with the c-Myc inhibitor 10058-F4 in RKO and CaCO-2 cells. c-Myc ubiquitination causes targeted proteasome-mediated degradation (c-Myc is a proto-oncogene that regulates cell proliferation, differentiation, and apoptosis. Dysregulation of c-Myc has been associated with the development of various cancers , includiradation . Tang etradation , on the radation . Despite4.3CRC development involves various genetic and molecular alterations, including dysregulation of glycolysis-related enzymes. Glycolysis converts glucose to pyruvate and plays a key role in energy metabolism, biosynthesis, and redox homeostasis in cancer cells. Numerous studies have explored the relevance of glycolysis-related enzymes to the pathogenesis of CRC, identifying a range of substances involved in its regulation Table 2.5Glycolysis is a metabolic process that plays a crucial role in a variety of diseases, including metabolic, neurological, vascular, inflammatory, and oncological diseases. There is sufficient evidence that glycolysis influences intestinal microbiota, the immune system, and intestinal barrier function in IBD, and is involved in signaling pathways and transcription factors in CRC pathogenesis. Understanding the role of glycolysis in disease pathogenesis may provide new therapeutic opportunities for the treatment of IBD and CRC. Targeting glycolysis-related enzymes and signaling pathways may be an effective way to develop new therapies for these diseases. Additionally, understanding the relationship between glycolysis and the immune system may lead to new immunomodulatory treatments for IBD and CRC. The development of glycolysis inhibitors as potential therapeutic agents is ongoing and is an active area of research. Future research should focus on developing more potent and selective inhibitors targeting glycolysis-related enzymes and signaling pathways. It is also important to investigate the use of glycolytic inhibitors in combination with other therapies to enhance their therapeutic potential. In conclusion, this paper provides valuable insights into the role of glycolysis in IBD and CRC and highlights the need for further studies to fully understand the mechanisms involved in developing effective therapeutic approaches targeting glycolysis.Material preparation and analysis were performed by YX, LZ, DO, QT, FM, and XS. The first draft of the manuscript was written by YX, DO, LZ, and QT. The manuscript was proof-read and edited by XS and FM, and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.


TM, a new ready-to-use-vehicle, and APIs from different pharmacological classes, such as 5-hydroxytryptophan (5-HTP) 50 mg, bromopride 5 mg, coenzyme Q10 20 mg, melatonin 3 mg, resveratrol 5 mg, tadalafil 10 mg, vitamin B12 1 mg, or vitamin D3 2000 UI. ODFs were compounded and, subsequently, the samples were assayed using HPLC at initial (t = 0), 7 days (t = 7), 14 days (t = 14), 30 days (t = 30), 60 days (t = 60), 90 days (t = 90), 120 days (t = 120), 150 days (t = 150), and 180 days (t = 180) after compounding. Given the percentage of recovery of the APIs within the films, the beyond-use date of the final products (API + vehicle) was at least 90 days for vitamin D3, 150 days for bromopride and 5-HTP, and 180 days for coenzyme Q10, tadalafil, vitamin B12, resveratrol, and melatonin, when stored at room temperature. The average disintegration time was 46.22 s. This suggests that the OrPhylloTM vehicle is suitable for compounding ODFs with APIs from different pharmacological classes, with good compatibility and fast disintegration.Orodispersible films (ODFs) are solid pharmaceutical forms for rapid local or systemic release of active ingredients. They are formed by a water-soluble polymer film that hydrates rapidly, adhering and dissolving immediately when placed on the tongue or in the oral cavity. In this paper, we describe the compatibility and disintegration times of compounded ODFs using OrPhyllo Orodispersible films (ODFs) are innovative solid pharmaceutical dosage forms intended to convey and quickly release active pharmaceutical ingredients (APIs) or food supplements locally or systemically. They are formed by a water-soluble polymeric film that moisturizes quickly, adhering and dissolving immediately when placed on the tongue or the oral cavity , with no need for water or chewing ,2,3,4,5.A vast body of evidence shows that ODFs are suitable for a broad range of therapeutic purposes. For instance, analgesics, anti-asthmatics, anticonvulsants, antiemetics, antihistamines, antihypertensives, anxiolytics, diuretics, anti-inflammatories, antiseptics, sedatives, etc. ,9,10,11.There are many processes for producing ODFs: hot-melt extrusion, solvent-casting, freeze-drying, rolling methods, and 3D extrusion printing ,15,16,17TM, Fagron, The Netherlands) and the necessary equipment to produce them safely, accurately, and in a suitable scale for personalization . To show the functionality of this set, we have compounded eight different ODF formulations and evaluated their organoleptic characteristics, average weight, disintegration, content uniformity, and stability. The APIs evaluated were coenzyme Q10 , tadalafil , vitamins B12 and D3, resveratrol , melatonin , bromopride  and 5-hydroxytryptophan (an amino acid used for sleep disorders) [This solution to produce films comprises a new ready-to-use vehicle for ODFs (OrPhyllosorders) . The aimThe products evaluated throughout the study are described in TM film base was reconstituted in the following manner: 22.5 g of the OrPhylloTM film base was transferred to a mortar and dispersed with 50 g of purified water (solvent); after that, 1 g of polysorbate 80 (surfactant), 3.75 g of polyethylene glycol 400 (plasticizer), 1.0 g of simethicone 7-9245 emulsion 30% (adjuvant to decrease bubble formation), and water q.s. 100 g were added and mixed until homogeneity. This was stored in amber glass bottles for up to 3 months before use.All APIs were obtained from Fagron and met United States Pharmacopeia (USP) and European Pharmacopeia grades. Previously to the compounding of the finished films, the OrPhylloTM until a paste was obtained.All APIs were sieved, crushed in a mortar, and then carefully mixed with the OrphylloThis mixture was laminated/spread onto glass plates using a laminating apparatus (FagronLab).The glass plates were transferred to a film dryer (FagronLab) previously equilibrated at 40 °C for 40 min.After completely drying, films were cut with a guillotine (paper trimmer) into squares of 3 × 3 cm, packed into individual laminated matte aluminum sachets, and stored at noncontrolled room temperature to mimic real-use conditions (15–30 °C).The compounding process of the finished