Xerogels are solid materials derived from gels which consist of interconnected particles or polymers dispersed in a liquid. This gel structure is subjected to a drying process , resulting in the removal of the liquid phase, leaving behind a solid material. During this drying process, the liquid is extracted from the gel while attempting to preserve its original shape and structure as much as possible. Although some shrinkage may occur, xerogels exhibit unique properties such as high porosity and a large surface area due to the interconnected network of pores formed during drying. These characteristics make xerogels valuable in a wide range of applications, including catalysts, adsorbents, sensors, membranes, and drug delivery systems. The field of materials science and engineering has seen a surge of interest in the development of innovative xerogels, leading to a focus on their design for various applications. With the ability to conveniently control their structures and morphologies during synthesis, xerogels have become a subject of great significance within the scientific community.Gels Special Issue is to assemble high-quality papers that showcase recent progress and discoveries in xerogel science, encompassing design and practical utilization. We sought original contributions exploring traditional and non-traditional approaches to synthesizing and characterizing xerogels. The aim is to deepen our understanding of the fundamental and applied aspects of various organic and inorganic xerogel-like materials.Taking these factors into account, the objective of this The recent advancements concerning the role of biopolymer-based xerogels in biomedical applications were thoroughly discussed by Khalil and colleagues. Through their systematic literature review, the authors provide insights into the biological properties of xerogels that make them suitable materials for various biomedical applications, including drug delivery, wound healing and dressing, tissue scaffolding, and biosensing .2/g.Furthermore, xerogels are widely utilized for the adsorption of ions and metals. Putz et al.  reported2O3, SiO2, TiO2, and CeO2, which possess large specific surfaces and thermal stability, can serve as catalyst supports. Within our special issue, we feature the research of Romanczuk-Ruszuk and colleagues, who synthesized binary xerogel systems of Sr/Al using the sol–gel technique. These systems incorporated a metallic strontium precursor and were evaluated as supports for platinum catalysts. The researchers successfully achieved highly dispersed and stable strontium carbonate phases, leading to a remarkable dispersion (42–50%) of platinum nanoparticles [Although silica xerogels are widely recognized as the most commonly used type, it is known that metal oxides such as Alrsion 42–0% of plaThe versatility of sol–gel approaches can be exploited to trap ions (as reported before) or molecules and macromolecules such as proteins to confer the final materials’ specific properties. For the sake of an example, Morosanova and colleagues reported the synthesis of a promising biosensor development by incorporating enzymes (horseradish peroxidase and mushroom tyrosinase) and crude banana extract in a silane-based structure to create optical biosensors for hydrogen peroxide in the range of 0.2–3.5 mM .The classic sol–gel process which involves hydrolysis reactions of (semi)metal alkoxides is a well-established method for creating organic–inorganic hybrid materials. However, alternative approaches utilizing non-aqueous or non-hydrolytic systems have also been investigated. In this context, Krupinski and colleagues presented a novel approach utilizing element chlorides and silylated precursors to produce “bridged” or “linearly expanded” silicas and silsesquioxanes through a non-hydrolytic sol–gel method. This study demonstrates that the non-hydrolytic approach to hybrid materials can be extended to other silylated precursors, as long as the reactivity of the corresponding chlorine compound is adequate .The responsibility of porous materials toward external stimuli is crucial for the obtainment of smart innovative materials, and the chemistry of N-oxide moieties offers a wide range of possibilities. In this context, Trofimov and co-workers report the synthesis of 4-dialkylamino-2,5-dihydroimidazol-1-oxyls with moieties at position 2 and at the exocyclic nitrogen able to act as pH-Sensitive spin labels , while J2 nanoparticles and a polyphosphonate as reinforcing additives. The favorable outcomes regarding precursor homogeneity, film quality, antimicrobial activity, and cytocompatibility demonstrate the potential suitability of these films for food packaging applications [Due to their versatility, xerogels and porous materials are becoming of great interest to scientists who focus their attention on food science and food packaging. Dried porous materials based on plant proteins have gained significant attention as potential sustainable food ingredients. However, plant proteins exhibit weaker gelling properties compared to animal proteins. To enhance plant protein gelling, optimization of gelation conditions involving protein concentration, pH, and ionic strength is necessary. De Berardinis and colleagues conducted a systematic study to investigate the impact of these factors on the gelation behavior of soy and pea protein isolates. The findings were used to create a map that identifies the gelation conditions for modulating the rheological properties of soy and pea protein hydrogels, with potential applications in the production of xerogels, cryogels, and aerogels . Innovatications .Xerogels offer unique properties for diverse applications, including catalysts, adsorbents, sensors, and drug delivery systems. Biopolymer-based xerogels show promise in biomedical applications, while metal oxides expand catalyst support options. Non-hydrolytic sol–gel approaches and additives enable hybrid materials. Intelligent food packaging and improved plant protein gelling are active areas of research. Composite films combining biodegradable polymers, natural polymers, and additives hold potential for food packaging. Exciting advancements in xerogel science drive innovation stimulating the interest of the scientific community.


Editorial on the Research TopicInsights in cardiovascular imaging: 2022Technical developments with cardiovascular imaging techniques, such as echocardiography, cardiac magnetic resonance (CMR), cardiac computed tomography angiography (CCTA), and intravascular imaging, including optical coherence tomography (OCT) and intravascular ultrasound (IVUS), have drastically improved both diagnostic classification and risk stratification of patients with cardiac diseases. In addition, cardiovascular imaging enabled a better understanding of cardiac physiology and pathophysiology, providing important links between genotypes and clinical features in patients with cardiomyopathies and other myocardial disorders. Due to the wider availability of both basic and advanced cardiovascular imaging tools, continuous training of cardiologists to use these tools and interpret cardiovascular imaging findings has become essential. Thus, the presentation of cases where cardiovascular imaging helped define the diagnosis and influence the therapeutic management of patients with cardiac diseases is essential, to increase awareness among clinicians about the role of cardiovascular imaging in modern cardiovascular medicine. Hereby, each imaging technique separately or the combination of imaging tools within a multimodality imaging approach may not only provide the correct diagnosis but also aid the monitoring of treatment strategies. This in addition to the continuous spread of knowledge among experts will contribute to more precise diagnostic algorithms, aiding prompter and more efficient subsequent patient management.Varghese et al.. The system provided images with a reasonable quality that enable evaluation of cardiac function, perfusion, viability, and tissue mapping. Although future technical developments are still necessary to improve image quality, such clinical CMR protocols may be utilized in patient cohorts with claustrophobia or severe obesity, who cannot undergo CMR examinations in conventional normal or high-field scanners with narrower bores.In total 28 research papers were published in this Research Topicand herein, the most important and impactful research findings are summarized. Several of the studies used cardiac magnetic resonance (CMR) for the characterization of cardiac disorders. The feasibility of comprehensive CMR using a low-field MR scanner (0.55 T system with an 80 cm bore) was demonstrated by Cheng et al., focuses on CMR techniques and especially those that may help to explore myocardial tissue morphology and function on a deeper level. Such CMR sequences, including