Pancreatic ductal adenocarcinoma is one of the most aggressive malignantneoplasms, with a one-year survival rate below 20%. Axial methods (computedtomography and magnetic resonance imaging) play a fundamental role in thediagnosis and staging of the disease, because they provide adequate anatomicalresolution in the assessment of key structures, mainly vascular structures.Pancreatic ductal adenocarcinoma is most often discovered in advanced stages,when surgical resection is no longer feasible. In that scenario, minimallyinvasive treatment alternatives have been developed in attempts to change thenatural history of the disease. Irreversible electroporation, an interventionalprocedure that minimizes deleterious effects on adjacent tissues, has provenuseful for the treatment of tumors traditionally considered unresectable.Despite the growing acknowledgment of this technique as a tool for themanagement of pancreatic ductal adenocarcinoma, it is still relatively unknownamong radiologists. In this study, we sought to provide an overview of the maincharacteristics and eligibility criteria that must be considered for theindication of irreversible electroporation in cases of pancreatic ductaladenocarcinoma. Thefive-year survival rate is 4%, the lowest among gastrointestinal neoplasms. The maindeterminant of this unfavorable prognosis is the indolent onset of the disease,which is oligosymptomatic, making early diagnosis difficult  follows the American Joint Committee onCancer international system of classification of tumors ,which c . Its cri ., which makesa surgical approach less feasible. In this context, therapeutic options have beensought, culminating in the development of minimally invasive methods in the lastdecade, including those employing ionizing radiation (percutaneous stereotacticradiotherapy) or high-frequency sound energy (high-intensity ultrasound), as well asthermal methods, such as radiofrequency ablation (by microwave emission) andcryoablation,4, all of which complementtraditional chemoradiotherapy regimens. A new non-thermal ablation technique, knownas irreversible electroporation (IRE), has recently been introduced. It has thecharacteristic of treating a tumor without changing the tissue temperature, thusproviding greater safety in cases of PDAC by preserving the nerves, bowel loops, andvasculature in proximity to the index tumor.Up to 90% of patients with PDAC have advanced (stage III) or metastatic (stage IV)tumors at diagnosis. In this process, the so-called“vascular block” coexists, where there is almost complete cessation of blood flow tothe ablation site, due to direct vasoconstriction  and indirect vasoconstriction (mediated by thesympathetic nervous system).In IRE, electrodes are inserted around a tumor to generate an electric field . Multipl. Because it does not generate heat, IRE avoids the heat-sinkeffect, a phenomenon related to the presence of large-caliber vessels near theablation zone, which reduces the effectiveness of thermal ablationmethods. It can beperformed percutaneously, guided by computed tomography (CT) or ultrasound, orintraoperatively, at the surgical site (immediately after resection of the maintumor), with the aid of ultrasound for proper positioning of theelectrodes. Currently,there is only one commercially available, IRE-specific electrode kit .The physical characteristics of IRE make it particularly attractive for use in thetreatment of locally advanced PDAC, given that the use of targeted electrical energydamages the tumor cell membranes while sparing extracellular macromolecules andconnective tissue, thus preserving delicate adjacent structures, such as the bileducts, bowel loops, and vascular walls.It is necessary to be aware of the eligibility criteria for IRE. The procedurerequires general anesthesia and deep neuromuscular block. Because of the effects(mainly cardiac effects) that electrical stimulation has on blood vessels and muscletissues, there are cardiovascular conditions that contraindicate it, such as ahistory of ventricular arrhythmias, pacemakers, poorly controlled hypertension, anddecompensated congestive heart failure. A history of epilepsy is an absolutecontraindication. In addition, the procedure is avoided when there is evidence ofclear involvement of the walls of hollow viscera, such as the duodenum and stomach,because of the high risk of rupture. Attention should also be given to patients withobstruction of the bile ducts or the portal vein, and it is necessary to treat thesecomplications before performing the IRE procedure, either with the interposition ofa biliary prosthesis or biliary-enteric anastomosis, in the first case, or theintroduction of a portosystemic stent, in the second, given the risk of stenosis orocclusion of these delicate structures due to the edema resulting from theprocedure gathered evidence that challenged traditional conventions inlocally advanced disease and proposed subclassifying PDAC according to the site ofvascular involvement (. It should be borne in mind thatsuch practices, in their consolidation phase, should be considered on a case-by-casebasis and are applicable only at specialized centers with experience in themultidisciplinary treatment of the disease.The main indication for IRE is for the treatment of tumors classified as stage III,which is the stage at which the greatest proportion of PDACs are diagnosed. Moststage III PDACs are considered unresectable or borderline resectable. However,advances in surgical technique and preoperative/intraoperative treatment have madeit possible to perform surgical resection with tumor-free margins, even in thisunfavorable scenario. Fromer et al.olvement , with thHigh-resolution CT is the main method employed for the diagnostic staging ofpancreatic cancer. As illustrated in Venous involvement, as illustrated in In tumors with a high risk of infiltration of the walls of hollow viscera  and 10, . In certainsituations, IRE is an adjunct to conventional surgery, increasing the likelihood ofachieving resection with tumor-free margins. Due to potential complications, the procedure isconsidered high risk and should be indicated judiciously. The flow chart shown inRadiologists play a fundamental role in the management of PDAC, not only in thesurgical planning but also in the indication of therapeutic alternatives such asIRE. This new treatment modality for locally advanced tumors has shown gains insurvival in comparison with the standard treatment of chemoradiotherapyonly


A comprehensive overview of the recent physics-inspired genome analysis tool, GenomeBits, is presented. This is based on traditional signal processing methods such as discrete Fourier transform (DFT). GenomeBits can be used to extract underlying genomics features from the distribution of nucleotides, and can be further used to analyze the mutation patterns in viral genomes. Examples of the main GenomeBits findings outlining the intrinsic signal organization of genomics sequences for different SARS-CoV-2 variants along the pandemic years 2020–2022 and Monkeypox cases in 2021 are presented to show the usefulness of GenomeBits. GenomeBits results for DFT of SARS-CoV-2 genomes in different geographical regions are discussed, together with the GenomeBits analysis of complete genome sequences for the first coronavirus variants reported: Alpha, Beta, Gamma, Epsilon and Eta. Interesting features of the Delta and Omicron variants in the form of a unique ‘order–disorder’ transition are uncovered from these samples, as well as from their cumulative distribution function and scatter plots. This class of transitions might reveal the cumulative outcome of mutations on the spike protein. A salient feature of GenomeBits is the mapping of the nucleotide bases  into an alternating spin-like numerical sequence via a series having binary  indicators for each A,T,C,G. This leads to the derivation of a set of statistical distribution curves. Furthermore, the quantum-based extension of the GenomeBits model to an analogous probability measure is shown to identify properties of genome sequences as wavefunctions via a superposition of states. An association of the integral of the GenomeBits coding and a binding-like energy can, in principle, also be established. The relevance of these different results in bioinformatics is analyzed. Bioinformatics methods used to identify genome signatures usually associate some numerical encoding to strands of symbolic nucleotide letters, such as (A)denine, (C)ytosine, (G)uanine and (T)hymine (or (U)racil nucleobase in the nucleic acid RNA). This implies that nucleotides are assigned some fixed numerical values for the purpose of extracting information. As a consequence of this mapping, some features of the original sequence have been derived, which are preserved when the associated numerical representation is unique. In general, the properties of large datasets correlate a genome sequence when there is an absence of mapping function degeneracy.For example, the well-known binary indicator of Voss  convertsMotivated by these simple numerical  representations of biological sequences, and in response to the urgent need of research on SARS-CoV-2 during the global pandemic years 2020–2022, we introduced a new numerical mapping algorithm, named GenomeBits, to unravel intrinsic signals from coronavirus (hCoV-19) sequences in FASTA format. In a series of papers written during the pandemic, interesting GenomeBits findings for different pathogen variants were reported in several references ,5,6,7. TThe significance of GenomeBits is to surpass some limitations of other statistical procedures, which seldom support a focused analysis at each single nucleotide level. Alternative frameworks for handling genomics information in the strands of DNA and RNA molecules from pattern matching consider symbolic codons  sometimes through manual examination. State-of-the-art methods for genomics analysis to identify variations and characteristic profiles still need algorithms to compare complete genome sequences quickly, accurately and efficiently . In thisThe article is structured as follows. k-base sums. The analysis of genomics sequencing throughout finite alternating sums allows us to extract distinctive features at each nucleotide base. From a statistics point of view, these alternating series correspond to a time series of discrete values.The GenomeBits mapping to retrieve special patterns of complete genome sequences assigns alternating sum series having multiple 0,1) values for the nucleotide variables equences . The map values fThe arithmetic progression in question carries, in fact, alternating terms, and a finite positive moment of independently distributed variables N. They are assumed to satisfy the relation:The individual terms k, then the next In this GenomeBits mapping, the binary indicator for the sequences assumes alternating positive and negative signs. The (±) signs are assigned sequentially, starting with A GenomeBits mapping example of the hCoV-19 genome fragment GTATACTGCTGC (having 12 nucleotides) converted to the alternating  array via Equation  that allowed for comparisons and classifications of the species of different emerging coronavirus variants and genome mutations from around the globe during all of the pandemic years 2020–2022. These data were extremely useful for genomics surveillance and, today, they form a rich source of information