The severe course of COVID-19 causes systemic chronic inflammation and thrombosis in a wide variety of organs and tissues. The nature of these inflammations remains a mystery, although they are known to occur against the background of a high level of cytokine production. The high level of cytokines provokes overproduction of the Serum amyloid A (SAA) protein. Moreover, the number of studies has shown that the severe COVID-19 causes SAA overproduction. The authors of these works regard a high level of SAA exclusively as a biomarker of COVID-19. However, it should be borne in mind that overproduction of SAA can cause systemic AA amyloidosis. SAA forms cytotoxic amyloid deposits in various organs and induces inflammation and thrombosis. The consequences of COVID-19 infection are surprisingly similar to the clinical picture that is observed in AA amyloidosis. Here I present the hypothesis that AA amyloidosis is a factor causing systemic complications after coronavirus disease. Identification of factors that cause systemic complications after coronavirus disease COVID-19) appears to be the next global challenge after vaccine development. Over two million people have already died from COVID-19, and the end of the pandemic is very difficult to predict. Severe course of COVID-19 causes systemic complications of unclear aetiology. The patients who have suffered severe forms of this viral disease develop inflammation of the lungs, kidneys, heart, gastrointestinal stroke, peripheral and central nervous systems 9 appears. In addiThe consequences of COVID-19 infection are surprisingly similar to the clinical picture that is observed in systemic AA amyloidosis (AA stands for amyloid A). This type of amyloidosis is associated with abnormal aggregation of the Serum amyloid A (SAA) protein . SAA is Generalization of all these published data suggests a hypothesis according to which AA amyloidosis is a factor causing systemic pathologies after a severe form of coronavirus disease.The severe course of coronavirus disease causes an increased production of cytokines, and sometimes a cytokine storm ;High cytokine level provokes SAA overproduction ;SAA overproduction causes formation of amyloid aggregates that are deposited on the walls of blood vessels in various organs and tissues ;Cytotoxic protein aggregates cause inflammation of the affected tissues  and vascAll these data are aligned in the following logical chain:Only one element in this hypothesis remains untested. It is necessary to prove experimentally that SAA overproduction against the background of a severe course of COVID-19 disease does lead to formation of amyloid deposits. This scenario appears to be most likely. As mentioned above, chronic inflammations after bacterial and viral infections are known to cause AA amyloidosis . ConfirmIf this hypothesis is verified, therapy aimed at suppressing inflammation and reducing the level of SAA production will be required. It is important to note that AA amyloidosis is treatable if diagnosed in time. Various therapies have been used successfully for treatment of this type of amyloidosis ,18–20. IThe hypothesis postulating that AA amyloidosis is a factor causing systemic pathologies after coronavirus disease appears to be very convincing, although the pathogenesis may also be associated with other factors. In particular, these complications could presumably be related to other types of systemic amyloidosis. In any case, the risk of AA amyloidosis induction in severe COVID-19 cases is quite high. Verification of this hypothesis appears to be an urgent task as identification of the factors causing systemic complications after COVID-19 could help to save many lives.


Objectives: Pediatric teams of emergency departments work under extreme stress, which affects high-level cognitive functions, specifically attention and memory. Therefore, the methods of stress management are being sought. Mindfulness as a process of intentionally paying attention to each moment with acceptance of each experience without judgment can potentially contribute to improving the performance of medical teams. Medical simulation is a technique that creates a situation to allow persons to experience a representation of a real event for the purpose of education. It has been shown that emergency medicine simulation may create a high physiological fidelity environment similarly to what is observed in a real emergency room. The aim of our study was to determine whether the technical and non-technical skills of medical students in the course of pediatric high fidelity simulations are related to their mindfulness and stress. Participants and methods: A total of 166 standardized simulations were conducted among students of medicine in three simulation centers of medical universities, assessing: stress sensation (subjectively and heart rate/blood pressure), technical (checklists) and non-technical skills  and mindfulness (five facet mindfulness questionnaire): ClinicalTrials.gov ID: NCT03761355. Results: The perception of stress among students was lower and more motivating if they were more mindful. Mindfulness of students correlated positively with avoiding fixation error. In the consecutive simulations the leaders’ non-technical skills improved, although no change was noted in their technical skills. Conclusion: The results of our research indicate that mindfulness influence the non-technical skills and the perception of stress of medical students during pediatric emergency simulations. Further research is needed to show whether mindfulness training leads to improvement in this field. Pediatric emergency department staff work in intense, chaotic and unpredictable environments and have been shown to have the highest levels of psychosocial distress among all healthcare providers . Stress Mindfulness is a process of intentionally paying attention to each moment with curiosity, openness and acceptance of each experience without judgment . This isMedical simulation is a technique that creates a situation or environment to allow persons to experience a representation of a real event for the purpose of practice, learning, evaluation, testing or to gain understanding of systems or human actions . It has No research has been performed concerning the association between being mindful, stress and performance in emergency medicine under standardized conditions. The aim of our work was to test the hypothesis that technical and/or non-technical skills of medical students during pediatric emergency simulations are related to their mindfulness and stress. In general, we anticipated that the results of our study could lead to better understanding of the mechanisms that influence performance of medical students during pediatric emergency cases and may enable them to improve their skills in their future professional life.The project was planned as an observational cohort study in a group of graduating medical students . The research was conducted between October 2017 and October 2018 in three Polish medical simulation centers. The inclusion criterion was being a graduating student of medicine and consent to participate in the study. The exclusion criterion was pregnancy. The design of the study is presented on figure 1 The simulations were constructed as high-fidelity scenarios in life-threatening situations in children . They started in the morning and were identical for all groups of students . The level of task difficulty was intermediate and was evaluated based on the pilot simulations with both students and young doctors. Each scenario had two equal goals - technical and non-technical e.g treatment of exacerbation of asthma due to pnemonia and avoiding fixation error . During the implementation of the simulation scenario, the students played different roles . The analysis concerns only the scenarios in which the students acted as team leaders (skills and interactions with the other participants of the simulation were assessed).th year of the faculty).The following data of medical students were assessed: age, sex and the fact of participating in mindfulness training or other secular or religious meditations. Stress and its impact on simulation were assessed both subjectively by participants  as well as by assessing the heart rate and blood pressure. Medicines taken and the amount of caffeine consumed by students every day and before the simulation were also noted, as well as the subsequent number of the simulation on a given day and during the entire medical studies .Ottawa GRS) and checklist . F. F15]. FThe study design was approved by the Ethics Committee at the Medical University of Bialystok in accordance with the Declaration of Helsinki (No R-I-002/358/2017). Signed informed consent was obtained from students. The rates of consent was 94.9%. The main reason for the consent refusal was lack of time to complete the survey. Students who agreed to participate in the study and those who did not give their consent did not differ in sex, age or in technical and non-technical skills assessment scores.Data are presented as means and standard deviation (SD) and rates of incidence of a given characteristic in the evaluated group of students. Univariate analysis was conducted using the Mann-Whitney U test for continuous variables and the Chi-square test for the nominal ones. Spearman's rank correlation coefficient was used to evaluate the relationships between mindfulness, stress and performance of medical students in simulations. A p<0.05 was considered statistically significant. Statistical analysis was performed using the Statistica 13 software . Only students with all data available were included in the analysis.In total, 166 students were qualified for the study. As each student played a role of a team leader in a pediatric emergency situation at least once, 166 simulations were analyzed. Data referring to age, sex, meditation/prayer, use of caffeine and medicines, and stress before and after simulations are shown in table 1 The students' perception of stress before and during simulation correlated with their mindfulness. The lower perception level of stress before simulation was related to total mindfulness, lower reactivity and lower level of judgment .The stress experienced before a simulation influenced some of the parameters on the non-technical skills scale (the Ottawa GRS). There was a positive correlation between the subjective feeling of stress before the simulation and the obtained results in terms of team management and communication in the team  was associated with a higher score in technical skills . This correlation was not observed in the case of technical skills (p>0.05).A comparison of the Ottawa GRS scores showed statistically significantly lower average scores for situational awareness skills (fixation error) than for other non-technical skills of medical students (p <0.001) . Similarly, the FFMQ scale total score was not related to the total score obtained using the Ottawa GRS for non-technical skills. However, avoiding fixation error (situation awareness skills) was positively associated with conscious action on the mindfulness scale  was the weakest non-technical skill among all the skills assessed using the Ottawa GRS scale. During the pre-briefing, students often uttered a probable diagnosis aloud and were fixating on it during the simulation, without verifying the