films included the following 4 steps :All APIsODFs were assayed by high-performance liquid chromatography (HPLC) at pre-determined time points to verify the compatibility of the API in the vehicle. This protocol followed general guidelines from USP for estimating beyond-use dates (BUDs) and previous works conducted by our research group ,20,21. BAnalyses were performed following the methods described in 2O2 35% (v/v) (at 25 °C).Methods were evaluated concerning their stability-indicating characteristics. API samples were subjected to the following stressing conditions to determine the capacity of the HPLC method to detect any possible degradation products that may arise during storage of the oral films: (i) dilution in acid ; (ii) dilution in base ; (iii) exposure to ultraviolet light at 365 nm (at 25 °C); (iv) heating at 70 °C; and (v) dilution in HMelatonin 3 mg, bromopride 5 mg, and 5-HTP 50 mg films were evaluated for their disintegration time using a disintegrator  and following the general guidelines from the USP and the British Pharmacopeia, with adaptations due to the lack of specific requirements for ODFs ,23. BrieODFs are pharmaceutical dosage forms that account for numerous advantages, such as (i) fast disintegration and dissolution in the oral cavity for local action or systemic absorption of the API; (ii) increased bioavailability, as some APIs can be absorbed from the mouth , pharynx, and esophagus as the saliva is swallowed and reaches the stomach; (iii) quick start of action ; (iv) no risk of choking or suffocation; (v) ease of administration in dysphagic, pediatric, geriatric, and psychiatric patients refusing to swallow tablets or capsules; (vi) do not require water or mastication for their administration (a convenient situation for patients who are traveling or with nausea and vomiting); (vii) flexible and portable , facilitating transportation, use, and storage ,14.Despite the previously mentioned advantages of the ODFs, some caution regarding dosage uniformity and stability of the compounded products should be addressed. For dosage uniformity, Raposo et al.  have alrTM base is a commercial product with a validated shelf-life of two years, as determined through comprehensive stability studies that encompass both physico-chemical and microbiological assessments. It is formulated using pullulan and xanthan gum, both of which have been designated as Generally Recognized as Safe (GRAS) ingredients by the United States Food and Drug Administration (FDA) [TM is also vegan, meaning it is not expected to contain Bovine Spongiform Encephalopathy (BSE) or Transmissible Spongiform Encephalopathy (TSE) agents. Furthermore, it is free from parabens, phthalates, propylene glycol, and alcohol, underscoring the safety profile of this base.Moreover, it is important to note that the OrPhylloon (FDA) . OrPhyllConcerning compatibility, we present data supporting a suitable BUD for the films. Studying the physicochemical compatibility of the compounded formulations is paramount to preventing non-homogeneous dosing, which can lead to medication errors. The final and stable film is a product of multiple factors, including the API’s chemical, physical, and microbiological stabilities, and interaction with the vehicle and the packaging. In this study, we evaluated the compatibility of selected APIs in the ODFs as a factor of degradation of the API with time.The APIs studied were coenzyme Q10, tadalafil, vitamins B12 and D3, resveratrol, melatonin, bromopride, and 5-hydroxytryptophan. The doses chosen for these APIs were based on several factors: available scientific literature, safety profiles, therapeutic ranges, and practical considerations. It is worth noting that dosage forms like ODFs have limited space for the active ingredient, which can influence the chosen dosage. For 5-HTP, often used to support serotonin production and mood regulation, the dosage of 50 mg falls within the lower end of the typical range (50–200 mg). Bromopride is commonly prescribed at doses ranging from 10 to 20 mg for gastrointestinal issues, so 5 mg is at the lower end of this range because at this concentration it can be used for pediatric patients. The same applies to coenzyme Q10 at 20 mg. The dosage of 3 mg/ODF for melatonin falls within its common range. For resveratrol at 5 mg/ODF, the dosage is relatively low compared to typical supplements, but this is justified because it is being studied for its use as a long-term supplement and the orodispersible route may have a positive impact on drug absorption. Tadalafil is typically used to treat erectile dysfunction and 10 mg is a common starting dose. The dosage of 1 mg for vitamin B12 is generally considered sufficient for individuals with a deficiency in vitamin B12. The dosage of vitamin D3 is within the typical range for daily supplementation, which can vary from 600 to 2000 IU or more depending on an individual’s needs and existing levels.It is noteworthy that all tested APIs were sensitive for all the stressing conditions tested, except resveratrol when exposed to UV light (as it is a polyphenol that can absorb these wavelengths and act as a sunscreen agent), and vitamin B12 when exposed to UV light and heating . This shThe chemical compatibility results are shown in To the best of the authors’ knowledge, there is no report in the literature dealing with the compatibility of such APIs in ODFs. The lack of this data highlights the importance of this study, and its innovative approach demonstrates the formulation’s effectiveness. For example, although the USP provides a BUD limit of 180 days for nonaqueous dosage forms with water activity lower than 0.60, they also state that a shorter BUD must be assigned when the physical and chemical stability of the compounded nonsterile preparation is less than the BUD suggested —the loweThe disintegration assay demonstrated that the formulation (vehicle) for the APIs was suitable for the desired application. The observed disintegration times were 47.8 s for melatonin 3 mg, 46.7 s for bromopride, and 46.2 s for 5-HTP 50 mg . Thus, it confirms the fast-dissolving property of ODFs. The disintegration time of ODFs typically exhibits brevity, frequently falling within a range of seconds to a few minutes. As an illustrative instance, El-Setouhy and El-Malak observed in vitro disintegration times of less than 60 s for newly developed tianeptine sodium ODFs . The priTM as a vehicle and the laminating production process represent a pharmaceutical form suitable for compounding APIs from different pharmacological classes, and have good compatibility and fast disintegration into the oral cavity.The proposed method  to produce personalized ODFs in a compounding pharmacy setting showed promising results. Disintegration rates were fast enough to suggest a suitable quick start of effects in vivo. Additionally, compatibility tests showed that the BUDs ranged from 90 to 180 days when stored at room temperature . This suggests that ODFs using OrPhyllo


Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare underdiagnosed genetic feature presenting less than 1% of symptomatic cholelithiasis, with variable clinical forms ranging from simple to complications. Diagnosis criteria are recurrent biliary symptomatology occurring in young patients (<40 years old) and/or recurrence after cholecystectomy and/or having a history of biliary gallstones in first-degree relatives and characteristic ultrasound findings. Early detection of this entity, due to the awareness of gastroenterologists, radiologists, and visceral surgeons, will allow an improvement in the quality of life of patients and the prevention of complications. We report three cases of the LPAC syndrome and discuss its different aspects. Low phospholipid-associated cholelithiasis (LPAC) syndrome is a genetic disease characterized by a decrease in the content of phospholipids in the bile, leading to a defect in the solubilization of cholesterol, resulting in the formation of both vesicular and intrahepatic cholesterol lithiasis .It is a particular form of cholelithiasis in young, non-overweight subjects, described in 2001 by the team of Saint-Antoine Hospital in Paris . We repoCase 1We report the case of a 40-year-old man, a chronic active smoker with 10 pack-years, nonalcoholic, complaining about recurrent biliary colic without a family history of cholelithiasis or neoplasia. He was admitted to the emergency department with severe acute pancreatitis and an initial systemic inflammatory response syndrome. His Bedside Index of Severity in Acute Pancreatitis (BISAP) score was 2, and his body mass index (BMI) was 23.6 kg/m². Physical examination was normal except for epigastric tenderness. Biological assessment on admission (24 hours after the pain) showed a blood lipase level of 30 x ULN , no cytolysis, slightly elevated gamma-glutamyl transferase (GGT) of 1.4 x ULN, and normal triglyceride and calcium levels. Abdominal ultrasound (US) revealed images of intrahepatic micro- and macro-stones with posterior acoustic shadow  was 10 and that GB contained sludge, without evidence of intrahepatic stones Figure .In view of the young age of the patient, the absence of risk factors for cholelithiasis, recurrent biliary symptoms, and the characteristic US images, the diagnosis of LPAC syndrome was made, and the patient was managed by UDCA (ursodeoxycholic acid) 1000 mg/d for the long term without cholecystectomy. After 3 months of treatment, clinical improvement was noted and GGT was normal at 13 IU/l.Case 2A 16-year-old patient, appendectomized 1 year ago, with a history of cholelithiasis in his mother, brother, and sister at a young age, presented with recurrent biliary pain. Physical examination was normal and his BMI was 16 kg/m². The blood count was normal except for hypereosinophilia of 720/mm3. There was no cytolysis nor cholestasis and the lipid profile was normal. Abdominal US showed gallstones, without either intrahepatic or main bile duct (MBD) dilatation. We noted the presence of hyperechoic foci, with comet tail artifacts in the intrahepatic area Figure .The US also showed a hydatid cyst between segments VI and VII measuring 80.5 x 68 x 60 mm, classified as CE2 according to the WHO classification, and the hydatid serologic test was positive.Given the young age of our patient, typical US images, and cholelithiasis in first-degree relatives, the diagnosis of LPAC syndrome was made, and then he was managed by UDCA 10 mg/d over the long term with favorable outcomes.Case 3A 27-year-old female patient, G4P3, on 3 months postpartum, presented with recent biliary colic with clinical cholestasis. In addition, the patient reported the occurrence of unexplored pruritus during the third trimester of pregnancy, and premature delivery at 32 weeks of amenorrhea. Clinical examination revealed a BMI of 29.3 kg/m² and tenderness of the right hypochondrium. On biological assessment, there was cytolysis (aspartate aminotransferase (AST) 2 x ULN, alanine aminotransferase (ALT) 3.8 x ULN) and cholestasis  1.6 x ULN). Hepatitis B and C testing were negative, and protein electrophoresis and IgG4 were normal. Abdominal US showed multiple hyperechoic intrahepatic "comet-tail" spots compatible with LPAC syndrome, sludge in the MBD that was not dilated, and gallstones.Magnetic resonance cholangiopancreatography showed adilated MBD at 9 mm with homogeneous contents, and edema of the papilla probably due to the oddities Figure .Because of the suspicion of LPAC syndrome, she was managed by UDCA at a progressive dose until reaching 10 mg/kg/d + trimebutine and cholestyramine, with a regular biological control. The clinical course was favorable. Liver biology at 1 month showed normal AST and ALT, GGT 1.6 x ULN, ALP 1.8 x ULN, and total bilirubin 14.ABCB4 gene (ATP-binding cassette subfamily B member 4), located on chromosome 7 locus 21 (7q21), leads to dysfunction of the MDR3 protein, a phospholipid transporter at the canalicular pole of hepatocytes. Therefore, the bile produced is low in phosphatidylcholine, the major phospholipid in human bile. As a consequence, bile exhibits a high degree of lithogenicity, containing a high concentration of cholesterol crystals that precipitate in bile ducts, resulting in the formation of intra- and extrahepatic cholesterol stones [The three main components of bile - phospholipids, cholesterol, and bile acids - are secreted into the bile by transporters and these transporters allow cholesterol to dissolve in micelles. Mutation of the l stones .ABCB4 mutation is present in only 30% to 50% of cases, most often heterozygous, missense, and without correlation with the phenotype. Other mutations are probably involved but have not yet been detected. The spectrum of mutations in the ABCB4 gene is also responsible for gestational cholestasis and progressive familial intrahepatic cholestasis (PFIC 3) [The PFIC 3) . Due to  . Due toClinical presentations can range from simple biliary pain to complications. The most frequent complication is lithiasis migration with elevation of transaminase levels Case 3), which is not usually demonstrated by echo-endoscopy or MRI . One pat, which iABCB4 mutations are encountered in 15% of cases of gestational cholestasis). Premature delivery may complicate gestational cholestasis in 2/3 of cases. Treatment with UDCA during pregnancy reduces the risk of exacerbation