mapping techniques and myocardial strain, can detect impaired microvascular integrity and early-stage myocardial fibrosis even without the need for contrast agent injection and within faster CMR scan protocols. Which types of heart disease will profit from such deeper phenotyping and if the latter can impact outcomes in patient care, merits further investigation in future studies.The work of Hashemi et al., demonstrated for the first time that patients without heart failure symptoms but at increased cardiovascular (CV) risk, demonstrate features seen in patients with heart failure with preserved ejection fraction (HFpEF), such as impaired myocardial deformation indexes at rest but normal strain during handgrip stress. Such individuals may lack clinical symptoms due to the compensation capacities of the myocardium and increased myocardial deformation during stress. This novel finding may imply that some patients at increased CV risk (stage A of heart failure by current guidelines) are candidates for developing HFpEF, which triggers the question if such individuals would be good candidates for preventive heart failure treatments in future pharmacological trials. Strain acquisitions were performed using strain-encoded MR (SENC) in this trial, which has been used in several previous studies for the diagnostic classification and risk stratification of patients with ischemic heart disease and non-ischemic cardiomyopathies  as well as with quality-of-life measures. In addition, the amount of preserved myocardial contractility by SENC enabled discrimination between symptomatic and asymptomatic individuals, even in those with normal LV-ejection fraction.Using a similar methodology, Gräni et al., used feature tracking imaging (FTI) to assess segmental myocardial strain in patients who underwent primary percutaneous coronary intervention (PCI) due to ST-elevation myocardial infarction (STEMI). Segments with late gadolinium enhancement (LGE) and additional microvascular obstruction (MVO) exhibited reduced strain; in this setting, FTI enabled the identification of such segments with MVO with relatively good diagnostic accuracy. Thus, a segmental strain may be a useful marker for contrast-free and fast detection of segments with a higher probability to remain dysfunctional during follow-up, aiding the early risk stratification of patients with STEMI. Using a similar methodology, Liu et al., combined myocardial strain by FTI and LGE imaging to differentiate patients with hypertrophic cardiomyopathy (HCM) from those with hypertensive heart disease (HHD). Based on multivariable regression analysis, a combined model of global radial strain by FTI and LGE allowed accurate classification of these two distinct clinical entities. This study may have important implications for patient care since therapeutic management largely varies between HCM and HHD.In another study, Massalha et al., investigated the presence of post-infarction pericarditis, diagnosed by pericardial LGE in patients with re-perfused STEMI. Pericardial LGE was present in 77.5% of the patients after STEMI and was not related to the presence of myocardial LGE or MVO. Unexpectedly, however, pericardial LGE was associated with a lower MACE rate during the follow-up period. This is an interesting finding, which possibly indicates that myocardial injury may activate the epicardium as a potential source of regenerative or reparative processes, and requires more in-depth analysis in future studies.Another CMR study, by Treiber et al., measured the influence of volume fluctuations due to different hydration statuses on the resultant native T1 values in 2,047 patients from a clinical all-comers CMR registry. For the first time in the current literature, a weak, albeit relevant influence of volume status was noted on native T1. Patients with volume expansion exhibited significantly higher native T1 values than non-volume-overloaded or dehydrated patients. Despite the effect of volume status on native T1, the latter was a predictor of all-cause mortality in this large, all-comer cohort. This is an important article highlighting the capabilities but also limitations of native T1 measures, which need to be considered by clinicians and scientists who study myocardial disorders such as myocarditis, cardiomyopathies, and cardiac amyloidosis. In this regard, an abnormal T1 value in the presence of normal metrics for myocardial morphology and function may not be enough for establishing the diagnosis of a myocardial disorder due to such variations, as described by Treiber et al. Thus native T1 needs to be judged together with other imaging parameters, clinical variables, and biochemical markers and not as a “stand-alone” value.In another study, Umer et al., summarized the role of CMR for the diagnostic classification and risk stratification of patients with Fabry disease. Hereby, the versatility of CMR provided an assessment of myocardial function and strain, LGE, native T1 mapping, and extracellular volume (ECV), which along with biomarker testing can effectively detect most cases with early organ involvement due to Fabry disease. In this context, it is important to note that fibrosis by native T1 mapping and LGE may become apparent with Morbus Fabry prior to left ventricular hypertrophy  markers, such as epicardial adipose tissue, pericoronary adipose tissue fat attenuation, and high-risk coronary plaque features such as positive remodeling, spotty calcifications, low-attenuation plaques, and the napkin-ring sign, including their role as potential precursors of plaque rupture causing acute coronary events. Epicardial adipose tissue (EAT) was recently shown to be associated with low-attenuation plaque burden , which is a known predictor of MACE. Indeed, a growing body of evidence supports the value of EAT as a surrogate marker of coronary wall inflammation, potentially triggering plaque progression and destabilization  in cardiovascular imaging is highlighted by Advances in cardiac imaging are of great clinical importance in current practice. Due to the plethora of imaging techniques and the associated costs, expansion of the diagnostic capabilities of each modality, and selection of the right imaging technique that will enable complete assessment of heart pathology is essential for optimal patient care. All the articles included in this Research Topic demonstrate how cardiovascular imaging can aid the diagnostic classification and risk stratification of patients with a wide variety of cardiac diseases. Standardization and harmonization of image analysis and interpretation among cardiologists and cardiac imagers need to be incorporated into the daily clinical practice, helping to further improve patient care and clinical outcomes.


Background and Objectives: Bone fractures contribute significantly to the global disease and disability burden and are associated with a high and escalating incidence and tremendous economic consequences. The increasingly challenging climate of orthopaedic training and practice re-echoes the established potential of leveraging computer-based reality technologies to support patient-specific simulations for procedural teaching and surgical precision. Unfortunately, despite the recognised potential of virtual reality technologies in orthopaedic surgery, its adoption and integration, particularly in fracture procedures, have lagged behind other surgical specialities. We aimed to review the available virtual reality systems adapted for orthopaedic trauma procedures. Materials and Methods: We performed an extensive literature search in Medline (PubMed), Science Direct, SpringerLink, and Google Scholar and presented a narrative synthesis of the state of the art on virtual reality systems for bone trauma procedures. Results: We categorised existing simulation modalities into those for fracture fixation techniques, drilling procedures, and prosthetic design and implantation and described the important technical features, as well as their clinical validity and applications. Conclusions: Over the past decade, an increasing number of high- and low-fidelity virtual reality systems for bone trauma procedures have been introduced, demonstrating important benefits with regard to improving procedural teaching and learning, preoperative planning and rehearsal, intraoperative precision and efficiency, and postoperative outcomes. However, further technical developments in line with industry benchmarks and metrics are needed in addition to more standardised and rigorous clinical validation. Traumatic bone conditions are an important contributor to global disease and disability burden. A worldwide incidence estimate using the framework of the Global Burden of Diseases, Injuries, and Risk Factors Study showed that there were 178 million new fractures in 2019, representing an increase of 33.4% since 