hypothesis, despite all data received . Loss of situation awareness can lead to errors. On the other hand the Simulation-Based Crisis Resource Management training implemented among pediatric cardiac intensive care unit providers has improved situational awareness including reporting of doubts concerning the appropriate procedure to the team leader .The FFMQ scores obtained by our medical students were similar to the results reported from the group of 800 Polish adults among whom the scale was validated, thus indicating that medical students are as mindful as other adult Poles . In our observation, a higher level of mindfulness not only reduced the subjective perception of stress before simulation, but also correlated with its more motivating impact during the simulation scenario. The results of some studies indicate a connection between mindfulness and well-being or education and work in medical professions and in students of medical courses. Such mindfulness effects as reduced stress, increased self-regulation (the ability to effectively manage one's thoughts and actions to complete a task) can be particularly useful for medical students during pediatric emergency cases. A meta-analysis of 19 studies concerning the use of mindfulness in medical students showed that mindfulness-based interventions decrease stress, anxiety, depression and improve mindfulness, mood, self-empathy and empathy . As reveThe strength of our study is the unique pediatric character of the simulation, a large number of participants and simulations, great experience of simulation centers involved in the project, lack of voluntary nature of the research and standardized conditions for study implementation. The limitations of our study are certainly the subjectivity and difficulty of the Ottawa GRS application for the non-technical skills. However, this tool is considered to be easier to use, more practical and more reliable than a similar instrument i.e. Anesthetists’ Non-Technical Skills (ANTS) behavioral marker system . Our proDoes greater mindfulness indeed influence the actions of doctors in real medical situations? Should mindfulness be included in the university curriculum for medical students? Should mindfulness be taught as an elective or obligatory subject? It would be interesting to check when the interventions are optimal – at the beginning or end of the study, at the start or finish of the residency period? These and many other questions should be answered in future randomized trials.The results of our research indicate a relationship between mindfulness of medical students and their non-technical skills and the perception of stress in simulations of pediatric emergency situations. Further research is needed to show whether mindfulness training leads to changes in this field. Perhaps mindfulness courses should be included in the medical university curriculum and early career of a young doctor to reduce stress and improve the diagnostic and therapeutic effectiveness of physicians working individually and in teams.ANTS – Anesthetists' Non-Technical SkillsFFQM – Five Facet Mindfulness QuestionnaireHRV – heart rate variabilityOttawa GRS – Ottawa Crisis Resource Management Global Rating ScaleJC, WL, GC, TB and KT designed the study; JC and WL were a major contributors in writing the manuscript; WL, KL, TB and KT collected and analysed the patient’s data; all authors read and approved the final manuscript.The raw data sets including data base (in Microsoft Access) used to support the findings of this study are available from the corresponding author upon request.The study was funded by Medical University of Białystok, Poland.The authors declare that they have no competing interests.


Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections. Perinatal infections caused by human cytomegalovirus (HCMV) are common and include both infections acquired in utero  and those acquired in the peripartum period and in early infancy. Although clinically significant perinatal infections occur in premature infants who acquire HCMV early in life, most severe HCMV infections and, in particular, those associated with long-term neurodevelopmental sequelae, result from intrauterine transmission of HCMV to the developing fetus. Congenital HCMV (cCMV) infection is relatively frequent in most regions of the world, with birth prevalence ranging from 5 to 10 cases per 1000 live births ,3. Thus,As shown in + and CD20+ lymphocytes and CD68+ macrophages in periventricular areas of the brain .,92.91,92phocytes . A robusIntrauterine HCMV infections of the developing fetus and the resulting adverse outcomes in infants with cCMV infection are of considerable importance because of the relatively common occurrence of this perinatal infection worldwide. Although investigators have long recognized the spectrum of clinical findings in infants with cCMV, more recent studies have strongly argued that the characteristics of CNS involvement with this infection are primary determinants of the long-term outcomes of infected infants. Similar to the challenges presented by investigations of other diseases of the human CNS, informative model systems are absolutely essential for defining mechanisms of disease in infants with cCMV infections. Although studies in CNS organoids offer exciting new opportunities for mechanistic studies that can be further refined in vitro, animal models remain the mainstay for investigating the impact of HCMV infection on the developing CNS. Murine models of CNS infection have been the most well characterized and offer numerous advantages over both nonhuman primates and other small-animal models secondary to the extensive amount of existing information on neurodevelopment and immunological development of laboratory mice. Currently employed models have taken advantage of the well-described CNS development in mice and have modeled the impact of virus infection at various time points during CNS development, including the development of auditory pathways in postnatal mice. These models have provided new understandings of mechanisms of virus-induced neurodevelopmental disease, including hearing loss. Findings from these murine models parallel histopathological findings in tissues from HCMV-infected fetuses, and importantly, in some cases, closely recapitulate clinical phenotypes of infants with cCMV infections. Further refinement of these models can be expected to enable more directed studies of mechanisms of disease that lead to adverse outcomes in infants with cCMV infections, and almost assuredly, the design and testing of interventions to modify long-term outcomes of infants infected in utero with HCMV.


Computed tomography (CT) is considered the gold standard technique for the assessment of trauma patients with suspected involvement of the eye and orbit. These traumas can result in dramatic consequences to visual function, ocular motility, and aesthetics. CT is a quick and widely available imaging modality, which provides a detailed evaluation of the orbital bony and soft tissue structures, an accurate assessment of the globes, and is used to guide the patients’ treatment planning. For a timely and accurate diagnosis, radiologists should be aware of fracture patterns and possible associated complications, ocular detachments and hemorrhages, and different appearances of intraorbital foreign bodies. This educational review aims to describe all post-traumatic orbital abnormalities that can be identified on CT, providing a list of tips and a diagnostic flowchart to help radiologists deal with this complex condition. Computed Tomography (CT) is the gold standard for orbital trauma assessment.CT enables evaluation of orbital fractures, soft tissue injuries, foreign bodies.CT multiplanar reconstructions help surgical planning of orbital fractures.CT allows the visualization of the ocular globe content and structures.Craniofacial trauma represents a public health issue of pivotal relevance due to its frequency and the high number of accesses to the Emergency Departments. These traumas may be often associated with damage of the eye and orbit, resulting in significant functional impairment if not timely diagnosed and properly managed.In the United States, eye injuries account for 3% of all Emergency Departments accesses, with more than 2.5 million new eye injuries each year –3.In a traumatic setting, clinical evaluation can be hindered by soft tissue swelling or damage and patients’ general conditions. In these cases, CT represents the gold standard for investigating suspected orbital fractures  and idenRadiologists have a key role in diagnosing, assessing bone and orbital soft tissue damage, as well as identifying potential complications. However, Radiological Departments do not always have neuroradiologists dedicated to reporting emergencies on duty, and the general radiologists who are faced with imaging of orbital emergencies may find the topic quite challenging.This article aims to display and describe the CT findings of traumatic orbital emergencies collected in a 24/7 Ophthalmological Emergency Department in the period from January 2019 to June 2021, and provide a structured flowchart to help the radiologist recognize the most frequent fracture patterns, assess and describe orbital, soft tissue and globe damage.This observational retrospective study follows international laws and guidelines (Helsinki Declaration), with experimentation Register Number 2018/ST/191. Patients provided written consent for the use of their anonymized images.Even if the orbit is a relatively small pyramidal space, it has a complex anatomy and includes critical structures.The orbital bony structure is made up of a floor, a roof, a medial, and a lateral wall. The orbital roof is the floor of the frontal sinus creating a division from the anterior cranial fossa; most of it corresponds to the orbital surface of the frontal bone. The lesser wing of the sphenoid bone contributes to a minor portion of the roof at the orbital apex . The orbFrom front to back, the maxillary bone, the lacrimal bone, the ethmoid bone, and the body of the sphenoid bone together contribute to the medial wall, which divides the orbital content from the ethmoidal cells .The lateral wall is made up of the zygomatic bone anteriorly and the greater wing of the sphenoid bone posteriorly .The globe is placed in the anterior part of the orbit, and its content is bordered by three layers: the sclera and cornea form the outermost layer, the uveal tract, with the ciliary body anteriorly and the choroid posteriorly, forms the middle layer, and the retina forms the inner layer. These layers are intertwined and cannot be distinguished on CT imaging in a healthy eye; therefore they are visualized as a single layer .The lens is an avascular proteinaceous component that divides the globe into an anterior segment filled with aqueous humor, and a posterior segment, containing the vitreous humor, accounting for 2/3rds of the total globe volume .The lens is attached to the sclera through the zonular fibers and is responsible for the accommodation. It contributes around 1/3rd of the total optical power .The anterior segment is further divided by the iris into an anterior and posterior chamber.The extraocular muscles are seven and together form a conical shape. Six of the extraocular muscles control the movement of the eye, while the