and prematurity [In pregnancy, 50% of women have cholestasis during the second or third trimester. This is shown by pruritus and biological cholestasis  and primary sclerosing cholangitis. The risk of secondary biliary cirrhosis and cholangiocarcinoma has been reported in the literature, but these complications are rare [ABCB4 genotyping is recommended, but the absence of a mutation does not banish the diagnosis and a therapeutic test employing UDCA can be suggested [When clinical and imaging findings are characteristic, the diagnosis of LPAC is confirmed and treatment with UDCA should be initiated without further investigation. In cases of uncertainty, uggested .UDCA is well tolerated and can be prescribed at a dose of 7 to 10 mg/kg/d. It could also be intensified to 20 mg/kg/d. In early forms, it reduces symptoms and improves them in advanced cases, but recurrence can occur when treatment is stopped. However, the disappearance of lithiasis is slower. The underlying hypothesis suggests that biliary symptoms are caused by inflammatory lesions of the cholangiolar epithelium and cholesterol microcalculi rather than macrocalculi . The mecThere is no strict diet recommended. In cases of associated hypercholesterolemia, statins are preferred over fibrates, which increase lithogenicity. Estrogen and progestin should be discontinued during the first weeks of treatment with UDCA because they inhibit the secretion of phospholipids and increase the symptoms . CholecyABCB4 mutation  to treat patients before symptoms and complications appear. A normal US scan in a young asymptomatic relative does not exclude the diagnosis and the scan must be repeated a few years later because radiological signs of LPAC syndrome may occur later [Family screening is recommended for first-degree relatives over 18 years of age by US or by testing for the ur later .Through the presentation of our observations and a literature review, we have tried to make an overall assessment of LPAC syndrome, especially its clinical, morphological, and therapeutic aspects, to facilitate diagnosis and prevent severe complications.We conclude that ultrasound performed by an experienced operator plays an essential role in the orientation of diagnosis, by displaying characteristic images. Therefore, an effective and simple treatment based on UDCA could be introduced and systematic cholecystectomy could be avoided.


Neural tube defects (NTDs) are serious brain and spine birth defects. Although NTDs are primarily pregnancy complications, such as abortion and stillbirth, they also contribute to under-five morbidity and mortality, as well as long-term disability and psychological impact. Despite these negative outcomes, the determinants of NTDs are not widely studied in Ethiopia, particularly in the country’s east. As a result, we sought to identify the risk factors for NTDs in neonates born in public referral hospitals in eastern Ethiopia.A facility-based unmatched case-control study was carried out at Hiwot Fana Comprehensive Specialized Hospital and Sheik Hassen Yabare Jigjiga University Referral Hospital in Eastern Ethiopia. We included 59 cases identified in the selected facilities between September 10, 2021, and February 5, 2022, and 118 control neonates, with a case-to-control ratio of 1:2. Data were gathered through the use of interviewer-administered questionnaires and medical record review. To identify determinant factors of NTDs, a multivariable logistic regression model was used, which included all predictor variables from the bivariable analysis. The results were reported using an Adjusted Odds Ratio (AOR) with a 95% confidence interval. A p-value of < 0.05 was considered statistically significant.In total, 59 cases of NTDs were identified out of 2915 live birth total births registered in the two hospitals, making the incidence of NTDs 202.4/10,000 births. In the final model analysis, determinant factors such as gender of newborn , having no history of antenatal care, having a poor food consumption score , having history of monotonous diet consumption , and coffee consumption of three or more cups per day during pregnancy  were statistically associated with NTDs.Modifiable and non-modifiable determinants were identified as major contributors of neural tube defect in this study. Early screening, dietary intervention counseling to increase consumption of a healthy diet, coffee consumption reduction, and pre-pregnancy supplementation programs should be developed to reduce NTDs in Ethiopia. Neural tube defects (NTDs) are complex congenital anomalies caused by neural tube malformations that affect the developing embryo’s brain and/or spine during the first eight weeks of embryogenesis. Primary neurulation occurs between 20 and 28 days of gestation and results in anencephaly, myelomeningocele (open spina bifida), and craniorachischisis, whereas secondary neurulation occurs between 45 and 53 days of gestation and results in spina bifida occulta to severe spinal cord tethering –5.Although the exact causes of NTDs are unknown, evidence points to a wide range of possible causes –8. AccorEvery year, more than 300,000 newborns worldwide are diagnosed with NTDs , 3. FurtThe rate is ten times higher than the report from eight WHO member countries in Africa  and 26 times higher than it should be . A studyLow socioeconomic status, maternal exposure to environmental factors , maternal smoking during pregnancy, genetic factors, delaying childbearing, low folic-acid supplementation before or during pregnancy, fetal sex, and lack of antenatal care have all been linked to NTDs , 18–21. Several studies have looked into the relationship between maternal caffeine consumption and birth defects. Caffeine use by mothers has been linked to an increase in the risk of neonatal birth defects ranging from 1.3 to 1. 