Bacteriophages have long been considered only as infectious agents that affect bacterial hosts. However, recent studies provide compelling evidence that these viruses are able to successfully interact with eukaryotic cells at the levels of the binding, entry and expression of their own genes. Currently, bacteriophages are widely used in various areas of biotechnology and medicine, but the most intriguing of them is cancer therapy. There are increasing studies confirming the efficacy and safety of using phage-based vectors as a systemic delivery vehicle of therapeutic genes and drugs in cancer therapy. Engineered bacteriophages, as well as eukaryotic viruses, demonstrate a much greater efficiency of transgene delivery and expression in cancer cells compared to non-viral gene transfer methods. At the same time, phage-based vectors, in contrast to eukaryotic viruses-based vectors, have no natural tropism to mammalian cells and, as a result, provide more selective delivery of therapeutic cargos to target cells. Moreover, numerous data indicate the presence of more complex molecular mechanisms of interaction between bacteriophages and eukaryotic cells, the further study of which is necessary both for the development of gene therapy methods and for understanding the cancer nature. In this review, we summarize the key results of research into aspects of phage–eukaryotic cell interaction and, in particular, the use of phage-based vectors for highly selective and effective systemic cancer gene therapy. Cancer is currently one of the leading causes of mortality in people worldwide. According to studies, 19.3 million new cases and 10 million deaths from cancer were registered in the world in 2020 [Gene therapy is an experimental personalized approach to cancer treatment with the potential to provide directed tumor destruction . The invVarious studies are an indication that bacteriophages can be used to create vectors that provide an efficient targeted delivery of genes and drugs to cancer cells following systemic administration . The strBacteriophages are obligate parasites of bacteria and represent the most numerous group of biological entities inhabiting the biosphere . Since tA key role in the popularity of bacteriophages was played by the peculiarities of their structure and the organization of their genomes. From a morphological point of view, bacteriophage particles have a well-defined three-dimensional structure .The vast majority of virions consist of a head and a tail . The hea2+. The fact is that some surface polysaccharides and proteins of bacterial cells bind divalent cations, significantly increasing their concentration in the area of interaction between the phage and the host. It has been established that, for some bacteriophages, the presence of calcium ions is a necessary condition for the infection of host cells [The baseplate coordinates not only the recognition of specific receptors on the surface of the cell membrane but also the binding of the phage particle to the host bacterium. Successful binding to the bacterial receptor triggers a conformational change in the baseplate that eventually results in tail shortening. The signal for the deployment of these events is a change in the orientation of the fibrils with respect to the baseplate . It shoust cells . The effst cells . It is wAfter the irreversible binding of the phage to the bacterium, the contraction of the protein coat of the virus tail occurs, during which the protruding rigid tail tube pierces the outer membrane of the cell. Next, the tube penetrates the periplasmic space and, with the help of enzymes located at its end (mainly lysozyme), locally destroys the peptidoglycan of the cell wall. The genetic information of the virus is then injected into the cytoplasm of the bacterium, while the protein shell of the phage remains outside .E. coli F-pilus with their minor pIII protein. The binding of the virus to the bacterial pilus likely induces its retraction. In this case, the end of the filamentous phage virion, which exposes the pIII protein, is in the periplasmic space of the cell. In this layer, the phage binds to the secondary receptor, the TolA protein, which is part of the TolQRA complex, anchored in the inner cell membrane. Presumably, the pIII protein is also responsible for the formation of pores in the inner cell membrane, which are necessary for the further injection of the genetic material of the virus into the cell [Tailless phages infect host cells in a different way. Filamentous bacteriophages (Ff-phages), for example, use cell pili to bind to and enter bacterial hosts. Ff-phages are known to bind the cell .Regardless of the mechanism of phage genetic information penetration into the host cell, there are two possible methods of its further implementation . When thA detailed study of the bacteriophages structure, their interaction with bacterial hosts and their life cycle makes it possible to actively use these viruses in many areas of modern applied and basic research. Due to the growing antibiotics resistance of bacteria, phage therapy for infectious diseases is currently experiencing a renaissance . The effCurrently, bacteriophages are considered as promising vectors for cancer gene therapy . They arThe first evidence of the ability of phages to directly interact with mammalian cells dates back to the 1940s and was provided by Bloch . This stThe possibility of the specific binding and penetration of the engineered bacteriophage into mammalian cells was first shown in a study conducted by D. Larocca et al. . HoweverIntegrin β3 is not the only surface protein of eukaryotic cells that promotes their specific interaction with bacteriophages. It is known that T4 and M13 phages can suppress the expression of the HSP90 gene in human prostate cancer (PC3) cells, which is responsible for the stimulation of mitosis, DNA repair and the prevention of apoptotic events. Such suppression is due to the specific binding of these phages to the HSP90 receptors .E. coli K1 lipopolysaccharide, providing the specific binding of the phage to the host cell. The binding of PK1A2 to polysialic acid initiates endocytosis, as a result of which the bacteriophage successfully enters the cell. Phage binding to β3 integrin and the HSP90 receptor should also initiate receptor-mediated endocytosis events leading to the entry of phage particles into the eukaryotic cell, but this assumption has not yet been experimentally confirmed.Another bacteriophage, PK1A2, has been shown to be able not only to bind specifically but also to penetrate into kSK-N-SH human neuroblastoma cells . These cBacteriophages can also use the mechanisms of nonspecific penetration into mammalian cells. The ability of some bacteriophages to freely penetrate into eukaryotic cells and overcome entire cell layers in the process of transcytosis is known . These vIn addition to transcytosis, phages also use other methods of nonspecific penetration into eukaryotic cells. The M13 filamentous phage is characterized by strong plasticity in choosing the mechanism of internalization into mammalian cells. It is known that it can enter both epithelial and endothelial cells by clathrin-mediated endocytosis, macropinocytosis or caveolae-mediated endocytosis  . AnotherInside the eukaryotic cell, bacteriophages encounter unfavorable environmental factors that seriously limit their activity in the cytoplasmic space. Like some eukaryotic viruses , phage pAlthough most bacteriophages are degraded after internalization into mammalian cells, there are data indicating a close interaction between phages and eukaryotic intracellular proteins. For some phages, their ability to activate Toll-like receptors localized on the endosome membrane and induce a cellular immune response has been proven ,50. At tIt is assumed that the genetic material of bacteriophages can interact with cytosolic proteins, participating in the activation of cGAS-STING and RIG-I pathways . HoweverAnother important and little-studied aspect of phage–eukaryotic cell interaction is the transfer of bacteriophage genetic material to the cell nucleus. The phage genome, like the genomes of eukaryotic viruses, can enter the nucleus during mitosis, while the nuclear envelope is temporarily destroyed . AnotherE. coli revealed the presence of TATA-box, eukaryotic transcription factor sites and polyadenylation recruitment sequences [It is now becoming clear that the interaction between bacteriophages and eukaryotes is much more complex and diverse than previously thought. The presence of functional NLS in the proteins of some phages and the discovered ability of phage genomes to integrate into mammalian DNA indicate the close interaction of prokaryotic viruses with eukaryotes and the existence of an active direct horizontal gene transfer between them . It has equences . This Stequences . The furGene therapy is an experimental approach to treating various diseases by introducing foreign therapeutic genes or manipulating disease-related genes . The mosCurrently, phage display technology is widely used to search for functional antitumor peptides, surface markers of cancer cells and their highly specific ligands. Random peptide libraries presented on T7 phage, for example, contributed to the discovery of a potent selective inhibitor of tumor K-RAS, which is one of the main growth factors in various types of cancer . At the The development of phage-based cancer vaccines appears to be one of the most significant and promising areas of modern biotechnology and medicine . At the Although the use of high-precision cancer-specific nanocarriers as delivery vehicles for therapeutic genes is a promising area of cancer therapy, clinical trials of gene therapy using in vivo gene delivery revealed an extremely low level of tumor targets transduction . Since tDespite the fact that bacteriophages were considered poor vectors for transducing cells of higher organisms, they unexpectedly suggested a new way to develop methods for delivering therapeutic genes. The lack of tropism for mammalian cells, the higher cloning capacity, the easy modifiability and the phage display technology distinguish bacteriophages as a promising cancer gene therapy tool . The proThe efficiency of the AAV/phage (AAVP) vector in suicide cancer gene therapy has been repeatedly confirmed in subsequent studies. AAVP-RGD4C-HSVtk, in combination with GCV, had a pronounced antitumor effect in preclinical tests on mouse models of Kaposi’s sarcoma, bladder and prostate carcinoma and breast tumors , nude raEven greater success in AAVP-mediated suicide gene therapy has been achieved with a combination of ligand-directed tropism and transcriptional targeting . The useDespite promising results, initial studies of AAVP-RGD4C also revealed a reduced efficiency of transgene expression by cells transduced with this vector . The stuThe improvement of AAVP by incorporating functional peptides into capsid proteins has been shown to be effective in cancer immunotherapy trials ,98. The The creation of transmorphic Phage/AAV (TPA) particles for the targeted delivery and expression of IL-12, IL-15 and TNF-α is a promising approach in the field of phage-mediated cancer therapy . Unlike Filamentous bacteriophages are not the only prokaryotic viruses that have found their way into immunogenic cancer therapy. In 2020, Y. J. Hwang and H. Myung constructed a T7 bacteriophage that provides targeted delivery of the mammalian granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine expression cassette to mouse melanoma cells . This cyFinally, one of the most promising developments in phage-mediated cancer gene therapy to date is its combination with advanced CRISPR/Cas9 genome editing technology. In a recent study, RGD4C-H5WYG-AAVP provided the effective delivery of elements of the CRISPR/Cas9 system as the first step in targeted p53 gene replacement therapy for human lung cancer . Lung adTo date, bacteriophages have been used as gene therapy vectors for cancer in an increasing number of studies and clinical trials. Despite the fact that eukaryotic viruses have a much greater evolutionarily determined efficiency of mammalian cell transduction, which previously defined them as the most preferred sources of gene therapy vectors, their natural tropism to eukaryotic host cells makes their therapeutic application very difficult. The oncogenic potential of retroviral and lentiviral vectors, the highly time-limited expression of the target transgene and the high immunogenicity of adenovirus-based vectors slow down the development of new gene therapy approaches for cancer . The creIn fact, the invention of phage display technology has turned bacteriophages into a powerful tool of molecular biomedicine. The easy modifiability and genetic plasticity of these viruses have made it possible to use engineered bacteriophages as therapeutic and diagnostic tools for various types of diseases, including cancer . To dateHowever, the further development of phage-mediated gene cancer therapy still requires the study of ways to create new vectors and improve existing vectors based on recombinant prokaryotic viruses. Although the chimeric AAVP vector is being used for targeted gene therapy for an increasing number of cancers, exploiting the unique strengths of other bacteriophages to create new hybrid viruses could raise the diversity of therapeutic approaches . A futurCancer therapeutic platforms based on bacteriophages represent a prime example of innovative biotechnologies. The enormous plasticity of their modifiability, proven safety, growing efficacy and variety of their therapeutic applications are expanding the horizons of cancer gene therapy. Numerous successful and promising trials of phage-mediated tumor cell transduction suggest that the vast potential of these viruses for cancer gene therapy has yet to be fully exploited.