for the development of new theories that may predict and catalog this class of genomics strands. For almost half of its genome, the coronavirus presented a unique lineage with only a few relationships to other known viruses, in particular, in the spike region encoding the S-protein.The complete genome sequences of the contagious SARS-CoV-2 coronavirus in humans were first reported by Chinese scientists in early 2020 . To thisN nucleotides on the order of 30k bp in length. These samples were taken from broad geographical regions and were collected during different periods of the pandemic starting from November 2020 up to March 2021. In [Using GISAID data, we presented in  the Geno2021. In , we disc2021. In . The LinAs mentioned, GenomeBits can be used to investigate the conventional DFT Power Spectrum to identify the base periodicity properties of genome sequences and classification variants during the pandemic. In general, the Power Spectrum of the microorganism sequence is usually considered as the sum of the partial spectra: As can be seen in the plots, the DFT of the alternating sum series of Equation  reveals main. In , it was The GenomeBits Equation  can alsoOn the left of It is important to observe the distinctive Guanine patterns for Delta and Omicron variants of coronavirus samples from Spain, as shown on the top right of The evolution of other infectious disease related to Monkeypox virus (MPXV) also alerted humanity in 2022. Soon after, the genome sequences for MPVX were analyzed using the GenomeBits method . In thatIn The resulting scatter diagrams for In this overview, we considered the distinctive patterns of the complete full letter sequence of all the genes of the coronavirus genome for single strands, as available from, and reported within, the GISAID Initiative for the building blocks of nucleic acid coding sequence Adenine, Cytosine, Guanine and Thymine. In RNA, Thymine is replaced by Uracil because of their six-member single-ring structural similarity referred to as pyrimidines. The chemical structures of Uracil and Thymine, composed of carbon and nitrogen atoms, are very similar. The presence of Thymine in a DNA strand in actively dividing cells is more stable thermodinamically and improves the efficiency of DNA replication when compared to Uracil in RNA. The complementary base of both Uracil and Thymine is Adenine. During the pandemic, it was observed that SARS-CoV-2 genomes contain more Uracil than any other nucleotide. The substitution of nucleotides to Uracil was the highest among the non-synonymous mutations observed.From these simple statistical imprints, we believe that the GenomeBits method can help to shed light behind the behavior of infectious diseases by focusing on single-nucleotide structures—structures which are different on each mutation of a virus.Acoustic-like sounds within a biological context can help to identify trends in genome sequences and characterize new properties. For example, sonification algorithms based on biological rules for DNA sequences have used codons to generate audio strings representative of synthesized RNA during transcription . AnotherIn this context, it is worthy to note that at the initial base position This means that the wavefunction The applicability of this approach to sound waves from complete genome sequences of coronavirus pathogens was discussed in . At the As shown by the illustrative results in Equation  vs. the The analogous time–frequency spectrogram of the nucleotide base of Adenine, showing large peak signals over time, is shown in A visual inspection of the spectrograms obtained from an audio file could help to identify significant virus mutations. Examples of the wav audio files generated via the present extended GenomeBits wavefunctions, by transforming the occurrence of nucleotides of the same class along the genome sequences, can be downloaded from GitHub . We haveThis overview summarizes the GenomeBits findings in ,5,6,7, oIn this work, we have considered distinctive patterns of a complete coronavirus genome code for a single strand folded onto itself, as available from the GISAID database, for the nucleotide bases Adenine, Cytosine, Guanine and Thymine. As we discussed in , the corF is applied force and To conclude this comprehensive bioinformatics overview of the underlying genomics features at the nucleotide level from the viewpoint of the physics-based GenomeBits approach, let us mention potential directions to explore in order to enrich the description of data sequencing. In theory, one can consider the GenomeBits progression This relation may correlate a negative binding energy Equation  of a supEquation  may provAll associations discussed in this review are likely to be relevant for the study of genomics encoding of new sequences in microorganisms. Consequently, the GenomeBits representation may be useful to target the evolution of sequences due to natural mutation. One advantage for this approach is that sequence data for single A,T,C and G can be handled statistically to find their diverse characterizations and determine if the altered coding regions (genes) may share similar behaviors to those archived and classified during the evolution of a pandemic. GenomeBits may be useful for the bioinformatics surveillance behind future infectious diseases by means of its simple letter sequence-to-alternating numerical mapping.


In all vertebrates, closed blood and open lymph circulatory systems are essential for the delivery of nutrients and oxygen to tissues, waste clearance, and immune function. Endothelial cells (ECs) line the vessel walls and regulate the passage of molecules and cells to and from the underlying tissue. Mural cells, such as vascular smooth muscle cells and pericytes, imprint vital characteristics onto the vasculature. Significant physical differences are seen between arteries and veins, whereas functional and morphological differences are illustrated by filtrating microvessels in the kidney and the highly impermeable blood–brain barrier (BBB). The vasculature is highly dynamic, as it has complex cellular programs that regulate typification, new blood vessel formation through vasculogenesis or angiogenesis, lumen formation, and EC migration in mature vessels. Recent data also demonstrate the intimate relationships between dynamic vascular functions and metabolic demands and availability. Importantly, regarding human disease, vascular abnormalities underly or accompany the majority of cardiovascular diseases, such as arteriosclerosis, as well as a variety of a priori non-vascular diseases, such as cancer, inflammation, neurodegeneration, or metabolic disease.Central to the homeostatic and pathological mechanisms of the vasculature are highly specific intra- and inter-cellular signalling pathways, as well as genetic programmes, which are exquisitely responsive to growth factors, cytokines, nucleic acids, and lipids. This Special Issue highlights several important recent developments.Since its discovery in the 1980s, Vascular Endothelial Growth Factor (VEGF) has been vital to our understanding of the regulation of vascular function. While its basic functions and receptors have been widely studied, many insights remain to be discovered. To exert its functions, VEGFA binds to its cognate receptors, namely VEGFR1 (FLT1) and VEGFR2 (KDR), and initiates the formation of a multiprotein complex that includes co-receptors such as neuropilin-1 (NRP1) and heparan sulfate proteoglycans (HSPGs) [Here, Dallinga et al. investigated the role played by HSPGs and NRP2 in the different steps of VEGFA-induced angiogenesis . In thisAngiogenesis is not only regulated by VEGFA and its receptors. Pathological release of ATP, including during hypoxia and inflammation, triggers angiogenic expansion of vasa vasorum ECs (VVECs) . In thisAmongst mural cells, pericytes have long been known to be indispensable supporters and regulators of vascular function, including sprouting and blood vessel formation. More recently, the cytological complexity of pericytes has been recognised, and via this process, the intricate regulatory signalling crosstalk between mural cells and the endothelium occurs, which regulates barrier function, blood flow via lumen diameter, and vessel dropout and repair during ischemic disease. Schmitt et al. investigated whether recognised angiogenic functions of Casein Kinase 2 were also attributable to pericytes , findingPericyte also play a major role in establishing barrier function in ECs. In particular, in blood vessels that line the CNS and the retina, they regulate the suppression of endothelial transcytotic pathways . The revAnother research paper included in this Special Issue investigated the effect of the amyloid-β precursor protein (APP) on ECs and their barrier functions . RistoriBesides molecules, cells can also cross the endothelial barrier. Transendothelial migration (TEM) of leucocytes occurs during inflammation and the homeostatic immune surveillance of tissues. During the cascading adhesion of leucocytes to the endothelium, the interaction between leucocyte integrins and the endothelial adhesion molecule ICAM-1 must occur to mediate firm adhesion before diapedesis can be initiated . MorsingResearch into the development and pathophysiology of the vascular bed in the retina has accelerated considerably over the past 10–15 years, and the reasons for this shift are primarily related to the intrinsic properties of the retina that make it a suitable research model. Firstly, due to its similarity to the BBB vasculature yet greater accessibility, the retinal vasculature is increasingly being used to study the biology of blood–neural barriers . SecondlAdditionally, a number of reviews included in this Special Issue focus on important aspects of ocular cell biology and signalling. Microglia are resident immune cells that are distributed in the plexiform layers, ganglion cell layer, and nerve fiber layer of the adult retina. They exert their surveillance function by surrounding the environment with their motile processes. Alves et al. discussed the current knowledge regarding microglial interaction with the retinal vascular system under physiological and pathological conditions . They fiEskandarpour et al. review the mechanisms behind non-infectious posterior uveitis (EAU) and highlight the hypothesis of a possible involvement of Leukotrienes (LT) in the genesis of the disease . Recent Lastly, Pouw et al. provide a comprehensive review of the role of the ECM in the eye in influencing health and disease progression . ECM layWhile EC energy generation during angiogenesis is dominated by glycolysis , mitochoThe study conducted by Chatterjee et al. focuses on hyperglycaemic ECs . Here, tIschemic damage leads to the underlying vasculature of tissues requiring repair and regeneration. The potential of endothelial progenitor cells (EPCs) or endothelial colony-forming cells (ECFCs) to regenerate vasculature and tissues in the context of various ischemic pathologies has been recognised for some time; however, clinical trials in humans using such cells have yielded mixed results, indicating that a greater molecular understanding of endothelial forming cells is required . Two revCollectively, the articles published in this Special Issue reflect the importance of vascular signalling to our understanding of key biological and physiological principles.