0.8  The studDespite the government’s efforts to implement a variety of interventions to address the issue of dietary diversity, many Ethiopians’ diets remain monotonous, with little variation in diet diversity. Despite rapid changes in food systems in Ethiopia, dietary diversity remains a challenge , 29. SimFolate deficiency and insufficiency are widespread public health issues in Ethiopia. Based on red blood cell folate levels, a recent assessment based on the most recent national micronutrient survey discovered that 84% of women of reproductive age are at risk of having a child with NTDs . NTD resThe study was conducted among neonates born in two public referral hospitals in Eastern Ethiopia, Hiwot Fana Comprehensive Specialized Hospital (HFCSH) and Sheik Hassen Yabare Jigjiga University Referral Hospital (SHJJURH), in Harar and Jigjiga town, respectively, from September 10, 2021 to February 5, 2022. HFCSH, one of Harar’s oldest hospitals, provides comprehensive referral services to the entire population of the country’s eastern region, with an average of 11,957 admissions and 5808 deliveries per year –35.SHJJURH is Jigjiga University’s teaching center and the busiest referral hospital in the Somali Regional State. The hospital serves a population of over seven million people living in all zones and districts of the Somali Region State, neighboring districts in the eastern part of Oromia, and a large portion of neighboring Somalia. Every year, the hospital serves over 38,523 outpatients, 7,690 hospitalized patients, 3,434 deliveries, and 9,270 emergency cases .A facility-based unmatched case-control study was conducted at HFCSH and SHJJURH from September 10, 2021, to February 5, 2022. In this study, the cases were all neonates born after 28 weeks of gestation (the age of viability for developing countries) with a confirmed diagnosis of any form of NTDs, while the controls were all neonates born after 28 weeks of gestation with no type of NTDs, no other anomalies, and no other anomalies. Pregnancies that were terminated before 28 weeks, as well as neonates whose mothers were unavailable or critically ill, were excluded from both the case and control groups.The sample size for this study was determined by taking into account the various factors that contribute to NTDs. As a result, the sample size was calculated using Epi-Info statistical software (version 7.1.0) with the following assumptions: the proportion of cases with a history of abortion (18.7%) and the proportion of exposed controls (4.8%) with a 4.9 odds ratio from similar studies , 37. a aA structured questionnaire that had been utilized in Ethiopia before , 38, 39 The dependent variable of this study was NTDs defined based on the ICD-10 criteria , and thePrior to data collection, a pretest was performed on 5% of the sample size at Karamara General Hospital to ensure that the questionnaire was functional, and any necessary changes were made. A one-day training was provided for data collectors and supervisors prior to data collection. Every day, all collected data was double-checked for completeness.Data was collected, checked for completeness, entered into EpiData version 3.1, and then exported and analyzed with SPPS version 25. The data was examined to ensure that it was normal and that other assumptions were met. The association between each independent variable and NTDs was evaluated using binary logistic regression analysis. An adjusted odds ratio was used in multivariable analysis to identify independent determinants of NTDs. In the bivariate analysis, variables with a p-value less than 0.25 were considered candidates for the multivariable analysis. The strength of the association between the independent variables associated with NTDs was measured using an adjusted odds ratio with a 95% confidence interval, and statistical significance was defined as a P-value less than 0.05.Haramaya University College of Health and Medical Science Institutional Health Research Ethics Review Committee provided ethical approval prior to data collection (IHRERC). Before data collection, We obtained consent directly from all people above the age of sixteen, regardless of their educational background. In fact, there are no legal guardians under the age of sixteen in our study. We confirm that all experiments were carried out in accordance with applicable guidelines and regulations (such as the Declaration of Helsinki). Participants were told they could refuse or withdraw at any time. To maintain confidentiality, their names and other personal identifiers were not registered. Furthermore, the interviews were conducted in a separate room to ensure confidentiality.This study included 59 cases and 118 controls, with a 98% response rate. When compared to the control group, a higher proportion of mothers in the case group were under the age of 25 (55.9% vs. 33.9%). When comparing maternal age at first childbirth, more mothers in the case group (86.4%) were under 25 years old than mothers in the control groups (61.9%). In comparison to their counterparts (29.7%), more than one-third (37.3%) of case mothers received only primary education. The majority of case mothers were housewives, as were their counterparts.  did not receive antenatal care than mothers in controls (16.5%). Furthermore, a higher proportion of case mothers (81.4%) than control mothers (73.7%) did not receive supplemental folic acid. In terms of adverse birth outcomes, such as stillbirth, preterm birth, low birth weight, and small for gestational age, similar differences were observed between mothers in the two groups (17% for cases and 11% for controls). Finally, the proportion of medical problems during pregnancy, such as diabetes, hypertension, human immunodeficiency virus, and urinary tract infections, was higher among case mothers compared to control mothers . Table .(Table ).In this study, more case mothers 32.2%) drank three or more cups of coffee per day than control mothers (15.3%). When compared to their counterparts (40.7%), more than half (55.9%) of case mothers had low food consumption scores. When compared to control mothers (33.1%), the majority of case mothers (64.4%) consumed monotonous diets. In terms of substance use during pregnancy, 13.6% of cases and 9.3% of controls used drugs, alcohol, khat, or cigarettes.2.2% dranBoth hospitals recorded 2915 live births during the study period. 1836 of them were from Hiwot Fana Specialized University Hospital, while the rest were from Jigjiga University Referral Hospital. During the study period, 59 cases of NTDs were identified, 39 of which were from Hiwot Fana Specialized University Hospital and 20 from Jigjiga University Referral Hospital. Thus, the incidence of NTDs was 20.24/1000 births, with Hiwot Fana Specialized University Hospital having the highest incidence at 21.24/1000 births. . A child born to a mother who had no antenatal care visits was four and a half times more likely to develop an NTD than their counterparts . Mothers with low food consumption scores were more than three times more likely to have NTDs than those with acceptable scores . Mothers who drank three or more cups of coffee or tea per day were four times  more likely to have a baby with NTDs than mothers who drank less than three cups per day. Maternal dietary diversification was strongly associated with the risk of developing NTDs in newborns. When compared to a more diverse diet, a mother with a monotonous diet was nearly 25 times  more likely to have a baby with NTDs.  may increase the risk of NTDs during pregnancy in younger