The incidence of tooth wear has steadily increased in all Western populations during the past decades. A through-care strategy, extendable for a lifetime, has become crucial to prevent the extensive loss of sound dental structure and to make an eventual retreatment affordable in the long term. An interceptive treatment using resin composite materials and no-preparation approaches meets these requirements. Moreover, continual developments in digital dentistry makes possible to predict the treatment plan for the restorative rehabilitation of the mouth. The availability of digital resources allows clinicians to increase predictability for excellent esthetics and good functional results. This article provides a step-by-step description of a full-mouth additive rehabilitation achieved by employing digital workflows and direct resin composite restorations. A comprehensive functional and esthetic evaluation of the treatment is proposed and discussed. Tooth wear is a concerning problem with a rising rate of occurrence, as the prevalence of dental caries is decreasing and teeth have longer life . The levPathological tooth wear is defined as “atypical to the age of the patient, causing pain or discomfort, functional problems, or deteriorations in aesthetic appearance, which, if progressing, may give rise to undesirable complications of increasing complexity” . Its etiDentinal hyper sensibility, a consequence of aggressive dental erosion, has been reported as a major possible issue for patients. In fact, when the progression of dental sound tissue loss surpasses the dentin-pulp complex reparative capacity, it might provoke toothache, pulpal inflammation, pulp necrosis, and periapical lesions of some dental elements. However, the major cause of patients’ complaints is the degradation of the esthetic appearance of the smile, with dentine exposure, chipping and fracture of incisal edges, loss of micro- and macro-anatomy, and tooth shortening .Dental erosion is the loss of dental sound substance as a consequence of intrinsic  or extrinsic  acid attacks. Such a phenomenon may possibly be diagnosed years after the beginning of the erosion activity, which occurs either by hydrogen ion attack or by the action of chelating anions that dissolves the integrity of enamel crystals . The devMinimally invasive and adhesive dentistry strategies of rehabilitation are now preferred when treating a worn dentition. This is especially important for young patients, for whom a comprehensive, lifelong approach is essential . Such teTreatment approaches should integrate minimal invasive concepts and prophylactic care, especially when young patients are involved . ConventThe development of digital technologies is helpful in measuring precisely the amount of dental hard tissue loss, and consequently in increasing the predictability of the rehabilitation . The conThe goal of this clinical report is to present a full mouth rehabilitation performed with direct resin composites using fully digital planning.A 28-year-old male patient presented to the dental clinic at the University of Geneva, having been referred to restore his worn dentition after completing orthodontic treatment. An intraoral clinical examination revealed excessive tooth wear, which had led to the exposure of dentinal tissue. An initial documentation of the patient was used to create the treatment plan and as a tool for designing a future smile. . The patThe functional evaluation of TMJ was initiated with the screening questionnaire from the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) . The queFirst, a motivational interview was organized with the clear goal of reducing the patient’s intake of carbonated beverages in order to stabilize the erosive process. The patient then received professional dental hygiene therapy, including oral hygiene technique instructions. Virtual files of the initial situation were recorded in the standard tessellation (STL) format by the use of a digital intraoral scan . A facial scan was also recorded using a specific application  with a personal smart phone.The intermaxillary relationship of rehabilitation was established following the myocentric position concept and according to the minimal space needed to restore the loss of tooth structure. The myocentric position is a position referring to the muscles established along the neuromuscular trajectory. In this position, muscles are simultaneously at their resting length and in balanced tonus in relation to one another .Mandibular muscles were deprogrammed using cotton rolls (8 mm thick) between the posterior teeth (from canine to second molar). The patient was asked to stay at rest, perform movements of the jaw, and swallow several times for a period of 5 min. The bite registration was done on hard silicone  after cotton rolls were removed and the patient was asked to close until the minimal space required for restorations was commensurate with a good anterior overjet and overbite. Initial evaluation was done subjectively during the clinical session. A validation of this step was obtained through subsequent analysis of digital models with the wax-up in the laboratory and measurement of spaces obtained with the VDO augmentation. The hard silicone was not removed until an STL file was created registering the intermaxillary relationship, in order to transmit to the laboratory the position and space available for the restorations.The extraoral and intraoral pictures and the STL files were sent to a laboratory technician along with the facial scan. A digital wax-up was created to plan the rehabilitation project, which was integrated with a 3D scan of the patient’s face .The digital version of the full-molding technique was used to guide the clinical restorative phase . After fIt was decided to rehabilitate the posterior teeth first to stabilize the occlusion. Each quadrant was treated separately. The mandibular arch was isolated with rubber dam  after thNo dental preparation was performed, except for a complete sandblasting of the occlusal surfaces  to clean the tooth surface and to remove the amorphous enamel domains, thus exposing the underlying prismatic structure, which has better adhesive conditions . A selecA preheated hybrid composite resin  was placed inside the plastic tray, positioned in the corresponding quadrant and pressed with gentle pressure until the tray fitted the mesial and distal stops . Before After two weeks, the restoration of the palatal and vestibular anterior surfaces was done. After isolation of the operatory field with a rubber dam, a free-hand composite was placed on the palatal surfaces from teeth 1.3 to 2.3, following the same adhesive protocol used in the posterior quadrants . SubsequThe final post-treatment documentation with intraoral and extraoral pictures  and X-raIn this present patient, the primary focus of advice to manage the tooth wear was decreasing frequency of dietary acid intake. It was accomplished by showing images of eroded teeth and the use of his 3D teeth scans, which were helpful in motivating the patient and increasing his compliance. With the use of digital monitoring software and the scored level of tooth wear employed (TWES 2.0), it will be possible to monitor and record the severity of dental wear in the future .Modification of the VDO has been one of the most controversial issues in restorative dentistry for a long time, but it can be successfully accomplished if proper diagnosis and treatment planning are performed . The theAfter the amount of increase of VDO was determined, a virtual 3D diagnostics wax-up between both arches was accomplished. The facial scan enabled the transferring of the position of the maxillary jaw to be aligned with the face of the patient, functioning as a facebow . This prThe selection of the most suitable material to restore severe tooth wear cases is still an open issue for discussion . ClinicaResidual anatomical references  guided composite shaping and allowed the molding tray to be repositioned precisely, without deformation. Besides the biological advantages of the non-invasive restoration approach, the full-molding technique allowed for the simplification of operative procedures, decreased the number of clinical sessions and, consequently, reduced the cost for the patient. Proper deletion and polishing of resin composite interproximal excesses are the critical steps in this technique, which may result in a possible inaccuracy of the restored anatomy, especially on the lingual side. However, such a risk may be mitigated with a precise definition of the tray limits and improvements in skill made by advancing the learning curve of the operator .The most frequent complications when using resin composite are minor failures such as marginal discoloration or chipping. They usually only require an uncomplicated and rapid repair procedure. In fact, Loomans et al. observed acceptable clinical performance  after 3.5 years of tooth wear treated with direct composite . MoreoveAdvancements in adhesive dentistry and minimally invasive concepts permit clinicians to take advantage of a wide spectrum of therapeutic options. Most of them result in success if they are well employed and carefully selected in relation to the comprehensive clinical examination. This report shows a worn dentition treated successfully with a combination of direct composites techniques. Hybrid solutions like these can represent valid options, and knowledge of them allows clinicians flexibility in treatment planning.