This systematic review highlights the impact of HPV diagnosis and the electrosurgical excision procedure (LEEP) on mental health and sexual functioning. Indeed, our results showed that there is a correlation between abnormal cytology results/HPV infection and subsequent treatment interventions (LEEP/LEETZ) and women’s mental health and sexual life. The conclusions of our review underline the importance of sex education and knowledge about sexually transmitted diseases. An improvement in this area could prevent such high transmission of oncogenic HPV. Furthermore, the number of studies evaluating the impact of the procedure (LEEP/LEETZ) and the number of female participants have been very small, thus further research in this direction could be very beneficial. Additionally, psychological support should be provided to any patient who needs it. In this respect, such care should be part of the routine management of patients receiving an HPV diagnosis. Finally, the diagnosis and information about the current state of health should be communicated in an appropriate manner by gynecologists. Proper communication could significantly reduce the patient’s stress and anxiety.The impact of HPV diagnosis and subsequent treatment with the electrosurgical excision procedure (LEEP) on anxiety, depression, psychosocial quality of life, and sexual functioning has not been thoroughly investigated. The aim of this review was to systematically summarize the available knowledge on this topic, according to PRISMA guidelines. Data from observational and intervention studies were analyzed. A total of 60 records were included, of which 50 papers addressed the impact of HPV diagnosis on patients’ psychosocial status, while 10 studies addressed the impact of the implemented LEEP procedure on patients’ mental health and sexual functioning. The results indicated a negative impact of HPV diagnosis on the occurrence of depressive and anxiety symptoms, poorer quality of life, as well as on the sexual functioning of the affected women. The results of the studies to date have not confirmed the negative impact of the LEEP procedure on mental health and sexual life, although more research is needed in this area. It is necessary to implement additional procedures to minimize anxiety and distress in patients receiving a diagnosis of HPV or abnormal cytology and to improve awareness of sexually transmitted pathogens. Human papillomavirus (HPV) is a micro-sized, envelope-free deoxyribonucleic acid (DNA) virus that infects the cells of the deep layers  of the skin or mucosa . HPV infOncogenic types of HPV called high-risk HPV (HR HPV), mainly HPV 16 and 18, tend to cause most precancerous conditions and cancers of the cervix, as well as of the vulva, vagina, anus, penis, oral cavity, and throat. Persistent HR HPV infection is a major risk factor for the development of HPV-associated cancers of the anogenital region, as well as the head and neck area. Infection with non-oncogenic types of HPV called low-risk HPV (LR HPV), mainly HPV 6 and 11, can cause genital warts, including condylomata, and recurrent respiratory papillomatosis. However, they are not risk factors for cancers of viral etiology .Methods that reduce the risk of developing cervical cancer include primary prevention, such as HPV vaccination, and health education through the use of condoms, reducing the number of sexual partners, and general health behaviors, such as smoking cessation; as well as secondary prevention with screening tests .One can venture to say that in Poland sex education is poor and does not meet contemporary expectations or the needs of adolescents and young adults. The elderly were in a comparable situation at the time of sexual initiation and later. As a result, there is no widespread public awareness of the health and emotional consequences of sexual contact without physical protection (condom) and, when possible, immunological protection (HPV vaccination). The only information about the consequences of sexual imprudence concerns the potential risk of unplanned pregnancy. What is missing is information on the risk of sexually transmitted infections, such as HIV, syphilis, hepatitis B, hepatitis C, chlamydiosis and parasitic diseases , and HPV infection . NeverthPersistent HPV HR infection in the cervix can lead to the formation of high-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (HSIL CIN-2/CIN-3) lesions that precede the onset of cervical cancer. Women with histologically confirmed high-grade lesions (CIN2+) in the cervical mucosa are typically recommended to undergo surgical treatment, which involves the removal of the affected area using a procedure known as the loop electrosurgical excision procedure (LEEP) or large loop excision of transformation zone (LLETZ). The stress of being diagnosed with a disease closely related to a woman’s sexual intercourse and her partners, the prospect of surgery, the altered anatomical relations within the cervix after surgery, and the change in the location of nerve endings can all take a toll on patients’ overall well-being, mental state, and perception of sexual satisfaction.Studies have indicated that emotional reactions to a HPV infection test among women in the general population are also influenced by socioeconomic factors. Women with a lower education level, unemployed, younger age, unmarried, or not cohabiting may be more likely to experience adverse psychological reactions  associated with a positive HPV infection test. Information regarding a positive HPV test result in Poland is usually preceded by an abnormal gynecological cytology result. This is often accompanied by anxiety, fear of cancer, feelings of harm and injustice, and a search for the culprit of HPV infection. Currently, various reports related to the impact of a positive HPV test result on patients’ emotional reactions are available. Studies indicated that women receiving such a diagnosis are at risk of anxiety and depression ,7,8,9,10At present, HPV-related genital precancerous lesions appear frequently. While LSIL (low-grade) lesions are likely to resolve within a few years, HSIL (high-grade) lesions can cause a well-founded fear of progression and tend to recur, especially during the first few years after excitotoxic treatment. Consequently, they may also raise concerns about the consequences on sexual health. Referral for in-depth diagnostics, including colposcopic evaluation with histopathological verification is an integral part of providing medical services for the diagnosis and treatment of precancerous conditions of the cervix. The psychosocial impact of a positive HPV test can result, not only in psychological stress, but also significantly affect treatment outcomes through compliance. The World Health Organization (WHO) recommends counseling as an interpersonal communication strategy between a health professional and the female patient, to learn more about HPV and cervical cancer prevention and to give room for conversations about intimate topics, such as sexuality, disease, and death, and thus to encourage women to take preventive measures . Thus, mGiven the relevance of the topic of HPV infection and its health consequences, we aimed to systematically review the literature and summarize the conclusions from the available studies.The aim of this study was to review the available literature in terms of (1) the impact of abnormal cytology results/HPV infection on women’s mental health and sexual life; and the impact of (2) subsequent treatment interventions (LEEP/LEETZ) on women’s mental health and sexual life.On 26 September 2022, a search for articles was conducted in the MEDLINE, Embase, PsycINFO, and BIOSIS databases, with the aim of reviewing the impact of abnormal cytology results/HPV infection on women’s mental health and sexual life, and the impact of subsequent treatment interventions (LEEP/LEETZ) on women’s mental health and sexual life. Terms targeting anxiety, mood disorders, and sexual dysfunction related to a HPV-positive test or LEEP procedure were used, employing medical subject headings (MeSH), text words, and keywords. The following combinations of words were used:  AND . The findings were organized in accordance with the recommended format of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines see . In accoOut of the 1351 records initially retrieved, 374 were found to be ineligible based on the inclusion criteria. After removing 374 duplicate articles, 609 articles were deemed eligible. Upon reviewing the titles and abstracts, an additional 1291 publications were excluded for the following reasons: involving animal models, being a review paper, or having a prospective observational design format. Other exclusion criteria included studies that did not describe patients with HPV diagnosis or an abnormal cytology result, related medical interventions, and psychological impact on mental health and sexual life. However, 60 articles met the inclusion criteria, of which two concerned the same clinical trial. The results are shown in We reviewed 609 publications on the impact of an abnormal cytology result, HPV infection, and subsequent medical interventions on women’s mental health and sexual life. Sixty records met the inclusion criteria . Fifty-fThe participants involved in the research had an abnormal cytology result or had received an HPV-positive test result. In order to understand the impact of an abnormal cytology result, HPV infection, and subsequent medical interventions on women’s mental health and sexual life, participants were screened and examined according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, using the Hospital Anxiety and Depression Scale (HADS) ,26,27,28This review includes 59 studies, where authors investigated the effect of HPV diagnosis on anxiety, depression, and psychosocial quality of life , while iThe observational studies were classified using the ROBINS-E tool. Fourteen of the fifty-six included studies were rated as ‘low risk of bias’ ,40,47,48Of the 49 studies assessing mental and sexual health among women with HPV infection, 45 were observational studies, of which 30 used validated tools to assess anxiety, depressive symptoms, quality of life and sexual function, and 15 were qualitative studies using unvalidated questionnaires, surveys, or interviews .Forty-six studies assessed the impact of the HPV diagnosis on depressive or anxiety symptoms: nine on quality of life, and 15 on sexual function .Nineteen studies simultaneously assessed more than one of the functional aspects mentioned above, and two concerned well-being in relation to the way medical personnel conveyed information. The following groups were considered: women positive for HPV (n = 22); women with genital lesions linked to HPV (n = 11); women with abnormal cervical cytology (n = 10); women with low-grade cytological abnormalities (n = 7), women diagnosed with high-risk HPV (n = 3); women diagnosed with a borderline smear (n = 3); and women undergoing a Pap smear, viral typing, or colposcopy (n = 2). Of the 44 studies assessing the impact of HPV infection on anxiety and depressive symptoms, 41 (93%) confirmed a negative impact of the diagnosis on these symptoms . Patients also reported feelings of fear and worry ,58,62,63The impact of the loop electrosurgical procedure on anxiety, depression, quality of life, and sexual functions was assessed in 10 studies . Seven oThis review summarizes the existing literature on the impact of an abnormal cytology result, HPV infection, and subsequent medical interventions on women’s mental health and sexual life. To the best of our knowledge, this is the first systematic review covering this topic. The available literature suggests that there was a broad diversity in the methodology used in the conducted studies. Most of the studies performed to date focused on the overall psychosocial impact, including