Postpartum depression (PPD) is a serious condition with debilitating consequences for the mother, offspring, and the whole family. The scope of negative outcomes of PPD highlights the need to specify effective diagnostics and treatment which might differ from major depressive disorder (MDD). In order to improve our clinical care, we need to better understand the underlying neuropathological mechanisms of PPD. Therefore, we conducted a systematic review of published neuroimaging studies assessing functional, structural, and metabolic correlates of PPD.Relevant papers were identified using a search code for English-written studies in the PubMed, Scopus, and Web of Science databases published by March 2022. Included were studies with structural magnetic resonance imaging, functional magnetic resonance imaging, both resting-state and task-related, magnetic resonance spectroscopy, or positron emission tomography. The findings were analyzed to assess signatures in PPD-diagnosed women compared to healthy controls. The review protocol was registered in PROSPERO (CRD42022313794).The total of 3,368 references were initially identified. After the removal of duplicates and non-applicable papers, the search yielded 74 full-text studies assessed for eligibility. Of them, 26 met the inclusion criteria and their findings were analyzed and synthesized. The results showed consistent functional, structural, and metabolic changes in the default mode network and the salient network in women with PPD. During emotion-related tasks, PPD was associated with changes in the corticolimbic system activity, especially the amygdala.This review offers a comprehensive summary of neuroimaging signatures in PPD-diagnosed women. It indicates the brain regions and networks which show functional, structural, and metabolic changes. Our findings offer better understanding of the nature of PPD, which clearly copies some features of MDD, while differs in others. Due to the physiological changes, disturbances in a sleep/wake cycle, and the number of accumulated psychosocial stressful events, perinatal and postnatal periods are challenging phases for women’s mental health. As a result, postpartum depression (PPD) may develop or exacerbate in vulnerable women with the estimated prevalence of 17%, which is higher than in any other period of women’s life . However, there are only few imaging studies focusing specifically on PPD. So far, most of them focused either on neural response to affective stimuli or on brain metabolism changes in PPD. Duan et al.  in theirThe perinatal period alone is associated with substantial changes in the brain connectivity and structural integrity in healthy mothers, as their brains undergo the process of adaptation to the maternal caregiving , 13. ConSince 2017, when the review by Duan et al.  was publTo examine the neural features of PPD would allow us (1) to detect functional, structural, and metabolic changes in mothers with PPD in comparison to healthy mothers, (2) to outline and discuss the functional, structural, and metabolic differences between PPD and MDD. The secondary objective was to discuss the results within the context of the brain functional networks: the default mode network (DMN), the salience network (SN), the cognitive control network (CNN), and the corticolimbic system as the most investigated circuits in the MDD research .1.The study protocol was registered in PROSPERO (CRD42022313794) under the title: ‘‘Structural, functional, and metabolic signatures of postpartum depression.’’ Screening of citations, full text review, assessment of risk bias and extraction of studies characteristics and outcomes in this systematic review were performed in the Covidence software platformWe searched systematically the PubMed, Scopus, and Web of Science databases for English written articles published by the end of March 2022, without bottom time limitation. The search code was identical to the one used originally by Duan et al. , so the For data synthesis, the studies were grouped according to the imaging techniques used . For functional magnetic resonance imaging (fMRI), studies were then assigned to either resting-state (rs) or task-related group. Based on the character of the task, participants in the task-related group were further classified into the emotional-task paradigm group or reward-task paradigm group. No additional type of tasks in the PPD imaging studies has been identified in our search.The inclusion criteria were: cohort or cross-sectional PPD studies using structural magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), or positron emission tomography (PET) to assess signatures of PPD; PPD in participants was determined by a structured clinical interview or other standardized diagnostic methods; study population consisted of a group of women diagnosed with PPD up to 12 months after the childbirth and the control group consisted of women without PPD up to 12 months after the childbirth.The exclusion criteria were: meta-analyses, systematic or non-systematic reviews; the use of non-validated method to diagnose PPD; time of testing exceeded 12 months after the childbirth; the study group included bipolar patients or any other psychiatric comorbidity except for anxiety disorders; the study did not have a control group.Other potential confounding factors were taken into consideration without being a reason for the exclusion: medication status; comorbid anxiety disorder; first-onset or previous history of depression; socioeconomic status; education level; and number of previous pregnancies. If relevant, their potential confounding impact was discussed in the results.For the assessment of risk of bias, we used quality assessment checklist adapted for neuroimaging studies evaluation, specifically designed for the purpose of the current review. Two authors (AH and HN) independently assessed the quality of studies and agreement between them was required in order to rate the final score. The studies were assessed with 14 items see  with theAfter the automatic duplicate elimination in the Covidence software, two authors (AH and HN) independently screened the titles and abstracts of all references identified by the search strategy, potential conflicts were resolved by a third author (AS). Subsequently, the full text review screening has been performed independently by two authors (AH and HN) and potential conflicts were resolved by a third author (AS). Data extraction  was then performed and the quality assessment was completed for each study independently by two authors (AH and HN). A consensus between the two authors was required for the final inclusion of a study in the systematic review sample.Since the characteristics varied highly across the studies, we could not perform originally planned meta-analysis to compare data statistically. Thus, for a systematic comparison of the functional, structural, and metabolic correlates of women with PPD and without PPD, a narrative analysis with the main outcome of changes in the brain regions, networks, and metabolic signatures of PPD was used.Of the 3,368 references retrieved from all the bibliographic databases, we identified 26 eligible studies that met the inclusion criteria. A PRISMA flowchart see  summarizThe included studies were of medium to high quality with the lowest score of 6 and the highest score of 12.5. They lacked mostly prospective study design and often did not show coordinates for localization of brain regions in the standard space. On the other hand, the studies generally used standardized methods for PPD diagnosis, they were controlled for the medication status and comorbidities. The studies tended to describe clearly the imaging techniques protocol to be potentially reproducible, provided statistical parameters for observed differences, offered conclusions consistent with results, and discussed their limitations. For full quality data assessment of each study, see the Functional connectivity research provides us new insights how the local and large-scale neural communication and information integration relate to human mental states and behavior via measuring cerebral blood-oxygenation-level (BOLD) dependent changes of neural activity in response to various activities or rest over a time resolution of seconds . RecentlIn the resting-state paradigm (rs), participants were asked to stay calm and not to think about anything. We have identified 10 studies with the total sample of 361 PPD-diagnosed women and 429 controls that examined fMRI changes in PPD during the resting state. Seven of the studies indicated alterations of the default mode network (DMN) which was mostly hyperactivated in women with PPD. Specifically, there were changes in connectivity and activity in the medial prefrontal cortex (mPFC) –21, the Wang et al.  were theChase et al.  focused Deligiannidis et al.  also exaThe role of the DMN in the pathophysiology of PPD was further corroborated by Che et al. , who demMao et al.  reportedZhang et al.  investigIn contrast to the previous findings, Schnakenberg et al.  found noIn a longitudinal perinatal project from Chengdu, China, that aimed to investigate the pathogenetic factors, prognosis, and effective interventions in women with PPD, the fronto-striatal neural circuit with the reward system central hub of the ventral striatum was found to be disrupted in women with PPD . The resThe same group of Cheng et al.  performeThe authors Cheng et al.  followedEmotional task related fMRI research has attracted greater attention than any other type of imaging research in the beginning of the neuroimaging research in PPD. Imaging research of emotion-related tasks mostly focuses on changes in the amygdala activity and connectivity. We identified 5 studies investigating the amygdala , with the total sample of 92 PPD-diagnosed women and 77 controls. The amygdala activity in response to negative emotional stimuli in PPD has been characterized as blunted , 31 withSilverman et al.  were theMoses-Kolko et al.  reportedWonch et al.  found inHo and Swain  examinedAn enhanced amygdala response to the unfamiliar infant smiling picture in PPD women in contrast to both non-depressed postpartum women and non-postpartum depressed women was also reported in the study by Dudin et al. . The resThere is a lack of studies focusing on the reward-task functional correlates in women with PPD. We identified only one study with such a design  where 12The motivational function of a response to infant’s needs, which is represented by a reward-driven neural mechanism, appears to be a core tool in the establishment of the mother-infant dyad and it is presumably impaired in PPD , 31. A hStructural MRI allows us to examine the gray matter (GM) with a measure of specific brain regions called regions of interest (ROI) or with a hypothesis-free approach of voxel-based morphometry (VBM) or surface-based measure, or the white matter (WM) morphometry with the determination of the location, orientation, and anisotropy of the WM tracts . We idenThe results of structural MRI studies of PPD are inconsistent. One structural study detected the changes of the white matter structure in various brain regions  , while oIt was not until 2020, when Sasaki et al.  used forLi et al.  investigCheng et al.  reportedIn contrast to the studies that found structural correlates of PPD, Schnakenberg et al.  failed tProton