remaining muscle, the levator palpebrae, is responsible for superior eyelid elevation . The fouThe levator palpebrae superioris originates from the lesser wing of the sphenoid bone and attaches to the superior tarsal plate of the upper eyelid .The optic nerve can be divided into an intracranial and extracranial tract . It is cThe ophthalmic artery originates from the internal carotid at the medial section of the anterior clinoid process and runs anteriorly, going through the optic canal, inferolateral to the optic nerve. All of the orbital structures are supplied by its branches . The supOrbital fractures are typically the result of middle third facial traumas with the application of forces that overcome the resistance of the orbital cavity bones .They can be single-wall or multi-wall, with the latter being the more prevalent. Moreover, there are complex facial fracture patterns with orbital involvement: the zygomaticomaxillary complex fracture, nasoorbitoethmoid fractures, and Le Fort fractures.Orbital fractures can be classified as blow-out and blow-in . BlowoutThe most common clinical signs of orbital fractures are periorbital edema, periorbital ecchymosis, subconjunctival hemorrhage, subcutaneous emphysema with crepitus, periorbital contusions, hematomas, soft tissue injuries involving the eyelids, and deficits of the infra-orbital tract of the optic nerve .BOFs are usually associated with injuries to surrounding soft tissues and orbital cavity contents. They may cause entrapment or herniation of orbital fat and extraocular muscles, resulting in limited eye movements and/or enophthalmos due to intra-orbital volume reduction .The inferior orbital wall is the most commonly involved site, followed by the medial orbital wall.2, and persistent diplopia due to entrapment or fibrosis of the extra orbital muscles .Fig.Fig16].FThe orbital floor BOF is the most common fracture and can occur alone Fig.  or in coThe most prevalent cause of injury is direct anteroposterior blunt trauma to the globe and orbital boundaries. The potential mechanism for this sort of fracture has been proposed as hydraulic energy and buckling of the floor from impact to the inferior orbital edge .Orbital floor fractures can be complicated by the intraorbital fat herniation towards the maxillary sinus, and entrapment of the inferior rectus muscle  Figs. 33, 4. TheA particular type of orbital floor BOFs is represented by the trapdoor fracture, which usually occurs in children and toddlers due to the distensibility of immature facial bones . In thisTips: assess the presence of the herniation of the intraorbital fat and/or inferior rectus muscle through the bone defect.Remember to check the integrity of the inferomedial orbital strut, a bony thickening that extends from the maxillary to the ethmoid bone, whose anterior part represents an attachment site for the suspensory ligaments. The fracture involvement of the inferomedial orbital strut increases the difficulty of surgical repair, with the risk of globe malposition and eye movement impairment.The medial wall is the second most common site of orbital fractures, occurring through the lamina papyracea. It can be isolated or associated with other wall fractures and caused by anteroposterior traumas directed to the globe and the orbital borders. The most common type of presentation is an association of the medial wall and floor (36%) fractures or medial wall, floor, and zygomatic complex (28%) fractures .Non-displaced lamina papyracea fractures can be difficult to detect: the presence of orbital emphysema can be considered its radiological indirect sign .The radiologist should accurately assess the orbit medial anatomical structures, such as medial canthal tendon, lacrimal apparatus, medial rectus, and superior oblique muscles .Indications for surgery include the restriction of ocular motility due to entrapment of the medial rectus muscle, diplopia, and clinically significant enophthalmos. Enophthalmos is a rare occurrence in isolated medial wall fractures but may be present in the case of associated floor fractures .Tips: assess the presence of herniation of the intraorbital fat through the bone defect and/or medial rectus muscle entrapment Figs. , 5.Fig. The superior orbital wall, also known as the orbital roof, separates the anterior cranial fossa from the intraorbital content. Fractures through the orbital roof are typically the result of a high-energy facial trauma to the forehead or superior orbital rim, usually associated with intracranial damages and involvement of the orbital rim . IsolateThe fracture fragments may be displaced superiorly (BOFs), or inferiorly (“blow-in” fracture), or non-displaced. Orbital roof fractures are usually treated conservatively; however, decreased ocular motility may occur in case of entrapment of the superior rectus and superior oblique muscles . FurtherTips: look for entrapment of the superior rectus and superior oblique muscles, and possible intracranial complications Fig. .Fig. 6CoThe lateral orbital wall is the hardest of all the orbital walls; therefore pure lateral wall fractures are extremely uncommon Fig. ; howeverZygomaticomaxillary complex fractures are the most common facial fractures with orbital involvement, usually caused by a high-energy direct traumatic blow to the malar eminence, resulting in fractures of the lateral and inferior orbital borders and extension into the anterior wall of the maxillary sinus, zygomatic arch, and internal lateral orbital wall Fig.  30].Fig.Fig30].FThe zygomatic maxillary complex is made up of four bony articulations. Superiorly, the zygoma frontal process articulates with the frontal bone; medially, the zygomatic bone articulates with the maxillary bone. The zygomatic bone articulates with the temporal bone zygomatic process on the lateral side, contributing to a part of the zygomatic arch. Posteriorly, it articulates with the sphenoid greater wing, to form the orbit internal lateral wall . FracturDisplaced fractures with considerable lateral angulation of the orbital internal lateral wall or simultaneous orbital floor blowout fractures can cause enophthalmos, which requires urgent surgical correction and intraorbital reconstruction . CT is cTips: check for the comminution and the position of the bone fragments of the internal lateral orbital wall Fig. .Fig. 9CoNaso-orbitoethmoidal complex fractures Fig.  are causnasolacrimal duct lesion with impaired tear drainage  and cereAccording to Markowitz and Manson's classification, the naso-orbitoethmoidal complex fractures can be divided into three types: Type I is a single-segment central fragment with no involvement of the medial canthal tendon attachment; type II is a comminuted central fragment with fractures external to the medial canthal tendon insertion, and type III is a medial canthal tendon avulsion with a comminuted lacrimal fossa fracture . InjurieTips: assess the fracture degree at the attachment of the medial canthal tendon. Look for nasolacrimal duct injuries.Fractures involving complete separation of all or a portion of the maxilla from the skull base are commonly described according to the classification proposed by French surgeon Rene Le Fort in 1901 . The pteThe Le Fort III pattern involves complete craniofacial dissociation, with fracture of the orbital medial and lateral walls and the zygomatic arch  Fig. 1111.The Le Fort II, also known as the pyramidal fracture, involves the inferior and medial orbital walls and results in a pyramid-shaped fracture of the central midface that may detach from the remaining lateral face and skull base, whereas type III involves the lateral orbital wall and zygomatic arch causing craniofacial separation .These fracture patterns may involve both sides of the midface symmetrically or asymmetrically .Tips: the use of all multiplanar and 3D reconstructions can help the characterization of Le Fort fractures.The orbital apex corresponds to the posterior portion of the orbit and is one of the most critical regions when involved in fractures. Fractures of the orbital apex can extend through the optic canal or superior orbital fissure, resulting in damage or impingement to the neurovascular structures that run through these bony canals.Two clinical syndromes may complicate orbital apex fractures: the superior orbital fissure syndrome and the orbital apex syndrome. The superior orbital fissure syndrome is the result of injury to cranial nerves III, IV, V1, and VI, that cross the superior orbital fissure, and present with ophthalmoplegia, diplopia, and ptosis. The combination with the damage to the optic nerve at the orbital apex results also in unilateral vision loss: this condition is known as orbital apex syndrome. Even if MRI remains the gold standard for optic nerve assessment , CT analTips: look for the intracanalicular tract of the optic nerve, and check for possible compression by bony fragments or retrobulbar hematoma.It consists of an acute injury to the optic nerve, resulting from direct trauma to the optic nerve or an indirect insult due to diffuse axonal injury from blunt head trauma.CT plays a limited role in diagnosing TON. It can demonstrate an optic canal fracture and, in a few cases, CT can visualize optic nerve stretching, swelling, and densitometric changes  Fig. 1212.Fig. 1CT can help the management of suspected TON: if the optic nerve is partially or completely avulsed, aggressive measures are not indicated. In the case of visual loss, with an intact optic nerve, high-dose intravenous corticosteroids may be considered as a treatment. Surgical exploration may be indicated in nerve impingement, especially if a bone fragment or other material is compressing the optic nerve.Tips: in patients complaining of sudden post-traumatic decreased visual acuity, the radiologist should pay attention to the orbit apex to exclude the presence of fractures.The anterior chamber is the fluid-filled space, delimited anteriorly by the cornea and posteriorly by the anterior iris surface. Hyphema is a hemorrhage within the anterior chamber of the globe, due to an injury of small blood vessels within the iris and ciliary body, visible on CT as an increased attenuation in the anterior chamber Fig.  30]. Du. Du30]. Tips: in the case of hyphema, the role of CT is to assess the posterior chamber and the presence of associated injuries.The normal vitreous is a high-water-content gel-like fluid, bounded by the posterior and anterior hyaloid membranes, with homogeneous fluid-like density on CT. Its post-traumatic increased density suggests the presence of a vitreous hemorrhage Fig. , which cTips: when the vitreal hemorrhage is present, look for the coexistence of foreign bodies and associated orbital injuries.It consists of an accumulation of blood in the retrobulbar space that causes an increase in the intra-orbital pressure resulting in compression or stretching of the optic nerve and reduced perfusion to the eye Fig.  13]. On. On13]. Tips: look for possible mass effects on the optic nerve.On CT the normal lens is easily recognizable, hyperdense, and well differentiable from the surrounding fluid within the posterior chamber.Traumatic deformation of the globe causes the stretch and disruption of the zonular fibers that hold the lens in place, resulting in lens dislocation: subluxation of the lens can either be anterior or posterior, with the latter