anxiety, anger, disappointment, depression, fear, feelings of shame and guilt, and sexual functioning.The fear and anxiety caused by abnormal Pap smear results or positive HPV tests are largely due to the screening program itself . WithoutDespite such varied methodologies, it can be summarized that receiving information about abnormal cytology results or an active HPV infection has a negative impact on women’s mental health and sexual life. Among studies focused on measuring the impact of HPV diagnosis on anxiety or depression, as many as 89% confirmed such a negative impact . The impIt is important to emphasize that the women participating in the studies described shame, especially when they were informed in advance that HPV infection occurs mainly through unprotected sexual intercourse. Since sexual intercourse is still considered a taboo topic for most of society, in particular accidental intercourse, the women felt humiliation. McCaffery et al. found negative social and psychological implications associated with a positive HPV test result. Women were found to be stressed about disclosing their results to others . In addiAs regards the impact of the LEEP procedure on anxiety or depression and quality of life, we identified only four studies addressing this issue. These studies did not indicate any particular negative impact of the LEEP procedure on mental health. However, more research is needed, as studies addressing this issue are lacking. In contrast, more work has been done on the impact of the LEEP procedure on the quality of sexual life. We found fairly divergent results, with a predominance of no adverse effects of the LEEP procedure on sexual function, as indicated by 60% of the analyzed papers. The study conducted by Gaurav et al. indicated an overall improvement in sexual satisfaction, by minimizing the occurrence of persistent dyspareunia symptoms and postcoital bleeding in female patients . The benAn additional important issue that is worth addressing is the education and socio-economic factors of those receiving a positive HPV test result. Women with lower education and lower socio-economic levels showed significantly higher levels of stress and anxiety. This fact may be related to the better education, understanding, and knowledge of the causes and consequences of the virus infection in women classified with a higher socio-economic level ,41,59. SOverall, the analysis of the studies indicated a huge deficit in women’s knowledge about sexually transmitted diseases, especially about HPV and its oncogenicity. This highlights the need for an increase in sex education in society, especially concerning knowledge about these diseases and routes of transmission. In addition, information on HPV vaccination could reduce the risk of infection and thus the risk of cervical cancer. It can be assumed that such knowledge would result in a reduced incidence of unprotected intercourse or accidental intercourse. Moreover, full information about the available and emerging new treatments, both surgical and non-surgical  , would aTraining midwives in this area could be a prudent step. Moreover, providing informational and educational brochures to patients, allowing them to learn about the topic in the comfort of their homes, could also be a valuable solution. Furthermore, sexological care can be important for women, who may experience changes in their sexual life or relationships after diagnosis and treatment. This type of care can provide women with information and resources to address sexual concerns and improve their sexual function and satisfaction.Due to the differences in the outcome of mental health and sexual functioning measures, it was not possible to conduct a meta-analysis. Given that there are disparities between countries associated with health and welfare systems, we cannot conclude with certainty that the insufficient number of studies from other parts of the world did not affect the results of this study. In addition, we only included studies written in English.The results of this systematic review show that receiving a positive HPV test or abnormal cytology result has a negative impact on women’s mental health and sexual function. Moreover, although studies focused on sexual well-being and functioning after the LEEP procedure showed divergent results, the majority of studies did not confirm negative consequences of the procedure. Nevertheless, more randomized trials are needed to investigate this topic further.In addition, the studies included in this review provide insights into patients’ perceptions of their situation. There is still much work to be done in sexual education, including providing information about sexually transmitted diseases. It seems crucial to provide patients with professional information about their condition or planned medical procedures, which could significantly reduce their stress and anxiety.It is crucial to recognize that each woman’s experience with HPV and the LEEP procedure may differ, and their requirements for psychological and sexological care may vary. Thus, healthcare providers should offer personalized care that meets each woman’s unique needs and preferences, to ensure optimal outcomes.This review highlighted the need to implement additional procedures to minimize anxiety and distress in patients receiving a diagnosis of HPV or abnormal cytology, and to improve awareness of sexually transmitted pathogens. The impact of the LEEP procedure on mental health and sexual life has not been confirmed by the current studies, and further research in this area, on a larger group of women undergoing this procedure, is necessary. In addition, it would be worth expanding the study to a larger group of people, after implementing the aforementioned broad psychological and sexological support, along with extending information and educational activities. Studies focusing on concerns about getting pregnant in women with a positive HR HPV test could also be valuable.


ANP is mainly synthesized by the atria, and upon excretion, it serves two primary purposes: vasodilation and increasing the renal excretion of sodium and water. The understanding of ANP’s role in cardiac systems has improved considerably in recent decades. This review focuses on several studies demonstrating the importance of analyzing the regulations between the endocrine and mechanical function of the heart and emphasizes the effect of ANP, as the primary hormone of the atria, on atrial fibrillation (AF) and related diseases. The review first discusses the available data on the diagnostic and therapeutic applications of ANP and then explains effect of ANP on heart failure (HF) and atrial fibrillation (AF) and vice versa, where tracking ANP levels could lead to understanding the pathophysiological mechanisms operating in these diseases. Second, it focuses on conventional treatments for AF, such as cardioversion and catheter ablation, and their effects on cardiac endocrine and mechanical function. Finally, it provides a point of view about the delayed recovery of cardiac mechanical and endocrine function after cardioversion, which can contribute to the occurrence of acute heart failure, and the potential impact of restoration of the sinus rhythm by extensive ablation or surgery in losing ANP-producing sites. Overall, ANP plays a key role in heart failure through its effects on vasodilation and natriuresis, leading to a decrease in the activity of the renin-angiotensin-aldosterone system, but it is crucial to understand the intimate role of ANP in HF and AF to improve their diagnosis and personalizing the patients’ treatment. In recent decades, the understanding of the role of natriuretic peptides (NPs) in cardiac pathophysiology has improved considerably, increasing their importance both for diagnostic and therapeutic purposes. The natriuretic peptide family consists of three peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and they represent the main cardiac endocrine function, as far as we currently know. Among these peptides, ANP is mainly synthesized by the atria, where the precursor form of these peptides split into prohormones and is stored in secretory granules in atrial cardiomyocytes ,2. Upon The diagnostic value of natriuretic peptides in cardiovascular disease, including AF and HF, has been extensively studied. ANP excretion is primarily regulated by mechanical stretch of the atrium during increased exercise, as observed in heart failure, and may also be influenced by the rate of atrial contraction. ANP release can also be stimulated by factors such as myocardial ischemia, adrenergic agonists, angiotensin II, and vasopressin. The half-life of ANP in plasma is approximately 2–4 min, and it is inactivated by neutral endopeptidase and lysosomal degradation. Elevated ANP levels are associated with left ventricular diastolic dysfunction and left ventricular end-diastolic pressure and may be a risk factor for AF recurrence. ANP levels also correlate with left atrial volume (LA) as determined by echocardiography and cardiac magnetic resonance. After an AF episode, plasma ANP levels decrease rapidly in response to filling pressure, and a steady normalization of ANP concentration occurs in association with improvement in atrial mechanical function .Measurement of NP levels can be useful in the clinical management of cardiovascular disease. In patients with HF, NP is a tool for diagnosis, prognosis, and therapy management, and there are established cut-off values. In addition, NP is useful in the management of AF by screening for new-onset AF, predicting the success of cardioversions and pulmonary vein isolations, and assessing the risk of stroke . In a stANP levels are typically very low in healthy individuals (20 pg/mL), but increase significantly in HF or AF patients. Measurement of the bioactive form of ANP can be challenging due to its short half-life (2 min), whereas the more stable N-terminal prohormone form (NT-proANP) is readily degraded. Therefore, the mid-region of NT-proANP (MR-proANP), which is less susceptible to degradation, is used in the clinical evaluation of HF patients. Measurement of the bioactive form of ANP can be challenging due to its short half-life (2 min) and the more stable N-terminal prohormone form (NT-proANP) is readily degraded. Therefore, the mid-region of NT-proANP (MR-proANP), which is less susceptible to degradation, is used in the clinical evaluation of HF patients . Figure p = 0.007). The higher NT-proANP levels persisted even after adjustment for underlying heart disease (p < 0.0001). In another study, Büttner et al. [In a study, Rossi et al.  aimed tor et al. , investir et al. , MeasureThere are also many studies on the most stable fragment of pro-ANP, namely MR-proANP in HF or AF patients, showing the diagnostic value of this peptide . Gohar eThe diagnostic value of MR-proANP was also reported by Yagmur et al.  in critiLast but not least, Schweizer et al.  in a recIn conclusion, ANPs have important diagnostic applications in AF and HF. They have been shown to be useful biomarkers for the diagnosis and severity assessment of these diseases. ANPs may also be a useful tool for predicting the risk of hospitalization and mortality in patients with HF. However, further studies are needed to explore the clinical utility of ANPs in these conditions.Since the PARADIGM randomized control trial showed that inhibition of neprilysin (NEP) improved outcomes in patients with HF, understanding the role of natriuretic peptides in this context has gained increasing interest . Data frOn the basis of these assumptions, several studies have examined the effect of sacubitril/valsartan on natriuretic peptide activity. Data from the PROVE-HF and EVALUATE HF studies confirmed a sustained decrease in NT-proBNP associated with positive remodeling as measured by left ventricular ejection fraction and left atrial