1990 ,6. The iCoexisting with the escalating burden of traumatic bone conditions is an increasingly challenging climate of orthopaedic training and practice. The changing trends in clinical work hours, healthcare budgets, legislative frameworks, patient safety considerations, and public expectations significantly impact surgical training and practice in the current era ,14,15. Aextended reality [augmented virtual reality is also used distinctively in some literature to describe the real-time representation of physical world events in a virtual environment [Driven by the rapid evolution of computing power and imaging capabilities over the past few decades, several reality technologies have been developed for clinical and pedagogical applications. In orthopaedic trauma surgery, different modalities of reality technologies are currently available to support procedural teaching, practice, and patient-specific simulations, namely, virtual reality (VR), augmented reality, and mixed reality. These three reality modalities may sometimes be collectively described with the umbrella term  reality  , Science Direct, SpringerLink, and Google Scholar databases to identify original reports and relevant reviews focusing on the review subject. The following medical subject headings (MeSH) terms were used in various combinations using the Boolean operators “AND” and “OR” in accordance with the advanced search algorithms of the searched databases: “virtual reality” with ‘fracture’ or ‘bone’ or ‘trauma surgery’ ‘orthopaedics’ or ‘orthopaedic surgery’. The terms were tested on the platforms to obtain the best search strategy. The following search criteria were applied: full-text-accessible articles, articles in English, peer-reviewed original research papers or relevant systematic reviews, without restriction to the year of publication. Additional literature was sourced by reviewing the reference lists of all the studies identified from the database search.Two researchers (C.K.U. and N.U.) independently assessed the search results and screened the studies for relevance. The eligibility of the studies was evaluated in a stepwise approach: screening by title, followed by a critical reading of the abstracts and the full texts of potentially relevant studies. Differences between the two independent researchers were settled by a joint discussion with the other authors. We included only studies that specifically focussed on the application of VR systems in orthopaedic trauma procedures and performed a narrative synthesis of the extracted data using a thematic approach. Reports describing VR systems primarily developed for elective arthroscopy or arthroplasty procedures were excluded from the synthesis and discussion, but those adaptable for trauma procedures are highlighted in the appropriate contexts. Each author independently re-evaluated the extracted data and the initial narrative synthesis during the manuscript preparation process and the final draft were critically reviewed by two orthopaedic surgeons experienced with VR tools.Based on technical features and capabilities, VR platforms may be loosely categorised into low- and high-fidelity systems. High-fidelity VR modalities enhance immersion by simulating clinical and surgical environments and procedures with increased interactivity, visual accuracy and appeal, and content specificity. They allow the replication of most or all aspects of a procedure or technique, closely emulating the operating room environment ,38,39. CWhile there is currently no formal classification system for VR modalities in orthopaedic trauma, for convenience, we have categorised existing simulation modalities into those for fracture fixation techniques, drilling procedures, and prosthetic design and implantation. Surgical repair of bone fractures involves the reduction and fixation of the fracture fragments by means of screws, plates, or implants as appropriate for the nature and complexity of the fracture. Procedural accuracy is imperative for creating optimal mechanical and biological conditions for bone healing and restoration of bone anatomy and function. In addition, when an articulating joint like the hip, knee, or ankle is affected, it is essential to repair the bone joint surface precisely to prevent post-traumatic osteoarthritis. Enhanced surgical precision in orthopaedic trauma improves procedural safety, promotes proper anatomic healing, and reduces post-operative morbidity and long-term complications such as delayed, mal- or non-union, and post-traumatic osteoarthritis ,47,48,49® wrist prosthesis [The TraumaVision software developed by Swemac, Melerit, and Simulution Inc.  simulates a variety of orthopaedic trauma scenarios, including femoral neck fracture, trochanteric fracture, subtrochanteric fracture, femoral shaft fracture, pelvis fracture, spinal surgery, slipped capital femoral epiphysis, and Motecosthesis ,52. The osthesis . During The BoneDoc DHS simulator is a web-browser-based non-haptic VR platform that operates on a regular PC and mouse and simulates screw and plate fixation of hip fractures . Two-dimThe first patient-specific biomechanical model developed by Boudissa et al. could replicate success or failure in the virtual reduction of an acetabular fracture depending on the selected surgical reduction strategy and sequence . To recrThe SQ Pelvis software, a PC-based preoperative planning VR program with 3D visualisation and surgical simulation tools for pelvic and acetabular fracture, was developed by clinicians at the University Clinical Centre, Ljubljana, in collaboration with computer engineers from Sekvenca Inc. . The proA system that employs a novel blend of cutting-edge 2D/3D image processing and surface processing algorithms to virtually recreate shattered bone pieces for severity classification or preoperative planning in complex bone fractures was proposed by Liu et al. . A numbeA volume-based orthopaedic surgery simulator for complex orthopaedic surgeries, including arthroplasty, corrective or open osteotomy, open reduction of fractures and amputation, was developed by Tsai et al. . The sysThe innovative minimally invasive plate osteosynthesis (MIPO) approach in orthopaedic trauma surgery requires substantial training for adequate skill acquisition. A VR platform was developed by Negrillo-Cárdenas et al. for training in the MIPO technique for surgical reduction of humeral supracondylar fractures . It was VR systems have also been developed for procedures in non-appendicular bones. A surgical planning VR system for the evaluation and reconstruction of severe atrophic mandibular fractures was described by Castro-Núñez et al. . The tooPrecision drilling is an integral skill in orthopaedic surgery. Nonetheless, bone drilling is a delicate procedure that demands a high degree of dexterity and expertise. The associated high drilling resistance and intense vibrations make it difficult to grip the handpiece and escalate the risk of damage to the drill. An assessment of the impact of haptic feedback in VR simulation of cortical bone drilling using changes in drill plunge depth as an evaluative metric suggests that bone drilling simulation with haptic feedback is effective in simulating the required motor skill dexterity and control and leads to a decrease in soft tissue injury .To simulate and predict the hip drilling process, Tsai et al. developed a volume-based surgical simulator with haptic functions utilising a force and torque computation model and demonstrated its practical application in screw and plate surgery for hip trochanter fracture positioning . The forVankipuram et al. developed a realistic drilling software deploying a Geomagic Touch X haptic device for visiohaptic interaction with virtual bones. The program permits horizontal drilling into the femoral body with simulated targets for precision and tracks and analyses the surgeon’s movements to assess surgical proficiency. The simulator was confirmed to have a learning effect that is transferable to actual drilling, and its surgical performance indicators could distinguish the hierarchy of expertise from senior surgeons, residents, and medical students . SimilarThe Haptic Orthopaedic Training (HOOT) simulator developed at the Imperial College London focuses on dynamic hip screw (DHS) operations for certain hip fractures . DrillinPettersson et al. developed a surgical simulator for the drilling procedure in cervical hip fracture surgery. The volumetric dataset obtained from the patient’s CT scan is used to produce visuohaptic feedback by replicating fluoroscopic images and the drilling procedure. Prior to simulation, the bone must be relocated into the correct position. An automatic segmentation based on nonrigid registration with the Morphon method is deployed to identify the fracture’s constituent pieces and estimate the link between