magnetic resonance spectroscopy (1H-MRS) and positron emission tomography (PET) provide biochemical evaluation of specific brain regions, enabling assessment of the viability, neurotransmission, energy metabolism, damage processes and cellular renewal of the underlying neuronal tissue. Hence, these imaging techniques are great tools to examine metabolic changes in PPD and psychiatric disorders in general , 43. We Some cortical regions  showed reduced serotonin-1A (5HT1A) receptor binding potential , while oEpperson et al.  examinedSerotonin system and its role in the pathophysiology of MDD and mood regulation has been intensively studied; thus, serotonin pathology is also of interest in PPD research. Moses-Kolko et al.  measuredMcEwen et al.  reportedMoses-Kolko et al.  assumed Rosa et al.  additionSteele et al.  targetedDeligiannidis et al.  did not In our review, we identified 3 brain regions that showed consistent differences in women with PPD from healthy controls, based on fMRI results. The most significant differences in fMRI studies were detected in the mPFC, a DMN hub , and the ACC, a SN hub (3 of 10 included studies showed significant difference during the state of rest); 2 studies additionally showed difference in metabolic function of these brain regions in the PPD group. Furthermore, the amygdala showed difference in all 5 identified studies that employed emotional task design. The structural and metabolite findings were not overly consistent in our review; it can be attributed to the fact that authors preferentially analyzed different regions of interest. In the current systematic review, we have collected studies covering the topic of neural signatures  in postpartum depression (PPD) with a perinatal onset up to 12 months after the delivery and summarized their principal findings. Throughout the years, major depressive disorder (MDD) has been characterized as a complex disorder with underlying changes preferentially detectable in the default mode network (DMN), the salience network (SN), and the cognitive control network (CCN) . TherefoThe DMN is a fMRI-measurable network of a highly interconnected set of brain hubs, mainly active during the rest and mostly suppressed during the tasks which demand focus of attention toward external stimuli .Various studies have concurred that the hyperactivity of the DMN represents the most common functional network feature of MDD –56. ThisThe dorsomedial prefrontal cortex (dmPFC) dysfunction has been previously associated with MDD , 59. In The Salience network (SN) refers to a network with cortical central hubs of the ACC and the ventral anterior insular cortex and additional nodes in the amygdala, hypothalamus, ventral striatum, thalamus, and specific brainstem nuclei. The SN plays a key role in integrating and transferring information between different functional modules. Additionally, the SN selects to which stimuli is our attention assigned and consequently coordinates the behavioral response to these “salient” stimuli .Cortical structures such as the ACC work as a regulator of the limbic structures and as so they co-determine the emotional stimuli processing. Some depressive characteristics  might be explained by a breakdown in this cortico-limbic circuit . The speThe insula is a key component of affective, memory and saliency processing. In our review, we found the disruption in the insula activity and structure to be a common correlate of PPD, which corresponds to the MDD studies –76. The The Cognitive control network (CCN) is a brain network comprising of the dorsolateral prefrontal cortex (dlPFC), the dorsal anterior cingulate cortex (dACC) and the parietal cortex. The CCN is preferentially active during tasks as it employs executive functions, such as attention, flexibility, planning, or working memory, to guide an appropriate behavior in order to achieve a specific goal .Disruption of the ability to control the executive inhibition and the elevated anxiety anticipation is mostly attributed to the left dlPFC hypoactivity in MDD patients , 79, whiEmotional dysregulation is considered to be one of the core features of depression. Understanding of the underlying neural basis of the impairment of emotional processing in depression could help us to uncover some of the leading causes/consequences of this debilitating disorder. Bottom-up emotional regulation is mostly influenced by the amygdala, the insula, the ventral striatum, the anterior cingulate gyrus (ACG), the ventromedial prefrontal cortex (vmPFC), and the OFC. These anatomical structures are thought to play a pivotal role in recognizing emotionally salient stimuli and they subsequently cooperate to generate the overall emotional state. Top-down emotional regulation allows to voluntary control emotions, preferentially through the activity of the hippocampus, the ACC, and the PFC. These two systems operate parallel and simultaneously .The amygdala as an important subcortical structure in generating emotions is of major interest in MDD research. Published studies suggested that in patients with MDD the amygdala is hyperactivated in response to negative stimuli, and the activation is extended and persists even after the negative stimuli is no longer present –87. The Therefore, these results might be considered as a specific neural correlate distinguishing PPD from general non-peripartum MDD. However, additional studies with a design incorporating various emotional stimuli are needed, since not all the PPD studies provided consistent results see ref. . The amyThe ventral striatum, which is predominantly involved in positive information processing, is less sensitive in depressed patients . SimilarThe ventrolateral prefrontal cortex (vlPFC) works as a value assigner and the negative attention bias is thought to stem from reduced activity in this brain region . The vlPThe OFC serves as an emotional inhibitory regulator and influences emotional decision making , 95. TheTemporal lobe disruption  has been previously reported in MDD patients , 99. SimDue to the fact that the majority of the included studies (17/26) were not covered by the previous comprehensive review of the PPD neural correlates Duan et al. , our curIt is also important to mention that in our review sample, we included studies with a more conservative approach in PPD diagnostics. Specifically, for women to be included in the PPD group they had to undergone a formal diagnostics interview. A self-reference or scoring above the threshold in the EPDS or other screening scales alone was not sufficient for the assignment to the PPD-diagnosed group, in contrast to the review by Duan et al. . BecauseEven though we used very conservative approach regarding the inclusion and exclusion criteria, the reviewed studies are still too heterogeneous in terms of their characteristics to draw unequivocal conclusions. First, the imaging parameters, such as scanner strength, slice thickness, or imaging sequences, varied across the studies. Second, there was a great variability in the study designs. For instance, the severity of PPD differed among the studies, included were women with mild, moderate, or severe depression. The duration of disorder also varied, some studies included first-episode depression patients only, while others did not distinguish between chronic and acute disorder state.There was also a great variability in methods used to determine the diagnosis of PPD. For consistency, we excluded studies in which the diagnosis was based on non-validated diagnostic methods. Studies included in the review mostly used structured clinical interview, others relied on standardized rating scales, such as the Hamilton Depression Rating Scale (HAM-D), the Edinburg Postnatal Depression Scale (EPDS) or the Beck’s Depression Inventory (BDI), some studies applied both approaches. Since there is still not a generally accepted agreement on the time of onset of depression to be considered PPD, the reported onset ranged from the antenatal period through the first 4 weeks after the delivery up to one year after the childbirth. This fact affects the results and impedes their generalizability. To specify this methodological discrepancy in our review, Schnakenberg et al.  obtainedAnother important factor is the medication status as the antidepressant treatment influences functional changes and structural integrity and may thus affect the results . Among tIt is noteworthy that several studies, namely by Cheng et al. , 24, 25,Another limitation of numerous included studies, especially those with MRI, was a small study sample. For example, Silver et al.  obtainedBased on the methodology discrepancies of the PPD studies identified via our search, we propose several recommendations for future research. Investigators should strive to recruit larger, more homogenous samples which will eventually help to eliminate the impact of the clinical confounding factors. First, the clinical group should be defined according to the current versions of diagnostic manuals. All comorbidities, except for the anxiety disorders, should be excluded since they can significantly interfere with the results. Moreover, medication status, the type, and the dose of psychotropic agents, needs to be accounted for.Whole brain analysis with a free estimation of the depression-related regions always offers less biased results and increased consistency which, in contrast to the region-focused analysis, allows to compare the results directly. Therefore, we suggest applying preferentially this type of analysis. Since the design of our review does not make possible to evaluate the differences between MDD and PPD directly, we suggest employing the between subject design with separate PPD and MDD groups. Such study design could help us to detect better the small, but important nuances between PPD, MDD, and other psychiatric disorders. Even though the number and variety of discrepancies of the findings do not allow us to use the imaging techniques directly in the clinical practice yet, they are important for our better understanding of the nature of PPD. Greater utilization of these techniques in research can, with the help of computer engineering, become in the future a useful clinical tool for PPD diagnostics and prediction of treatment outcome.Women with postpartum depression exhibit functional and structural abnormalities preferentially in the default mode network. Furthermore, postpartum depression is associated with structural and functional changes in the salient network. These findings correspond fully to the neuroimaging correlates of major depressive disorder. Additionally, women with postpartum depression manifest attenuated amygdala activity in response to the negative emotional stimuli and increased activity in response to the positive stimuli, which is in opposite direction from the findings in major depressive disorder.The original contributions presented in this study are included in the article/AH participated on the methodology of the review, search of included studies, and drafting the manuscript of the review. HN participated on the search review process. PM reviewed the draft manuscript and approved the final version of manuscript. AS contributed to the methodology of review, reviewed the draft manuscript, and approved the final manuscript. All authors contributed to the article and approved the submitted version.


Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders generally characterized by repetitive behaviors and difficulties in communication and social behavior. Despite its heterogeneous nature, several metabolic dysregulations are prevalent in individuals with ASD. This work aims to understand ASD brain metabolism by constructing an ASD-specific prefrontal cortex genome-scale metabolic model (GEM) using transcriptomics data to decipher novel neuroinflammatory biomarkers. The healthy and ASD-specific models are compared via uniform sampling to identify ASD-exclusive metabolic features. Noticeably, the results of our simulations and those found in the literature are comparable, supporting the accuracy of our reconstructed ASD model. We identified that several oxidative stress, mitochondrial dysfunction, and inflammatory markers are elevated in ASD. While oxidative phosphorylation fluxes were similar for healthy and ASD-specific models, and the fluxes through the pathway were nearly undisturbed, the tricarboxylic acid (TCA) fluxes indicated disruptions in the pathway. Similarly, the secretions of mitochondrial dysfunction markers such as pyruvate are found to be higher, as well as the activities of oxidative stress marker enzymes like alanine and aspartate aminotransferases (ALT and AST) and glutathione-disulfide reductase (GSR). We also detected abnormalities in the sphingolipid metabolism, which has been implicated in many inflammatory and immune processes, but its relationship with ASD has not been thoroughly explored in the existing literature. We suggest that important sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), ceramide, and glucosylceramide, may be promising biomarkers for the diagnosis of ASD and provide an opportunity for the adoption of early intervention for young children. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that shows up in early childhood and is a lifelong condition. Although the heterogeneous nature of this disorder creates difficulties when diagnosing people, most ASD patients lack verbal and nonverbal communication skills, insist on the same routine, and show restricted and repetitive behaviors . The preA number of studies emphasized that various brain parts, such as the frontal lobes, amygdala, and cerebellum, may show structural and functional differences in ASD and can take part in the pathology of the disorder . For insSeveral central nervous system-based cellular and metabolic dysregulations, such as inflammation, oxidative stress, and mitochondrial dysfunction have been implicated in various neurodegenerative, neuropsychiatric, and neurodevelopmental diseases such as Alzheimer’s disease, schizophrenia, bipolar disease, depression, and ASD . SpecifiAlthough genome-scale metabolic models (GEM) are comparatively new, they are very useful systems biology tools that can provide a holistic model for the whole metabolism and can also be used to decipher the relationship between genotype and phenotype and predict the effects of environmental changes on the metabolism. GEMs have been used for many applications, such as cell factory design for the production of chemicals and prediction of microbial community interactions . AdditioDespite the fact that ASD is a prevalent disorder, the underlying mechanisms behind its pathogenesis are still unknown. The current work aims to investigate to which extent several cellular processes, including neuroinflammation and oxidation stress, in the prefrontal cortex of ASD children are perturbed at the genome-scale. Thus, ASD-specific and neurotypical prefrontal cortex genome-scale metabolic models have been constructed using transcriptomics data to better understand the ASD brain metabolism and consequently to decipher novel biomarkers for ASD. To uncover the ASD-specific metabolic traits, the healthy and ASD-specific models were compared, and the increased neuroinflammatory and oxidative stress-related markers in the ASD model identified. Understanding the metabolic reprogramming in autistic brains not only sheds light on the molecular mechanisms that lead to ASD, but it may also help to direct early intervention strategies.The postmortem prefrontal cortex transcriptome data for autistic people and neurotypical controls aged between 2 and 56 were acquired from the Gene Expression Omnibus database with the ID GSE28475 ,21. The A flowchart of the methodology used in this work can be seen in The RAVEN toolbox  was used2/CMRglu for the young ASD patients and controls [max value between astrocytes and neurons. For the exchange reactions of other essential nutrients, such as amino acids, the cerebrospinal fluid (CSF) concentrations were converted to flux units using CSF flow rates, and these were assumed to be equal to the maximum uptake rates for the corresponding reactions [For the ASD and control models, separate reaction bounds were set if the information was available. The glucose uptake rate was set to the cerebral metabolic rate (CMR) of glucose in the frontal cortexes of the ASD and neurotypical children . The maxcontrols , and thecontrols . The enecontrols . The maxcontrols , glutamicontrols , and glucontrols  reactioneactions .Most steady-state analysis methods, such as flux balance analysis (FBA), require a predefined objective function for the optimization of the problem. For organisms like bacteria, the selection of the objective function is mostly straightforward; they aim to maximize their growth and proliferate. However, for human cells, especially for brain cortex cells, maximization of the growth function is not applicable. Thus, we maximized the reaction rates for the glutaminase, glutamine synthetase, and glutamate carboxylase reactions to provide the replenishment of the glutamine in the neurotransmitter pool through the glutamine–glutamate–GABA cycle. Uniform sampling was used in order to obtain the distribution of attainable flux values rather than one of the optima obtained by the FBA. The lower and upper bounds of the reactions were set to the minimum and maximum flux values obtained through flux variability analysis (FVA) with a loopless solution option by maximizing the glutamine–glutamate–GABA cycle, if possible. A total of 10,000 samples were collected using the artificial centering hit-and-run (ACHR) algorithm within the COBRA Toolbox.All statistical analyses and data visualizations were performed in R software version 3.6.3. Due to the large dataset, effect size estimations were reported instead of the significance of the difference between group means/medians. The effect sizes between samples were determined using Cliff’s d using the effsize R package . The CliThe selection of the flux constraints for model reactions is a significant step in genome-scale modeling. The phenotype of an organism or cell is determined by its environment and thermodynamic limitations, as well as by its genotype. Thus, appropriate constraints should be set for the simulations to obtain a realistic set of solutions. Since the metabolisms of children and adults are dissimilar, the search for the constraints was concentrated on experimental data for children aged 2–14, but if the information was not available, the values obtained from the adult ASD and control cases were used.The extracellular fluid of the brain and spinal cord consists of blood plasma, cerebrospinal fluid (CSF), and interstitial fluid (ISF). The brain tissue is surrounded by ISF, while the CSF fills the brain ventricles and subarachnoid space. The compositions of ISF and CSF are very similar, although they are significantly different from the composition of blood since the blood–brain barrier is a highly selective barrier that allows the passage of small non-polar molecules and lipophilic molecules and blocks the passage of molecules such as neurotransmitters out of the brain . The comThe glucose utilization rates were also determined to be not significantly different between ASD and control children aged between 2 and 18 . The metThe human prefrontal cortex mostly consists of astrocytes, glutamatergic excitatory pyramidal neurons, and GABAergic inhibitory interneurons. A simplified illustration of the exchanges between the astrocytes and neurons can be seen in Mitochondria is the main ATP generation unit of the cells through oxidative phosphorylation and is also responsible for the regulation of reactive oxygen species (ROS). Although only 5% of ASD children are diagnosed with mitochondrial disease, up to 80% of ASD children show signs of mitochondrial dysfunction . MitochoThe brain only constitutes 2% of a human’s body weight, yet it accounts for nearly 20% of the body’s required daily energy. Glucose is the primary energy source for brain cells, and glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation are the mechanisms for producing ATP by breaking glucose. Theoretically, a maximum of 36 ATPs can be produced per consumed glucose molecule, two produced by glycolysis, two by the TCA cycle, and 32 by oxidative phosphorylation. Several studies detected that the genes that play a role in oxidative phosphorylation are downregulated in the brains of autistic patients ,44.2+) in the mitochondrial matrix [2+ may create disruptions in the mitochondrial metabolism. Indeed, genetic variants of voltage-gated calcium channels (VGCCs), transmembrane proteins mediating the Ca2+ flux to neurons, were detected in ASD and speculated to be a part of the pathophysiology of ASD [2 secreted for every glucose molecule uptook. Theoretically, 6 CO2 molecules are formed per glucose molecule by complete aerobic respiration, while none are formed after glycolysis. As seen in 2 secretion per glucose uptake for the ASD-specific model is found to be lower compared to the control model with a large effect size, which is an indicator of incomplete aerobic respiration.In our genome-scale metabolic brain model, the attainable flux distributions for the aerobic respiration-related pathways showed that the glycolysis pathway is more active in the ASD model . In paral matrix , and they of ASD . Alteraty of ASD ,49,50. TThe disturbance of the TCA cycle reduces the aerobic respiration rate, and this phenomenon generally results in elevated levels of pyruvate, as well as its derivatives, lactate and alanine . In our The mitochondrial electron transport chain (ETC) is located in the inner membrane of the mitochondria and produces ATP by generating a proton gradient between the mitochondrial matrix to the inner membrane space. ETC consists of 5 complexes: complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome bc1 complex), complex IV (cytochrome c oxidase), and complex V (ATP synthase) . We comp2O2) to GSSG and water. Our results reveal that the total rate of GPx-catalyzed reactions in the cytosol and mitochondria have similar flux ranges in both models, indicating that both the ASD and control models scavenge similar amounts of H2O2  and catalase (CAT) are two other significant antioxidant enzymes. SOD catalyzes the dismutation of superoxide anion  and choline-containing compounds are two indicators of neuroinflammation in the brain and are generally detected via proton magnetic resonance spectroscopy analyses. Activation of glial cells is thought to be correlated with higher inositol and choline-containing compound levels . The actPhospholipases, enzymes hydrolyzing phospholipids to fatty acids, are at the center of the fatty acid mechanism. Specifically, phospholipase A2 (PLA2) breaks the phospholipids into arachidonic acid and polyunsaturated free fatty acids (PUFA), which are further hydrolyzed to eicosanoids such as prostaglandins and leukotrienes. We found that the reaction catalyzed by the PLA2 enzyme has significantly higher fluxes in the control model . A smallProstaglandins and leukotrienes are two important classes of eicosanoids present in inflammatory conditions. Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins in the human body and is a mediator for many biological functions, including inflammation . PGE2 maCompared to other tissues, the nervous system, especially the brain, has the highest lipid content and complexity. Sphingolipids, being one of the major classes of lipids that are essential for eukaryotic cells, are highly enriched in the brain. They have several structural roles in the plasma membranes and are also signaling molecules regulating cellular events such as cell growth, differentiation, senescence, and apoptosis ,89. SphiCeramides participate in important signaling processes, such as inflammation, and can be generated by pro-inflammatory cytokines . CeramidOn a special note, our simulations indicated altered sphingolipid metabolism between the ASD and neurotypical control models and this metabolism needs further research to shed light on the effect of sphingolipids on the pathogenesis of ASD. The research on the relationship between sphingolipid metabolism and ASD has been limited. In fact, the majority of studies on ASD omics have focused on transcriptomics or metabolomics, and it is only recently that lipidomics analyses have been conducted, although lipids constitute 36–66% of the dry weight of the human brain depending on grey or white matter, and nearly one-third of the total lipids are sphingolipids . The incOur simulations on reconstructed ASD-specific and neurotypical control GEMs demonstrated that several pathways, which have already been shown to be disturbed in ASD, generally yield complementary results with literature findings. The energy metabolism is altered in ASD, as indicated by the distinct patterns in glycolysis and the TCA cycle. One of the most prevalent comorbidities of ASD, mitochondrial dysfunction, is also supported by the disparities in the activities of ETC complexes and the increase in the mitochondrial dysfunction biomarkers. In addition, the reactions catalyzed by the oxidative stress marker enzymes, as well as the ones catalyzed by oxidative-stress protective enzymes, showed higher fluxes in ASD, indicating the presence of oxidative stress in ASD. Pro-inflammatory markers are found to have higher fluxes in ASD, whereas contradictory results are found for anti-inflammatory metabolites. Sphingolipid metabolites, especially S1P and ceramide, are promising biomarkers for ASD and should be thoroughly investigated by in vitro experiments.Omics data, such as transcriptomics, proteomics, and metabolomics, enhance the predictive power of systems biology tools such as genome-scale modeling. However, the lack of adequate knowledge about ASD was the most significant challenge encountered throughout this modeling study. Despite the limited number of omics studies conducted on the brains of ASD patients, all of them are post-mortem studies due to inaccessibility to the area, which may have distinctive features compared to ante-mortem analyses. Additionally, the number of studies reporting the enzyme activities in the brain, specifically the prefrontal cortex, is quite low, and in most cases, they conflict with each other. Thus, the neuro-modeling studies, including ours, have inadequate resources to validate the computational results. Furthermore, the heterogeneity of the disease and the complexity of the nervous system hinders the efforts to understand the underlying conditions behind ASD and the impact of altered pathways on the symptoms of ASD. However, customized forecasts of patients’ phenotypic characterization can be improved by employing genome-scale metabolic models. The metabolic models tailored to individual conditions, tissues, and patients shed light on cell-specific changes in the metabolic network, allowing for the prediction of disease metabolism biomarkers. All in all, we may conclude that genome-scale modeling may be beneficial in investigating the disturbed mechanisms in ASD.