dimensions ,20.On the other hand, the association between inhibition of NEP and BNP levels was weaker, and the change in the effector pathway of cyclic guanylate cyclase was somewhat independent of BNP trajectory . Two stuFor example, the aforementioned study by Nougué et al. confirmed a strong inhibition of the activity of NEP and showed a sustained 4-fold increase in ANP levels during sacubitril/valsartan therapy. Similarly, a biomarker substudy  of the POverall, these findings support the concept that ANP has an underlying biological effect in heart failure and those strategies that restore its physiological properties could improve the clinical outcomes. This concept applies to NEP inhibition, because ANP appears to be a more potent substrate for NEP and a more potent activator of the cGMP pathway than BNP but could as well pave the way for more targeted ANP substitutive therapy. Such strategies are currently under investigation and could in the future open a new chapter in the treatment of heart failure .Heart failure (HF) is a clinical and pathophysiological syndrome caused by ventricular dysfunction, leading to a different combination of volume overload and decreased cardiac output. The hemodynamic changes of HF lead to activation of renin-angiotensin-aldosterone and the sympathetic nervous system to restore homeostasis. Activation of neurohormonal systems causes sodium and water retention along with vasoconstriction to restore blood flow. However, in chronic heart failure, these mechanisms lead to a dysfunctional adaptation that further exacerbates hemodynamic derangement and pathological cardiac remodeling.Natriuretic peptides play an important role in heart failure through their effects on vasodilation and natriuresis, leading to a decrease in the activity of the renin-angiotensin-aldosterone system . Among NIn heart failure, volume overload leads to atrial distension, which promotes the release of ANP in response to these hemodynamic changes. However, it has been reported that patients with heart failure may have a significant deficiency of ANP and an attenuated renal response to ANP, leading to retention of sodium and water . AccordiRenal ANP resistance is caused by several mechanisms, including decreased ANP availability at the renal site, decreased binding of ANP to its receptor (NPR), or degradation of ANP at the renal site; these mechanisms can result in sodium and water retention at elevated ANP levels. Interestingly, both left ventricular dysfunction and renal failure, which is promoted by impaired renal response, are important markers of heart failure, to the extent that renal failure is considered one of the strongest markers of mortality . SeveralAF is the most common cardiac arrhythmia worldwide with multifactorial etiology. Several factors contribute to the disease, including aging, left atrial enlargement, left atrial dysfunction, heart failure, respiratory conditions, or mitral valve disease. AF induces irregular contractions in the atrium, resulting in electrical and structural remodeling. AF is also reported to be associated with endothelial damage, inflammation, and fibrosis ,32,33. SAtrial fibrillation causes the atria to lose efficiency in pumping blood to the ventricles , resulting in increased stress on the atrial walls and mechanical stretch. Therefore, ANP is secreted to stabilize hemodynamics through natriuresis and vasodilation, and this increase is directly related to the increase in left atrial stretching. Although ANP concentration increases during AF, it has been reported that a prolonged AF leads to a decrease in ANP level, due to the structural changes in the left atrium leading to a loss of ANP production sites . MaartenAs shown in These seemingly contradictory results should be considered in light of the different patient population, as catheter ablation is generally performed in subjects with less advanced atrial remodeling, and the difficulty in defining the natural history of atrial remodeling in AF. Detailed assessment of the time course of loss of atrial “integrity” will be an important milestone in this topic, and further studies are needed. Interestingly, ANP production itself could contribute to the development of atrial fibrosis by amyloid deposition. Amyloid deposits (misfolded proteins) can result from aging and various diseases. Among the types of amyloidosis, isolated atrial amyloidosis (IAA) is characterized by misfolded ANP proteins. Maarten et al.  discusseHowever, despite this potential mechanism, strong clinical evidence is lacking, and the interplay between these entities and their pathophysiology is yet to be elucidated. These complex interactions are illustrated in Current treatments for AF focus on restoring the sinus rhythm of the heart, which is not as effective because atrial remodeling and structural damage are the leading causes of AF, which can be irreversible if not diagnosed and treated in time ,42. An iIn another study, Nishino et al.  analyzedAccording to these results, the recovery of atrial contraction  takes about one month. In contrast, the concentration of ANP (as an indicator of endocrine function) drops rapidly and recovers within a week. With a similar behavior, peak A-wave velocity should increase to higher values as ANP drops to almost zero within 4 h. However, we have no such increase in mechanical function, showing a mismatch between recovery times. The point of view here is that due to the rapid drop in ANP concentration (within 4 h) in comparison with left atrial stretch and mechanical dysfunction, acute heart failure may occur.There are numerous studies on the effects of catheter ablation on ANP and its prognostic role. Sacher et al.  studied An interesting finding that emerged from the studies is the kinetics of ANP after catheter ablation. These data  showed tData from both cardioversion and catheter ablation consistently demonstrated delayed recovery of mechanical and endocrine atrial function estimated from ANP kinetics. These findings provide the basis for formulating hypotheses about the interplay between these aspects of atrial physiology after restoration of the sinus rhythm. Data from surgical treatment of atrial fibrillation with the Maze procedure  show thaThe production of natriuretic peptides represents the major endocrine function of the heart. While the role of BNP in the diagnosis and treatment of HF is currently well established, the assessment of ANP levels is still a subject of research without any clinical implication. Among the various factors hampering this, such as a shorter half-life, the most important is most likely the higher complexity of the endocrine function of the atria combined with several unresolved questions in the available literature regarding the mechanism of regulation during different diseases (such as HF and AF), the presence of a specific site for ANP secretion, the specific interplay between filling pressure, atrial contraction, and the presence of fibrosis. The intriguing link between AF, ANP, and atrial amyloidosis can be a possible explanation not only for the AF phenomenon , but we


Dear readers,Cardiac resynchronization therapy (CRT) is a primary treatment for patients with congestive heart failure (CHF) and conduction system disease. The benefit of this treatment modality has been demonstrated in many studies. Yet, despite many years of research and technological advances, a significant number of patients still do not experience improvement after CRT, and some studies estimate the percentage of non-responders to be >30%.1 It consists of acquiring a modified surface electrogram and generating dyssynchrony maps. Based on these maps, CRT optimization, including right and ventricular differential pacing, could be modified to improve electrical synchrony, which led to an improvement in LV ejection fraction. Another approach is mechanical-based and aims to pace areas of latest contraction in the LV. Identifying the areas of latest contraction has been conventionally guided by echocardiography. In this issue of The Journal of Innovations in Cardiac Rhythm Management, Abdellatif et al.2 describe the use of single-photon emission computed tomography for the identification of the areas of latest contraction and their proximity to the pacing lead to enable the prediction of CRT response.Over the years, different approaches have been used to improve the selectivity of the targeting areas in the left ventricle (LV) that would result in maximum resynchronization. One approach is electrical-based and aims to target areas of latest activation in the LV. Along this line, a novel technology, electrical dyssynchrony mapping, was recently described.Both electrical- and mechanical-based approaches to LV lead placement have led to only a small improvement in the rate of non-responders. The lack of a full response is probably due to the limitations imposed by the anatomy of the coronary venous tree rather than the knowledge of where to pace the LV. As a result, more focus should be directed toward the discovery of novel pacing technologies that overcome unsuitable coronary anatomies, including direct LV pacing, physiologic pacing, and others.Sincerely,md, fhrs, faccMoussa Mansour, Editor in ChiefThe Journal of Innovations in Cardiac Rhythm ManagementMMansour@InnovationsInCRM.comDirector, Atrial Fibrillation ProgramJeremy Ruskin and Dan Starks Endowed Chair in CardiologyMassachusetts General HospitalBoston, MA 02114


Fluid-structure interaction algorithms are utilized to examine how the human circulatory system functions by simulating blood flow and capturing mechanical responses within blood vessels. These sophisticated algorithms take into account interactions between fluid dynamics, vessel walls, heart walls, and valves. By combining advanced medical imaging techniques with fluid-structure interaction models, it becomes possible to customize these models for individual patients. This customization enables clinicians to create personalized treatment plans. In this comprehensive article review, we explore various applications of fluid-structure interaction models in studying the cardiovascular system.Using fluid-structure interaction algorithms to simulate the human circulatory system is an innovative approach that can provide valuable insights into cardiovascular dynamics. Fluid-structure interaction algorithms enable us to couple simulations of blood flow and mechanical responses of the blood vessels while taking into account interactions between fluid dynamics and structural behaviors of vessel walls, heart walls, or valves. In the context of the human circulatory system, these algorithms offer a more comprehensive representation by considering the complex interplay between blood flow and the elasticity of blood vessels. Algorithms that simulate fluid flow dynamics and the resulting forces exerted on vessel walls can capture phenomena such as wall deformation, arterial compliance, and the propagation of pressure waves throughout the cardiovascular system. These models enhance the understanding of vasculature properties in human anatomy. The utilization of fluid-structure interaction methods in combination with medical imaging can generate patient-specific models for individual patients to facilitate the process of devising treatment plans. This review evaluates current applications and implications of fluid-structure interaction algorithms with respect to the vasculature, while considering their potential role as a guidance tool for intervention procedures. The human circulatory system, also known as the cardiovascular system, is a complex network of blood vessels, organs, and tissues that transports oxygen, nutrients, hormones, and other essential substances throughout the body . It playThe prospective utilization of computational models to augment our comprehension regarding the circulatory system and hemodynamics