age groups .In this study, poor food consumption was linked to NTDs. Another study conducted in Ethiopia’s Tigray region yielded similar results . HealthyIn this study, being a female newborn increased the risk of NTDs threefold when compared to males. This finding is consistent with findings from three teaching hospitals in Addis Abeba, Ethiopia , Tigray,Coffee consumption was linked to NTDs. This finding is consistent with hospital-based studies conducted in Addis Abeba, Ethiopia , 46. AltA strong study design was used in this study (case control). Despite the rarity of the cases, we collected primary data that was confirmed by a physician. Because some of the variables in this study were sensitive , there might be social desirability bias. Second, the study was conducted in a hospital, and home births were not included. Finally, the study did not address the genetic and chromosomal determinants of NTDs, which folic acid does not prevent. Furthermore, the other limitations were due to the small sample size.According to this study, female newborns, few antenatal care visits, maternal coffee consumption of three or more cups per day during pregnancy, and a low food consumption score were all independently associated with NTDs. As a result, comprehensive preventive strategies focusing on the identified risk factors are required at the regional and national levels.The findings suggest that primary preventative strategies, such as active promotion of preconception care services and food fortification, as well as promoting good dietary practices and household food diversification, should be strengthened in order to reduce the burden of NTDs. Furthermore, ensuring that mothers avoid harmful substances, particularly alcohol and tobacco, increasing and strengthening the education of health staff and others involved in promoting the prevention of congenital anomalies, pre-and peri-conception, and neonatal screening, developing and improving registration and surveillance systems, reducing coffee and tea consumption during pregnancy, improving diets for adolescent girls and women of reproductive age, and developing e-prevention programs are all priorities. Finally, further research is recommended to address the genetic factors of NTDs.


The mainstay of the treatment of constrictive pericarditis ispericardiectomy. However, surgery is associated with high early morbidityand mortality and low long-term survival. The aim of this study is todescribe our series of pericardiectomies performed over 30 years.A descriptive, observational, and retrospective analysis of allpericardiectomies performed at the Institute of Cardiology andCardiovascular Surgery of the Favaloro Foundation was performed.A total of 45 patients underwent pericardiectomy between June 1992 and June2022, mean age was 52 years (standard deviation ± 13.9 years), and73.3% were men. Idiopathic constrictive pericarditis was the most prevalent(46.6%). The variables significantly associated with prolongedhospitalization were preoperative advanced functional class , persistent pleural effusion , and although there was no statistical significance with the useof cardiopulmonary bypass, a trend in this association is evident(P<0.07). We found that 100% of the patients with an onset of symptomsgreater than six months had a prolonged hospital stay. In-hospital mortalitywas 6.6%, and 30-day mortality was 8.8%. The preserved functional class is17 times more likely to improve their symptomatology after pericardiectomy.Advanced functional class at the time of pericardiectomy is the variable moststrongly associated with mortality and prolonged hospitalization. Onset ofthe symptoms greater than six months is also a poor prognostic factor mainlyassociated with prolonged hospitalization; based on these data, we stronglysupport the recommendation of early intervention. Constrictive pericarditis (CP) is a disease of the pericardium characterized byimpaired ventricular diastolic filling resulting from constriction caused by afibrotic and scarred pericardium. The typical clinical manifestation ischaracterized by signs and symptoms of right heart failure with preserved rightventricular (RV) and left ventricular (LV) function.-3.CP is due to two pathophysiological phenomena: ventricular interdependence due toconfinement of the heart within a rigid pericardium and loss of transmission ofbreathing pressures through the pericardium, hence early LV filling is impaired. Asa consequence, the volume of the right ventricle increases, and septal rebound orprotodiastolic displacement of the interventricular septum occurs.Physical exam findings include jugular ingurgitation with or without Kussmaul’s signand symptoms/signs of right heart failure. In the electrocardiogram, the mostcharacteristic feature is a low voltage tracing. Currently, the transthoracicechocardiogram is the most accessible diagnostic tool, and diagnostic signs arepericardial thickening and notch in the interventricular septum, changes in Evelocity > 25% in relation to respiratory movements, a restrictive ventricularfilling pattern, reverse diastolic expiratory flow in the suprahepatic veins, anddilated inferior vein cava (IVC) without respiratory variability. On cardiacmagnetic resonance imaging, pericardial thickness > 3-4 mm and real-timeventricular interdependence are diagnostic signs. Typical findings during cardiaccatheterization include square root sign (dip and plateau), equalization ofdiastolic pressures, and ventricular interdependence assessed by a systolic arearatio > 1.1,2,4,5.The most frequent etiologies are idiopathic (IDP) and infectious/inflammatory,followed by postradiation (RDT) and postsurgical. Tuberculosis is no longer the mostfrequent cause, but it continues to be very prevalent in patients with humanimmunodeficiency virus. However,surgery is associated with relatively high early morbidity and mortality and lowlong-term survival compared to the sex- and age-matched group.The mainstay of treatment of CP is pericardiectomy, class IC, according to EuropeanguidelinesThe aims of this study are to describe our series of pericardiectomies performed over30 years and to analyze the etiologic spectrum, echocardiographic findings, as wellas postoperative complications and mortality.We performed a descriptive, observational, and retrospective analysis of allpericardiectomies performed at the Institute of Cardiology and CardiovascularSurgery of the Favaloro Foundation. All patients undergoing surgical pericardiectomyfor CP from June 1992 to June 2022 were included.The etiology of CP was determined based on the patient’s history, defining aspostcardiotomy (PCT) CP those patients with a history of previous