A renewal of interest in the cognitive assessment of people with schizophrenia was related to the increasing acknowledgement of the strong relationships of cognitive deficits with functional outcome. In the early 2000’s, research focused on those aspects of cognition that demonstrated a strong correlation with a variety of functional outcome measures . Later on, social cognition, which was not included in neuropsychological batteries, became also a focus as it represents a mediator of the impact of neurocognition on functioning. The renewed interest and the association with functional outcome stimulated the development of batteries specifically devoted to the cognitive assessment of subjects with schizophrenia. The MATRICS Consensus Cognitive Battery (MCCB) is the instruments with the largest evidence of good psychometric properties and strong relationship with functional outcome. The MCCB has been proposed as the gold standard in assessing cognitive impairment in subjects with schizophrenia and has been translated into 24 languages and validated in many different countries. Different instruments are also available to assess emotional processing and theory of mind which should complement MCCB and similar batteries. The long administration time limits the use of batteries in everyday clinical routine and short-administered instruments were developed as screening tools. A brief, interview-based assessment of cognitive functioning, the Cognitive Assessment Interview, has also been developed and validated for use in clinical settings or as a co-primary measure in clinical trials. The development of a guidance paper might promote the routine assessment of cognition in subjects with schizophrenia.Honoraria, advisory board, or consulting fees from Angelini, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer, and Pierre Fabre, for services not related to this abstract


One of the most important diagnostic challenges in clinical practice is the distinction between pulmonary hypertension (PH) due to primitive pulmonary arterial hypertension (PAH) and PH due to left heart diseases. Both conditions share some common characteristics and pathophysiological pathways, making the two processes similar in several aspects. Their diagnostic differentiation is based on hemodynamic data on right heart catheterization, cardiac structural modifications, and therapeutic response. More specifically, PH secondary to heart failure with preserved ejection fraction (HFpEF) shares features with type 1 PH (PAH), especially when the combined pre- and post-capillary form (CpcPH) takes place in advanced stages of the disease. Right ventricular (RV) dysfunction is a common consequence related to worse prognosis and lower survival. This condition has recently been identified with a new classification based on clinical signs and progression markers. The role and prevalence of PH and RV dysfunction in HFpEF remain poorly identified, with wide variability in the literature reported from the largest clinical trials. Different parenchymal and vascular alterations affect the two diseases. Capillaries and arteriole vasoconstriction, vascular obliteration, and pulmonary blood fluid redistribution from the basal to the apical district are typical manifestations of type 1 PH. Conversely, PH related to HFpEF is primarily due to an increase of venules/capillaries parietal fibrosis, extracellular matrix deposition, and myocyte hypertrophy with a secondary “arteriolarization” of the vessels. Since the development of structural changes and the therapeutic target substantially differ, a better understanding of pathobiological processes underneath PH-HFpEF, and the identification of potential maladaptive RV mechanisms with an appropriate diagnostic tool, become mandatory in order to distinguish and manage these two similar forms of pulmonary hypertension. Pulmonary hypertension (PH) is a progressive disorder of the pulmonary vasculature that has received great attention over the past years, with significant advances in the comprehension of pathophysiology, hemodynamic mechanisms, and the involvement of the right side of the heart. The latest European guidelines define PH as a “hemodynamic and pathophysiological condition characterized by an increase in mean pulmonary arterial pressure (PAPm) of up to ≥25 mmHg at rest, assessed by right heart catheterization” . The 6thLeft heart diseases (LHDs), or group 2 PH, are recognized as the most common causes of PH . Their uIn the context of heart failure with preserved ejection fraction, there is increasing evidence of an overlap between the advanced stages of PH-HFpEF and those of the PAH phenotype. Most PH-HFpEF patients have isolated post-capillary PH (IpcPH) , where aThe identification of a pre-capillary component in PH-HFpEF is crucial, as CpcPH has a considerably worse prognosis with a reduced exercise capacity, different management, and a different response to PAH-specific vasodilator compared to IpcPH ,13,14,15The 5th WSPH proposed a 3-step approach in order to help differentiate group 2 and PAH using pre-test probability scores to define patients who would more likely undergo the invasive hemodynamic definition and to predict the outcome and prognosis . CompareData on PH prevalence and severity are often unclear, with a wide range of inclusion criteria ,25 due tPAH and PH-LHD are hemodynamically differentiated by pulmonary artery wedge pressure. In PAH, the mean PAWP is ≤15 mmHg, whereas in PH-LHD, the mPAWP is >15 mmHg . This heIn CpcPH, the remodelling of the pulmonary arterial system contributes to the augmentation in PVR and to the decrease in pulmonary vascular compliance. Namely, in the pulmonary vascular bed, the arterial compliance (PAC) is distributed over the entire vessel system, and the distal vessels primarily determine the resistance and compliance, unlike the systemic circulation, where 80% of the compliance is from the proximal aorta . As thesIn pulmonary hypertension, the increasing vascular load is transmitted to the right side of the heart, with right ventricle adaptation being a common consequence of both PAH and pulmonary hypertension in HFpEF (PH-HFpEF). The survival of patients with PAH and PH-HFpEF is closely related to right ventricular (RV) function ,54,55,56The augmentation of the resistive and pulsatile load of the pulmonary circulation affects RV function, causing the remodelling of the right ventricular chamber to counteract the elevated afterload. The progressive increase in PAP triggers a process based on the myocardial fibres’ adaptation and leads to concentric hypertrophy, with a higher mass-volume ratio and increased contractility in order to preserve systolic and diastolic function . This reVentriculoarterial uncoupling occurs when the stretching of myocardial fibres and chamber stiffness prevail over hypertrophy, thus unbalancing the relationship between cardiac contractility and vascular load. Maladaptive remodelling is represented by eccentric hypertrophy of the RV and subsequent systo-diastolic dysfunction . In the The left and the right ventricle uncoupling leads to augmented oxygen consumption, deterioration of ventricular interaction, and RV dyssynchrony. The left and right ventricle are actively interconnected, and they share both a diastolic phase and systolic phase. Ventricular interdependence can be altered because of both the lowering of the RV stroke volume and/or the interventricular septum bowing toward the left ventricle, which can hamper LV filling . It has The impact of RV dysfunction and pulmonary hypertension was proven to be independently related to survival and outcome in left heart disease ,65,66. AThe relation between TAPSE and PAPs was studied as an index of the RV length/force relationship  first by Guazzi et al. They demonstrated that a TAPSE/PAPs ratio < 0.36 mm/mmHg is associated with increased cardiac-related mortality in both HFpEF and HFrEF . The samAmong other functional and morphological right ventricle measures, a pulsed wave Doppler applied on the right ventricular outflow tract can be useful to assess hemodynamic properties of PH. The presence of a mid-systolic notch was shown to be significantly related with RV dysfunction and CpcPH, whereas its absence was prevalent in IpcPH . MoreoveNew echocardiographic techniques, such as strain analysis and 2D/3D-speckle tracking echocardiography, should also be taken into consideration for the evaluation of the RV. A post-processing evaluation of the longitudinal functional analysis of the RV free wall, together with the characteristics we listed before, can add important information on right ventricle function .The use of these parameters is of high value for the definition of the clinical and non-invasive probability of PH in HFpEF and for distinction from PAH. Each feature can have a prognostic and/or diagnostic value, but neither can be used alone to identify the presence of pulmonary hypertension. Together, with increasing interest in PH due to HFpEF, the difficulties of management, and the low availability of therapies, more studies are needed to assess the correct diagnostic and prognostic pathway in the field of pulmonary hypertension. A multi-modality imaging approach is fundamental for the definition and follow-up of RV coupling and uncoupling, with a focus on PH-LHD, as no therapies have been so far validated to improve its outcome and prognosis.RV dilatation and dysfunction are well-known features of the adverse outcome of heart failure when LHD is complicated by pulmonary hypertension. RV dysfunction is often associated with advanced HF, systemic congestion, and worse clinical conditions. This scenario is related to increased left atrial pressures transmitted backward on pulmonary vessels, causing combined PH and right ventricle overload. Mechanisms of the development of PH in HFpEF appear to be significantly different compared to the haemodynamic adaptations typical of patients with HFrEF. They are mostly related to pulmonary vascular dysfunction, diffuse extracellular collagen deposition, and reduced pulmonary compliance in patients with suggestive echocardiographic findings and clinical phenotypes. When PH-HFpEF evolves from isolated post-capillary to combined pre- and post-capillary PH, hemodynamic changes overlap the typical alterations described in PAH. Specific studies investigating the triggers of PH in HFpEF are needed to precisely recognize the complex venous arterial and capillary alterations in order to achieve a better definition and a more appropriate targeted management.