being more frequent . The diaMoreover, the lens capsule may be damaged, resulting in a post-traumatic cataract , 31: thiTips: the radiologist should be familiar with the appearance of the lens after surgical treatment of cataracts: the native lens is removed and replaced with a silicone or acrylic lens. The post-surgical lens is thinner than the native one and can be confused in the evaluation of orbital traumas.The retina is the innermost sensory layer of the globe and consists of an outer layer strictly attached to the choroid, and an innermost layer responsible for visual perception. The layers unite at the ora serrata, which marks the retina's anterior limit and the ciliary body's posterior limit .Retinal detachment is defined as the separation of the sensory retina from the underlying choroid, with the accumulation of subretinal fluid/blood .Different patterns can be visible on CT images, according to the extension of the damage: (I) folded layers with hyperdense fluid in the subretinal space, (II) retinal detachment limited anteriorly by the ora serrata, (III), diffuse retinal detachment, visible as a V-shaped image with the apex at the optic disk Fig.  30].Fig.Fig30].FRetinal detachments can be treated using scleral bands  and acquired (staphyloma) ocular malformations can mimic an open globe injury.Moreover, the radiologist should be aware of the radiological appearance of the various ocular interventions: previous treatments for retinal detachment and scleral buckle can complicate the diagnosis of an open globe injury. Perfluoropropane gas bubbles Fig. a, b, lowOcular traumas can result in entrapment, avulsion, and laceration of the extraocular muscles. Medial and inferior rectus muscles are mostly involved Figs. , 3, 4, 5Tips: Use the coronal reconstruction to better evaluate extraocular muscles and their relationship with the fracture edges.The identification of intraorbital foreign bodies within the globe is crucial, as retained foreign bodies increase the risk of infectious or inflammatory endophthalmitis .CT is usually the first diagnostic tool, as it is extremely sensitive in detecting metallic foreign bodies both in the superficial and deeper structures of the globe as well as soft tissue spaces of the orbit Fig. a, b.Fig.CT also showed high sensitivity in the identification of glass foreign bodies (96% for foreign bodies of 1.5 mm) .The CT sensitivity decreases when dealing with the plastic ones: in these cases, the presence of air within the globe is suggestive for an open-globe injury.Wooden foreign bodies can present as linear air density images .Indications for surgical removal include reduced visual acuity, mechanical restriction of ocular movements, development of acute or chronic infection, or suppurative reactions. Removal of foreign bodies located close to the apex is also generally discouraged due to the risk of intraprocedural complications.Tips: wooden foreign bodies can be hypoattenuating and linear and can be mistaken for air: radiologists should be aware of their appearance.Senile scleral plaques and drusen can also be mistaken for foreign bodies by inexperienced radiologists: it is essential to be aware of these entities Fig. c, d.We propose a flowchart to help the radiologist in the analysis of maxillofacial CT for orbital traumas Figs. , 23.Fig.Orbital trauma can occur isolated or in association with craniofacial injuries, resulting in fracture patterns of variable complexity. CT represents the gold standard to assess injuries related to orbital traumas and guides the appropriate management.Understanding and being familiar with fracture patterns, possible damages to soft tissues, eye and globe abnormalities is crucial for the radiologist for a quick and appropriate diagnosis, and mandatory for the right treatment planning to avoid long-term invalidating consequences.


In this study, the impact of steel fibres and Silica Fume (SF) on the mechanical properties of recycled aggregate concretes made of two different types of Recycled Coarse Aggregates (RCA) sourced from both low- and high-strength concretes were evaluated through conducting 60 compressive strength tests. The RCAs were used as replacement levels of 50% and 100% of Natural Coarse Aggregates (NCA). Hook-end steel fibres and SF were also used in the mixtures at the optimised replacement levels of 1% and 8%, respectively. The results showed that the addition of both types of RCA adversely affected the compressive strength of concrete. However, the incorporation of SF led to compressive strength development in both types of concretes. The most significant improvement in terms of comparable concrete strength and peak strain with ordinary concrete at 28 days was observed in the case of using a combination of steel fibres and SF in both recycled aggregate concretes, especially with RCA sourced from high strength concrete. Although using SF slightly increased the elastic modulus of both recycled aggregate concretes, a substantial improvement in strength was observed due to the reinforcement with steel fibre and the coexistence of steel fibre and SF. Moreover, existing models to predict the elastic modulus of both non-fibrous and fibrous concretes are found to underestimate the elastic modulus values. The incorporation of SF changed the compressive stress-strain curves for both types of RCA. The addition of steel fibre and SF remarkably improved the post-peak ductility of recycled aggregates concretes of both types, with the most significant improvement observed in the case of RCA sourced from a low-strength parent concrete. The existing model to estimate the compressive stress-strain curve for steel fibre-reinforced concrete with natural aggregates was found to reasonably predict the compressive stress-strain behaviour for steel fibres-reinforced concrete with recycled aggregate. Concrete is considered the most widely used construction material in the world ,11,12,13The properties of concrete made by recycled aggregates have been analysed in many research studies ,28. TherLike concrete-containing natural aggregates, recycled aggregate concrete also exhibits brittle behaviour in tension and flexure . TherefoTo mitigate the weaker performance of RCA and make it more comparable to conventional concrete, multiple approaches have been utilized in previous research, including the addition of supplementary cementitious materials (SCMs) such as fly ash, electric arc furnace slag, ground granulated blast furnace slag, and SF . Such SCIn addition to the desirable impact of the mentioned materials, previous research studies indicate the superb performance of SF in the enhancement of mechanical and durability properties of recycled concrete . The addCarneiro et al.  measuredMeesala  studied A better understanding of the compressive stress-strain behaviour and elastic modulus of recycled aggregate concrete containing steel fibre, SF, and their combination needs to be accepted by many designers, contractors, and policymakers as a sustainable alternative to conventional concrete. Therefore, the current study aims to evaluate the impacts of steel fibre and SF and their combination on the compressive stress-strain behaviour and elastic modulus of different recycled aggregate concretes. In published research, it is proven that the replacement levels of up to 30% of NCA by RCA does not significantly jeopardise the mechanical properties of concrete. A recent study reported a 5.0–9.3% reduction in compressive strength when different amounts of RCA were utilized . However, respectively. The attached mortar was obtained according to the thermal method, as recommended by other researchers [mi and mf are the initial and final masses of the sample, respectively.The cementitious materials used in this study were ordinary Portland cement (OPC), equivalent to ASTM Type I, and SF. Their chemical compositions and physical properties are summarised in Table 2earchers ,71. In tThe mix design of the concrete samples is shown in A constant water-to-binder ratio equal to 0.4 was used in all the mixtures. Two different RCA contents included the partial replacement of NCA (50% by mass) and full replacement (100% by mass). It should be noted that the replacements were made by mass because the RCA featured a different density compared with the NCA.The trial-and-error method was used to find the suitable mixing procedure. First, the fine aggregates and binders were mixed using a Hobart mixer for one minute until a homogenous mixture was obtained. Next, half of the mixing water and super-plasticiser were added to the mix of binder and aggregates and were mixed for two minutes. The coarse aggregates and the other half of the water were then added, and the mixing process was resumed for five minutes. Finally, the fibres were added, and the mixing was resumed for five minutes.The freshly mixed concrete was poured into cylindrical moulds with a 100 mm diameter and 200 mm in height to undergo the compressive strength tests and determine the stress-strain curves ,72. NextThe slump values of all the mix designs adopted in this study were set to be between 50 mm and 75 mm, which is a reasonable value for practical applications. Moreover, the workability of the samples was slightly reduced while replacing the natural aggregates with both types of recycled concrete aggregates, or by using higher amounts of silica fume. Detailed information regarding the sample preparation, compression tests, and the used standards can be found in recent research studies conducted by the authors ,74. The The compressive stress-strain behaviours of the non-fibrous concretes containing RCA types A and B are shown in The typical failure patterns of all the concrete samples are shown in The calculated elastic modulus values of all the concretes are presented in 2 equal to 0.87. The measured elastic modulus values were compared with those predicted by existing models for both the non-fibrous and steel fibre-reinforced concretes to examine the feasibility of using existing models. In the case of the non-fibrous concrete, the models proposed by Warner et al. [A correlation between the compressive strength and the modulus of elasticity of the non-fibrous recycled aggregates concretes was established, as shown in r et al.  and Thomr et al.  for steeThe effect of SF addition on the toughness of both types of steel fibre-reinforced recycled aggregates concretes was calculated from the area under the compressive stress-strain curve in each concrete. The results are summarised in The consequences of adding SF on the peak compressive strain and compressive strength of both non-fibrous and fibrous recycled aggregates concretes are shown in As shown in coε is the strain corresponding to the compressive strength , and the combined use of steel fibres and SF on the mechanical properties of recycled aggregate concretes containing 50% and 100% recycled coarse types aggregates (RCA), sourced from both low- and high-strength concretes, were investigated. The following main conclusions were drawn based on the experimental and prediction studies:For future research studies, it is recommended to explore the effects of different water/cement ratios on the same mix designs. The investigation of the impact of using other types of fibres on the engineering properties of the mix designs adopted in this research is also suggested.