is significant. Advanced imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) can be leveraged for the creation of three-dimensional models of blood vessels. Computational fluid dynamics, also known as CFD, constitutes one tool that facilitates analyzing the bloodstream through a vessel with tri-dimensional innovation geometry along with inlet–outlet velocity profiles that are extracted from non-invasive sources, like MRI scans detecting fluid movement . The CFDNonetheless, the effectiveness of CFD is impeded by restricted resolution capabilities and an inability to consider wall movements associated with elastic artery walls during the computation of blood flow through these vessels, leading researchers to explore alternative approaches, such as the employment of FSI techniques. These methods effectively account for deformable structures and their interactions with the fluids, thereby surpassing the effectiveness and practicality achieved by conventional CFD. Furthermore, FSI methods enable a more realistic simulation of flow patterns and provide improved insight into how blood flow phenomena in vessels are affected overall ,5.The study of blood flow within the human circulatory system plays a vital role in understanding various cardiovascular diseases and designing effective treatment strategies. Computational modeling techniques have emerged as valuable tools for simulating blood flow dynamics. Among these techniques, FSI computational algorithms have gained considerable attention due to their ability to capture the complex interplay between fluid dynamics and deformable vessel walls. This literature review aims to explore the current state of research on the use of FSI computational algorithms to simulate blood flow in the human circulatory system, highlighting their applications, challenges, and potential clinical implications.FSI modeling involves the simultaneous solution of fluid dynamics equations and structural mechanics equations to accurately capture the interaction between blood flow and the compliant vessel walls. Numerical methods, such as the finite element method (FEM) and finite volume method (FVM), are commonly employed to solve the coupled equations ,7. TheseThe immersed boundary method (IBM) is a technique for incorporating boundary conditions and collaborating with different solvers. It can be utilized in conjunction with both FEM and FVM, as well as other methods. The fluid component can be computed using the lattice Boltzmann methods, which have been proven to be highly effective compared to alternative approaches. The IBM has already been successfully employed in simulations of blood flow, exhibiting faster execution times than traditional CFD methods .Alternatively, mesh-free approaches, also known as meshless methods, may be employed. These computational techniques do not require conventional structured or unstructured grids for discretizing the computing domain. Instead of using these traditional structures, distributed data points or particles are utilized to represent geometry and solve governing equations in a diverse manner. For blood vessel interactions applicable to FSI simulations, utilizing meshless methodologies can offer several advantages over other alternatives.Key factors considered in FSI methods encompass wall shear stress, strain, stress, elastic modulus (E), and pulse wave velocity (PWV). Elevated levels of stress and strain on a blood vessel can increase the risk of complications such as rupture . By utilFSI computational algorithms have been extensively utilized in cardiovascular research to investigate a wide range of physiological and pathological conditions. These include the assessment of hemodynamic parameters, such as wall shear stress, pressure distribution, and flow patterns, which are crucial for understanding disease progression and identifying regions of high stress and vulnerability. FSI models have been employed to study phenomena such as arterial stenosis, aneurysm formation and ruptures, atherosclerosis, and the performance of cardiovascular devices, such as stents and heart valves. The ability to simulate patient-specific geometries and conditions has opened up avenues for personalized medicine, allowing clinicians to tailor treatment strategies based on individual patient characteristics .Despite their potential, FSI computational algorithms present certain challenges and limitations. Accurate and efficient modeling requires a realistic representation of both the fluid and structural domains, which demands high-fidelity imaging data and detailed constitutive models for vessel walls. The computational cost associated with solving the coupled equations is another challenge, especially for large-scale simulations and real-time clinical applications. The validation of FSI models against in vitro experiments or clinical data remains crucial to ensuring their reliability and clinical relevance. Additionally, the complexity of the circulatory system, including its pulsatile nature, multi-scale dynamics, and interactions with other organs, poses further challenges in accurately capturing the physiological behavior .The use of FSI computational algorithms in simulating blood flow has the potential to significantly impact clinical practice. Patient-specific simulations can aid in preoperative planning, allowing surgeons to assess the effects of interventions on blood flow patterns and vessel mechanics. By providing insights into disease progression and rupture risk, FSI models can assist in the diagnosis and treatment of cardiovascular pathologies . FurtherThe FSI simulations involve solving a set of coupled partial differential equations that describe the fluid flow equations  and the structural mechanics equations  . These e–Monolithic approach: In the monolithic approach, the governing equations for fluid flow and structural mechanics are solved simultaneously within a single computational framework . This ap–Partitioned approach: The partitioned approach separates the fluid and structural equations into two independent solvers, which are then coupled through an interface. Each solver operates independently, and the information is exchanged at the interface during the simulation. This approach allows for the use of existing specialized solvers for fluid and structural problems, making it computationally efficient .The partitioned approach is further distinguished into two distinct strategies using computational techniques known as one-way and two-way methods. These approaches vary in their methodology towards simulating the interplay between fluid flow and solid structures.–One-way FSI: In one-way FSI, also known as loosely coupled FSI, the fluid and structural domains are treated as separate and independent simulations. The fluid flow is first simulated using CFD techniques, and the resulting fluid forces are applied as boundary conditions to the structural analysis. The structural deformation, in turn, influences the fluid flow indirectly through these imposed boundary conditions. The information exchange between the fluid and structural domains is performed in a one-way manner, with the fluid providing the driving forces for the structural response. This approach is computationally efficient but assumes that the structural deformation has a negligible impact on the fluid flow .–Two-way FSI: On the other hand, two-way FSI, also known as fully coupled FSI, considers the fluid and structure as a coupled system that interact with each other. In this approach, the fluid and structural equations are simultaneously solved in a fully coupled manner, accounting for the mutual influence between the two domains. The fluid forces affect the structural deformation, and the resulting deformation alters the fluid flow patterns. The information exchange occurs bidirectionally, allowing for a more accurate representation of the fluid-structure interaction. Two-way FSI is more computationally demanding but provides a more realistic representation of the physical phenomena involved .The main difference between one-way and two-way FSI lies in the level of coupling and information exchange between the fluid and structural domains. One-way FSI assumes a one-sided influence of the fluid on the structure, while two-way FSI considers a fully coupled interaction where both the fluid and structure mutually affect each other. It is worth noting that the FSI algorithm choice depends on various factors, including the complexity of the problem, computational resources, desired accuracy, and the specific objectives of the simulation. Researchers and engineers select the most appropriate algorithm based on these considerations to ensure accurate and efficient simulations of fluid-structure interactions. The following are some commonly used FSI algorithms.In the subsections below, the partitioned FSI approach is described using different methods. The coupling between the two solvers is achieved by explicitly defining boundary conditions at the fluid-structure interface, either through explicit iterations or other suitable strategies. A partitioned FSI approach is one of several methodologies used in FSI simulations. In contrast to the partitioned approach, some FSI techniques involve solving a monolithic system of equations, where the coupled equations for fluid and structure are solved simultaneously. In this monolithic approach, the fluid and structure equations are combined into a single set of equations, and a unified solver is used to solve them. The choice between the partitioned and monolithic approaches depends on various factors, such as the complexity of the problem, computational efficiency, and desired accuracy. However, the numerical methods presented in this manuscript specifically pertain to different approaches for solving the fluid dynamics component within the partitioned FSI framework. These methods offer researchers a range of options to tackle the fluid dynamics problem while adhering to the principles of partitioned coupling. By exploring and comparing these diverse numerical methods, researchers can gain insights into the strengths and limitations of each approach within the context of their FSI simulations.The interaction between fluid and its surrounding structures is an ever-present aspect of biology that plays an integral role in the vasculature of the human body . Such inThe ALE method combines the advantages of Lagrangian and Eulerian formulations by tracking the motion of the fluid mesh. It enables the mesh to move with the fluid, accommodating structural deformations, while also providing a fixed Eulerian framework for solving the fluid equations. This method is widely used in simulating FSI problems with large deformations. The ALE method can be implemented within both partitioned and monolithic approaches in FSI simulations, depending on the specific implementation and computational framework used.–Partitioned approach: In the partitioned approach, the ALE method separates the fluid and structural equations into independent solvers. The fluid equations are solved using an Eulerian formulation, where the fluid mesh moves with the fluid motion. The structural equations are typically solved using a Lagrangian formulation, where the structural mesh remains fixed. The information is exchanged between the fluid and structural solvers at the fluid-structure interface, allowing for the interaction between the fluid and structure.