Penetrating traumatic brain injury (pTBI) affects civilian and military populations resulting in significant morbidity, mortality, and healthcare costs. No up-to-date and evidence-based guidelines exist to assist modern medical and surgical management of these complex injuries. A preliminary literature search revealed a need for updated guidelines, supported by the Brain Trauma Foundation. Methodologists experienced in TBI guidelines were recruited to support project development alongside two cochairs and a diverse steering committee. An expert multi-disciplinary workgroup was established and vetted to inform key clinical questions, to perform an evidence review and the development of recommendations relevant to pTBI. The methodological approach for the project was finalized. The development of up-to-date evidence- and consensus-based clinical care guidelines and algorithms for pTBI will provide critical guidance to care providers in the pre-hospital and emergent, medical, and surgical settings. Penetrating (pTBI) traumatic brain injury (TBI) is a catastrophic primary wounding mechanism encountered in military and civilian settings and is characterized by the violation of the skull and brain by a foreign body. For those who survive, the constellation of cerebral injuries in the setting of either pTBI or blast-related pTBI creates complex management scenarios for pre-hospital and in-hospital healthcare providers. Recovery and rehabilitation are often protracted and complicated for these patients.2 The high lethality of civilian pTBI likely relates to the predominance of missile injury, including gunshot wounds, the absence of protective gear, and the violent circumstances that frequently surround the injury . From the military perspective, pTBI was prevalent in recent conflicts in Iraq and Afghanistan and most often results from a blast mechanism. pTBI outcomes in these modern conflicts are better than in past reports,3–10 most likely because of more aggressive clinical care.6 Before the conflicts in Iraq and Afghanistan, management in those who survived to reach care included limited surgical debridement and wound closure.11 In contrast, the new military model includes early cranial decompression and prevention of cerebrospinal fluid leak with skull base repair, causes of secondary brain injury are aggressively sought and mitigated , and a multi-disciplinary approach to cranial reconstruction is used.Civilian pTBI accounts for an estimated 20,000 deaths in the United States each year with mortality in up to 90% of victims.12 Topics addressed included antibiotic prophylaxis, antiseizure prophylaxis, management of cerebrospinal fluid leaks, surgical management, vascular complications, intracranial pressure monitoring, and prognosis. The 2001 guideline has not, however, been updated to reflect modern military experiences nor incorporate newer evidence- and consensus-based practices. There are no known published pTBI treatment algorithms informing patient management, despite the tremendous popularity of blunt TBI management algorithms13–15 and despite important changes to medical and surgical care over the past two decades. In response, the Brain Trauma Foundation (BTF) in collaboration with military and civilian TBI experts in the field, and with funding from the American Department of Defense  will generate an updated, evidence- and consensus-based pTBI clinical practice guideline and new care algorithms. The BTF has published numerous clinical practice guidelines for TBI care over the past quarter century17 and is undertaking this update with permission from the original pTBI guideline authors.pTBI clinical practice guidelines were first published in 2001 by an independent group.For this work, pTBI will be defined as a head injury with violation of, at minimum, the skull and likely dura and brain by a foreign body . Linear BTF leadership, alongside civilian and military clinicians with topical expertise in pTBI, comprise the pTBI Expert Workgroup. The workgroup and its efforts are led by two cochairs with guidance and governance provided by a core multi-disciplinary steering committee. Workgroup members were selected for diversity among disciplinary expertise relevant to the management of TBI, scientific expertise, and demographic and geographical representation. Represented medical disciplines include neurosurgery, plastic surgery, neurology, general/trauma surgery, orthopedic surgery, ENT  surgery as well as emergency medicine, physical medicine, pediatrics, pre-hospital care, and rehabilitation. A military medic and a patient (service member recovered from a pTBI) are included. Sex and ethnic diversity was also specifically sought.Workgroup members were divided into three areas of clinical focus: pre-hospital and emergent management; surgical management; and medical management, led by A.L.B., B.A., and J.G., respectively. Each workgroup will update the topics included in the 2001 guidelines and will develop clinically relevant key questions as well as inclusion and exclusion criteria using the Population, Interventions, Comparators, Outcomes, Timing, Setting and Study design (PICOTS) framework. The present effort will endeavor to only inform aspects of care in which pTBI care would be distinct from, or otherwise insufficiently informed by, the “umbrella” recommendations found in the fourth edition of the Severe Traumatic Brain Injury Guidelines, which largely focus on blunt head injury.Generated recommendations aim to be relevant to all patients with pTBI. However, evidence supporting distinct recommendations for key patient subgroups will be reported and may include differentiation by wounding mechanism , military versus civilian victims, and adult versus pediatric victims.We will search Ovid MEDLINE, EMBASE, and Cochrane CENTRAL without date limits. The search strategy will be developed and executed by a specialized medical research librarian with experience in systematic reviews with peer review by a second librarian.Review of abstracts and full-text articles will be informed by pre-specified PICOTS and corresponding inclusion and exclusion criteria. All abstracts identified by the literature search will be assessed by one reviewer and excluded abstracts confirmed by a second reviewer. Independent, dual review of the full text of any potentially relevant article identified at abstract level will be conducted. Disagreements will be resolved by consensus or with the addition of a third reviewer. Included and excluded articles, and reasons for exclusion, at the full-text level will be provided to the Guideline Panel for review and will be included as an appendix in the full Evidence report.Studies meeting inclusion criteria will be in children, adolescents, and/or adults with traumatic injuries that violate the skull and that provide evidence for a key question. Included outcomes of intervention studies consist of mortality, morbidity, function, and selected intermediate outcomes . We willWe will abstract data from all studies that include population characteristics , intervention and comparator characteristics , numbers enrolled and analyzed, relevant outcomes , and funding source.All included studies will be assessed for risk of bias using criteria specific for the type of study design. Randomized trials will be assessed for risk of bias based on the randomization process, method for allocation concealment, similarity of baseline characteristics, blinding, missing data overall and differences between groups, whether intent-to-treat analysis was used, and possible reporting bias. Assessment of non-randomized studies with a comparison group will include selection of participants, whether differences in prognostic factors between groups were present, missing data, pre-specification of outcomes, whether ascertainment of outcomes was unbiased, and adjustment for potential confounding. Assessment of single-group trials will include selection of participants, pre-specification of outcomes, whether ascertainment of outcomes was unbiased, and assessment of missing data. Case series and case reports are studies with high risk of bias and will not be individually assessed. Study risk of bias will be assessed by two independent reviewers.When there is more than one study of an intervention, data will be synthesized quantitatively if a meta-analysis is appropriate . When statistical heterogeneity is present in a pooled analysis, we will explore the reasons for this using stratified analysis and sensitivity analysis, as appropriate. We will also consider the potential effects of various participant subgroups  on intervention effects. When data cannot be pooled, we will provide a qualitative summary and analysis of findings.9 The quality of the body of evidence will be rated high, moderate, low, and very low. As an example, the highest-quality evidence (rated high) would come from multiple, well-conducted randomized trials with consistent findings, a precise pooled estimate of effect of the intervention on an included outcome, and be absent other bias. The lowest-quality evidence (rated very low) would come from expert opinion in the absence of any study data. We will generate a summary of findings table that includes ratings for quality of the body of evidence.We will assess the quality of the body of evidence by outcome using the GRADE  approach with the following criteria: risk of bias of included studies, consistency of effect, precision of the estimate, directness of the evidence, and potential publication bias.The development of recommendations is the next step after the evidence has been identified and synthesized and rated for risk of bias. Evidence-based recommendations are based on the quality of the body of evidence, applicability, and generalizability. For topics where there is little or no research, recommendations may be developed using rigorous Delphi consensus methodology.Level I recommendations are based on high quality of the body of evidence.Level II recommendations are based on moderate quality of the body of evidence.Level III recommendations are based on low quality of the body of evidence.Level IV recommendations are based on very low quality of the body of evidence.Level C: recommendations based on consensus in the absence of research evidence.Recommendations will be assigned a level based on the quality of the body of evidence. We will recognize five levels of recommendation based on the quality of the body of evidence:Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC) effort.18 A week-long in-person meeting will be held 18 months into the 2-year project to finalize the recommendations and algorithm. A private company will facilitate electronic, blinded voting at this meeting to enable the Delphi methodology.Blinded consensus voting will be conducted to establish consensus for key aspects of the project. This will be particularly important for consensus-based algorithm development. A vote of 80% will be required to declare consensus as having been achieved where at least 80% of the panel participates in the vote. This is the same threshold used for consensus in the recent 16 and their implementation has been credited with an ∼50% reduction in mortality.20 Because of their demonstrated benefit, compliance with the BTF guidelines is mandated for U.S. trauma centers to maintain trauma accreditation.Clinical practice guidelines evaluate and consolidate available literature into evidence-based recommendations designed to inform best care. Guidelines for the management of TBI created by the BTF were the first surgical clinical practice guidelines published,22 and TBI guidelines have been developed for numerous additional topics, including pediatrics,23 combat, pre-hospital care,24 and prognosis.25 The BTF's infrastructure has been key for disseminating and updating these important documents, with the most recent fourth edition TBI guidelines largely addressing closed head injury published in 2017.22Because of the success of the BTF guidelines and their demonstrated benefit, multiple editions of the BTF adult guidelines have been published,26 In contrast, no such algorithms for the management of penetrating and blast-penetrating TBI have ever been published.Algorithms for care bridge published evidence and its gaps with the realities of practice. Such care pathways were included with the first and second editions of the BTF adult guidelines, and they were the most popular aspect of these documents. These algorithms are inherently and necessarily consensus based, and their construction requires methodologies distinct from those for developing evidence-based clinical practice guidelines. To address the gap between evidence-based recommendations and patient care for severe