the fracture elements .This category of VR systems is mostly applied to elective orthopaedic procedures but is nevertheless highlighted for potential relevance in certain contexts related to orthopaedic trauma.The Virtual Operation Planning in Orthopaedic Surgery (VIRTOPS) software is a VR system for 3D planning and simulation of hip and pelvic surgeries, including endoprosthetic hip reconstruction with hemipelvic replacement . The sofAnother prosthetic placement VR modality is HipNav, an image-guided surgical navigation system. It combines a 3D preoperative planner, a simulator, and an intraoperative surgical navigator to precisely measure and direct the placement of prosthetic components during total hip arthroplasty . The useSeveral studies have reported the advantages of both high- and low-fidelity VR over conventional surgical training modalities ,83,84,85Validity assessments of bone trauma VR simulators show wide methodological variability, and no formal evaluation protocol currently exists. Twenty-two orthopaedic surgery residents participated in a stratified, randomised, controlled study that evaluated their performance on a virtual haptic-enabled ulnar fracture fixation simulator compared to the conventional synthetic manikin simulator (Sawbones simulator). It was noted that both methods demonstrated evidence of construct validity , but although the virtual simulator showed potential value as a surgical educational tool, it failed to attain similar standards as the Sawbones simulator ,89. CompWhen compared with a technique guide, VR was shown to improve both the procedural accuracy and completion rate in intramedullary tibial nail insertion in a recent randomised control trial, demonstrating its capacity to assist trainees in understanding surgical processes and manoeuvres . A similA recent randomised, controlled, double-blinded trial assessed the educational value of integrated haptic feedback in a VR bone drilling simulation comparing the performance  of 31 junior surgeons randomly allocated to a haptic or non-haptic group. The trainee doctors experienced a VR training module for drilling bicortical holes for screw insertion on a VR tibia bone model with either haptic or no haptic feedback, followed by an ex vivo identical test on a tibial sawbone model. The authors proved the higher performance of participants included in the haptic group, highlighting the potential educational role of haptic feedback in orthopaedic training simulation models .For training in the distal interlocking of intramedullary nails, the Digitally Enhanced Hands-On Surgical Training (DEHST) concept and technology scored highly in terms of training capability and realism and reliably differentiated between experts and novices . DEHST iIn a slipped capital femoral epiphysis model, orthopaedic trainees rated VR training as more valuable than reading/video methods despite similar performance outcomes  to training with physical simulations . FollowiVirtual preoperative planning enables the precise evaluation of fracture features and simulation of fracture reduction and internal fixation prior to surgery. Several studies have also evaluated surgical outcomes with virtual preoperative planning compared to traditional preprocedural planning. A range of intraoperative and postoperative indices have been applied for comparison, including surgical duration, intraoperative blood loss, radiation exposure frequency, clinical and radiographic quality of fracture reduction, and postoperative complications. Overall, compared to conventional planning, VR-based preoperative planning for fracture fixation was shown to be associated with enhanced intra-operative efficiency  and superior postoperative outcomes  ,104,105.Immersive VR has also been exploited as a form of distraction therapy and adjunct to surgical anaesthesia to alleviate pain and anxiety and promote patient relaxation ,107,108.While several advantages and benefits of VR simulation systems in bone trauma surgery have been highlighted, some important drawbacks and limitations should be equally understood. Currently, most immersive VR technologies suffer remarkable limitations with regard to image quality, degree of immersion, haptic accuracy, and other technical issues  . The disOver the past two decades, an increasing number of VR systems for orthopaedic trauma surgeries have been introduced, although a considerable number are still in the experimental phases. The use of VR simulation modalities minimises the reliance on patients, cadavers, and animals for surgical training and skill practice. VR training simulators aid in developing a visuospatial appreciation of anatomy and provide learners with a controlled, low-risk environment to practise techniques before attempting them on a real patient . Besides


Altered self-awareness or anosognosia may impact patients’ everyday life by interfering with their safe and independent functioning. Symptom awareness has been linked to executive dysfunctions caused by damage to frontal regions. Apathy is a frequent neuropsychiatric manifestation of Parkinson’s disease (PD) and is considered a consequence of altered functioning of cortico-subcortical circuitries connecting the prefrontal cortex (PFC) with the basal ganglia. Thus, apathetic PD patients may be not be fully aware of their condition due to shared neuropathophysiological mechanisms. The present study aimed to explore the awareness of apathy in PD patients by comparing the self-reported evaluations with their caregivers’ ratings. Moreover, we explored the clinical predictors of possible discrepancies and their consequences on patients’ self-reported evaluation of quality of life (QoL). We found a fair agreement between patients’ self-reports and caregivers’ ratings on apathy scores, with patients reporting less severe apathetic symptoms, especially those related to executive and auto-activation processing, compared to their caregivers’ reports. Executive functioning was found to mediate the relationship between disease stage and awareness of the apathetic state. Awareness of executive apathy impacted patients’ self-reported QoL. Therefore, PD patients might be unaware of their apathetic symptoms, especially those with worse executive functioning, which plays a key role in metacognitive processes such as self-monitoring and error detection. Anosognosia for apathy in PD patients may affect their QoL perception and leads to misleading self-report evaluations that delay diagnosis and treatment. Accurate awareness of one’s own abilities is essential for optimal everyday functioning, as this capacity allows one to select the most appropriate activities according to one’s own possibilities and limitations . AlteredAnosognosia frequently occurs in neurodegenerative and neurological diseases that cause progressive impairments in several functional domains  . TherefoAwareness deficits have been consistently linked to frontal dysfunctions, possibly because of the functionally integrative role of the prefrontal cortex (PFC) . More spIn non-demented PD patients, a reduced ability to recognize their own motor state has been reported regardless of functional impairment  ,8. HowevApathy, defined as a “simultaneous diminution in the cognitive and emotional concomitants of goal-directed behavior” , is a frConsidering that the possible under/over-estimation of apathy by patients may affect their identification and management and influence both QoL and overall prognosis, the present study aimed to explore the degree of awareness for each subtype of apathy in non-demented PD patients comparing self-reported evaluations with their caregivers’ ratings. Furthermore, we examined the possible clinical predictors of discrepancy in apathy scores and whether and how reduced awareness of apathy impacts self-reported QoL.Consecutive PD outpatients referred to the Movement Disorders Unit of IDC-Hermitage Capodimonte  were screened. PD patients were included in the study whether they met the following inclusion criteria: i. a diagnosis of idiopathic PD according to the clinical diagnostic criteria; ii. absence of cognitive decline by means of the Italian version of the Montreal Cognitive Assessment (MoCA > 15.5 ); iii. aDemographic  and clinical aspects  and part III of the Unified Parkinson’s Disease Rating Scale (UPDRS), Levodopa Equivalent Daily Dose (LEDD), and depressive symptomatology evaluated using the Beck Depression Inventory-II (BDI-II)  were recAll participants gave their written informed consent to participate in the study, which was approved by the Local Ethics Committee and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.Apathy was evaluated using the Italian version of the Dimensional Apathy Scale (DAS) ,24, a quPatients and their caregivers completed DAS. All caregivers were patients’ relatives who routinely cared for