cardiac orthoracic surgery, RDT CP those with a history of radiation to the thorax ormediastinum, and miscellaneous (MSL) CP those with a history of tuberculosis,purulent or bacterial pericarditis, uremic, autoimmune, or neoplastic infiltrationof the pericardium, and history of thoracic trauma. Finally, IDP CP was defined asall those patients who did not fit into any previously described categorization orwho had suffered at least one event of acute pericarditis during their lifetime.Preoperative, intraoperative, and postoperative demographic characteristics wereanalyzed, renal failure was categorized according to the Kidney Disease ImprovingGlobal Outcome classification, and the Global Initiative for Chronic ObstructiveLung Disease classification was used for chronic obstructive pulmonary diseasepatients. Functional class (FC) was evaluated according to the New York HeartAssociation (NYHA) classification, and this variable was recategorized as preservedFC for stages I and II and advanced FC for classes III and IV.The echocardiographic variables analyzed were: LV end-diastolic and LV end-systolicdiameters in millimeters (mm), LV ejection fraction (%), RV systolic function, diastolic relaxation pattern, transmitral E velocity (cm/s), left atrial size, pulmonary artery systolic pressure in mmHg, IVC defined as normaland dilated with and without inspiratory collapse, pericardial thickening, andpericardial effusion.Within the postoperative intercurrences, vasoplegia was categorized according to thedose of noradrenaline used, being mild < 0.1 ug/kg/min, moderate between 0.1 and0.5 ug/kg/min, and severe > 0.5 ug/kg/min. The same criteria were used toclassify the severity of low cardiac output syndrome, being mild when they requireda dose of dobutamine < 5 ug/kg/min, moderate between 5 and 10 ug/kg/min, andsevere > 10 ug/kg/min.In-hospital and 30-day mortalities were analyzed. For both clinical andechocardiographic follow-ups, the last visit registered at the institution wasconsidered.th percentile of the hospitalization variable was usedto define prolonged hospitalization being > 15 days.The data were analyzed with the Stata 13 program. Categorical variables wereexpressed as absolute value and percentage; continuous variables were expressed asmean and standard deviation (SD) or as median and interquartile range (IQR), asappropriate. The 75t-test for thosevariables with normal distribution and with the Mann-Whitney U test for variableswith non-Gaussian distribution. A P-value < 0.05 was consideredsignificant.Categorical variables were analyzed with Chi-square or Fisher’s test, as appropriate;continuous variables were compared with the A total of 45 patients underwent pericardiectomy between June 1992 and June 2022,mean age was 52 years (SD +/-13.9 years), and 73.3% were male. The time from symptomonset to pericardiectomy was 365 days (IQR 354-730 days). History and clinicalcharacteristics are described in Among etiologies, IDP CP was the most prevalent with 46.6%, followed by PCT CP with23.9%. Within the latter, 50% corresponded to recurrences of CP, and the averagetime of recurrence was 16 years. RDT CP constituted 8.8%, and the causes ofradiation were lung cancer, lymphoma, breast cancer, and a mediastinal carcinoidtumor. The average time between the application of radiotherapy and pericardiectomywas 18.5 years (IQR 11-23.5 years). MSL CP corresponded to 20%. The specificationsare described in Regarding the surgical approach, 71.1% were by sternotomy, and the remaining were byanterior bithoracotomy. Cardiopulmonary bypass was used in 11% of patients with amedian time of 50 minutes (IQR 42-71 min). No surgery involved aortic clamping asall pericardiectomies were isolated procedures.P=0.06) towards postoperativeimprovement.The preoperative and postoperative echocardiographic characteristics are described inAmong the postoperative intercurrences, atrial fibrillation represented 29.5%; acuterenal failure was 13.6%, of which none required hemodialysis; and the mediancreatinine was 2 mg/dl (IQR 1.2-2.8 mg/dl). The incidence of postoperative pleuraleffusion was 46.3%, and postoperative infections were 20%. We found an incidence ofvasoplegia of 33.3%, of which only two patients (13.3%) required > 0.5 ug/kg/minof noradrenaline; low cardiac output syndrome accounted for 35.5%, and there were nosevere cases.P<0.04), persistent pleuraleffusion , and although there was nostatistical significance with the use of cardiopulmonary bypass, there was a trendin this association (P=0.07). In addition, we found that 100% ofthe patients with an onset of symptoms > 6 months had a prolonged hospitalstay.The median of days of hospitalization in the cardiovascular intensive care unit wasone day (IQR 1-3 days), and length of hospital stay was eight days (IQR 5-15 days).A prolonged hospital stay (> 15 days) was observed in 26.6% of the patients. Thevariables significantly associated with prolonged hospitalization were preoperativeadvanced FC ; theetiology mostly linked to mortality was RDT CP (two patients), and the other twopatients corresponded to the MSL CP group, one with lymphoma/leukemia and one withpurulent CP. No patient with IDP or PCT CP died. The causes of mortality in thepatients who died were chronic myeloid leukemia with conversion to acute leukemiaand subsequent septic shock with multiple organ failure, cardiorespiratory arrestdue to asystole evolving with encephalic death, acute RV failure requiringmechanical circulatory support with extracorporeal membrane oxygenation, and finallyone patient with septic shock secondary to mediastinitis/purulent CP due toP<0.05). Only 13% of patients remained with impairedFC.Follow-up time was 135 days (IQR 15-365 days). During follow-up, there was evidenceof improvement in FC, with 65.7% of patients remaining in NYHA I and 21% in FC II. In the  has the largest series published so far, 1,066patients over 80 years of experience, followed by Bertog et al. with 166 patients.CP and, therefore, pericardiectomies are a rare entity, so large registries arescarce; in Argentina, this analysis is the only one of its kind and has a number ofpatients similar to the series analyzed. Murashita et al.