blunt TBI patients, the SIBICC was recently convened, which led to two well-received and high-impact publications.Journal of Trauma more than two decades ago27–33 and, of course, do not reflect important subsequent advances in the literature and clinical standards of care (see Literature Search below).34 The combination of outdated pTBI guidelines and non-existent treatment algorithms may negatively impact morbidity and mortality because of the lack of consolidated clinician guidance on best practices for the medical and surgical care of pTBI. Because BTF did not lead the 2001 guideline, the organization sought permission to update the pTBI guidelines from the leadership of the original effort and this was granted.Guidelines for the management of pTBI were last published in the https://www.ncbi.nlm.nih.gov/pubmed) and the basic search term “penetrating brain injury.” A total of 968 references were identified when limiting the search criteria to publication dates between January 1, 1933 and December 31, 2001. This search time frame includes the references that formed the foundation of the existing and outdated pTBI guidelines referenced above and specifically includes all periods of armed conflict from World War II to 2001. When using the same search term and limiting publication dates from January 1, 2002 to the present, 2413 candidate references were identified. This suggests that the overwhelming majority of the existing information on pTBI has been published after the last guidelines were generated in 2001 and, in large part, reflect the experiences and care provided during the conflicts in Iraq and Afghanistan. This affirms the strong need for updated pTBI guidelines.To estimate the volume of new studies to be screened and assist resource planning, a preliminary literature search was conducted , using PubMed ; penetrating injury resulting from fragments propelled by blast (secondary blast injury); results of persons propelled or thrown by the blast wind (tertiary blast injury); and all explosion-related injuries . Given the importance of blast injury accompanying pTBI in the military, we have decided to include an analysis of such patients in this project. Given the risk of vasospasm inherent to blast-related pTBI, this patient subgroup mandates consideration of distinct management.35The recent conflicts in Iraq and Afghanistan have created renewed interest in blast as a mechanism of TBI. The Centers for Disease Control and Prevention (CDC) has defined blast injuries as “…characterized by the anatomic or physiologic changes from the direct or reflective over-pressurization force impacting the body's surface.”17 Future work will strategize and examine dissemination and implementation of the finalized guideline and algorithm to assess impact.A methodologically rigorous BTF effort, funded by the U.S. Department of Defense, is underway to update 2001 recommendations for the clinical care of pTBI. The vetted, multi-disciplinary workgroup will also develop the first treatment algorithms for pTBI to bridge gaps in published evidence with the practicalities of patient care.


A wide range of pathogens, including bacteria, fungi, parasites, and viruses, are capable of causing IK. However, the clinical features are often poorly differentiated, especially in patients with late presentation (common in LMIC populations), and may be complicated by the presence of polymicrobial infections (occurring in 2–15%) , the culture yield is hindered by invariably low sensitivity (30–50%) and slow turnaround time for positive results . A negative culture result can lead to significant therapeutic challenges, particularly in cases with poor initial treatment response to broad-spectrum antimicrobial therapy, as clinicians are often pressured to subject the affected patients to polypharmacy  to ensure the maximal coverage of possible causative organisms (a “blanket approach”). This can in turn lead to undesirable dose-dependent ocular toxicity, impede corneal healing and exacerbate corneal ulceration/melt, culminating in corneal opacity and blindness.The limitations of the current diagnostic approaches are varied in different settings and may be more specific or relevant to certain populations/countries. For instance, in LMICs, the lack of access to healthcare services and the lower level of patient education can result in late presentation of the disease. This can lead to poorly differentiated clinical features, less accurate diagnosis, and most importantly, worse clinical outcomes. In addition, the relative lack of resources in such settings  limits the clinician's capacity to make the clinical diagnosis. On the other hand, patients residing in high-income countries (HICs) have better access to healthcare systems, and in these settings, improving the likelihood of a microbiologic diagnosis would be beneficial. Understanding the diagnostic limitations specific to certain regions or populations will enable a more efficient and effective implementation of future innovations for improving the diagnosis and treatment of IK.In recent years, the simultaneous advancement in deep learning (DL)-based artificial intelligence (AI) techniques, computer processing power, internet-of-things, and big data analytics have unlocked the potential of digital health. Within ophthalmology, AI-assisted models have facilitated image-based automated medical diagnosis for a range of ocular diseases and assisted in clinical triage and decision making, thereby enhancing the workflow efficiency in healthcare services in both high-income countries (HICs) and LMICs -based molecular diagnostics have proven to be a useful diagnostic tool for various infectious diseases, including IK , corneal biopsy, and in vivo confocal microscopy were unrevealing. During the first 2 months of treatment (prior to the correct diagnosis), the patient progressively worsened despite being on various antibiotic and antifungal treatments. Fortunately, the initiation of the appropriate therapy  successfully eradicated the infection and inflammation within 6 weeks, highlighting the clinical value of metagenomic NGS in IK. Moreover, the sensitivity of NGS is not affected by the prior use of antimicrobials, which is a common impediment to culture yield (a common issue that is observed in HICs due to widespread use of antibiotics).So far, NGS has demonstrated promise in augmenting clinical microbiology and public health laboratory practice  and telemedicine have demonstrated their potential clinical utility in improving the rapidity, efficiency and accuracy for diagnosing IK in the recent years, though the deployment of such technology in this field still remains in its infancy. Other than diagnosing and distinguishing IK from other ocular surface diseases, potential AI research areas for IK may further include the prediction of culture positivity, clinical outcomes and complications of IK, including need for surgical interventions, based on the initial clinical presentations and photos. These digital innovations can provide a much-needed solution in LMICs where IK is most prevalent and healthcare services are constrained by physical, financial, workforce, societal, environmental and policy limitations Mills, . An ideaAlthough NGS has demonstrated significant promise in improving the diagnosis of various types of infection, the routine use of NGS in clinical practice is hindered by its high cost , though parallel sequencing of multiple samples and pathogens may improve laboratory efficiency and reduce cost. In addition, NGS can result in non-selective amplifications of the RNA / DNA of the causative organisms and normal ocular surface commensals, which will require special bioinformatic consideration and analysis . Another issue that has been highlighted is that NGS may produce inconsistent results to the conventional culture methods, which may complicate the clinical findings and decision making in IK  Clinical Research Fellowship (MR/T001674/1).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 rapid expansion of the Information and Communication Technologies (ICTs) has transformed learners into digital learners, requiring teachers to integrate technology into their pedagogical approaches, where teachers’ attitudes, technological knowledge, and skills play a significant role in its effective integration. From this perspective, the current study presents teachers’ perceptions regarding technology integration in their teaching-learning practices at all educational levels in light of the previous studies performed in the last 5 years in Pakistan. The findings reveal that teachers exhibit positive perceptions regarding technology integration in teaching-learning practices. They believe that technology-incorporated teaching assists them in enhancing their instructional practices effectively, making the learning process exciting and interactive, and keeping learners motivated. Regarding barriers, the slow speed of the internet, load shedding, lack of infrastructure, online teaching experience, and training were reported as the main obstacles that hinder teachers from effective integration of ICT into their teaching practices. Accordingly, the study findings suggest that concerned authorities should set clear and effective policies to make efficient use of ICT by allocating a sufficient budget and ensuring all necessary facilitation  in all educational institutions. Furthermore, particular attention should be devoted to supplying adequate opportunities for the career development of teachers in developing technological competencies, which help them successfully use ICT in their instructional practices. By putting it briefly, ICT integrated teaching-learning is the requirement of time, which allows the learners to satisfy their learning needs and helps teachers align their teaching approaches with global standards.Being an essential part of the present time, Information and communication technology (ICT) significantly influences all domains of human life . Similartivities . RecogniCorrespondingly, Pakistan has also recognized the importance of ICT in education, and the national educational policies have proved that the government has special concerns about integrating ICT into the teaching-learning practices to meet the global needs . HoweverThe central objective of this systematic analysis was to present a succinct account of representative literature dealing with the teachers’ perceptions and experiences while integrating ICT in their teaching-learning practices. The best literature review provides a full reflection, which helps develop theory, indicate needed areas, and put them in a nutshell . By consThe employed systematic review approach entails the, which entails the selection, evaluation, and analysis of reports and findings of the prior studies, which subsequently allows a researcher to come to clear conclusions regarding the subject unidentified by the previous researchers. Originally, this method was initially used for medical studies, but Phase-1: structuring questions/objectivesPhase-2: Finding prior studiesPhase-3: Selecting and evaluating prior studiesPhase-4: Analyzing and synthesizing prior findingsPhase-5: Using and reporting the results.Among these five phases, the first phase was depicted in the introduction, whereas the subsequent stages were discussed in the methodology and the result sections. Furthermore, to increase the transparency of the findings, each step of the systematic review was explained precisely .The study adopted the approach of Keeping in view to report the updated literature, the articles from the last 5 years between the time-span of 2017–2021 were selected . In thisThe data from the selected articles was analyzed by means of content analysis, which is a rigorous approach used to analyze prior documents such as official reports, books, and publications. This approach is commonly known as an efficient way to reduce the number of sources and qualitatively analyze the features of the documents . TeacherEvery study includes certain limitations due to a number of constraints faced by the researcher. Similarly, this study was also gone through some limitations. Primarily, to gain authentic insights for the systematic review analysis, only peer-reviewed articles from reputed publishers were included. Secondly, the key terms used to search publications involve some limitations; for instance, key terms were searched by combining with specific terms such as primary, secondary, and higher education teachers to explore a wide range of research articles.The identified information of the outlined articles was found in line with the purpose of this study, which was later sorted chronologically. Keeping in view to identify the integration of ICT in