them and lived in the same household. None of participants had cognitive impairments or significant psychiatric disorders, and they were previously informed of the aims of the study.All participants underwent a neuropsychological assessment covering different aspects of executive control ,27,28, sWe calculated descriptive statistics about the demographic, clinical, and neuropsychological variables of the sample.To evaluate the agreement between patients’ self-reports and their caregivers’ ratings on the occurrence of apathy (apathetic vs. non-apathetic) , Cohen’sBoth patients’ self-report and caregivers’ rating scores were converted into Z scores based on Italian normative data , with hiMoreover, to explore the clinical predictors of a discrepancy, we carried out multiple regression analyses entering the discrepancy scores for the DAS total score and its subscales as dependent variables and age, UPDRS-III, H&Y, LEDD, and executive control score as predictors. In the same way, to investigate whether and how discrepancy scores affected the self-reported quality of life scores, multiple regression analyses entered clinical variables and discrepancy scores as independent variables and QoL (PDQ-8) as dependent variables.Subsequently, designed mediation models were tested to examine the exact nature of these relationships. The bootstrapping procedure with 5000 samples and replacement from the full sample was used to construct bias-corrected 95% confidence intervals . Mediation models were carried out using SPSS Macro PROCESS . The sigWe included 67 PD patients. Descriptive statistics about demographic, clinical, and neuropsychological are reported in p = 0.037). A significant difference between patients’ and caregivers’ ratings emerged on the DAS total score  = 8.250; p = 0.005; η2 = 0.111), with caregivers reporting higher scores  than patients , with caregivers reporting higher scores  than patients   and lower executive control scores . Moreover, lower H&Y scores were associated with a higher discrepancy on the DAS executive subscale , while higher UPDRS-III scores were associated with a higher discrepancy on the DAS behavioral/cognitive initiation subscale . No significant association was found between the discrepancy on the DAS emotional subscale and the clinical variables.Multiple regression analysis revealed that higher discrepancies in DAS total scores (patients’ underestimation of apathy) were related to less severe H&Y stage , and consequently, lower H&Y  and poorer executive control  were related to a higher discrepancy on the DAS total scores (patients’ underestimation of apathetic symptoms). Examining the indirect effects, using the bootstrap-generated bias-corrected CI approach, a significant indirect effect of the H&Y stage on discrepancy through executive control was found . Thus, better patients’ executive control mediated the effect of H&Y stage, leading to less discrepancy in apathy ratings, while worse executive control mediated the effect of H&Y stage, producing a more pronounced discrepancy in apathy ratings.Subsequently, a mediation model was designed to explore the nature of the relationship between H&Y stage, executive control, and the discrepancy in the DAS total score. We found that a less severe H&Y stage was related to higher executive control  and less discrepancy on the DAS executive subscale (patients’ overestimation of apathy)  were associated with poorer QoL.Multiple regression analysis indicated that more severe H&Y stage  and lower discrepancy on the DAS executive subscale (patients’ overestimation of apathy) , but not to executive control . Analyses of the indirect effects revealed a significant indirect effect of H&Y stage on self-reported QoL through discrepancy on executive subscale  and of H&Y stage on QoL self-report scores through a mediation pathway involving executive control and discrepancy on the DAS executive subscale  . Therefore, the less severe H&Y stage associated with more preserved executive control and less discrepancy in executive apathy ratings generated poorer ratings of QoL. In contrast, the more severe H&Y stage related to worse executive control and more discrepancy in executive apathy ratings resulted in better QoL ratings  . CognitiIn contrast, apathy related to an “auto-activation” deficit results from a failure to reach the threshold of initiation/activation of thoughts or actions on an internal basis and can be reversed by external stimulation (“hetero-activation”). Alterations in the dorsal-medial regions of the PFC, including the supplementary motor area (SMA) and the dorsal part of the anterior cingulate cortex (ACC), have been related to “auto-activation” deficits . This diTaking this into account, the lack of awareness of PD patients in these dimensions of apathy might be explained by common neuropathophysiological mechanisms involving both the DLPFC and ACC, which exert a pivotal role in the online monitoring of performance and error detection ,33,34,35Nevertheless, a dissociation emerged between patients’ unawareness of apathy, expressed by the executive and initiation dimensions, and their preserved emotional reactivity resulting from the DAS emotional subscale. These findings are in line with previous studies conducted in the AD population, showing that AD patients are not prone to awareness deficits of emotional aspects of functioning, manifesting appropriate emotional reactivity to the experience of failure in cognitive tasks despite limited awareness of the condition or performance ,38.The evaluation of possible clinical predictors of discrepancy scores revealed that worse executive control and less severe functional disability  were associated with greater discrepancy scores. Interestingly, an inverse relationship between unawareness of motor symptoms and disease severity has been observed in PD ,40, leadWithin this context, executive functioning emerged as a mediator of this relationship, with worse executive control associated with unawareness of the apathetic state. Executive models of self-awareness focus on the role of higher-order executive processes that regulate self-monitoring mechanisms and relate to several metacognitive abilities, such as recognition of deficits, understanding their functional implications, and setting realistic goals accordingly ,42. AlteMoreover, exploring whether and to what extent discrepancy scores on the DAS subscales can predict the level of QoL reported by patients, we found that poorer patients’ QoL ratings were affected by more severe PD stage/functional disability (H&Y) and more awareness of executive apathy. More specifically, awareness of executive apathy mediated the relationship between functional disability and subjective QoL reports, with greater awareness associated with worse QoL. To this, our findings suggest that executive control and awareness of executive apathy mediate the relationship between disease stage/functional disability and subjective QoL reports (H&Y -> executive control -> awareness of executive apathy -> subjective QoL reports), further highlighting the inaccuracy of apathetic symptoms and QoL when subjectively reported by patients. Paradoxically, patients in a more severe PD stage and with poorer executive control were unaware of their apathetic symptoms, scoring better QoL; on the contrary, patients in a less severe PD stage and with preserved executive functioning were more aware of their apathetic symptoms and reported worse QoL. Overall, our findings confirm the key role of executive functioning, especially self-monitoring, in symptom awareness in PD and suggest the need to investigate neuropsychiatric aspects such as apathy not only through self-report measures but also using an informant version of tools, since patients might not be aware of their condition.However, some limitations should be addressed. First, subjective features such as personality traits and psychological burden may impact patients’ reports, resulting in under/overestimation of symptoms. Moreover, it should be considered that the knowledge each caregiver has of patients’ symptomatology may vary across participants; however, in our study, we identified the person most involved in patients’ everyday life and care. To this, the development of objective measures such as performance-based tools  and the In conclusion, the present study aimed to investigate PD patients’ apathetic symptoms also through informant-report measures, especially in those with poorer executive functioning, as they might be unaware of their condition. Unawareness of apathy in PD patients provokes frustration in their caregivers and family members who must assist resistant patients, but also has profound implications for themselves as it can delay the diagnosis and implementation of targeted treatment strategies and ultimately affect the overall prognosis.