We present the case of a 21-year-old female, with a history of bipolar disease, observed at the emergency department of our institution for voluntary ingestion of two foreign bodies. She complained of localized neck pain, dysphagia and odynophagia that started 2 hours before observation. Initial evaluation identified two thumbtacks lodged in the left pyriform sinus and valeculae. Despite swift preparation for removal of the foreign bodies under sedation, progression on the digestive tube occurred. One thumbtack was removed by endoscopic techniques from the gastric fundus. The other was expelled naturally in an uncomplicated fashion at day 8.


Paget's disease of the breast is a rare cutaneous eczema-like condition that occurs in the nipple-areolar complex of the breast. The current study aims to report a rare case of Paget's disease of the breast associated with invasive ductal carcinoma in a male breast.A 54-year-old male presented with ulceration of the left nipple-areolar complex that has been progressing over the last 6 months. On examination; there was a palpable axillary lymph node. On ultrasound, a small hypoechoic heterogenous mass was seen beneath the areola (8*4 mm) with surrounding vascularity, and a few axillary lymph nodes with normal morphology and cortical thickness. The mammography revealed some points of calcification arranged in clusters. The patient underwent left side mastectomy and sentinel lymph node biopsy. The result of histopathological examination showed left side unifocal invasive ductal carcinoma.There are two main theories that explain the histogenesis of Paget's disease of the breast with and without underlying malignancy: epidermotropic theory, which suggests an epidermal infiltration of the nipple with Paget cells, and transformative theory, which proposes a malignant transformation of normal glandular cells of the epidermis.The clinical presentation of Paget's disease of the breast is characteristic and should always warn the surgeon of the possibility of underlying malignancy. •Paget's disease of the breast (or nipple) is a very rare cutaneous entity.•Paget's disease of the male breast is an extremely rare clinicopathologic condition.•Breast cancer in male is likewise very rare. It makeThe current study aims to report a rare case of PD of the breast associated with IDC in a male breast. The report has been arranged in line with SCARE 2020 guidelines with a brief literature review .2Patient's information: A 54-year-old male presented with ulceration of the left nipple-areolar complex that has been progressing over the last 6 months. He had no past medical or surgical history.Clinical examination: The patient had ulceration of the left nipple-areolar complex and palpable axillary lymph nodes.Diagnostic assessment: On ultrasound, a small hypoechoic heterogenous mass was seen beneath the nipple-areolar complex (8*4 mm) with surrounding vascularity, and a few axillary lymph nodes with normal morphology and cortical thickness. The mammography showed some points of calcification arranged in clusters (20*15mm). Core biopsy revealed high grade DCIS with no invasion. Wedge resection of the nipple and areola revealed Paget's disease of the nipple with dermal lymphatic permeation by tumor cell emboli. Fine needle aspiration cytology (FNAC) of the left axillary lymph node was negative for malignancy.Therapeutic intervention: The patient underwent left side mastectomy and sentinel lymph node biopsy. The result of histopathological examination showed left side unifocal invasive ductal carcinoma, grade 2, moderately differentiated, 60% intermediate-high grade DCIS, cribriform and solid patterns with comedo necrosis within and outside of the invasive tumor along with nipple PD with dermal lymphatic permeation. Two lymph nodes were isolated and one of them was involved with micro-metastases without extra-nodal extension, pT1cN1m (sn).Follow up: Post-operative period was uneventful. The patient left the hospital on the second post-operative day.3Paget's disease is characterized by infiltration of the nipple and areolar epidermis by large tumor cells of glandular differentiation . It accoThere are two main theories explaining the histogenesis of PD with and without underlying malignancy. The first one is the epidermotropic theory which suggests an epidermal infiltration of the nipple with Paget cells . This isThe identified risk factors include advanced age, genetic conditions such as Klinefelter's syndrome, conditions that may lead to estrogen and progesterone imbalance , benign diseases of the breast (breast cyst and trauma), and radiation exposure . Up to 1The presenting case is 54 years old with negative past medical and family history. The most common presentations of PD include eczematous destruction of the nipple, crusting, scaling, bleeding, and ulceration . The eczThere are many conditions that may mimic PD of the breast such as psoriasis, contact dermatitis, erosive adenomatosis of the nipple, intraductal papilloma, nipple adenoma, basal cell carcinoma, Bowen's disease, malignant melanoma, and Toker cell hyperplasia . It is cMammography should be recommended for all cases with clinical features of PD to detect any underlying malignancy and to follow up cases who undergo conservative treatment . The feaThe duration from the onset of symptoms to treatment ranges from 12 to 14 months .Mastectomy with and without axillary lymph node dissection is the surgical procedure of choice for PD patients because of the high likelihood of association with multifocal or multicentric lesions of the breast parenchyma . Breast The prognosis of PD with associated malignancy depends on the characteristics and the staging of the underlying malignancy . Chen etIn conclusion, the clinical presentation of Paget's disease of the breast is quite straightforward. It should always alert the surgeon of underlying malignancy which will alter the diagnostic and therapeutic approaches. This in turn will affect the overall prognosis.Consent has been taken from the patient and the family of the patient.Not commissioned, externally peer reviewed.There is no conflict to be declared.No source to be stated.Approval is not necessary for case report in our locality.Consent has been taken from the patient and the family of the patient.Abdulwahid M. Salih, Zuhair D. Hammood, Shaban Latif: surgeons diagnosing the case, follow up the patient, and final approval of the manuscript. Fahmi H. Kakamad, Snur Othman, Razhan K. Ali: literature review, writing the manuscript, final approval of the manuscript.Registration is not required for case report.Fahmi Hussein Kakamad is the Guarantor of submission.