teaching-learning practices at the educational level, the articles were sorted out across different educational levels, i.e., from the school to the university level shown in . Most ofThe nature of research articles with regards to their adopted methodologies contributes significantly to conducting good literature reviews. Hereby, the sampled studies were sorted out across their mode of methodological approaches, which is shown in Teachers’ perceptions of the integration of technology were classified into two paradigms to illustrate the significance and barriers of ICT in their teaching-learning practices. These are described below:However, the practical employability of technology in teaching-learning practices is yet to be achieved in Pakistan. Prior studies have highlighted several benefits of integrating ICT into our education system see , which aAccording to the majority of the studies, the utilization of ICT for teaching-learning purposes enables teachers and students to stay connected and facilitates learners irrespective of their location and time . TeacherRegarding the benefits of ICT integration at the secondary school level, Based on the self-efficacy perspective, effective integration of ICT in education highly depends upon teachers’ self-efficacy , as selfFurthermore, the findings by Teacher plays an important role in cultivating successful students’ online learning. ICT utilization in teaching-learning practices enables a student to make meaningful use of technologies in education by accessing, selecting, establishing, and interpreting the information. Its effective integration help in meeting the learners’ educational needs by providing creative solutions to different types of learning inquiries . Severalvia social media platforms helped learners to continue their learning activities  activities in the classroom to strengthen students’ understanding, which would help them enhance the level of collaboration with their teachers and peers .Recognizing the needs of the time and setting educational goals and objectives accordingly is the core responsibility of governing bodies to acquire the desired outcomes . In contAdequate time plays a significant role in fulfilling the teaching responsibilities of teachers required to incorporate ICT in their instructional practices efficiently. In contrast, the reviewed articles inform that teachers don’t find adequate time to perform all the pedagogical tasks required to integrate ICT in their educational practices, such as lesson planning, making notes, or lectures. A similar barrier has been identified by The systematic review affirms that teachers exhibit adequate acceptance of ICT in the teaching-learning practices and assist learners in acquiring learning objectives in several ways, which is why inevitable at all educational levels. However, technology use at the secondary school level is still found at the initial stages than at the higher level. Still, the changes brought by the COVID-19 pandemic brought an opportunity to enhance the effectiveness of teaching-learning practices through ICT integration at all levels. Findings also specified several barriers that hinder effective technology integration in teaching-learning practices, including lack of resources, leadership support, accessibility of ICT infrastructure, inadequate time, unclear policies, professional development, technical support, and lack of appropriate pedagogical models. In this context, concerned authorities should work on the needs and gaps which hinder educational practices from effective technology integration to acquire maximum benefits from technology-integrated teaching and learning.HA was the principal investigator of the study and conducted from conceptualization to the data analysis. AHA, ASA, and MR refined the study and helped in the revision.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.


Cancer is one of the leading causes of death worldwide, and battling cancer has always been a challenging subject in medical sciences. All over the world, scientists from different fields of study try to gain a deeper knowledge about the biology and roots of cancer and, consequently, provide better strategies to fight against it. During the past few decades, nanoparticles (NPs) have attracted much attention for the delivery of therapeutic and diagnostic agents with high efficiency and reduced side effects in cancer treatment. Targeted and stimuli-sensitive nanoparticles have been widely studied for cancer therapy in recent years, and many more studies are ongoing. This review aims to provide a broad view of different nanoparticle systems with characteristics that allow them to target diverse properties of the tumor microenvironment (TME) from nanoparticles that can be activated and release their cargo due to the specific characteristics of the TME  to nanoparticles that can target different cellular and molecular targets of the present cell and molecules in the TME. Cancer is one of the principal causes of death all over the world. Generally, cancer occurrence and death rates are speedily rising worldwide; this demonstrates both aging and an increase in the population, along with alterations in the occurrence and spreading of the main risk factors for cancer, which are mostly associated with socioeconomic growth. In 2020, approximately 19.3 million new cancer cases and almost 10.0 million cancer expiries occurred worldwide  (DSPE-MPEG-2000), which could encapsulate 3-BPA in its hydrophilic core. For further targeting efficacy, the surface of liposomes was modified with an EGFR-specific peptide known as GE11 (YHWYGYTPQNVI), which can be coupled to the liposome surface via a heterobifunctional PEG chain with maleimide (MAL) functionality. The efficacy of the nanoparticles was studied for penetration inside ovarian cancer spheroids, and it was observed that the liposomal nano-systems had improved cytotoxic effects in spheroids in comparison with the solution form of 3-BPA .Zhang et al. encapsulated 3-BP in liposomal nanoparticles covalently functionalized with a tumor-targeting pentapeptide  to their surface. It was observed that nanoparticles targeted the tumors after systemic administration in tumor-bearing mice with the least side effects in major organs .Extracellular matrix (ECM) controls cell replication by the complex effects of its components, including proteoglycans, collagen, elastin, polysaccharides, hyaluronan, various enzymes, and growth factors. When these components assemble, they result in various biological tasks and regulation of cell activities . The ECMPhysical features of ECM, such as density, porosity, rigidity, and orientation, could explain the scaffolding and backup pathways of ECM in keeping the integrity of the connected tissue. In the TME, mechanical, chemical, and physical characteristics of ECM have re-formed a way that they could encourage carcinogenesis along with metastasis. Increased binding of collagen and components originating from lysyl oxidase results in higher stromal rigidity and density. The enhanced collagen crosslinking offers improved mechanical support for tumor progression and simultaneously obstructs the penetration of chemotherapeutic drugs, thus resulting in drug resistance .Collagen is an essential element of the ECM. Several reports have revealed that collagen contributes to tumor progression. Collagen ratio and cross-linking are significantly associated with tumor stiffness. Higher stiffness is also related to the poor prognosis of various types of tumors, such as breast tumors ,129,130.A common approach is to co-deliver the nanoparticles with collagenase. This co-delivery could be based on a modification of the surface of nanoparticles with collagenase or encapsulation of collagenase.Based on the first approach, Murty et al. developed PEGylated gold nanoparticles modified with collagenase and studied their behavior in a murine tumor xenograft. Within the tumor, collagenase-modified nanoparticles showed a 35% increase in accumulation in comparison with unmodified nanoparticles .Villegas et al. developed a novel nano-system with collagenase encapsulated in pH-responsive polymeric nano-capsules. The polymeric shell consisted of acrylamide (AA) as a structural monomer, hydrochloride salt of 2-aminoethyl methacrylate (Am) for providing amino groups on the nano-capsule surface, and ethylene glycol dimethacrylate (EG) as pH-sensitive cross-linker. These nano-capsules were attached to the surface of mesoporous silica nanoparticles. This hybrid nanoparticle system showed a significantly high penetration into human osteosarcoma cells (HOS), which contain a high amount of collagen in the ECM and could provide a platform for the delivery of anti-cancer drugs in cancerous tissue .Zinger et al. reported the design of nano-liposomes containing collagenase (collagozome) for cancer therapy of pancreatic ductal adenocarcinoma (PDAC). It was reported that PDAC tumors, undergone pretreatment with the collagozome and followed by applying paclitaxel micelles were 87% smaller in size than the tumors pretreated by blank liposomes and then treated with paclitaxel micelles and digesting the ECM did not show any increase in the quantity of circulating tumor cells in the blood or metastasis .2+ and an acid-responsive benzoic-imine organic bond and then adjusted by polyethylene glycol (PEG). These nano-systems displayed effective aggregation inside the tumor site so that collagenase would be liberated due to the degradation of nanoparticles in the acidic TME. The released collagenase can particularly destroy collagens, the significant factor of ECM, resulting in a relaxed ECM structure, relieved hypoxia, and improved tumor perfusion. Therefore, the secondary nanoparticles, chlorin e6 (Ce6)-loaded liposomes (liposome@Ce6), would display higher penetration inside the tumor  to these nanoparticles. The cell uptake studies by confocal microscopy and MTT assay revealed the specific targeting of these nano-systems to the mentioned cell line .In addition to all these targets, there are several other biomarkers on the cells corresponding to one or more types of cancer, and many more are to be discovered by researchers. These markers may be upregulated on the cancer cells or other cells present in the TME and can be used for targeting the desired nanoparticles in the cancer environment.Nanoparticles have provided a promising platform for cancer therapy in the past decades because of their specific characteristics and modifiable features. Nanoscale systems have many advantages over traditional drug delivery systems as they can be designed with different features, such as size, zeta potential, loaded cargo, and targeting ligands. The formulation of nanoparticles for cancer therapy can take advantage of many targeting mechanisms at cellular and molecular levels. The tumor microenvironment (TME) has many specific characteristics; it is hypoxic, with a significant amount of reducing agents, and has an acidic pH. The extracellular matrix of the TME is more dense and rigid, with different concentrations of molecules compared with normal ECM. Nanoparticles can be designed to release cargo in these conditions or be modified to prevent drug resistance for other therapies, such as radiotherapy and photodynamic therapy.Nanoparticles can also be designed for the delivery of therapeutics to the cells present in tumors, such as tumor cells and various types of immune cells. They can be modified with the ligands of the cell targets or target the specific features of the present cells in the TME.One of the most significant problems of cancer therapy is the limited information about the behavior of the immune system in the tumor development process. The immune system consists of complex mechanisms, and the effect of elaborating on each component of this system is not totally clear to scientists. The other reason relies on the heterogeneity of tumors, which makes the therapy path even more difficult. The immune systems of different individuals do not respond the same way to the same cancer therapies. Due to the complexity of the cancer progression process, it seems reasonable that nanoparticles employing multiple approaches for drug delivery would be more successful in cancer therapy. For instance, recently, many nanoparticles have been designed that can release their cargo in the specific conditions of the TME  and are modified on their surface by different ligands of the present cells in the TME, such as targeting antibodies, aptamers or targeting peptides. Employing multiple targeting approaches can lead to more effective nanoparticles with less chance of developing tumor resistance and therapeutic failure, leading to more clinically efficient cancer treatment.