–Monolithic approach: In the monolithic approach, the ALE method involves solving the fluid and structural equations simultaneously within a single computational framework. The fluid and structural equations are coupled and solved together in a fully coupled manner. This approach provides a more tightly coupled representation of the fluid-structure interaction, where the motion of the fluid mesh and the structural deformation are considered concurrently.Both approaches have their advantages and drawbacks. The partitioned approach allows for flexibility in choosing specialized solvers for fluid and structural problems, which can be computationally efficient. On the other hand, the monolithic approach provides a more integrated and accurate representation of the fluid-structure interaction but can be more computationally demanding. The choice between the partitioned and monolithic approaches depends on various factors, including the complexity of the problem, computational resources, desired accuracy, and the specific objectives of the simulation. Researchers and engineers select the most suitable approach based on these considerations to effectively capture the FSI using the ALE method.An alternative to body-fitted models is the immersed boundary formulation . First iThe embedded or embedded-boundary method involves representing the solid structure as a mesh embedded within the fluid mesh. This method allows for efficient simulations by using the fluid mesh to solve the fluid equations and incorporating the solid boundary conditions within the embedded structure . It is p–Partitioned approach: In the partitioned approach, the embedded or embedded-boundary method involves separating the fluid and structural equations into independent solvers. The fluid equations are typically solved using a traditional fluid solver, such as a finite volume or finite element method, where the fluid mesh remains fixed. The structural equations are solved separately using a structural solver. The information is exchanged at the fluid-structure interface to account for the interaction between fluid and structure.–Monolithic approach: In the monolithic approach, the embedded or embedded-boundary method solves the fluid and structural equations simultaneously within a single computational framework. The fluid and structural equations are coupled and solved together in a fully coupled manner. This approach provides a more tightly coupled representation of the fluid-structure interaction, where the fluid mesh and structural deformations are considered concurrently.Both approaches have their advantages and limitations. The partitioned approach allows for flexibility in using specialized solvers for fluid and structural problems, which can be computationally efficient. The monolithic approach provides a more integrated and accurate representation of the fluid-structure interaction but may be more computationally demanding. The choice between the partitioned and monolithic approach for the embedded or embedded-boundary method depends on various factors, such as the specific problem, computational resources, desired accuracy, and the objectives of the simulation. Researchers and engineers select the most appropriate approach based on these considerations to effectively model and simulate the fluid-structure interaction using the embedded or embedded-boundary method. These algorithms can be further complemented with advanced numerical techniques, such as finite element methods, finite volume methods, or meshless methods, depending on the specific requirements and characteristics of the FSI problem.Meshless methods, also known as mesh-free methods, are numerical techniques that do not rely on traditional structured or unstructured meshes for discretizing the computational domain . InsteadOne popular meshless method used in FSI simulations is the smoothed particle hydrodynamics (SPH) method. SPH represents the fluid and structure as a set of particles, where each particle carries properties such as position, velocity, and other relevant physical quantities. In SPH, the computational domain is discretized by placing particles throughout the domain, including the fluid and structural regions. For fluid simulation, SPH applies a smoothing kernel to evaluate the interactions between neighboring particles, allowing for the computation of fluid properties like pressure and velocity. The fluid equations, such as the Navier–Stokes equations, are solved by evaluating the interactions among the particles using this kernel function. The fluid particles interact with each other and with the solid particles representing the blood vessel walls, enabling the simulation of fluid-structure interactions.In the case of blood vessel interaction, the deformations and motions of the vessel walls are typically governed by structural equations, such as the equations of linear elasticity. The solid particles representing the vessel walls are subject to external forces from the surrounding fluid particles, allowing for the simulation of the interaction between the fluid and the deformable vessel walls. Meshless methods in FSI simulations for blood vessel interaction offer several advantages. They can handle large deformations and complex geometries without the need for re-meshing or re-gridding. They are well-suited for modeling free surface flows and multiphase flows, where the fluid domain and interfaces can evolve dynamically. Meshless methods also provide flexibility in capturing fluid-structure interfaces and handling fluid-structure coupling. Ongoing research and advancements in meshless methods continue to improve their efficiency and accuracy in modeling FSI with complex geometries .Similarly, meshless methods can be implemented using both partitioned and monolithic approaches in FSI simulations, depending on the specific implementation and computational framework used.–Partitioned approach: In the partitioned approach, the meshless method separates the fluid and structural equations into independent solvers. The fluid equations are typically solved using the meshless method, where the computational domain is discretized by a set of particles or scattered data points. The structural equations are solved separately using another meshless method or a different numerical technique suitable for structural analysis. The information is exchanged at the fluid-structure interface to account for the interaction between fluid and structure.–Monolithic approach: In the monolithic approach, the meshless method involves solving the fluid and structural equations simultaneously within a single computational framework. The fluid and structural equations are coupled and solved together in a fully coupled manner. This approach provides a more tightly coupled representation of the fluid-structure interaction, where the fluid particles and the structural particles or nodes interact directly and are solved concurrently.The SPH technique has the inherent characteristic of preserving mass balance, and its ability to trace a surface automatically eliminates the need for repeated regeneration of mesh in response to deformations ,31. SPH The choice between the partitioned and monolithic approaches for meshless methods in FSI simulations depends on various factors, including the complexity of the problem, computational resources, desired accuracy, and the specific objectives of the simulation. Researchers and engineers select the most suitable approach based on these considerations to effectively capture the FSI using meshless methods. In FSI algorithms, the “added mass effect” refers to the phenomenon where the surrounding fluid exerts an inertial force on a structure undergoing motion, or, in other words, the surrounding fluid moves with the same velocity as that of the immersed boundary . This efStrongly coupled methods necessitate achieving convergence of the fluid and solid variables at the boundary . DespiteThe arteries are intricate formations that show non-linear reactions to experiencing finite distortions. When creating models of such intricacy, multiple variables, including vessel elasticity and flow patterns, must be taken into account in FSI ,44. PatiCheng et al. challenged the classical Windkessel model by demonstrating that in addition to the heart’s power, the strain energy stored in deformed arterial vessels can contribute to propelling blood flow . The stuThe predictive capabilities of a biomechanical model in evaluating the risks associated with a non-dilated thoracic aorta affected by Stanford type A dissection, a life-threatening condition, are assessed in . A comprAzarnoosh et al. aimed to assess the impact of coarctation of the aorta (CoA) severity and duration on mechanical stimuli and arterial geometry changes using a rabbit model . DiffereThe effect of uncertainty in the elastic module (E) on a patient-specific aortic model was investigated using an FSI approach . The uncThe accuracy of pulse wave imaging (PWI) in estimating PWV in stenotic vessels was assessed . ConsequThis study investigates the relationships between twelve multi-directional/topological wall shear stress (WSS) metrics; moreover, the formation of coronary plaques was investigated using both the CFD and dynamic FSI frameworks . The resThe role of biomechanics in coronary artery disease was investigated using FSI simulations to analyze patient-specific coronary biomechanics in both spatial and temporal domains . A threeIn the context of blood flow within vascular pathways, using FSI (as opposed to CFD) is significantly important because it enables a comprehensive understanding of the intricate relationship between the fluid dynamics of blood, the structural behavior of blood vessels, and the complexity of the entire circulatory system. It helps in predicting the impact of blood flow on the structural integrity of the vessels, such as the potential for wall deformation, vessel dilation, or the development of aneurysms. Furthermore, FSI simulations provide insights into hemodynamics, including the evaluation of factors such as blood velocity, pressure distribution, and shear forces within the vessels . UnderstModels of the heart have been generated using FSI accounting for precision in the opening and closing of valves with fluid flow throughout the heart chambers . Such moA study by Bornoff et al. focused on the use of a total artificial heart (TAH) as a bridge to transplant device for end-stage biventricular heart failure patients . The ReaCat et al. investigated the mechanics of calcified aortic valve stenosis (CAVS), a common cardiovascular disease characterized by calcium buildup and tissue thickening in the aortic valve . Using aBileaflet mechanical heart valves (BMHVs) and the complications associated with their use, such as valve dysfunction, tissue overgrowth, hemolysis, and thromboembolism, were studied using FSI . ThromboA two-way immersed FSI computational model was developed and validated to study the impact of aortic annulus eccentricity and leaflet rigidity on the performance, thrombogenic risk, and calcification risk of bioprosthetic aortic valve replacements (BAVRs) . The modPatient-specific post-surgery type A aortic dissection (TAAD) models were created using computed tomography angiography images, and fully coupled two-way FSI simulations were conducted . In thisMost FSI models simulate the mitral valve, aiming to enhance the detection of blood leakage and assess the quality of valve closure. An FSI model utilizes the immersed boundary method to create a contact map, accurately representing the closure of the mitral valve without the appearance of orifice holes . The stuFang et al. conducted an FSI analysis to calculate hemodynamic parameters and employed particle residual rate (PRR) and blood renewal rate (BRR) analyses to assess thrombogenesis dynamics . This stThe utilization of computational techniques can be a viable and economical approach for assessing the flow parameters associated with heart valves. The inherent difficulties relating to long-term stability and biocompatibility in valve replacement or repair have underscored the necessity for more resilient methods that could address valvular disease effectively . A thoroIn relation to the blood flow within the heart, FSI plays a crucial role as it facilitates an all-encompassing