Peripheral ossifying fibroma (POF) is a localized reactive enlargement of the gingiva often associated with the papilla and originate from underneath the periodontium. POF occurs predominantly in females, especially in the anterior maxillary region of young adults. The histopathological examination provides a confirmatory diagnosis of such lesions due to their heterogeneous clinical and radiographic characteristics. This case report describes an atypical presentation of POF in the anterior mandible in an adult male patient. Treatment consisted of complete surgical excision and gingival curettage resulting in uneventful healing during the postoperative follow-up period. Gingiva in the oral cavity is constantly subjected to numerous stimuli resulting in numerous localized growths. Reactive gingival growth is the most common lesion in the oral cavity and usually exhibits an indolent behavior . OssifyiA 41-year-old male patient reported to the Department of Oral and Maxillofacial surgery complaining of a swelling on the right side of his lower jaw for the past two years. History revealed that the swelling was initially the size of a pea and grew rapidly to the present size. The patient complained of difficulty in speech and mastication due to the swelling. The patient gave a history of a similar growth in the mandibular anterior region two years ago, which was excised and diagnosed as ossifying fibroma epulis. Medical history revealed that the patient was hypertensive and was consuming medications.Extraoral examination revealed no gross asymmetry, but the patient’s lips were incompetent due to the presence of swelling. Regional lymph nodes were not palpable. Intraoral examination showed a pink, sessile, fibrous, exophytic mass extending from 42 to 45 region obliterating the buccal sulcus Figure . The groCone-beam computed tomography revealed opacification of the soft tissues in the right anterior mandible region, with no displacement, resorption, displacement of the tooth, or any bone loss in the associated region Figure . Based oUnder local anesthesia, a crevicular incision was done for the involved teeth and the flap was elevated along with the lesion. The whole growth was excised through a wedge incision around the lesion Figure , and thoThe excised specimen was sent for histopathological examination Figure . HistoloThe connective tissue of the periodontium of the oral cavity can exhibit distinctive focal overgrowths, corresponding to 90% of gingival biopsies . CommonlPOF has a peak incidence in young and teenage individuals, with a female predilection. Overall, 60% of POFs occur in the maxillary jaw, especially in the incisor-canine region. Our case had an atypical presentation in the anterior mandible in the middle-aged male person. POF manifests clinically as well-demarcated gingival overgrowth, pink to red in color with an ulcerated surface, and the base of the lesions may be sessile or pedunculated. It usually does not blanch upon palpation and frequently originates from an interdental papilla with a size less than 2 cm in its greatest dimension . DiffereRadiographic evaluation of these lesions exhibits radiopaque calcifications in soft tissues and sometimes with the presence of associated bone destruction. In only 5% of the cases, the radiographic appearance of tooth migration is seen . In our Treatment of POF includes complete excision of the lesion with the underlying periosteum and periodontal ligament, as well as the removal of local irritants by thorough curettage to prevent relapse. Extraction of the teeth adjacent to the lesion is rarely required . In untrDiagnosing POF is challenging as it exhibits features similar to other conditions in the oral cavity. Careful clinical and radiographical examination correlated with histopathological findings is required for prompt diagnosis. POF should also be considered in the differential diagnosis of acute and big-sized lesions of the oral cavity. POFs are treated by complete surgical excision and gingival curettage, followed by good oral hygiene maintenance. Patients should be followed up for a longer period of time due to high relapse rates.


Trajectories of Brain Abnormalities in Early Schizophrenia” provide some new insights to address the question of which or how many trajectories of brain changes can be detected in the early phases of the disorder and to which extent they are related to the multidimensional outcome of the disorder.Several brain abnormalities in schizophrenia have been demonstrated by a large number of structural and functional neuroimaging studies. The nature and meaning of such abnormalities, their time of occurrence, whether they are static or progressive as well as the role of potential confounders of brain changes have been investigated by several studies over the last 40 years. The findings of these investigations support the notion that some structural and functional brain anomalies predate the onset of schizophrenia and are detectable to a larger extent in first-episode patients (FEP). Despite the large amount of literature on brain changes in the early stages of schizophrenia, the findings to date do not allow definite conclusions to be drawn about the pathophysiological trajectory of schizophrenia and to resolve the dispute between the so-called “neurodevelopmental” and “neurodegenerative” hypotheses of brain abnormalities of the disorder. The papers included in this Research Topic on “Takahashi et al. analyzed longitudinal gray matter changes in the insular cortex of FES patients during a 3 years Magnetic Resonance Imagine (MRI) follow-up evidencing dynamic volumetric changes at different time points over the early course of illness. Kim et al. investigated throughout diffusion tensor imaging (DTI) the association between white matter integrity and Theory of Mind (ToM) impairment in first-episode patients compared to healthy controls. The study findings suggested a possible neural basis for ToM deficits in schizophrenia. Moreover, In their contribution, González-Vivas et al. analyzed longitudinal changes in brain fMRI BOLD over a 2 years follow-up in first-episode patients and healthy controls. Interestingly, the study also took into account the potential moderating role of antipsychotic medication on brain functional measurements. Cheng et al. investigated the clinical predictors of persistent remission (PR) within the 1st year of antipsychotic treatment in a large sample of first-episode patients (n = 301). Among several psychopathological and neurocognitive variables considered, the results of the study showed that the severity of negative symptoms at baseline was the best predictor of PR within 1 year of antipsychotic treatment.Here we present a brief overview of the contents and highlights of the present Research Topic. A number of original papers investigated clinical and biological predictors of outcome in first-episode schizophrenia (FES). Takayanagi et al. performed a cross-sectional structural MRI study of the planum temporale (PT) comparing 73 individuals with an at-risk mental state (ARMS) and 74 healthy controls using labeled cortical distance mapping. The study did not show significant between groups differences of PT measures, suggesting that structural changes associated with schizophrenia may occur just before or during the onset of the disorder. Collin et al. examined the default mode network (DMN) in children at familial high risk (FHR) for psychosis compared to healthy children. The study evidenced an hyperactivity of posterior DMN in pre-adolescent FHR children as compared to healthy controls. As suggested by the authors, this finding may posit DMN-related disturbances as a developmental brain abnormality associated with familial risk factors that predates psychosis.Two original studies in this issue investigated structural and functional brain parameters in patients at clinically (CHR) or genetically (GHR) high risk for psychosis. Mackintosh et al. investigated the effect of antipsychotic medication on EEG parameters in FEP patients. The results demonstrated significant differences of EEG resting-state microstates between medicated and non-medicated FEP patients. Mazer et al. studied auditory event-related potentials (ERP) in a cross-sectional controlled study. In particular, the paper examined the modulation and habituation of ERPs early components N1 and P2 in 26 FES patients and 27 healthy participants. The study findings evidenced anomalies of sensory gating processes yet in the course of early schizophrenia.Two electrophysiological studies in early schizophrenia also contributed to this special issue. Kraguljac and Lathi critically considered a number of key scientific questions both methodologically and clinically relevant in the context of neuroimaging studies to understand the pathophysiology of schizophrenia. Yang et al. performed a selective review of 36 structural and functional longitudinal MRI studies in FES patients before and after antipsychotic treatment. Kose et al. conducted a qualitative review of the evidence regarding the potential role of peripheral inflammatory markers as predictors of treatment response in schizophrenia and the association between peripheral inflammatory markers with neuroimaging data. Merritt et al. reported a qualitative review to determine longitudinal structural MRI findings in GHR and CHR individuals for psychosis. Lastly, Hinney et al. investigated, through a meta-analytical approach, whether hippocampal volume may serve as a biomarker for psychosis. This quantitative review included those studies that compared hippocampal volume changes over time in patients at risk for psychosis who developed illness as compared to patients who do not have such a transition.Finally, some qualitative and quantitative reviews completed the present Research Topic, with an useful update on biological research in early schizophrenia. In their contribution, In conclusion, the present collection of research papers offers a multidisciplinary perspective of the topic of trajectories of brain abnormalities in early schizophrenia, which may help to understand the pathophysiology of the disorders and contributes to the discussion on the etiopathogenetic hypotheses of the disorder. The main implications provided from the studies collected in the topic can be summarized as follows: (1) there is evidence of dynamic structural and functional brain changes at different time points in the early course of schizophrenia; (2) brain changes in early schizophrenia involves both gray and white matter structures; (3) structural and functional brain anomalies are detectable even before the overt clinical onset of the disease as demonstrated by longitudinal studies in patients clinically or genetically at risk for schizophrenia; (4) antipsychotic medication represents a major confounder of brain changes over time in schizophrenia. This evidence once again questions the clinicians about the risk/benefit balance of antipsychotic treatment also in the early course of the disease.With all these clinical and research implications in mind, we wish that the present Research Topic may receive interest and activate debate among the readers and contributors and solicit new ideas for original research and further hypotheses on this fascinating field of psychiatric research. The future directions of neuroimaging research in schizophrenia indicate the need to set new methodological standards both for developing truly innovative hypothesis-driven neuroimaging research and for reliably interpreting structural and functional multimodal imaging databases with the aim to overcome the current limits and to reach the target of diagnostic and prognostic biomarkers at the individual subject level. Otherwise, the scientific community will have to deal with redundant or weak findings with the potential risk of dissipating even well-grounded notions about the pathophysiology of schizophrenia deriving from almost 50 years of neuroimaging research.AV and LDP wrote the paper. SB revised and completed the Editorial. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The high dimensionality of software metric features has long been noted as a data quality problem that affects the performance of software defect prediction (SDP) models. This drawback makes it necessary to apply feature selection (FS) algorithm(s) in SDP processes. FS approaches can be categorized into three types, namely, filter FS (FFS), wrapper FS (WFS), and hybrid FS (HFS). HFS has been established as superior because it combines the strength of both FFS and WFS methods. However, selecting the most appropriate FFS (filter rank selection problem) for HFS is a challenge because the performance of FFS methods depends on the choice of datasets and classifiers. In addition, the local optima stagnation and high computational costs of WFS due to large search spaces are inherited by the HFS method. Therefore, as a solution, this study proposes a novel rank aggregation-based hybrid multifilter wrapper feature selection (RAHMFWFS) method for the selection of relevant and irredundant features from software defect datasets. The proposed RAHMFWFS is divided into two stepwise stages. The first stage involves a rank aggregation-based multifilter feature selection (RMFFS) method that addresses the filter rank selection problem by aggregating individual rank lists from multiple filter methods, using a novel rank aggregation method to generate a single, robust, and non-disjoint rank list. In the second stage, the aggregated ranked features are further preprocessed by an enhanced wrapper feature selection (EWFS) method based on a dynamic reranking strategy that is used to guide the feature subset selection process of the HFS method. This, in turn, reduces the number of evaluation cycles while amplifying or maintaining its prediction performance. The feasibility of the proposed RAHMFWFS was demonstrated on benchmarked software defect datasets with Naïve Bayes and Decision Tree classifiers, based on accuracy, the area under the curve (AUC), and F-measure values. The experimental results showed the effectiveness of RAHMFWFS in addressing filter rank selection and local optima stagnation problems in HFS, as well as the ability to select optimal features from SDP datasets while maintaining or enhancing the performance of SDP models. To conclude, the proposed RAHMFWFS achieved good performance by improving the prediction performances of SDP models across the selected datasets, compared to existing state-of-the-arts HFS methods. The software development lifecycle (SDLC) is a formal framework that has been specifically planned and built for the production or development of high-quality software systems. To ensure a timely and reliable software system, gradual steps in the SDLC, such as requirement elicitation, software system review, software system design, and software system maintenance, must be closely followed and applied –3. NeverSoftware defect prediction (SDP) is the use of machine learning (ML) methods to determine the defectivity of modules or components in software. SDP, in particular, is the application of ML methods to software features identified by software metrics to detect faults in software modules or components –12. For The application of FS methods results in the creation of a subset of features containing germane and critical features from a collection of trivial and unnecessary features, thus resolving the high dimensionality of the dataset. In other words, FS methods choose the most significant features while retaining dataset performance –29. TherTo develop a novel rank aggregation-based hybrid multifilter wrapper feature selection (RAHMFWFS) method for the selection of relevant and irredundant features from software defect datasets.To empirically evaluate and validate the performance of RAHMFWFS against rank aggregation-based multifilter feature selection (RMFFS) and enhanced wrapper feature selection (EWFS) methods that are constituents of the proposed RAHMFWFS.To empirically evaluate and validate the performance of RAHMFWFS against existing hybrid FS methods.The main contributions of this study are as follows:The remainder of this paper is structured as follows. Reviews on existing related works are presented in High dimensionality is a data quality problem that affects the predictive capabilities of SDP models. In other words, the frequency of redundant and noisy software features as a result of the number and increase in software parameters used to determine the output of a software system has a negative impact on SDP prediction models. Existing research has shown that FS methods can be used to solve the high dimensionality problem. As a result, numerous studies have suggested various FS approaches and investigated their implications on the predictive efficiency of SDP models.Cynthia et al.  evaluateIn their research, Balogun et al.  exploredWahono et al.  improvedMuthukumaran et al.  used 10 K features were chosen based on the average rating of each element in the respective rating list. Their findings revealed that models based on the HFS approach outperformed models based on individual FFS methods . Nonetheless, the distorted rankings of each feature will have an impact on the efficacy of averaging rank lists [K features may not be the right method, since valuable features may be overlooked during the selection process [Jia  has suggnk lists . Further process .In another context, Onan  deployedAs a result, FS approaches are effective at decreasing or eliminating dataset features and amplifying the performance of models in SDP. Even so, choosing a suitable FFS approach remains a challenge. Also, trapping in local maxima and the high computational cost of WFS methods is an open problem for HFS. Hence, this study proposes a novel rank aggregation-based hybrid multifilter wrapper feature selection (RAHMFWFS) method for the selection of relevant and irredundant features from software defect datasets.This section contains information on selected classifiers, baseline FFS methods, the proposed RAHMFWFS method, the experimental procedure, datasets studied, and the performance evaluation measures.Decision Tree (DT) and Naïve Bayes (NB) algorithms were used as prediction models in this analysis due to their high prediction efficiency and their potential for operating on imbalanced datasets , 55. FurIn terms of baseline FFS methods, three FFS methods with varying computational characteristics were chosen for this study. Specifically, chi-square (CS), Relief (REF), and Information Gain (IG) are utilized as baseline FFS methods in this study. CS is a statistic-based FS method that evaluates an attribute's independence from the class label. As an instance-based FS process, REF samples features from a given dataset, compares each sampled feature to its respective neighbourhood, and then assigns a significance score to each feature. IG selects features using an entropy mechanism that is focused on selecting appropriate features by eliminating uncertainties associated with defining the class label when the feature's value is unknown. The broad choice of these FS approaches  is based on the actual research findings , 24. MorFinding a way to hybridize FFS and WFS methods to maintain high performance and a generalizable result is still an open research issue. This is due to the filter rank selection problem and the complex search method used in the FFS and WFS parts of HFS methods, respectively. That is, HFS methods inherit both the best features and some of the problems of FFS and WFS, as depicted in However, the filter rank selection problem and complex search method in HFS methods can be addressed by introducing multifilter and reranking mechanisms into FFS and WFS parts of the HFS method, respectively. Consequently, this study proposes the RAHMFWFS method, which takes filter-filter (multifilter methods) and filter-wrapper (HFS methods) relationships into account to provide optimal feature subsets with high predictive performance. The conceptual framework of the proposed RAHMFWFS is presented in The proposed RAHMFWFS method aims to take into account and incorporate the computational capabilities of multiple independent FFS and enhanced WFS methods. RAHMFWFS addresses high dimensionality issues in SDP tasks by selecting optimal features using multiple FFS methods and reranking strategy-based WFS methods.Specifically, the proposed RAHMFWFS can be divided into two sequential stages: the rank aggregation-based multifilter FS (RMFFS) stage and the enhanced wrapper FS (EWFS) stage.As depicted in minimum (min) and maximum (max) rank aggregation functions select features using the minimum and maximum significance score provided by the generated aggregated rank list, respectively, while the arithmetic mean (mean) rank aggregation function aggregates multiple rank lists into a single aggregated rank list by calculating the arithmetic mean of the significance scores assigned to each element on the individual rank lists. The resulting rank lists generated by the respective rank aggregation functions  are ensembled using the majority voting mechanism to produce a single aggregated rank list. As observed, the rank lists generated from each of the rank aggregators are mutually exclusive subsets of features that are considered relevant and important based on each of the rank aggregator methods.In particular, the In the end, a backtracking function is applied to the aggregated rank list to validate the significance of each feature in the list by assessing the significance score of features on the aggregated rank list with corresponding significance scores of feature in the baseline FFS methods . The backtracking function aims to further refine the features on the generated aggregated rank list in line with the respective significance score of features from the FFS methods. This is a logical procedure to further remove irrelevant or redundant features from the generated aggregated rank list.B ranked features selected by the entropy by log2  N that are passed to the incremental wrapper method. Thereafter, the remaining features in B are reranked using the conditional mutual information maximization (CMIM) algorithm while considering the initially selected features. Using a multiobjective cuckoo search method, CMIM balances and selects features by optimizing their shared knowledge with the class label while minimizing any codependency that might occur between or within features. The incremental wrapper approach is then deployed on the newly ranked set, which has been initialized by the features first selected from B. This procedure is replicated until no changes are detected in the chosen features. Consequently, the EWFS method reduces the number of wrapper evaluations, since only a few features will be considered during each iteration, thus retaining or improving the prediction efficiency of the chosen features.EWFS is the second stage of the proposed RAHMFWMFS method that further refines the HFS process by deploying a reranking mechanism that dynamically and iteratively selects features. That is, the EWFS method incrementally selects features while considering previously selected features in its search space. In the beginning, an entropy measure is used to rank features and then the ranked features are passed through an incremental wrapper method. However, it is only the first In summary, the proposed RAHMFWMFS is developed to take advantage of filter-filter and filter-wrapper relationships, select optimal feature subsets with high predictive performance, and also improve the search strategy in the wrapper to reduce its evaluation cycle and subsequently improve the performance of SDP models. The pseudocode for the proposed RAHMFWFS method is presented in This study's experimentation used defect datasets from four publicly accessible repositories. Twenty-five datasets of differing granularities were chosen from the PROMISE, NASA, AEEEM, and ReLink repositories. Shepperd et al.'s  variant (i)Accuracy is the sum or percentage of data that is correctly calculated out of the total amount of data, as seen in the following equation:(ii)The F-measure is calculated using the harmonic mean of the precision and recall values of the observed data. The formula for calculating the F-measure value is as follows:In terms of efficiency, SDP models based on the proposed method and other methods were evaluated using accuracy, the area under the curve (AUC), and F-measure values. These metrics are widely used in SDP studies to evaluate the efficiency of SDP models , 68.