-5,7,9-14. The second etiology that usually follows inprevalence is PCT CP, representing between 17 and 39% of the cases, coinciding withour report as well,11,12,14. As forthe MSL group, if we break it down, only 11% corresponds to tuberculosis. Both Portaet al. and Montero etal. in their series of140 and 53 patients, respectively, report infectious/inflammatory CP (includingtuberculosis) as second in frequency, after IDP CP. In contrast, the group ofMurashita et al. and Porta etal. explain that thereis a change in the etiological spectrum with a greater tendency towards PCT and RDTCP due to the decrease in tuberculosis and its complications.In all the series analyzed, IDP CP is the predominant etiology, which we were able tocorroborate with our analysis,7,8,13. Bertog et al. describe an average of 11 years (range between 2-20years) between exposure to radiation and pericardiectomy, in our case it was 18.5years.On the other hand, RDT CP is a less prevalent etiology in most series but with highmorbimortality, which we were also able to prove since 50% of our mortality was dueto this etiology. Several authors describe radiation as a poor prognostic factor inthe development of CP and its subsequent surgical resectionvs. 30%bithoracotomy or left anterior thoracotomy,7,11-14. With their analysis over 80years, dividing their study into two periods - “the old era” until 1990 and “the newera” since 1990 -, Murashita et al. reported a change in trend over time from left anteriorthoracotomy to median sternotomy, due to the possibility of being able to extend theanterior pericardiectomy from phrenic to phrenic, the diaphragmatic pericardium,and, when possible, the posterior pericardium. Furthermore, these authors maintain,as do some other authors, that greater aggressiveness in the resection of thepericardium is a good long-term prognostic factor,10,12,14. For example, Nozohoor et al., in their series of 41 patients, where theycompare the results of radical vs. subtotal pericardiectomy,describe a 10-year survival rate of 94% for radical pericardiectomy, and 54% forsubtotal pericardiectomy. In our experience, the trend regarding the surgicalapproach has changed over the last 15 years or so towards anterior bithoracotomy(Clamshell incision), which, like sternotomy, provides better bilateral andposterior access to the pericardium when the use of cardiopulmonary bypass is notnecessary; the same authors recently mentioned also clarify that pericardiectomywithout cardiopulmonary bypass has a better prognosis than when it isused,7,12,14. In our analysis, cardiopulmonarybypass was used in only 11% of the cases, and we observed a strong tendency towardsprolonged hospitalization in this group.The surgical approach by median sternotomy was the most prevalent, as in most of theseries compared, with an average of 70% sternotomy Regarding the preoperative and postoperative echocardiographic findings, theimprovement of the restrictive diastolic relaxation pattern was notable in 47%, aswell as the dilatation of the IVC in 54%, which strongly coincides with theimprovement in FC - 65% remained in FC I and 21% in FC II after pericardiectomy. Onthe other hand, patients who came to surgery with RV dysfunction not only did notimprove dysfunction after pericardiectomy, but there was even a 15% increase in theprevalence of such dysfunction. Both cardiac magnetic resonance and computedtomography are currently extremely useful tools, not only to confirm the diagnosisof CP, but also in the contribution with new information that escapes theechocardiogram, for example, pericardial inflammation by cardiac magnetic resonanceor the evaluation of pericardial calcifications in the case of computed tomography,both methods constituting a great tool for surgical planning; in our analysis, wehave very few patients who were evaluated by these techniques, but there is no doubtof their usefulness and potential uses.-5,14. On theother hand, the most serious postoperative complication seems to be acute renalfailure requiring hemodialysis with an incidence that varies from 1.8 to 7%; asreported by several authors, renal replacement therapy significantly worsens theprognosis,8,13,14. Our incidenceof renal failure was 13%, but no patient required hemodialysis.Among the postoperative intercurrences, the most frequently described was low cardiacoutput syndrome with an incidence of 35% in our analysis, which coincides with otherseries and Bertog et al. describe a mortality of 5.2% and 6%, respectively.The rest of the authors with smaller series report a mortality that varies between 0and 13%,11,12,14. In a self-referential analysisof hospital mortality reported by Santos et al. in this same institution in 2008, we found a significantdecrease of 50% from that date to the present.In our analysis, we found that in-hospital mortality was 6.6% and 30-day mortalitywas 8.8%. Larger series such as those by Murashita et al. who stronglyrecommend early surgical intervention due to these findings, considering early as< 6 months from the detection of CP or the onset of symptoms until theprocedure.All authors, regardless of the number of patients or mortality reported, agree thatadvanced FC at the time of pericardiectomy is the variable most strongly related tomortality. Although we could not demonstrate an association between mortality andFC, probably due to the limited number of patients in our study, we were able tocorroborate a statistically significant association between prolongedhospitalization and preoperative advanced FC, as well as with the onset of symptomswhen > 6 months, which makes us agree with authors such as Depboylu etal.,8,13. On the otherhand, IDP CP has the best prognosis,12. The causes ofdeath in general are linked to low cardiac output syndrome and sepsis.Regarding the relationship between mortality and CP etiologies, we observed that RDTCP has the worst prognosis, since in our case it corresponds to 50% of the deaths;this association also coincides with that reported in the literatureThe main limitations of our study were its retrospective nature and its limitednumber of patients, and we were not able to recover all the controlechocardiograms during follow-up, which limits our analysis in terms of thesevariables.IDP CP continues to be the most frequent etiology and with the best prognosis; on theother hand, RDT CP, although it has a low incidence, has high morbimortality, whichis why radiation is considered a predictor of poor prognosis.The greater aggressiveness in pericardial resection, as well as avoiding the use ofcardiopulmonary bypass, means a better long-term prognosis.Advanced FC at the time of pericardiectomy is the variable most strongly associatedwith mortality and prolonged hospitalization. In addition, we were able tocorroborate that the onset of symptoms > 6 months is also a poor prognosticfactor mainly associated with prolonged hospitalization; it is because of these datathat we strongly support the recommendation of early intervention (< 6 months) inpatients with less advanced FC.Randomized and prospective studies will be necessary in the near future to confirmthese assertions given the high morbimortality that still occurs in thispathology.