More than two-thirds of epithelial ovarian cancer (EOC) patients are diagnosed at advanced stages due to the lack of sensitive biomarkers. Currently, exosomes are intensively investigated as non-invasive cancer diagnostic markers. Exosomes are nanovesicles released in the extracellular milieu with the potential to modulate recipient cells' behavior. EOC cells release many altered exosomal cargoes that exhibit clinical relevance to tumor progression. Exosomes represent powerful therapeutic tools (drug carriers or vaccines), posing a promising option in clinical practice for curing EOC in the near future. In this review, we highlight the importance of exosomes in cell–cell communication, epithelial–mesenchymal transition (EMT), and their potential to serve as diagnostic and prognostic factors, particularly in EOC. Exosomes are nanovesicles released in the extracellular milieu by diverse cell types and serve as carriers of proteins, and nucleic acids, with the potential to modulate the recipient cells. Understanding the functions of exosomes as messengers between cancer and healthy cells unfolds new avenues in intercellular signaling mechanisms. In this review, we have highlighted the importance of exosomes in cell–cell communication and their potential to serve as diagnostic and prognostic factors in EOC. Furthermore, we believe that exosomes could represent a powerful therapeutic tool due to their ability to function as drug carriers or vaccines posing a promising option in curing EOC.  Ovarian cancer is a lethal gynecological malignancy and is commonly regarded as a silent killer due to the lack of symptoms in the early stages of the disease ,2. EpithStage I EOC patients account for only 10% of the total EOC cases and are characterized by a more favorable prognosis ,9. HowevExosomes have recently been implicated in a plethora of physiological and pathological processes, including cancer ,27. FurtExosomes are a subset of extracellular vesicles (EV) composed of a lipid bilayer ranging from 30–100 nm in diameter . It is rThe biogenesis of exosomes involves early endosome formation through the invagination of the plasma membrane ,38, a fuvia direct signaling through surface molecules, receptor-mediated endocytosis, or phagocytosis ..66].via these factors ..137].miR-16, miR-21, miR-93, miR-100, miR-126, miR-200b, miR-223, and miR-320) was reported in EOC patients as compared with healthy individuals. Furthermore, elevated expression levels of exosomes were observed in the plasma of EOC patients, particularly FIGO IV patients, compared with healthy women, indicating that higher exosomal release correlated to higher invasive potential [For example, deregulated expression of eight exosomal miRNAs  in OC cells following exosome treatment, which regulated, in turn, the PTEN/AKT pathway [Similarly, several studies implicate lncRNAs as cancer-associated molecules enriched within exosomes see  and haverognosis . Similar pathway .miR-21 to OC cells promoted resistance to paclitaxel by targeting the APAF1 gene [miR-433 was observed to cause the downregulation of cyclin-dependent kinase 6 to promote paclitaxel resistance in OC cells [miR-223 obtained from hypoxic macrophages induced chemoresistance of OC cells by regulating the PTEN-PI3K/AKT signaling pathway [One of the main obstacles to the treatment of cancer patients is chemoresistance, with the highest chemoresistance rates observed in OC patients. Recent studies have revealed the role of exosomal miRNA in developing chemoresistance in OC cells . ExosomaAF1 gene . SimilarOC cells . In OC p pathway .UCA1 was elevated in serum exosomes derived from cisplatin-resistant OC tissues and cell lines compared with normal ovarian samples. Moreover, inverse relation was observed between UCA1 and miR-143 in serum exosomes obtained from OC samples. Hence, UCA1 induced cisplatin resistance in OC by sponging miR-143, which resulted in the upregulation of FOSL2 [Similarly, long noncoding RNA of FOSL2 .Exosomes contain several proteins such as cytosolic, common membrane proteins, and origin-specific sub-set of proteins that reflect cell function . Numerouet al. showed the enrichment of cancer-associated signaling pathway proteins within the exosomes such as epithelial cell surface antigen (EpCAM), epidermal growth factor receptor (EGFR), apolipoprotein E (APOE), proliferation cell nuclear antigen (PCNA), with a potential role as diagnostic markers and therapeutic targets for OC treatment [et al., exosomal protein content was higher in advanced stages than in the early stages of OC. Furthermore, TGF-β and MAGE3/6 could be used as markers to distinguish patients with benign tumors from OC patients [In EOC, exosomal proteins play a role in tumor growth and metastasis . A previreatment . In the patients . Hence, patients .in-vivo has been characterized by emerging techniques such as liquid biopsy, thereby unraveling their clinical importance [The therapeutic potential of exosomes portance . Furtherportance ,158. Undportance .miRNA-155 inhibitor were successfully delivered to the mouse hepatocytes resulting in the downregulation of TNF in the recipient cells, demonstrating its application in nanomedicine [miRNAs and lncRNAs play a key role in human pathologies such as cancer. Profiling exosomal miRNAs serve as a promising tool for cancer and may be used for monitoring disease recurrence and responses to therapies . Recentlmedicine .et al. demonstrated 50-times higher cytotoxicity in drug-resistant cancer cells upon treatment with paclitaxel-loaded exosomes compared with paclitaxel alone [in-vivo [Several reports have identified the ability of exosomes to precisely deliver drugs to the tumor cells, thereby enhancing the efficacy of cancer treatment. Kim el alone . Similar[in-vivo . In trip[in-vivo . Similar[in-vivo .Exosomes have proved to be an attractive tool for scientists to examine the diversified roles in the transduction of different contradictory signals based on the information they carry. They are suspected of playing crucial roles in EMT, promoting metastasis, cell survival, and drug resistance. Interestingly, recent data pinpoint exosomes as potential biomarkers for several diseases, including cancer of the ovary. This can be an essential step in improving therapies and managing conditions.One of the reasons for the failure of EOC treatment is the detection of the disease at advanced stages in addition to either ineffective drug delivery to the tumor site or acquired resistance to chemotherapy. Therefore, biological markers with the potential to detect EOC at early stages would help improve therapies and overall survival. Exosomes can potentially serve as an effective noninvasive tool as they are carriers of nucleic acids and proteins, which are known to be altered according to the pathological conditions of the patients.Liquid biopsy, a minimally invasive blood test, is increasingly used for the early detection and prognosis of EOC patients, and circulating exosomes are a great source of liquid biopsy analysis. The circulating exosomal ncRNAs are gaining wide attention as they represent a crucial source of liquid biopsy markers in cancer diagnosis, prognosis, and response to treatment. In addition, exosomes could be utilized in real-time cancer detection, identifying tumor stages and therapeutic responses . FurtherDespite the strides in elucidating exosome-associated molecular mechanisms of tumor progression, further efforts are required to utilize the therapeutic potential of exosomes for clinical practice. In addition, further studies on the enormous sample size are required to attain knowledge of its diagnostic value as well as a standardized protocol should be devised for the isolation and characterization of exosomes. Hence, a deeper understanding of the exosome heterogeneity and its use as a drug delivery tool can open new avenues for combating EOC.Exosomes are nanovesicles released in the extracellular milieu by diverse cell types and serve as carriers of proteins, and nucleic acids, with the potential to modulate the recipient cells.Understanding the functions of exosomes as messengers between cancer and healthy cells unfolds new avenues in intercellular signaling mechanisms.Functional characterization of exosomal contents through different techniques opens a new approach to discovering novel EOC biomarkers with the potential to discriminate patients at early stages.Several findings have highlighted the involvement of exosome encapsulated genes in EOC angiogenesis, proliferation, migration, and tumor growth, thereby serving as diagnostic and prognostic factors in EOC progression and metastasis.Exosomes could represent a powerful tool for therapeutic interventions due to their ability to function as drug carriers or vaccines posing a promising option in curing EOC.