Identifying new prognostic markers can provide a reference for the treatment of lung adenocarcinoma (LUAD) to improve its prognosis. Circadian rhythm disturbances are closely linked to the initiation, progression and prognosis of lung cancer. We aimed to explore the value of circadian miRNA (cmiRNA) as a prognostic marker of LUAD. A prognostic signature comprising seven pairs of cmiRNAs was established, and it exhibited excellent predictive value for overall and progression-free survival. High-risk patients showed higher sensitivity to primary chemotherapy drugs and targeted medicine compared with low-risk patients. Overall, the novel circadian-related miRNA pair signature could provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for LUAD. The cmiRNA–Cgenes network and corresponding enrichment analysis might provide clues for studying the underlying circadian dysregulation mechanisms involved in the progression of LUAD in the future.Lung adenocarcinoma (LUAD) is the primary histological subtype of lung cancer with a markedly heterogeneous prognosis. Therefore, there is an urgent need to identify optimal prognostic biomarkers. We aimed to explore the value of the circadian miRNA (cmiRNA) pair in predicting prognosis and guiding the treatment of LUAD. We first retrieved circadian genes (Cgenes) from the CGDB database, based on which cmiRNAs were predicted using the miRDB and mirDIP databases. The sequencing data of Cgenes and cmiRNAs were retrieved from TCGA and GEO databases. Two random cmiRNAs were matched to a single cmiRNA pair. Finally, univariate Cox proportional hazard analysis, LASSO regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature consisting of seven cmiRNA pairs. The signature exhibited good performance in predicting the overall and progression-free survival. Patients in the high-risk group also showed lower IC50 values for several common chemotherapy and targeted medicines. In addition, we constructed a cmiRNA–Cgenes network and performed a corresponding Gene Ontology and Gene Set enrichment analysis. In conclusion, the novel circadian-related miRNA pair signature could provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for LUAD. Lung cancer remains the leading cause of cancer-related deaths in the world ,2, with Chronic circadian rhythm disturbances are closely linked to the initiation, progression and prognosis of tumors ,7. For eThe microRNAs participate in crucial physiological balance and pathological processes, including the malignant characteristics of cancer, and have been identified as excellent signatures associated with the diagnosis and prognosis of cancer ,15,16. IWe downloaded the miRNA and RNA-seq expression data of LUAD from TCGA and GEO databases. Patients lacking corresponding clinical information and those who survived for <30 days were excluded. Postoperative tumor and adjacent normal tissues of 11 patients with LUAD in the Union Hospital  were collected. All the patients signed an informed consent form. The study complied with the Declaration of Helsinki and was approved by the Institutional Review Board of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (protocol: [2020](S363), 30 December 2020).The samples and data were collected from 10 March to 10 July 2022. http://cgdb.biocuckoo.org (accessed on 5 March 2022))  = 1.414, 95% confidence interval [CI] [1.112–1.797]) and risk score  remained independent prognostic factors after adjusting for clinical and pathologic factors  and risk score to fit a Cox proportional hazards regression model using the total TCGA dataset A. As shoThe immunosuppressive microenvironment is one of the main factors contributing to poor prognosis in patients with LUAD. Therefore, we tested the correlation between the risk score and the tumor immune landscape . The resBased on the pRRophetic algorithm, we explored the correlation between the risk score and drug sensitivity in the TCGA dataset. As shown in The relative expression of the 11 cmiRNAs between cancerous and adjacent normal tissues of patients with LUAD were further quantified by qRT-PCR. Only eight out of 11 miRNAs were confirmed to be significantly different between tumor and normal tissues, which might be explained by the low number of samples. A. The 48The five-year survival of lung cancer is 10–20% in most countries . It has Studies have suggested that clock genes and other genes related to the killing function  have a circadian oscillatory rhythm, which is altered by chronic shift-lag. These alterations may be associated with the inhibited circadian rhythm of the cytolytic activity of NK cells and the progression of lung cancer . AnotherThe classical biological role of miRNAs is to degrade or to inhibit the translation of target genes to reduce the level of protein-coding genes expression . In addiSeveral shortcomings are present in this study: First, the cmiRNA was predicted by the database based on circadian genes. Although we set strict criteria to increase the reliability of this targeting regulation, and the partial targeting regulation relationship has been validated by other studies, the true targeting regulation relationship of them requires further verification. Second, owing to the difficulty in collecting clinical samples and the limited time, no large-scale clinical cohort study was carried out to verify the prediction model. Finally, the cmiRNA–Cgene network pathway and its target regulation mechanism were only preliminary explorations and require further in-depth validation.To the best of our knowledge, as this is the first study to explore the role of cmiRNAs in lung adenocarcinoma. The established prognostic model based on cmiRNA pairs exhibited good performance in predicting the overall, progression-free survival and sensitivity to chemotherapy and targeted therapy.


Infectious diseases  dramatically impact human life, economy and social development. Exploring the low-cost and energy-saving approaches is essential in removing infectious virus particles from indoors, such as in classrooms. The application of air purification devices, such as negative ion generators (ionizers), gains popularity because of the favorable removal capacity for particles and the low operation cost. However, small and portable ionizers have potential disadvantages in the removal efficiency owing to the limited horizontal diffusion of negative ions. This study aims to investigate the layout strategy (number and location) of ionizers based on the energy-efficient natural ventilation in the classroom to improve removal efficiency (negative ions to particles) and decrease infection risk. Three infected students were considered in the classroom. The simulations of negative ion and particle concentrations were performed and validated by the experiment. Results showed that as the number of ionizers was 4 and 5, the removal performance was largely improved by combining ionizer with natural ventilation. Compared with the scenario without an ionizer, the scenario with 5 ionizers largely increased the average removal efficiency from around 20% to 85% and decreased the average infection risk by 23%. The setup with 5 ionizers placed upstream of the classroom was determined as the optimal layout strategy, particularly when the location and number of the infected students were unknown. This work can provide a guideline for applying ionizers to public buildings when natural ventilation is used.the Appendix is available in the online version of this article at 10.1007/s12273-022-0959-z. Appendix to: Impact of ionizers on prevention of airborne infection in classroom


Wu et al. trained a classification model on facial expressions video clips, and their deep learning method is shown to accurately classify patients with or without pain. This important study implies that pain assessment can be achieved by an automated computer system, thereby providing high granularity time-varying facial expression data for patient management. Sepsis-Associated Thrombocytopenia (SAT) is an important complication in sepsis patients and early risk stratification can help to tailor individualized treatment. Jiang et al. trained multiple machine learning (ML) models for the prediction of SAT in a Chinese cohort, and then these models were validated in an open-access critical care database.Two years have passed since the first launch of the Research Topic on the application of artificial intelligence (AI) in emergency and critical care settings . We haveLiu et al. developed an AI algorithm to dictate MV weaning. This study paves the way for the realization of personalized medicine in the management of MV patients.The second step in patient management involves the treatment strategy. Since critically ill patients are usually treated with multi-module strategies, the effectiveness of treatment strategies is time sensitive, and varies across the individual subject. Thus, an individualized treatment strategy is needed, in line with the idea of precision medicine. Mechanical ventilator (MV) weaning is an important medical decision-making process for the management of patients on MV. Hegselmann et al. developed an explainable boosting machine to predict ICU re-admission using a German dataset.Finally, the prognosis is also important for the management of critically ill patients. Risk stratification for intensive care unit (ICU) patients is useful for clinicians to make better decisions and for consulting with family members. The diagnosis and prognosis can be studied with the supervised ML algorithm. The difference lies in the study design. While the studies on diagnostic performance require cross-sectional data to train the model, those involving prognostic performance require a follow-up period allowing the outcome (label) to occur. ICU readmission is an important indicator of the quality of care and is an important outcome measurement. In this topic issue, In conclusion, the successful launch of the special issue on the application of AI in critical care medicine indicates that researchers continue to be interested in this particular field. The power of big data and AI are revolutionizing clinical practice in the near future. The ICU is a highly technological environment where each patient generates a large volume of data per day, such special characteristics make it the best place for AI applications.ZZ conceived the idea and drafted the manuscript. LS and QM revised the paper. RK worked to organize the topic issue and made contributions to the editorial contents. All authors contributed to the article and approved the submitted version.