comprehension of the intricate relationship between blood fluid dynamics, heart wall structural mechanics, and valve performance. This is particularly significant in understanding blood flow mechanisms within the heart. The FSI analysis enables the investigation into how the flow of blood interacts with the flexible and dynamic nature of the heart valves, which play a crucial role in ensuring proper unidirectional blood flow through the different chambers of the heart. By considering the interaction between the fluid and the valve leaflets, FSI simulations can provide insights into valve dynamics, including the evaluation of valve function, assessment of regurgitation or stenosis, and prediction of potential complications related to valve performance. Consequently, FSI studies contribute to advancing our knowledge of cardiovascular health, aiding in the development of diagnostic tools, treatment strategies, and the design of more effective prosthetic heart valves.Aneurysms can form anywhere within the arterial system, including the intracranial, aortic, abdominal, visceral, and peripheral arteries. Aneurysm diameter and expansion rate are risk factors that are assessed to estimate rupture risk. In cases in which the aneurysm is the result of thrombosis, diameter is also used to guide anticoagulant treatment. Computational models can be used to predict growth and likelihood of rupture of aneurysms based on parameters such as wall stress, oscillatory shear index, and patterns of blood flow .Blood flow in the brain occurs at different scales from large arteries with diameters of greater than 0.5 mm to smaller arteries and arterioles that can be as narrow as 10 μm. Cerebral aneurysms can have devastating consequences, such as subarachnoid hemorrhage, which leaves 60% of those afflicted with it dead or disabled. Most cerebral aneurysms go unnoticed until they rupture, or are incidentally noticed by brain imaging for another condition . QuantitFSI has also demonstrated its use in modeling aneurysms that occur within the aorta . FSI modCertain genetic conditions, such as Marfan syndrome, affect the elasticity of the aorta and predispose patients to aneurysms. FSI computations using a hyperelastic model of the aorta have compared the wall shear stress in Marfan syndrome patients as compared to controls and determined that wall shear stress was lower in those with Marfan syndrome, indicating vascular remodeling in the regions with the aneurysm . A phenoThe use of FSI modeling can further be incorporated into the treatment and management of aneurysms, as it can guide stent placement. FSI analysis was used to evaluate four different stents of varying materials, and factored in properties such as mechanical stresses, wall shear stress, and wall compliance . Such anA computational framework was developed to investigate and compare flow patterns in the aorta before and after thoracic aortic aneurysm (TAA) formation . The fraFSI models have been used to compare and contrast flow velocity, pressure distribution, deformation, and wall stress of two different methods of aortic aneurysm repair: stenting and wrapping. Wrapping involves placing polytetrafluoroethylene (PTFE) material around the aneurysm. It has been found that stenting creates significant changes in blood flow patterns within the aneurysm, while wrapping increases the thickness of the aneurysm and the strength of the vessel wall. Moreover, wrapping was found to have a significantly reduced amount of von Mises stress compared to the stent models .A tool combining measured aorta displacements and computed blood velocity field was developed to estimate blood flow-induced loads on the artery wall . The SPHIn the context of aneurysm repair, FSI holds particular significance as it can contribute to the selection of appropriate treatment strategies . By inteThe utilization of FSI holds significant value in assessing and analyzing a diverse array of vessels within the human body. By considering the dynamic interaction between the fluid flow and the structural response of the vessel walls, FSI simulations provide insights into the complex biomechanical behavior of the cardiovascular system. By employing FSI algorithms, researchers and clinicians can unlock a deeper understanding of the complex hemodynamic characteristics of the circulatory system. FSI simulations provide a powerful means to explore the intricate interplay between blood flow and vessel mechanics, shedding light on crucial aspects such as blood pressure distribution and flow patterns. These simulations offer insights into the development and progression of cardiovascular diseases, unraveling the underlying mechanisms and identifying potential targets for intervention. Furthermore, FSI simulations play a vital role in the design and optimization of medical devices used in cardiovascular interventions . By asseExperimental validation of computational studies is crucial, especially when simulating processes within the human body, due to several reasons. First and foremost, the human body is a complex and intricate system with numerous variables, making it challenging to capture all aspects accurately in computational models . ExperimNumerical FSI methods for simulating blood flow within the human circulatory system can be enhanced by incorporating artificial intelligence (AI) techniques . AI has The field of FSI offers a powerful quantitative approach to modeling patient-specific anatomy and the vasculature, enabling clinicians to gain detailed insights into the dynamics of blood flow within individual patients. Incorporating patient-specific geometries and physiological properties, FSI simulations provide a comprehensive view of how blood flows through the vasculature and the resulting forces acting on the vessel walls. This capability allows clinicians to identify regions of the vasculature that are subjected to varying forces, such as shear stress and von Mises stress, which are crucial indicators of vascular health. Through FSI modeling, clinicians can detect and analyze vascular disorders, including aneurysms, characterized by abnormal dilatation of blood vessels. By observing the effects of different types of stent treatments using FSI models, clinicians can make informed decisions on stent selection and placement, optimizing the restoration of blood flow and improving patient outcomes.The use of FSI computational algorithms in simulating blood flow within the human circulatory system holds immense promise for advancing our understanding of cardiovascular diseases and enhancing clinical practice. The ability to capture the intricate interplay between fluid dynamics and vessel wall mechanics empowers researchers and clinicians to conduct detailed investigations of both physiological and pathological conditions. FSI simulations enable the study of complex phenomena, such as thrombosis, atherosclerosis, and hemodynamic abnormalities, facilitating a deeper understanding of disease mechanisms and potential treatment strategies. However, it is essential to address technical challenges associated with FSI modeling, including computational efficiency, accuracy, and model validation against experimental and clinical data.This review has shed light on the current applications of FSI techniques in medical fields. By employing FSI, researchers and clinicians can explore a wide range of possibilities for improved diagnostics and treatments. However, it is essential to continuously assess the computational efficiency and accuracy of FSI techniques in comparison to experimental and clinical approaches, e.g., vFFR. Such a comparative analysis would provide a comprehensive understanding of the strengths and limitations of FSI. Furthermore, the path toward standardization emerges as a critical consideration. Standardization efforts are necessary to ensure consistent and reliable results as FSI techniques gain prominence. By discussing the current state of standardization, challenges faced, and potential strategies to achieve it, the review can contribute to the field’s advancement ,106.Hence, to fully realize the potential of FSI modeling, further research is necessary to refine and optimize the computational algorithms and numerical methods employed. Validation of FSI models against experimental and clinical data is crucial to ensure their reliability and accuracy in predicting real-world scenarios. Moreover, establishing guidelines for integrating FSI simulations into routine clinical practice is vital for effectively utilizing this technology for patient care . With co


Peptides and proteins have emerged as more important therapeutic molecules compared to small molecular chemicals due to their high specificity and efficacy and low toxicity. However, the intrinsic properties of peptides and proteins, including their large molecular weight, poor chemical and conformational stability, short half-life and low permeability, pose tremendous challenges to clinical use, as well as to researchers of medical and pharmaceutical science ,2. In or®  and Lipancrea® . In order to ensure their efficacy in the harsh gastrointestinal environment, various formulation approaches are always required to protect against degradation. In other words, their clinical efficacies highly depend on protection by formulations [Although peptides and proteins are difficult to be orally absorbed into blood circulation, some oral peptides can play a critical role in the treatment of local gastrointestinal tract diseases . The seculations .In addition, the blood–brain barrier (BBB) lies between blood circulation and the brain, impeding the transport of peptides and protein into the brain. Yue and colleagues gave a systematic review of localized delivery strategies for peptide/protein therapeutics in the treatment of central nervous systems (CNS) diseases, such as intracerebroventricular, intraparenchymal convection-enhanced, intrathecal and intranasal administration. Local delivery strategies could circumvent the blood–brain barrier to increase protein/peptide concentration. On the other hand, it is noteworthy that complications after surgical implantation and potential foreign repulsion responses could occur .To efficiently deliver proteins and peptides, the formulation approaches and penetration enhancers are always the most critical factors. Cui et al. reviewed recent advancements in oral liposomes for the delivery of peptides or proteins. Considering the vulnerability of liposomes along the digestive tract, improvements in the components of liposomes or surface modification were developed. The authors envisaged that deeper understanding of the processes involved in the oral absorption of liposomes could contribute to designing more efficient delivery systems and thus improving the bioavailability of oral polypeptides or proteins . In addiPulmonary administration, another alternative to the injectable route, can not only accelerate the absorption rate of peptide drugs, but also improve bioavailability. Huang et al. provided several perspectives regarding the design of metered-dose inhalers (MDIs) to solve the bottleneck of low-peptide drug loading .Having underlined the significant role of delivery systems of peptides and proteins, this Special Issue covers early development and later industrialization. Questions remain about the manufacturability, cost and toxicology of delivery systems. The rapid advancements in protein chemistry, formulation and drug delivery are anticipated to accelerate the emergence of superior delivery systems of peptides and proteins. With thorough consideration, versatile and efficient drug delivery systems will progress toward clinical trials or even clinics. Finally, the Guest Editors would like to sincerely thank all the authors and reviewers for their valuable contributions. We would also like to thank MDPI for deciding to publish this Special Issue.