Intrauterine growth restriction (IUGR) represents a condition where the fetal weight is less than the 10th percentile for gestational age, or the estimated fetal weight is lower than expected based on gestational age. IUGR can be caused by various factors such as maternal, placental or fetal factors and can lead to various complications for both the fetus and the mother, including fetal distress, stillbirth, preterm delivery, and maternal hypertension. Women with gestational diabetes are at an increased risk of developing IUGR. This article reviews the different aspects of gestational diabetes in addition to IUGR, the diagnostic methods available for IUGR detection, including ultrasound and Doppler studies, discusses the management strategies for women with IUGR and gestational diabetes and analyzes the importance of early detection and timely intervention to improve pregnancy outcomes. Fetal growth results from the intricate interplay between the fetus’s genetic capacity for growth and the effects of the intrauterine environment on the mother. The three leading sources of intrauterine growth restriction (IUGR) are placental, maternal, and fetal. Although these components frequently overlap, such a separation is more theoretical than practical. Low birth weight puts the child at risk of cardiovascular diseases and type 2 diabetes mellitus, in addition to the increased risk of short-term problems caused by impaired fetal growth, with intrauterine fetal mortality as the most serious ,2. IUGR In diabetes pregnancy, fetal growth anomalies are common, with large for gestational age (LGA) as the commonest. LGA is extensively researched and is particularly commonly related to maternal hyperglycemia. Nevertheless, other variables such as prenatal weight gain and maternal lipids could also have an impact ,9,10,11.The pathophysiology of fetal growth in the context of gestational diabetes mellitus is intricate and multifaceted. Gestational diabetes, characterized by glucose intolerance during pregnancy, can significantly impact fetal development, and has been associated with several fetal complications, including macrosomia and intrauterine growth restriction (IUGR) . Many riWhile macrosomia is a common outcome, gestational diabetes can also lead to IUGR. One of the mechanisms proposed for IUGR involves maternal microangiopathy—damage to small blood vessels—which is associated with longstanding diabetes . MicroanMaternal microvascular complications, such as microangiopathy, can lead to a decrease in uteroplacental blood flow, resulting in fetal hypoxia and nutrient deprivation . These cIn addition to glucose, other metabolic substrates such as amino acids are essential for fetal growth. Altered amino acid metabolism, as seen in gestational diabetes, can contribute to deviations in fetal growth. Gestational diabetes-associated changes in the maternal and fetal amino acid profile, specifically, reduced levels of essential amino acids, can lead to fetal growth restriction .It is important to note that gestational diabetes-associated fetal growth abnormalities can have long-term health implications for the offspring, including an increased risk of obesity and type 2 diabetes in later life . This unFetal growth is stunted when an unhealthy intrauterine milieu prevents the fetus from receiving enough of the nutrients it needs to grow. In one rat model of UPI, the pregnant rats (Sprague Dawley rats) have the bilateral uterine artery ligation surgery on day 18 where the term is 22, of their pregnancies and then give birth naturally. Lowered levels of insulin, glucose, IGF-1, oxygen, and amino acids are observed in uteroplacental insufficiency (UPI) fetal rats, mirroring the metabolic profile of human babies with a developmental delay ,26. UntiMitochondrial reprogramming could be an essential mechanism that lets the developing fetus survive in a low-energy setting, but it can have negative effects on cells that have higher energy demands. Islets from children exposed to UPI showed steady increases in reactive oxygen species production and oxidative stress . ATP proA diabetic background can cause a variety of histopathological abnormalities in the placenta. While some are not unique to diabetic placentas, villus maldevelopment, fetal vasculitis, and vascular malperfusion may be regarded as risk factors for fetal growth restriction. Maternal vascular malperfusion develops due to insufficient and partial trophoblast infiltration and poor spiral artery transformation ,31. FurtIt is well-established that preeclampsia occurs at a much higher rate in pregnancies where the mother has type 1 diabetes. The risk also increases over time, with the highest occurrence being observed in females with diabetic nephropathy, who are thus at the highest possible chance of developing IUGR . In termCurrently, gestational diabetes mellitus can be identified by specific serological markers . HoweverOne such marker of primary interest is hemoglobin A1c (HbA1c), a form of hemoglobin that is chemically linked to a sugar, typically glucose. The higher the level of glucose in the blood, the more HbA1c is formed. As such, it provides an accurate estimate of average blood glucose levels over the past 2–3 months. While HbA1c is traditionally used in diagnosing and monitoring type 1 and type 2 diabetes, its role in gestational diabetes is currently a subject of extensive research .Another serological marker related to gestational diabetes is insulin. Pregnant women often exhibit some degree of insulin resistance due to the hormone changes that occur during pregnancy. However, when the body cannot compensate for this resistance by producing enough insulin, gestational diabetes can develop. Monitoring insulin levels, therefore, can be crucial in the early detection and management of gestational diabetes .Apart from these, there are several other biochemical markers associated with inflammation, oxidative stress, and endothelial dysfunction that have been linked to gestational diabetes. These include, but are not limited to, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and adiponectin. Elevated levels of these markers suggest an inflammatory response, which can contribute to insulin resistance and the development of gestational diabetes ,37,38.Finally, emerging research has pointed to the potential role of certain gut microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO), as serological markers for gestational diabetes. Recent studies have shown that elevated TMAO levels are associated with an increased risk of gestational diabetes, suggesting that gut microbiota dysbiosis may play a role in the disease’s pathogenesis .Except for early diagnosis of gestational diabetes, an increasing body of evidence suggests the use of important serological markers has proven to be an invaluable tool in identifying IUGR.One key marker that has been identified is advanced glycation end products (AGEs). These compounds are typically formed when proteins or lipids become glycated after exposure to sugars, and they can be particularly harmful in the context of diabetes, where blood glucose levels are often poorly controlled. AGEs can interfere with normal cellular function and induce inflammation, leading to endothelial dysfunction and vascular complications. Studies have shown that high levels of AGEs are often present in women with gestational diabetes, signifying the occurrence of microangiopathy .Another crucial serological marker in the context of gestational diabetes and IUGR is the vascular endothelial growth factor (VEGF). This protein plays a pivotal role in blood vessel formation, a process that is crucial to the development and function of the placenta. Alterations in VEGF levels have been associated with many pregnancy complications, including IUGR. In cases of gestational diabetes, elevated blood glucose levels can cause overexpression of VEGF, leading to abnormal placental vasculature and impaired nutrient and oxygen transport to the fetus, thereby inducing IUGR .Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are also important serological markers to consider. These substances are typically elevated in response to stress and can contribute to inflammation and endothelial dysfunction, further complicating the picture of gestational diabetes and IUGR ,43.Although placental histopathology observations give significant and clinically reliable information, they are always comprehensive and reflect pathogenic mechanisms and alterations that occurred weeks or months prior to delivery. Doppler ultrasound, which allows for real-time evaluation of placental and fetal circulation, is commonly employed in the management of high-risk pregnancies. Furthermore, irregular uterine and umbilical Doppler velocity waveforms are linked to abnormal placental pathology in IUGR ,45,46,47Pietryga et al. found that pregnant women having type 1 diabetes who had vasculopathy had considerably higher uterine artery vascular impedance. Additionally, rising uterine artery scores were linked to a higher frequency of SGA babies. White found that aberrant uterine Doppler was nearly entirely detected in females with R/F retinopathy and nephropathy in this investigation ,49. DoppSalvesen et al. found that diabetic vasculopathy is directly related to impaired placental functioning. It involved 41 females with type 1 diabetes that had cordocentesis within 24 h of giving birth. Researchers discovered that all fetuses of mothers with hypertension and nephropathy had an umbilical vein pH significantly below the normal gestation mean (5th percentile) .Generally, IUGR fetuses are distinguished by an approximated fetal weight (EFW) lower than the 10th percentile. However, the Royal College of Obstetricians and Gynecologists (RCOG) indicates that IUGR diagnosis may be determined by means of the fetal abdominal circumference (AC) that is below the 10th percentile ,4,5. As Monitoring pregnant women with gestational diabetes mellitus (GDM) is a multi-faceted process that requires regular