There are three primary challenges in the automatic diagnosis of arrhythmias by electrocardiogram (ECG): the significant variation among individual patients, the multiple pathologies in the ECG signal and the high cost in annotating clinical ECG with the corresponding labels. Traditional ECG processing approaches rely heavily on prior knowledge, such as those from feature extraction and waveform analysis. The preprocessing for prior knowledge incurs computational overhead. Furthermore, standard deep learning methods do not fully consider the dynamic temporal, spatial and multi-labeling characteristics of ECG data. In clinical ECG waveforms, it is common to see multi-labeling in which a patient is labeled with multiple classes of arrhythmias. However, multiclass approaches in current research mainly solve the multi-label machine learning problem, ignoring the correlation between diseases, resulting in information loss. In this paper, an arrhythmia detection and classification scheme called multi-label fusion deep learning is proposed. The objective is to build a unified system with automatic feature learning which supports effective multi-label classification. First, a multi-label ECG-based feature selection method is combined with a matrix decomposition and sparse learning theory. The optimal feature subset is selected as a preprocessing algorithm for ECG data. A multi-label classifier is then constructed by fusing CNN and RNN networks to fully exploit the interactions and features of the time and space dimensions. The experimental result demonstrates that the proposed method can achieve a state-of-the-art performance compared to other algorithms in multi-label database experiments. Cardiovascular disease has become the “number one killer” that seriously threatens people’s health. According to statistics released by the World Health Organization (WHO) in 2018, cardiovascular diseases claim 17.7 million lives each year, accounting for 31% of all global deaths [A typical ECG signal is shown in ECG signals usually contain multiple cardiovascular diseases at the same time. Therefore, the limitation of one class per label of classical learning (single label) cannot be satisfied. The study of multi-label ECG signal classification is more important than the study of single-label ECG signal classification ,6.Traditional electrocardiogram recognition technology includes four parts: electrical signal acquisition, signal preprocessing, feature extraction and electrical signal classification and recognition. At present, the most commonly used electrical signal acquisition method in clinical practice is the twelve-lead method, which includes 6 limb leads and 6 front chest leads, which can record the changes of electrical signals more accurately. The preprocessing of the ECG signal is the prerequisite and basis of the whole ECG recognition. Since the ECG is collected with plenty of noise over a weak electrical signal, it will adversely interfere with the final classification result.Electrocardiogram preprocessing can filter out interference noises and eliminate baseline drift of electrical signals, such as skin surface noise, respiratory interference, and myoelectric noise. The ECG feature extraction is an intermediate step of the ECG recognition technology. The efficacy of the extraction directly affects the final classification result. When the ECG signal features are extracted effectively, the performance of the classifier will also be significantly improved. Dealing with the high dimensionality of ECG features is one important issue. Mapping ECG signals to multivariate feature space often results in high-dimensional data. In addition, the original ECG features obtained by different ECG feature extraction methods may be redundant or irrelevant for arrhythmia classification tasks. Redundant features may lead to high computational complexity and high-dimensionality catastrophe. Irrelevant features will confuse classification algorithms and reduce learning performance. Therefore, appropriate feature selection is necessary before classifying arrhythmias.The classification and recognition of the electrocardiogram is the last step of the entire process. It is used as the basis for determining whether the heart rhythm is normal. Classification and recognition are divided into two types: multi-label and single-label. Most research experiments so far are based on single-label classification. Single-label classification is to tell whether a certain disease is present in a patient from a segment of the electrocardiogram. In reality, multiple diseases often co-exist at the same time. Single-label classification cannot precisely reflect the patient’s disease situation. Since the entire process of ECG recognition and classification presents the characteristics of high coupling, dynamics and uncertain labels, so far, few studies have been conducted to deal with multi-label problems throughout the entire process of ECG diagnostic. Therefore, the automatic recognition and classification method of ECG is still a research direction that requires continuous improvement.Firstly, we designed an integrative framework consisting of multi-label feature selection and classification for ECG signals to handle the multi-label and high-dimensionality problems of ECG characteristics simultaneously.Secondly, we further developed an effective multi-label arrhythmia classification model for ECG signals. An ECG classification neural network based on feature extraction and time series data processing abilities was constructed.Thirdly, by mining the best subset of features among numerous attributes, specific features that can adequately represent the disease association were extracted. The performance of the proposed method was verified to be improved by going through a performance comparison with other multi-label feature selection and classification algorithms.The contribution of this research consists of the following parts:With the advances of computer hardware and deep learning, the automatic recognition and classification technology of ECG has been widely studied by scholars worldwide. Benefiting from the continuous improvement and establishment of ECG public data sets, more and more ECG recognition and classification methods have been proposed. According to the standards set by the American Association for the Advancement of Medical Instruments (AAMI), heartbeats can be divided into five categories: non-ectopic (N), supraventricular ectopic (SVEB), ventricular ectopic (VEB), fusion heartbeat (F) and unknown heartbeat (Q), in which different heartbeats show significantly different waveforms.The feature extraction of the ECG signal refers to the extraction of the feature value in the multi-dimensional space of the signal before the recognition and classification of the ECG. Effective feature extraction can lay a good foundation for recognition and classification. If the extracted features are accurate and easy to recognize, the performance of the classifier will be significantly improved, and vice versa.The feature selection for ECG signals aims to select relevant and indispensable features from the original set of ECG features to form an optimal feature subset while ensuring classification accuracy. It should not only be able to represent the original model to some extent, but also minimize the loss of information. Kamath et al.  proposedAlthough traditional arrhythmia classification methods use various classifiers to achieve certain results in some test datasets ,12, theyWith the rapid development of computer storage and computing capabilities, the performance of deep learning and neural networks has been considerably improved. Deep neural networks have demonstrated strong detection capabilities in cancer , brain dHannun et al. proposed a 34-layers Convolutional Neural Network (CNN) for abnormal heart rhythm detection and obtained cardiologist-level recognition accuracy . Fan et In the above-mentioned research work, the timing characteristics of the ECG are usually ignored. Most of the ECG data is split into data blocks for research and learning, and the timing characteristics of the ECG are not considered, and they lack certain clinical practical significance. In order to address the above-mentioned problems, in other studies, the ECG signal is regarded as a time series signal as a consideration and processed by deep neural networks.Li et al. proposed a model based on deep neural networks and hidden Markov chains to detect intermittent sleep apnea symptoms in ECG signals . ChauhanIn summary, although ECG research has undergone long-term and extensive research, and has continued to break through with the development of computers, there are still many problems that need to be solved and improved urgently. Traditional ECG processing methods require a strong theoretical basis. They require a large amount of pre-learning knowledge for the data, and each electrocardiogram recognition step needs to be completed independently. The classification result depends on the previous feature extraction and waveform analysis, which is difficult to operate in actual clinical practice.The neural network method reduces the data preprocessing and feature extraction steps as well as the pre-knowledge requirements for the data, and partially improves the accuracy . HoweverThe organizers of the China Physiological Signalling Challenge (CPSC)  collecteThe ECG signal shown in According to the above feature extraction method, 118 ECG attribute features Given a series of ECG signals In this section, we introduce the proposed AS-CNN-GRU model; the attribute-selection-based deep learning fusion structure is developed to handle the multi-label ECG recognition. To better mine the spatio-temporal features of the ECG signal, the two networks, CNN and GRU, are fused. GRU is developed from LSTM networks, both of which alleviate the gradient explosion and gradient vanishing problems during training compared to traditional recurrent neural networks (RNNs). In fact, the use of GRU in this work is motivated by two main aspects: firstly, GRU can remember the state of the previous training process, which is ideal for time series analysis; secondly, GRU has only two gates  compared to LSTM, so it is more computationally efficient to use GRU and can reach convergence faster .The structure of the proposed method consists of three parts, as shown in W denotes the matrix of coefficients obtained in the regression model. S and C, respectively. C is the correlation matrix composed of the instance similarity between each pair of instances evaluated by KNN, and F denotes the output matrix.We use the multi-label attribute selection method  to fullyi et al. , a commok < 118) at a timestamp, and the column denotes timestamp In this layer, the input data of the CNN model is a matrix consisting of the ECG signal and selected feature variables, as shown in Equation (1), where the rows represent the ECG signal values and the features selected from the four types of attributes. Here, The CNN model mainly contains convolutional and pooling layers. In this study, the CNN model convolutional and pooling layers are used to extract deeper features between the corresponding time length and transformed attributes. The trained feature vectors are then applied to train the GRU layer. Based on the spatial feature information extracted by the CNN, the GRU layer is subsequently used to extract temporal information from these features . The outith convolutional kernel iK of size lS will be slid from sample 1 to N value to extract a feature, and the lth feature map kG can be output asf is the activation function, b is the ith bias of the kth feature map, and N is the number of convolutional kernels used in the convolutional layer. Assume that the data signal in a single time window can be denoted as mSI, where m is the number of samples in a single time window. In this work, mSI which can be considered as G0, the rectified linear unit (ReLU) is usually chosen as the activation function. Since the features extracted by the CNN follow a time series, the temporal information embedded in the ECG signal is preserved and will be used as input to the GRU layer [In RU layer . It is kAs shown in In the CNN-GRU training layer, the first input is a series of matrices under timestamps. The convolution layer extracts features from the input matrices, where the convolution acts to maintain the spatial relationships of the variables.The common methods for pooling layers are maximum pooling and average pooling, which can reduce the number of nodes in the later fully connected layers by reducing the matrix size without changing the depth of the feature map. The model uses maximum pooling. By building multiple convolutional and pooling layers, a complex feature matrix representing the information of each timestamp is extracted for classification, and then the feature matrix is spread into feature vectors to be fed to the fully connected layers. In the proposed model, the CNN model contains two convolutional layers and two pooling layers. And only the feature vectors are used as the input of the next layer. The two convolutional layers and two pooling layers of the CNN model can accurately transform the input data into a feature vector F.Ft denotes the input sequence of GRU, and ht denotes the output sequence, which is the predicted value of GRU. In addition, σ denotes the vector format of sigmoid and tanh denote the hyperbolic tangent functions, respectively. ⊙ denotes the pair-wise operation. rb, zb and cb are the bias vectors to be trained. In this work, the cross-entropy is selected as the loss function for training. In other words, the optimization model of the proposed CNN-GRU-based algorithm can be represented asy and N is the number of batches in the training process and M is the number of feature data sources to be identified. Finally, multi-label classification is performed by minimizing the loss function. In summary, the system model of the proposed CNN-GRU network is shown in The internal structure of GRU is shown in Under the same experimental conditions, the confusion matrix and the following evaluation indicators will be used as performance comparison standards.Accuracy: The classification accuracy of the model test set can directly reflect the classification performanceJaccard similarity: It is a measure of distance between the prediction and the ground truth, i.e.,Hamming Loss: It is a label-wise measure that counts the proportion of the labels that are misclassified in all instances, i.e.,F value: It is the weighted harmonic average of precision rate and recall rate, which can better evaluate the quality of the classification model.Based on the ECG features, we trained multi-label ECG signal classifiers respectively, and the specific parameters of the model are shown in The training network for the classifier learns the hierarchical features by convolution and pooling operations based on the parameters provided in To demonstrate the generalization capability of the proposed method, purposive tests were conducted on real ECG signal data. The proposed attribute selection method selected the most important 20 features for ranking, as shown in A model called AS+FusionGC is proposed to explore a new method for arrhythmia classification by ECG signals in terms of both data pre-processing and deep feature learning. The model first improves the discrimination of the deep feature learning of the signal by conducting matrix decomposition and sparse learning of the obtained signals. Five out of six performance metrics were achieved by incorporating data pre-processing. Compared to the literature ,9,10, thIn this study, our perspective focuses on the three aspects of spatio-temporal sequence variation, deep attribute selection and multi-label recognition in the ECG recognition process, and the most disease-characterizing attribute features are obtained by fully data mining the multi-disease association information in the extracted features through discriminable attribute selection methods. A hybrid neural network, CNN-GRU, is then established to handle the recognition and classification of ECG, achieving an organic combination of medical and artificial intelligence. New solutions are proposed to improve the multi-label classification and recognition of ECG. The simulation results show that the proposed approach achieves better performance in most cases of multiple metrics testing by refining the attribute features in the ECG signal and fusing deep learning techniques to fully exploit the spatio-temporal features. This method is therefore proven to be useful in the task of ECG multi-label disease classification.