(i)AThe area under curve (AUC) is a measure of the trade-off between true and false positives. It indicates an overall performance evaluation across all classification thresholds.Recall=(TP/TP+FN), Precision=(TP/TP+FP), TP = True Positive (represents accurate prediction), FP = False Positive (represents inaccurate prediction), TN = True Negative (represents accurate misprediction), and FN = False Negative (represents inaccurate misprediction).This section presents and discusses the experimental design of this study, as illustrated in To evaluate the effects of the proposed RAHMFWFS method on SDP model prediction results, software defect datasets as presented in   RQ1: How effective is the proposed RAHMFWFS method compared to existing HFS (IWSS and IWSSr) methods?  RQ2: How effective is the proposed RAHMFWFS method compared to its constituent (RMFFS and EWFS) methods?Results and observations based on the above-mentioned experiments were used to answer the following research questions:R lang. [SDP models based on the experiments mentioned above were trained and evaluated using the 10-fold cross-validation (CV) technique. The CV technique can guard against data heterogeneity problems that can arise in defective datasets. Furthermore, the CV technique is known to generate models with low bias and variance –75. ExpeR lang. , and OriThis section presents and discusses the performance of the proposed rank aggregation-based hybrid multifilter wrapper feature selection method (RAHMFWFS). Also, the performance of the proposed RAHMFWFS is compared with those of existing hybrid FS methods and the duo of RMFFS and EWFS.Based on the preceding observations, the positive prediction performance of NB and DT models based on the RAHMFWFS method demonstrates its capability to address the filter rank selection problem, local optima stagnation, and subsequent high dimensionality problems by exploiting the filter-filter relationship by aggregating rank lists from multiple FFS methods into a single robust rank list and reducing the wrapper evaluation cycle of its wrapper component while maintaining or enhancing the prediction performance of SDP models.The performance comparison of RAHMFWFS against existing IWSS and IWSSr methods is presented and discussed in the next subsection.In this subsection, the performance of the proposed RAHMFWFS is compared with those of state-of-the-art HFS. In particular, the prediction performances of NB and DT models based on the proposed RAHMFWFS are compared and contrasted with hybrid Incremental Wrapper-based Subset Selection (IWSS) as proposed by  and hybrAdditionally, Furthermore, Also, Furthermore, similar findings are observed in the case of average F-measure value as presented in In this subsection, the performance of the proposed RAHMFWFS is compared against those of its constituent methods, RMFFS and EWFS, respectively. This comparative analysis of performance is conducted to further ascertain and establish the effectiveness and efficacy of the proposed RAHMFWFS method for the feature selection task in SDP processes.The box-plot representation of average accuracy values of NB and DT models with RAHMFWFS against RMFFS and EWFS methods is presented in Additionally, Concerning F-measure values, Based on the experimental results, RAHMFWFS, which is a hybrid of RMFFS and EWFS methods, was superior to the individual RMFFS and EWFS methods. This observation can be explained by the further enhancement of the performance of RMFFS by the EWFS as designed in the proposed RAHMFWFS.Further statistical analyses using Scott-KnottESD were conducted to ascertain the statistical significance in the performance of RAHMFWFS over RMFFS and EWFS methods based on average accuracy, average AUC, and average F-measure values. These are presented in Figures 14Furthermore, As presented in In summary, the proposed RAHMFWFS focuses on selecting optimal features for the SDP process while maintaining or enhancing the prediction performance of SDP models. The experimental results have demonstrated the superiority of the proposed RAHMFWFS, as it outperformed the existing HFS methods based on empirical and statistical test results. Also, RAHMFWFS significantly outperformed RMFFS and EWFS in most of the experiments. This can be attributed to the fact that RAHMFWFS is a hybrid of the RMFFS and EWFS methods. Therefore, these results showed that RAHMFWFS can be effectively and practically used for the high dimensionality problem in SDP processes.How effective is the proposed RAHMFWFS method compared to existing hybrid FS (IWSS and IWSSr) methods?  RQ1:   The proposed RAHMFWFS method indeed produced a significant improvement as compared with existing hybrid FS methods such as IWSS  and IWSSHow effective is the proposed RAHMFWFS method compared to its constituent (RMFFS and EWFS) methods?  RQ2: To provide answers to the research questions (RQs) raised in this study see , the folSimilarly, the proposed RAHMFWFS method outperformed the RMFFS and EWFS methods.The RAHMFWFS method recorded a superior and significant positive effect on the prediction performances of the NB and DT classifier as compared to RMFFS and EWFS methods. That is, RAHMFWFS not only selects optimal features better than RMFFS and EWFS but also handles filter rank selection and local optima stagnation problems.Finding a way to hybridize FFS and WFS methods to maintain high performance and a generalizable result is still an open research issue. Based on this premise, this study has proposed a novel rank aggregation-based hybrid multifilter wrapper feature selection (RAHMFWFS) method for the selection of relevant and irredundant features from software defect datasets. The proposed RAHMFWFS method was developed to take advantage of filter-filter and filter-wrapper relationships to provide optimal feature subsets with high predictive performance and also to improve the search strategy in the wrapper to reduce its evaluation cycle and subsequently improve the performance of SDP models. The experimental findings demonstrated the efficacy of the RAHMFWFS technique, which had a greater positive impact on the prediction performances of NB and DT models compared to existing HFS methods in the majority of cases. That is, the proposed RAHMFWFS method was able to address filter rank selection and local stagnation problems in HFS methods by deploying and integrating a rank aggregation-based multifilter method and a dynamic reranking strategy solution for both problems, respectively. Also, the RAHMFWFS method recorded the ability to select optimal features from SDP datasets while maintaining or enhancing the performance of SDP models.As a continuation of this study, in-depth analysis and investigation on the number of FFS methods in developing multifilter FS methods will be conducted. The relationship between diversity and the number of FFS methods to be considered for the multifilter FS method is also worth exploring. Finally, the possibility of using informed approaches that can resolve ambiguities that may result from combining rank lists ought to be considered. Perhaps, novel approaches that address redundancy introduced during aggregation of individual rank lists can also be developed.


Functional genomics applied in clinical disease diagnosis and prognosis allow the achievement of the progress in all aspects of biology in health and disease. This Special Issue of IJMS on the topic of “Functional Genomics in Health and Disease” has practical importance, trying to encompass the full biology of the coding and non-coding genes.In this Issue, Maestri presents a Long-Read Sequencing Approach for Direct Haplotype Phasing in Clinical Settings. This has great translational significance, as analysis can be performed for multiple samples. These predictive biomarkers can be used for patient selection for treatment groups in clinical settings .Vyse and colleagues cover the important topic of Trans-Ancestral Fine-Mapping and Epigenetic Annotation used as tool to Delineate Functionally Relevant Risk Alleles in Systemic Lupus Erythematosus .Dudea-Simon and colleagues report the involvement of certain coding genes in cervical cancer, using an integrative analysis, and the diagnostic and prognostic potential of key core genes for this disease .Biswas and colleagues review the role of a highly expressed miRNA pattern, and discuss the data related to its potential interaction of miRNAs with key signaling pathways in infected monocyte-derived macrophages and peripheral mononuclear blood, allowing the identification of unique biomarkers that can differentiate HIV-1 and HIV-2 infection based on an altered miRNA pattern .Zayed present a novel bioinformatics method for the assessment of the molecular genetic susceptibility pattern in asthma. This paper led to the identification of novel genetic risk factors responsible for the development of moderate-to-severe asthma, serving as a platform for better treating asthma .Potashkin et al. present bioinformatics analysis, which was focused on the key genes and molecular pathways that may trigger dementia. This study identified phosphodiesterase 4D-Interacting Protein as key factor for the frontal cortex dementia switch gene .Chitoiu and colleagues discuss the roles of extracellular vesicle biology, a particularly important topic in light of the recent success of the multi-omics data .The review by Jurj et al. gives an overview of the genome wide association studies, mainly in triple negative breast cancer, providing significant and new knowledge for both research and clinical studies .Thus, the aim of this Special Issue is to answer to many of our readers’ questions regarding this topic, and we also hope that will open new avenues of research, providing important discoveries in this ongoing revolution.