Over the past two decades, major technological developments and progress have been reached for all imaging modalities applied to clinical cardiology, from echocardiography to magnetic resonance, computed tomography, nuclear imaging, etc. All these advancements and achievements progressively aid in filling the numerous gaps present in the current knowledge in the clinical practice of cardiology, as well as those of the disappointing unmet needs and goals for helping each patient, starting with clinical history, physical examinations and the standard 12-lead electrocardiogram (ECG) as a first step.In this context, all cardiologists should be able to select the most appropriate imaging modality to solve each specific problem whilst aiming to avoid a standardized, undifferentiated sequential approach to the universe of available modalities without taking into account a preliminary detailed analysis and discussion in regard to which modality could be the most appropriate for each clinical situation and with which sequentiality, in a complementary step by step selective approach. Selected and appropriate indications should also help to overcome accessibility problems due to the uneven geographical distribution and availability of each technique for cardiology in different areas, often being in competition with other medical specialties for the access to each specific imaging modality.Journal of Clinical Medicine.This editorial would like to focus on the subject through the window of opportunity offered by the papers published last year in the Coronary artery disease (CAD) represents the most common cardiovascular disease, presenting with high morbidity and mortality. Historically, and following guidelines, patients with chest pain of suspected coronary origin have been assessed with functional tests capable of detecting the haemodynamic consequences of coronary obstructions and related prognosis through the depiction of electrocardiographic changes, myocardial perfusion defects or novel regional wall motion abnormalities under stress conditions . Recent Myocardial and pericardial disorders encompass hypertrophic, dilated, arrhythmogenic, infiltratory, restrictive, inflammatory and other diseases of different aetiologies. Multimodality cardiac imaging techniques are extremely helpful in the definition of diagnosis, the assessment of prognosis and for monitoring the evolving natural history of these disorders through the planning of adequate follow-ups and treatments ,6,7,8,9.Congestion is the main cause of hospitalization in patients with acute heart failure; however, its precise assessment with simple clinical evaluations remains elusive. The complementary assessment of clinical, natriuretic peptides and other laboratory parameters, together with echocardiographic and lung ultrasound scan information, can be implemented in clinical practice, allowing physicians to more precisely quantify pulmonary congestion in order to achieve a more complete temporal evaluation of the clinical picture, as well as to determine the prognostic power of each measurement or parameter .Heart failure patients frequently develop brain deficits that lead to cognitive dysfunction. There is an important interaction between the brain and heart that becomes crucial for survival in patients with heart failure. An emerging experimental role of the combined brain/heart magnetic resonance imaging evaluation has the capability of diagnosing brain/heart lesions at an early stage and, potentially, facilitating their treatment . AdditioAfter a negative left ventricular remodelling, consequent to acute myocardial infarction, characterized by an increase in LV volumes and a depression in LVEF, operative treatment options can be considered to achieve a LV volume reduction and shape reconstruction. Conventional surgical LV reconstruction through a full median sternotomy has evolved towards the use of an experimental hybrid transcatheter and less invasive LV reconstruction . A comprThe assessment of the right ventricular morphology and function has gained increasing attention due to the prognostic importance of RV dilatation and dysfunction in patients with various cardiac and pulmonary diseases. A real-time evaluation of the right ventricular morphology and function through the use of three-dimensional echocardiography, combined with RV pressure-volume loops, could be useful in estimating RV-pulmonary arterial coupling, as previously experimentally assessed in an animal model .The research assessment of left atrial function could be of clinical and prognostic relevance in restrictive cardiomyopathy and heart failure. A decrease in the left atrial reservoir strain, as assessed using CMR, has been shown to be independently associated with time to adverse events in patients with restrictive cardiomyopathy . A left Sarcopenia is a progressive and generalized disorder characterized by the accelerated loss of skeletal muscle mass, strength and functionality. It was found to be associated with an increase in morbidity and mortality in various conditions, such as cancer and orthopaedic and abdominal surgery . The useTwo-dimensional, three- dimensional and Doppler transthoracic and transoesophageal echocardiography are the first-line imaging modalities for the diagnostic and prognostic assessment of valvular heart disease (VHD), followed by cardiac magnetic resonance for tissue and flow characterization and the detection of myocardial and papillary muscle fibrosis ,20,21,22The use of a transcatheter edge-to-edge repair for the treatment of mitral regurgitation has markedly increased in the last few years ,23. The Staphylococcus aureus bacteraemia without an echocardiographic evaluation, either transthoracic and/or transoesophageal (TEE). The usefulness of PREDICT, POSITIVE, and VIRSTA scores to rule out infective endocarditis without echocardiography was assessed together with the secondary purpose of evaluating whether not performing an echocardiogram could be associated with higher mortality [Staphylococcus aureus bacteraemia patients [It is unclear whether the use of clinical prediction rules is sufficient to rule out infective endocarditis (IE) in patients with ortality . PREDICTortality . In patiortality . Not perortality . Furtherpatients . Besidespatients ,26,27, wpatients ,26,27. FAthlete’s heart refers to a wide spectrum of morphological and functional changes that occur in the heart and circulation of subjects practicing regularly physical activity, usually following a training program. When the morphofunctional changes associated with athlete’s heart are more relevant, they can overlap phenotypes mimicking structural cardiac diseases, including cardiomyopathies, valvular diseases, aortopathies, myocarditis and coronary artery anomalies. In these situations, a precise differential diagnosis is of paramount importance. This can be reached by applying an appropriate and selective approach to different imaging modalities, including rest and exercise stress echocardiography, speckle tracking echocardiography, cardiac magnetic resonance, computed tomography and nuclear scintigraphy ,29. In tMultimodality imaging is the basis for the diagnosis, follow-up and surgical management of congenital bicuspid aortic valve patients. The complementary role of transthoracic and transoesophageal echocardiography for valvular phenotyping and function, the measurement of thoracic aorta, exclusion of other aortic malformations, and assessment of complications such as infective endocarditis, aortic dilatation and dissection has been outlined ,32. In tThe relationship between pulmonary regurgitation and ventriculoarterial interactions in patients with the postearly repair of the Tetralogy of Fallot was studied by using a cardiovascular magnetic resonance (CMR)-derived wave intensity analysis . A correThe association of gestational age and echocardiographic markers as image modalities and levels of plasma N-terminal pro-B-type natriuretic peptides could help to predict the closure rate of a haemodynamically significant patent ductus arteriosus (PDA) . InfantsMultiple cardiac imaging technique tools have been developed for the assessment of the left atrium. Although transthoracic echocardiography is the most widely employed procedure for the calculation of atrial size and function (due to its ease of use and wide availability), transoesophageal echocardiography, cardiac magnetic resonance, computed tomography and electroanatomical mapping can all be very useful for the management of cardiac rhythm disorders of atrial origin . The mulEndovascular pulmonary vein isolation (PVI) has become an important strategy for rhythm control in patients with symptomatic atrial fibrillation. Transseptal access is a critical step of this procedure, and can result in potentially life-threatening complications. TEE guidance may allow for safe transseptal access to the left atrium in patients undergoing PVI .