COVID-19 has had a huge impact on the health system and the world at large. Patients with kidney failure are a select group which have been affected significantly by the scourge of the disease. In the COVID-19 era, renal replacement therapy (RRT) in the form of dialysis and kidney transplantation required modifications in many centres in order to maintain high quality care and reduce infection rates among this susceptible group of patients. The objectives were to describe some of the challenges experienced in one of the leading renal care centres in Nigeria during the height of the COVID-19 pandemic and analyse the impact of practice changes on select outcomes.a retrospective cross-sectional review of haemodialysis activities and kidney transplantation among chronic kidney disease patients was done over a 15-month period ranging from April, 2019 to June, 2021. Data was extracted from the electronic media record (EMR) and analysed using SPSS version 22.there was an initial significant drop in the number of haemodialysis sessions and kidney transplant surgeries by 16.7% and 66% respectively in the first 2 months of COVID-19 in our centre following the national lockdown. The mean monthly kidney transplant rate was 9±3.29 before the COVID-19 and the national lockdown, this figure reduced to 3.0±0.1 during the lockdown. Activities however normalized at 6 months following the initial lockdowns have remarkable exceeded pre-COVID numbers as at early 2021.after the initial drop in numbers of patients for haemodialysis and renal transplantation, there was an increase in numbers in the following months. It was instructive to put several steps in place in order to continue to offer high level RRT in the COVID-19 pandemic. RRT can safely be practiced in the COVID-19 pandemic. COVID-19 is caused by a newly identified enveloped RNA virus named SARS-CoV-2 [th, 2022 . At the COVID-19 has had an enormous impact on medical systems across the globe, with effects ranging from disruptions to complete shutdown of established medical models. In many countries, the overwhelming impact of COVID-19 on health care systems has resulted in limited resources like operating space, doctors, nurses and bed spaces for admissions from other medical conditions ,5. TheseThe field of renal care, especially dialysis and kidney transplant experienced disruptions, with organizations making necessary changes to protocols and policies in the wake of the pandemic. A major reason for this was the concern that pandemic conditions may not be optimal for dialysis and transplant patients considering the infectious nature of the virus, the invasive nature of the whole dialysis connection and the susceptibility of post-transplant patients to infections . The preDespite these facts, some dialysis and kidney transplant programs have remained active in European countries where deceased donors make up a significant population of kidney donor pools . In NigeStudy design, participants, and setting: this study was carried out in Zenith Medical and Kidney Centre, Abuja, Nigeria. A retrospective review of haemodialysis activities and kidney transplantation among chronic kidney disease patients was done over a 15-month period ranging from the pre-COVID-19 era  to June, 2021.Variables, data sources and bias: data were collected from electronic medical records, including monthly reports of dialysis and transplant activity. All data collected were included in the analysis. This data allowed for comparison in number of haemodialysis and kidney transplant activities during the lockdown period and afterwards. Other peculiarities during the study period on the haemodialysis and transplant activities were also described in this paper.Statistical methods: data were entered into and analysed using IBM SPSS Statistics for Windows, Version 20.0.  and visualized using Microsoft Office Excel . Simple descriptive analysis was used to interpret the collected data. Some continuous variables were presented as mean ± standard deviation while comparative data for periods of time were presented in bar charts and trend lines.Ethical approval: this study analysed secondary data from the electronic medical records of our transplant centre. The data were already anonymized in the output sheet therefore, no explicit consent to use this data was necessary. Ethical approval for the study was sought and obtained from the research and ethics review committee of the Federal Capital Territory Administration (FCTA) Department of Health with approval number FHREC/2021/01/159/14-12-21.For the duration of one year before the declaration of a lockdown in Nigeria (April 2019 till March 2020), there was a mean monthly living-related donor kidney transplants rate of 9±3.29. There was rapid decline in number of kidney transplantation surgeries performed during the initial 2 months of the COVID-19 lockdown in Nigeria with a transplant mean monthly rate of 3.0 ±0.1 . This inIt is expected that missed transplant opportunities would result in an increased number of patients on maintenance dialysis. Instead, in April and May 2020, there was a drop in the number of patients receiving haemodialysis, this number slightly increased in the next month . The aveThis study has quantified the impact of the COVID-19 pandemic on renal care and transplant activity in a single centre in Nigeria.Haemodialysis has been the mainstay of management for patients with end stage renal disease (ESRD) worldwide . The lasThe decision to continue the kidney transplant program was taken after careful consideration of donor risks in view of the absence of deceased donor program in Nigeria and the life changing nature of the procedure. The preparation and execution of kidney transplantation suffered some major setbacks during the height of the pandemic. Some of the encountered challenges include: the lockdown and embargo on inter-state travels imposed by the government of Nigeria limited many patients from gaining access to the hospital in order to run their hemograms, renal function tests, ABO compatibility tests and renal angiography. The lockdown affected the availability of consumables for other preliminary tests that can be done in the laboratories in country. Haemodialysis also became inadequate among many patients due to this movement restriction. Secondly, at that time there were no advanced molecular laboratories in Nigeria capable of running high quality human leukocyte antigen (HLA) testing, donor specific antibody titres and crossmatches, this meant that many transplant centres in Nigerian relied on foreign laboratories for credible results. Thirdly, kidney transplantation and haemodialysis require a strong haematological support in view of blood transfusion requirements with Zenith Medical and Kidney Centre, having the highest blood requirements in the whole Abuja metropolis. Blood drive campaigns and networking with other big haematological laboratories were significantly hampered during the lockdown period with only few voluntary donors able to make their way for blood.et al. [These challenges demanded some strategy by the hospital management in order to sustain renal care for the large number of CKD patients requiring forms of renal replacement therapy during this period. Some of these modifications include: downsizing of the work force in the hospital to ease the implementation of social distancing. This was aimed to limit possible transmission of the disease. Apart from wearing personal protective equipment (PPEs), one of the recommendations by the US Department of Labour´s Occupational safety and health administration  in respoet al. , doctorsSecondly, the hospital commenced a series of seminars and presentations (including making posters and short videos) about what is known about the virus and its transmission. There is a positive relationship between education and health. Health education and promotion is one of the frontline strategies effective against disease outbreaks -30. It het al. [Thirdly, PPEs were acquired and made available to the hospital staff on duty. Following guidelines by World Health Organization (WHO) , adequatet al.  in the sLastly, periodic screening for surgeons and theatre staff was commenced to allow for early detection and prompt isolation in case of infection with the virus. This is in line with extant guidelines by the government and also designed to further protect the patients from contracting the virus. Both patients and healthcare workers are at constant risk of nosocomial transmission of the COVID-19 virus, considering that the virus is airborne and very infectious . The WHOIn our centre, there was a progressive decrease in transplant activities following the declaration and implementation of lockdown by the government as shown in Limitations: this is a single centre study in a super-specialized renal care centre in Nigeria, a multicentre study would have provided more robust data.Renal replacement therapy in the forms of haemodialysis and kidney transplantation provides a life-saving option for patients with ESRD and is increasingly available in Nigeria. The impact of COVID-19 was felt in the availability of these services in our centre during the study period which a rapid decline in number of haemodialysis sessions and kidney transplants done. These however peaked afterwards following re-strategizing and modified management protocols. While COVID-19 remains an international pandemic, it is important for RRT to continue in order to meet the needs of these highly vulnerable group of patients.The COVID-19 pandemic significantly disrupted kidney transplantation in affected countries;Mortality among kidney transplant waitlisted patients is significantly increased during the height of the pandemic;Kidney transplant programs in Nigeria are still in early stages of development; centres offering kidney transplant are very few and there is no deceased donor programThis study quantified the impact of COVID-19 on the kidney transplant program in a Nigerian super-specialized renal care centre;Development of sustainable infrastructure and expertise should remain a priority for the kidney transplant program in Nigeria;This study shows the value of readily available healthcare data to inform strategic planning in the event of future crises.


Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer worldwide and is the second most common cause of cancer-related deaths. However, the Omani population shares the major burden as the most prevalent carcinoma. The disease is comparatively higher in males than females. Patients with pre-existing risk factors, including inflammatory bowel disease, are at increased risk of developing neoplasia. Among the various histopathological subtypes of adenocarcinoma in the rectum, signet ring cell carcinoma is the rarest and accounts for approximately 1% of the cases. Given the aggressive nature of this tumor, advanced presentation, stage, and poor prognosis, regular endoscopic surveillance is essential. Hereby, we report a rare case of signet ring cell carcinoma arising in the rectal stump in an already diagnosed and operated patient of Ulcerative colitis. Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer worldwide and is the second most common cause of cancer-related deaths.The Omani population witnesses colorectal cancer as the most common cancer. It is the second most common cancer in males and the 4th most in females. The incidence has increased in the last 15 years. The rectum is the most common site of colorectal cancer, followed by the sigmoid colon, ascending colon, descending colon, and transverse colon.The pathogenesis of IBD-CRC is related to cellular damage that interacts with tumorigenesis transcription factors leading to dysplasia and adenocarcinoma.A 40-year-old gentleman with comorbidities like hypertension, chronic kidney disease, and IBD was referred to our institution for further treatment. The patient had a history of ulcerative colitis with recurrent severe bouts for long-standing for about 13 years and underwent surgery . The histopathological examination of the colectomy specimen performed in outside hospital was reported as severe pancolitis favoring ulcerative colitis and polyps with low-grade dysplasia. The medical management of ulcerative colitis and its clinical and endoscopic response to the medications used was not documented in our medical records as the patient was referred from outside the hospital.The possible risk factors for the development of ulcerative colitis-associated colorectal cancer in this patient include long-standing duration of disease for about 13 years and severe pancolitis.The patient was subjected to surveillance before and after the surgery as per medical records. The patient was on regular follow-up for his fluctuating renal function. The proctoscopy performed in-house showed a rectal stump mass with stricture located at 3 cm from the anal verge, through which the scope couldn’t be passed. Positron Emission tomography (PET) fluorodeoxyglucose (18F-FDG) whole body scan showed increased metabolic activity in the rectum with mildly FDG avid perirectal fat stranding with thickening of mesorectal fascia with mildly FDG avid perirectal, presacral, inferior mesenteric, bilateral external iliac, bilateral internal iliac, bilateral common iliac and aortocaval and paraaortic lymph nodes, likely metastatic.The lesion was biopsied and sent for histopathological examination. The microscopic evaluation showed ulcerated mucosa with reactive epithelial changes and the lamina propria distended with signet ring cells exhibiting typical morphology of peripherally pushed eccentric nuclei and a large mucin vacuole .Immunohistochemistry shows the tumor cells were positive for CDX-2 , CK20 F, Cam 5.2The patient did not undergo surgery for the rectal stump due to the fluctuating renal function and to preserve the sphincter function. Hence only biopsy was performed for tissue diagnosis. 6 cycles of mFOLFOX  chemotherapy were administered after the confirmation of adenocarcinoma in the rectal stump biopsy. The follow-up PET scan showed complete resolution of the enlarged nodes and a significant reduction in the FDG rectal uptake. The patient is under follow-up with a good response to chemotherapy.,,Compared to the general population, the incidence of colorectal cancer was found to increase among patients with ulcerative colitis.The pathogenesis of the development of neoplasia in IBD is attributed to repeated cycles of inflammation leading to the initiation and progression of carcinogenesis.Adequate surveillance of patients identified as at-risk patients might significantly improve the management of IBD-CRC risk. Current evidence-based guidelines recommend surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis; further surveillance is decided on the basis of the patient’s risk factors. A new technique, chromoendoscopy, proved to be highly effective for monitoring programs and suggested its use with targeted biopsy.It is a fact that the risk of neoplasia exists in the rectal stump. However, postoperative endoscopic surveillance could detect dysplasia/cancer at an early stage. Patients with ileorectal anastomosis (IRA) had a greater risk of developing neoplasia than those with ileal pouch-anal anastomosis (IPAA).In a study done by Belli et al.Signet ring cell carcinoma is defined as > 50% of the tumor cells with prominent intracytoplasmic mucin, typically with displacement and molding of the nucleus. This subtype has a very low (1%) incidence rate in the rectum and is more common in the right colon.The histopathological diagnosis of signet ring cell carcinoma is sometimes challenging due to the presence of benign signet ring cell change. This was first described as a pseudo-neoplastic phenomenon seen commonly in gastric xanthomas and transurethral prostatectomy specimens. However, in the gastrointestinal tract (GIT), most benign signet ring cell changes are reported in areas of injury or ischemia and are usually limited to the mucosa. The morphological features that favor benign signet ring change are circumscription and lobulated appearance, absence of single-cell infiltration and bland cytological features.In the present case, the distinction from benign signet ring cell change was made based on single-cell infiltration in the lamina propria and cytological atypia. However, this is quite challenging in some cases. The Immuno-markers routinely used to differentiate between benign mimics and true signet ring cell carcinomas are p53 and Ki-67. In a study done by Khan et al.In conclusion, signet ring cell carcinoma is a very aggressive and rare subtype of colorectal adenocarcinoma. Its occurrence at the rectal stump region is rare. Owing to its advanced presentation stage and dismal prognosis, regular endoscopic surveillance must be undertaken in patients with ulcerative colitis, irrespective of surgical status. Further studies are encouraged because there is a lack of literature on the development of neoplasia after colectomy.


Infectious diseases have always been a major threat to the prosperity of society. The COVID-19 pandemic is evidence that contagious diseases are evolving to remain as relevant as ever in our modern interconnected world. In recent years, vaccine development has been a bright spot and entered a golden age that was ushered in with help from the intimate knowledge of molecules tied to the disease-causing pathogens . UtilizaNeisseria -linked bacterial meningitis (Pietri et al. examines the potential for polysaccharide-based vaccines in combating an emerging Neisseria meningitidis serogroup. The study examines monoclonal antibody-immunogenic epitope interactions with a combination multiple biophysical and structural techniques, including ELISA, SPR, NMR, X-ray crystallography, and in silico docking analysis. The authors identified a minimal polysaccharide length required for immunogenic response. Mycobacterium tuberculosis, the causative agent of tuberculosis, is another well-known and dangerous pathogenic bacterium with significant global interest in its eradication. In the article by Ruggiero et al., a structural model of the protein antigen, HtpGMtb, was supported by evidence from biophysical experiments and utilized to predict the region of the protein with immunogenic epitopes. A rationally designed HtpGMtb-derived antigen of optimal length and stability was experimentally determined to have high immunoreactivity. These articles illustrate the advantage of merging insights from multiple structural and biophysical approaches to aid in the engineering of vaccine antigens.Bacterial pathogens with resistance to traditional antibiotics pose a serious health risk and are therefore the target of numerous vaccine development efforts. Some of the first pioneering work establishing structure-based vaccines as an effective strategy were developed against ningitis . The artMasoomi Nomandan et al. examined the effects of glycosylation on a nanoparticle composed of the SARS-CoV-2 receptor binding domain and ferritin. Molecular dynamics simulations revealed an enhancement in nanoparticle stability when glycosylation was positioned along protein-protein interfaces. Beeckmans et al. provides an informative review of several SARS-CoV-2 structural proteins of interest to vaccine development. The authors describe bioinformatic tools that are easily accessible to help the average biochemist, immunologist, or infectious disease specialist build a detailed molecular understanding of the key features of antigenic targets. The lessons-learned from SARS-CoV-2 vaccine research has provided a blueprint for vaccine development against other serious viruses illustrating how to effectively apply structural and biophysical knowledge to the process.Vaccine development in viruses has advanced more rapidly as the generally smaller genome size offers fewer targets to dissect; however, the multifunctional and dynamic nature of viral proteins can make their study challenging. The sudden widespread emergence of SARS-CoV-2 in 2020 was met with the rapid development of effective vaccines and demonstrated a powerful role for structural and biophysical characterization . In a coThe aim of this Research Topic is to highlight biophysical and biochemical studies and methods that bridge the gap between the molecular-level details of a native antigen afforded by a structure and the final engineered vaccine. This topic is composed of articles that explore the structural and biophysical properties of antigenic molecules and assemblies thereby providing knowledge that may be useful in vaccine development. Continued work in the field of structure-based vaccine design is critical to maintain a broad knowledge base of our microscopic enemies’ armor, camouflage, and artillery as well as their strategies. The editors are grateful for the contribution of the authors and reviewers to this Research Topic as well as to the field of vaccine research.


Increased age is associated with an increased prevalence of chronic inflammatory diseases and conditions. The term inflammaging has been used to describe the age-related changes to the immune response that results in a chronic and elevated inflammatory state that contributes, in part, to the increased prevalence of disease in older adults. Periodontal disease is a chronic inflammatory condition that affects the periodontium and increases in prevalence with age. To better understand the mechanisms that drive inflammaging, a broad body of research has focused on the pathological age-related changes to key cellular regulators of the immune response. This review will focus on our current understanding of how certain immune cells  change with age and how such changes contribute to inflammaging and more specifically to periodontal disease. Advances in medical care and technology have resulted in increased life expectancy. The populations of those over age 65 are expected to grow substantially within the United States and globally over the coming decades , 2. DespChronic diseases, such cardiovascular disease, type II diabetes, and Alzheimer’s disease and related dementias all increase in prevalence with increasing age. In addition, periodontal disease is one of the most common chronic diseases and the prevalence of periodontal disease also increases with age , 4. MuchThe focus of this review will be on the age-related changes that affect the immune system and contribute to disease. The changes that occur to the immune system with age are quite diverse and differ across the adaptive and innate immune systems as well as across the different immune cell types . These pGiven the current understanding of periodontal disease pathogenesis, immunosenescence and inflammaging may both be important factors contributing to the increased prevalence of periodontal disease in older adults. Within the periodontium, a strict regulation of the host inflammatory response to the oral microbes that inhabit these tissues is required to maintain periodontal health. As a result of immunosenescence, there may be a decreased ability to mount an effective immune response and adequately clear the invading oral pathogens. Similarly, the effects of inflammaging may result in a hyperreaction to the inflammatory stimuli resulting in collateral damage to the periodontal tissue as well.The cause of inflammaging and immunosenescence is likely multifactorial. This review will examine the current understanding of age-related changes that affect neutrophils, macrophages, and T cells. These cells have been chosen here due to their known involvement in the pathogenesis of periodontal disease and their involvement throughout the initiation, propagation, and resolution of inflammation. It is also important to appreciate that there are many other factors that contribute to age-related immune dysregulation but are outside the scope of this review. For instance, in addition to neutrophils, macrophages and T cells, many other immune cells have been implicated in periodontal disease pathogenesis, including dendritic cells, B cells and natural killer T cells . Each ofThis review will provide a brief explanation of the normal function of neutrophils, macrophages and T cells during infection and regulation of inflammation. The current understanding of how such functions change with age will be presented, highlighting how these age-related changes can be pathogenic in periodontal disease. A better understanding of the pathogenic age-related changes to these immune cells during periodontal disease may lead to improved therapeutic targets and better options for managing disease in older adult populations.Neutrophils are present within the periodontium in health and disease. Recruitment of neutrophils locally to the periodontium is initiated by a cascade of chemotactic signals from oral microorganisms . At the In vitro investigations of the chemotactic response have shown that neutrophils from older adult subjects demonstrate a reduced response to granulocyte-colony stimulating factor (G-CSF) and N-formyl-Met-Leu-Phe (FMLP) peptide  as an antimicrobial defense mechanism. Neutrophils release ROS intracellularly to kill phagocytized microbes or extracellularly to kill microbes within the tissue . Some stto young .in vitro studies have demonstrated decreased NET formation by neutrophils from old subjects compared to young . In response to certain microbial stimuli, neutrophils will undergo a form of cell death known as NETosis, where the nuclear and plasma membrane disintegrate and a decondensed DNA structure is released extracellularly forming the physical NET . NET forto young -41. ReseIn summary, increased age has a pathological effect on the antimicrobial function of neutrophils and less of an effect on the number of neutrophils recruited locally. This attenuation in antimicrobial activity likely contributes to the increased prevalence of periodontal disease in older adults, as has been shown in other age-related disease . The ageThe two general classes of macrophages are tissues resident macrophages and circulating monocyte-derived macrophages. Circulating monocyte-derived macrophages appear in tissue in response to infection or injury. Circulating monocytes are recruited locally where they differentiate into macrophages and migrate into tissue . Within Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, macrophages demonstrated an inflammation propagating response via the production of pro-inflammatory cytokines  that propagate further immune cell recruitment  , 53. TheIt is important to appreciate that the antimicrobial and immune propagating functions of M1 macrophages are part of a necessary immune response to effectively defend against microbial infections. However, the same functions have also been implicated in the pathogenesis of periodontal disease where prolonged pro-inflammatory processes ultimately lead to tissue destruction. M1 macrophages have been identified in gingival samples of humans with periodontal disease at higher levels compared to healthy gingival samples. The increased M1 macrophage numbers were also associated with the presence of increased inflammatory cytokines in the gingiva . SimilarThe effect of age on macrophages is of significant interest and studies have evaluated the number of macrophages that locally respond to infection or injury as a function of age. In a mouse model of periodontal disease, the number of macrophages that were present in the periodontium was similar in old and young mice during health, during periodontal disease, and during disease recovery . Others in vitro study designs, age-related changes to macrophage activity have demonstrated conflicting results. Studies evaluating cytokine production by macrophages isolated from old animals and humans have shown increased (in vitro cell culture environment compared to the in vivo environment. Aging is associated with changes in the bone marrow microenvironment, the progenitor cell source of monocyte-derived macrophages (in vitro environment.Recent evidence has suggested that macrophage activity and the associated phenotypes may be detrimentally affected by age and such age-related changes may be pathogenic in disease including periodontal disease . Howeverncreased , decreasncreased , or no cncreased  in pro-increased , decreasncreased , or not ncreased  as a funrophages . Aging irophages . TogetheA better understanding of how age affects macrophages is now emerging with the use of next generation sequencing methodologies. One bulk RNA sequencing study isolated macrophages that had responded locally to an injury in bone in old and young mice . MacrophStudies that have attempted to directly implicate age-related changes in the macrophage with the pathogenesis of periodontal disease have been limited. A recent study showed that depleting macrophages in old mice enhanced the recovery from periodontal disease after the ligature was removed, with improved resolution of inflammation and decreased disease severity compared to untreated old mice . Interesin vivo phenotype, and such findings support the conclusion that macrophage phenotypes are affected by age and assume a more pro-inflammatory phenotype that may contribute to inflammaging. In the treatment of periodontal disease, the removal of the bacterial inflammatory stimuli results in an active shift toward resolution of inflammation driven, in part, by macrophages. Thus, an age-related delay or perturbation in the switch to M2-driven resolution of inflammation would result in the continued propagation of the osteolytic processes driven by M1 macrophages, or their downstream mediators, and an increase in disease severity.In summary, these studies demonstrate that macrophages undergo age-related changes that likely contribute to the pathogenesis of periodontal disease. Significant work within the periodontal and wider medical fields has supported the importance of proper regulation of macrophage phenotype in the prevention of inflammatory-related disease. The emerging next generation sequencing methodologies are providing a more accurate assessment of the The innate immune response is responsible for the initial host defense to microbial pathogens within the periodontium. The prolonged presence of pathogens and the sustained innate immune response will eventually illicit an adaptive immune response. T cells are an important driver of the adaptive immune response and demonstrate a heterogenous repertoire that can recognize a broad range of antigens. Naïve T cells will interact with antigen presenting cells, such as dendritic cells, macrophages, Langerhans cells and B cells, that will promote their differentiation toward a variety of T cell subpopulations that are equipped to mount a more specific immune response . Many T CD4+ T helper cells are the most abundant T cell subpopulation found in gingiva . They arTh1 and Th2 subsets are both present in the gingiva during health and disease, with a shift toward an increased ratio of Th1 over Th2 cells occurring during periodontal disease . A furthTh17 cells are a subset of Th1 cells and secrete IL-17 in the promotion of inflammation . They haAs discussed here, the multiple subsets of T cells contribute to the promotion or resolution of inflammation, but both were found to be present with the periodontium in health and disease. This demonstrates an ability of the oral microbiota to illicit an adaptive immune response even in conditions of health. It also supports the need for a precise balance of pro- and anti-inflammatory activities to properly respond to the microorganisms and to limit peripheral tissue damage that would contribute to periodontal disease. Therefore, it is of interest to try to understand how age affects the T cell activityAge-related changes to T cells have been implicated in contributing to immunosenescence. The thymus is the site of naïve T cell production and, with increasing age, an involution of the thymus is observed . A reducOther age-related changes to T cells appear to result in an up regulation of an inflammatory response that could also contribute to disease pathogenesis. Age-related changes to CD4+ T helper cells have been reported to affect their responsiveness to receptor stimulation, resulting in a decreased Th2 response and a preference toward Th1 differentiation , 92. TheProper regulation of the host immune response is critical in maintaining periodontal health. As discussed here, age-related changes affecting neutrophils, macrophages, and T cells appear to promote a pathogenic immune response and contribute to the increased prevalence of periodontal disease in older adults. The burden of disease in older adults is well appreciated across dentistry and medicine. The field of geroscience works to understand how age-related physiological changes contribute to diseases that impact older adults. An improvement in our understanding of the basic cellular and molecular changes that occur with age will translate to a more targeted and individualized clinical care that focuses on the specific altered physiology that occurs with increased age. Research has already been performed showing the benefit of targeting the age-related perturbations to the immune system to improve outcomes in aging populations. Indeed, replacing components of the immune system of young mice into old mice, either by bone marrow transfer or heterochronic parabiosis, has demonstrated significant benefit in many different disease and injury models including fracture healing, skeletal muscle regeneration, cognitive performance, and Alzheimer’s disease , 96-98.


Idiopathic toe walking (ITW) is a gait deviation characterized by forefoot contact with the ground and excessive ankle plantarflexion over the entire gait cycle observed in otherwise-typical developing children. The clinical evaluation of ITW is usually performed using optoelectronic systems analyzing the sagittal component of ankle kinematics and kinetics. However, in standardized laboratory contexts, these children can adopt a typical walking pattern instead of a toe walk, thus hindering the laboratory-based clinical evaluation. With these premises, measuring gait in a more ecological environment may be crucial in this population. As a first step towards adopting wearable clinical protocols embedding magneto-inertial sensors and pressure insoles, this study analyzed the performance of three algorithms for gait events identification based on shank and/or foot sensors. Foot strike and foot off were estimated from gait measurements taken from children with ITW walking barefoot and while wearing a foot orthosis. Although no single algorithm stands out as best from all perspectives, preferable algorithms were devised for event identification, temporal parameters estimate and heel and forefoot rocker identification, depending on the barefoot/shoed condition. Errors more often led to an erroneous characterization of the heel rocker, especially in shoed condition. The ITW gait specificity may cause errors in the identification of the foot strike which, in turn, influences the characterization of the heel rocker and, therefore, of the pathologic ITW behavior. Toe walking is a condition characterized by forefoot contact with the ground, normally present in the first developmental stage of walking . It is aAlthough there are no clear and univocal guidelines for ITW treatment , therapeEcological gait assessment can be facilitated by wearable measurement systems (WMSs) for estimating ankle mechanics. Thanks to the development of MEMS technology, Magneto-Inertial Measurement Units (MIMUs), composed of three mono- or tri-axial accelerometer, gyroscope, and magnetometer, allow the measurement of lower limb joint kinematics; pressure sensors, providing the force orthogonal to the sensor surface, can be used to estimate joint kinetics. WMSs have been widely used in many clinical contexts ,19, allo(i) The foot modelling approach, which influences the potential of gait analysis to highlight deviations specific of ITW behaviour. Modelling the foot as a multisegment rigid body and tracking the talocrural behaviour from the rearfoot seems a preferable approach ;(ii) The anatomical calibration procedure. The relevant accuracy and reliability, validated in healthy individuals ,24,25, s(iii) The anatomical coordinate systems (ACS) defined to obtain foot and shank orientation. ACSs should match the anatomical description commonly used in clinical settings  while grThe determination of gait events delimiting the gait cycle (stride segmentation) is complementary but not secondary to the joint kinematics assessment. The identification of foot strike (FS) is critical since the severity classification of ITW relies on assessing ankle angular excursion at specific time instants or intervals of the gait cycle—GC—delimited by two subsequent FSs and then normalized to 100 points. Precisely: (i) the heel rocker  is defined as an angle at FS greater than −5 deg, with a down going pattern in the first 12% GC; (ii) a premature forefoot rocker  is defined as a peak dorsiflexion angle being present in the first 30% GC. Given the rapid change of the ankle angular excursion that occurs at the beginning of the GC (during loading response), even an error of a few samples could lead to an incorrect estimation of the ankle angle at FS and thus to a wrong identification of the presence/absence of the first rocker. Several MIMU-based algorithms for gait events detection have been validated in different clinical populations ,28,29. TThe main purpose of this study is to evaluate the accuracy and precision of a selection of MIMU-based algorithms for foot strike estimation in children with ITW. Secondarily, the influence of the relevant errors on ITW severity classification  is evalu®, ITOP Officine Ortopediche, Italy; Six children with ITW  were enrolled after an informed consent was signed by their parents. The study was approved by the institutional review board . Participants were included in the study after being diagnosed with ITW; thus, children with any pathologies that may cause toe walking and children younger than 3 years of age were excluded. The diagnosis of ITW and the prescription of a foot orthosis  was used to measure gait kinematics and to segment the gait cycle. A total of 14 markers were placed on the child for static and dynamic trials according to the Plug-in Gait lower-body model  Figure . The texA set of four MIMUs  was also worn by the participants on shank and foot  to segme(i) Sensors’ mass and dimensions were small enough to minimise its influence (encumbrance) on the child’s movement;(ii) Sensors were positioned to be in line with the articles presenting the MIMU-based algorithms. Precisely, shanks MIMUs were fixed on the lateral inferior portion of the segments compatibly with the marker-set and the foot orthosis used . Feet MI(iii) Sampling frequency was appropriate for the measured movement and outcome parameters ;(iv) Sensor capacity  was appropriate to capture the true biomechanics of the movement of the distal segments .diff) of the vertical component of the two markers was considered:Foot strikes and foot offs (FO) were identified using stereophotogrammetric markers’ kinematic data. For FS, the algorithm proposed by Ghoussayni et al.  was used2) was set as the average height difference during a static trial:A threshold (th1) of 500 mm/s was set for forward velocity (VF) of HEE and TOE to detect a FS as the time sample k for which the following conditions were both satisfied:During the walking trials, a threshold  was identified as the first sample k, occurring after the local minima, satisfying the following conditions:Three MIMU-based algorithms were used to detect gait events (FSs and FOs) and to test whether it was better for this population to use a MIMU placed on the shank ,39 or onentified , the samFO) was detected as the first sample k corresponding to a local maximum and occurring before the considered local minimum.In a similar way, the sample of FO  calculated performing Bland–Altman analyses (lab-based parameters—MIMU-based parameters) . The imptrue positive rate (TPR)The choice of the algorithms was driven by the criterion of having the highest TPR and TNR and the lowest FPR and FNR.Results for all the algorithms in both conditions are summarized in In the barefoot condition, the most accurate and precise algorithms for FSs identification were WUM (bias: 21 ms) and SAL (LoAs: 22 ms), respectively. For FOs identification, SAL was the most accurate and precise algorithm . For all the gait temporal parameters estimation, the most precise algorithm was SAL . The most accurate algorithm for stride duration estimation was WUM, with null bias. For stance and swing duration estimation, the most accurate algorithm was TRO . In the shoed condition, FSs were most accurately and precisely estimated with WUM . For FOs identification, the most accurate and precise were SAL (bias: 2 ms) and WUM (LoAs: 23 ms), respectively. For all the gait temporal parameters, WUM was the most accurate and precise algorithm . Given the high biases for stance and swing duration estimation, WUM and SAL were used in combination, the former for FSs identification and the latter for FOs identification. With this combination the results for both stance and swing duration estimation improved .The characterization of the heel and forefoot rockers are graphically represented in terms of true and false positive and negative rates . For theIn the shoed condition, for both heel and forefoot rockers characterization, the highest TPR (97%) and TNR (100%) were achieved using WUM and SAL, respectively, while the lowest FPR (0%) and FNR (3%) were achieved using SAL and WUM, respectively.This study compared the performance of three MIMU-based algorithms in identifying gait events in children with ITW walking barefoot and while wearing a foot orthosis. Although no single algorithm emerges as the best one from all perspectives, a selection of preferable algorithms for event identification, temporal parameters estimation and ITW classification was devised, depending on the barefoot/shoed condition. Concerning gait events identification, FSs and FOs were best identified by different algorithms: FSs identification had the smallest bias when performed with the WUM algorithm, while FOs were identified more accurately via SAL algorithm. Regarding gait temporal parameters, when calculating stride duration, only the bias of FSs identification affects the duration, with errors similar for all algorithms and conditions (about 2 ms). On the contrary, stance and swing duration are affected by the combination of the biases of FSs and FOs identification. In a barefoot condition, TRO tends to identify both FSs and FOs with similar delayed biases, while the other algorithms have different biases for FSs and FOs. Consequently, stance and swing duration have the smallest bias when using the TRO algorithm . Nevertheless, complementing bias information with the LoA values  WUM appears to be the best algorithm to estimate gait temporal parameters in a barefoot condition. In the shoed condition, all the algorithms presented average biases of FSs and FOs that differs within each other in terms of magnitude and/or sign. Therefore, the biases for stance and swing duration were higher compared to barefoot walking. These biases can be reduced by combining two algorithms with similar biases of FSs and FOs identification. The best combination uses WUM for FSs and SAL for FOs B, resultRegarding the identification of foot rockers, the forefoot rocker was almost always correctly identified, both when normal (2 FP) and when anticipated (1–4 FN). Conversely, none of the analyzed algorithms performed clearly better than the other for the characterization of the heel rocker. This is not surprising since even a small error in the identification of the initial contact can lead to a misidentification of the presence of a heel rocker . A heel rocker is present if the planta-dorsiflexion angle is over −5 deg at FS. Indeed, even a slightly anticipated or delayed FS (the highest bias being 5 samples for SAL in the shoed condition) can cause an important difference in the estimation of this angle at foot strike. In children with ITW, the plantar-flexion movement can occur either in the terminal swing phase or during the loading response phase, leading to toe or heel strikes, respectively. For a toe strike, the identification of an FS prior to the real event could lead to identifying a nonexistent heel rocker. For a heel strike, the identification of an FS after the real event could lead to denying a real heel rocker. The WUM algorithm overestimated the presence of a heel rocker, while underestimating its absence in both conditions. On the contrary, TRO and SAL underestimated the presence of the heel rocker, still underestimating its absence. Overestimating the presence of heel strikes is to be avoided at a diagnosis stage, whereas it is important to early identify a child as a toe walker. Conversely, underestimating it could lead to considering an effective rehabilitation intervention as not effective. Clinicians could choose if dealing with a higher false positive or negative rate for heel rocker identification according to the clinical need; alternatively, the evaluation could be performed with different algorithms and be integrated with a video analysis in case of a discrepancy.The study must be interpreted considering the following limitations. First, to increase the number of identified gait events, reference data was obtained from marker trajectories and not using force platforms. The accuracy of the marker-based approach has been assessed in the order of 1 and 6 ms for children with a toe walking and a typical walking pattern, respectively. Such discrepancies are unlikely to affect the results of this study since differences between marker-based and MIMU-based events were in the range 14–21 ms. Second, the analysis of how an anticipated or delayed identification of FSs would influence the characterization of the heel and forefoot rocker must be interpreted with caution. In the current study, to set apart the errors entailed in estimating ankle kinematics with MIMUs  from thoFuture studies shall develop a wearable measurement system to perform instrumented gait analysis in an ecological environment. A step forward from the segmentation of the gait cycle to the assessment of ankle kinematics using MIMUs is required. Such a system would be capable of correctly revealing the typical walking patterns of this population that may be hindered using lab-based optical motion capture. Lastly, wearable systems could inform clinicians on the severity of the condition by monitoring its development, hence, proving the efficacy of eventual treatments if prescribed.The present study found that among the analyzed algorithms, WUM shall be used every time only FSs are used in the analysis (FS identification and stride duration), while SAL is indicated for FOs identification and for computing stance and swing duration. Although relatively small compared to the whole gait cycle duration, the errors induced by the MIMU-based algorithms for foot strike estimation led to an erroneous characterization of the heel rocker, especially in the shoed condition. Nevertheless, the WUM algorithm allowed a promising characterization of heel and forefoot rockers, provided that its tendency to overestimate the presence of heel rockers is taken in due account.