assessment of both maternal and fetal health parameters. Low APGAR scores, intrauterine fetal death (IUFD), neonatal mortality, preterm delivery, and impaired neurodevelopment of the child are all risks of IUGR of serious pregnancy results. The goal of careful monitoring of the fetus with IUGR is to determine the most risk-free timing for delivery. Even the most skilled obstetrician may struggle with this, particularly in instances of fetal preterm birth. As a result, various considerations must be carefully considered when deciding on the date and style of delivery for an IUGR fetus. The etiology of IUGR is always essential in terms of management. Determining the underlying cause of restricted fetal development is critical, and placental inadequacy is among the most significant challenges to monitoring unexpected types of IUGR, particularly in females with preeclampsia and nephropathy.The primary goal of monitoring is to maintain blood glucose levels within a specific target range to minimize the risks of GDM-related complications . Blood gThe decision to deliver is frequently based on proof of deterioration of the maternal condition and acute fetal distress or both. Adequate prenatal surveillance and timely delivery could minimize the likelihood of perinatal morbidity and mortality in diabetic women. Furthermore, because of the unanticipated delivery time, the RCOG advises that a single dose of corticosteroids be administered during pregnancy with restricted fetal development and expected preterm delivery until 35 + 6 weeks of gestation . Aside fDiabetes and IUGR-complicated pregnancies among women must be handled by maternal–fetal medical professionals competent in diabetic pregnancy within a perinatal facility with accessibility to a neonatal intensive care unit.Women with different types of diabetes may experience changes in their fetus’s growth patterns, making serial ultrasound measurements all the more important. It is now up to clinical discretion to decide how long to wait between scans because no optimal intervals have been identified. The risk of a false-positive diagnosis can be reduced, however, by taking further measurements at least every three weeks. Fewer gaps in fetal biometry monitoring may be beneficial for women with IUGR and type 1 diabetes .Ultrasound imaging during pregnancy typically includes an evaluation of the fetus’s AFV (amniotic fluid volume). Although oligohydramnios has been associated with perinatal mortality and SGA, its ability to predict an individual’s risk of these outcomes is limited. Thus, AFV evaluation is not sufficient for monitoring IUGR fetuses alone. Nevertheless, when combined with Doppler ultrasounds or included in biophysical profiles, this may offer additional information on fetal well-being that may be utilized for therapeutic purposes (BPP). The amniotic fluid volume (AFV) can be calculated in two ways: subjectively  and objectively (using the amniotic fluid index [AFI] and the single deepest pocket [SDP]). When subjective assessments reveal a lower AFV or when patients are at rising risk of IUGR, objective AFV assessment is encouraged. A contrast of SDP and AFI found that AFI was related to a greater rate of erroneous positive oligohydramnios diagnosis, which might also lead to unwarranted induction of labor. As a result, SDP assessment could be preferable to AFI, particularly in preterm pregnancies .Doppler ultrasound accurately reveals impairments of fetoplacental and uteroplacental circulation associated with maternal vasculopathy in the event of IUGR. Umbilical Doppler velocimetry is extensively suggested as a primary tool for the IUGR fetus follow-up. Additionally, it is critical in diagnosing the reason for restricted fetal development . Women having type 1 diabetes who are at risk of IUGR, particularly the ones with diabetic nephropathy, might benefit from starting low-dose aspirin at 12 weeks of gestation. Delivery needs to be considered when Ductus Venosus (DV) doppler anomalies or Umbilical Vein (UV) pulsation are observed in fetuses with lacking or reverted end-diastolic velocity detectable before 32 weeks. Antenatal steroids need to be given until 35 + 6 weeks of gestation if preterm delivery is expected .Gestational diabetes mellitus and its correlation with intrauterine growth restriction present a complex interplay of physiological, metabolic, and molecular factors. This review illuminates the multifactorial pathophysiology, underlining the role of hyperglycemia, microangiopathy, placental abnormalities, and altered nutrient transport. Further, it emphasizes the pivotal role of early diagnosis of gestational diabetes in preventing the onset of IUGR and other adverse pregnancy outcomes. Current diagnostic approaches, including the use of serological markers and ultrasonography, have been discussed, highlighting their efficacy and limitations. The management of gestational diabetes-induced IUGR involves maintaining optimal blood glucose levels, regular fetal monitoring, and timely delivery to avoid further complications. The importance of a comprehensive approach, including lifestyle modifications and, if necessary, medication, has been underscored. Despite significant advancements in understanding the pathophysiology and management of gestational diabetes and IUGR, there remain several areas that warrant further research. These include the identification of novel serological markers for the early detection of gestational diabetes, a deeper understanding of placental abnormalities, and the development of more effective therapeutic strategies. The goal is to improve both immediate and long-term health outcomes for mother and child. The complexity of gestational diabetes and its impact on fetal growth necessitates ongoing, interdisciplinary collaboration and research efforts to ensure the best possible outcomes for these pregnancies.


Streptococcus pneumoniae VE ranges from 80% to <10%, depending on the season and infecting strain/serotype. Nonetheless, for all three pathogens VE decreases with age, which is caused by deficiencies in the capacity of older adults’ immune systems to mount productive and persistent antibody and/or cell-mediated responses to the vaccine [As illustrated by the COVID-19 pandemic, older age, particularly when accompanied by common chronic illnesses of aging, is arguably the most significant population attributable factor for severe outcomes of acute respiratory infection, including the risk of hospitalization, disability and death. In the absence of widely available and highly effective treatments, vaccines remain our most powerful tool to help overcome this vulnerability through the prevention of primary infection, and far more importantly, by improving clinical outcomes once infection does take place. In the case of SARS-CoV-2, vaccine effectiveness (VE) against hospitalization was remarkable for dominant strains prior to omicron, whereas for influenza or Two FDA-approved seasonal influenza vaccines have been developed to overcome aging-related declines in immune responses, one employing an adjuvant  and the other increased dosage . Both vaccines are safe and improve VE and vaccine immunogenicity to a greater extent than earlier non-adjuvanted or standard dose formulations; however, they are also associated with higher rates of non-fatal adverse events and can cost upwards of three times that of standard formulations. Considering that many adults above 65 maintain the immunological fitness required to generate protective immunity from standard vaccine formulations, utilizing a “blanket” approach where all older adults at a specified age are provided these improved vaccines may not be optimal. However, a question remains: how do we identify those vulnerable individuals who require the additional protection of an enhanced vaccine platform?higher in those with an older or accelerated biological age [Although informative, cross-sectional studies comparing immune parameters across age groups to understand “immune aging” risk ignore the degree to which departures from healthy aging might contribute. Healthy aging can be considered a health trajectory where sufficient function is maintained, thereby enabling optimal well-being until end of life; hence, significant deviations from this trajectory will drive vulnerability to adverse outcomes beyond what can attributed to chronological age alone. To date, most studies evaluating such deviations from normative aging do so by enumerating a defined set of clinical manifestations of the frailty syndrome, or a more cross-cutting set of health deficits that comprise a frailty index . Althougical age . The effical age , and cauical age .On one level, our findings demonstrating enhanced humoral responses in individuals with evidence of more rapid biological aging may seem counterintuitive, given that VE decreases with chronological age and frailty. However, a careful evaluation of immune aging through a systems-based lens, one that highlights the dynamic and temporal nature of immune responses , sheds aUltimately, while both chronological and biological age appear to be important determinants of vaccine-preventable outcomes in older adults, the underlying context and mechanisms of their effects remain unclear. Do deviations from a healthy aging trajectory merely exacerbate age-related defects in vaccine-induced immune mechanisms, aligning with the hypothesis that these individuals are experiencing a form of “accelerated aging”? Alternatively, do these deviations comprise independent cellular and molecular alterations that impair vaccine responses, or in the case of our recent work , improve


In light of the disappointing termination of clinical trials with potent complex I inhibitors, such as IACS-010759, justification for oxidative phosphorylation inhibitors and mitochondrial targeting strategies has been called into question. Consideration of these agents’ potency, tissue selectivity and toxicity demonstrate what lessons can be learned from this failure and where new opportunities lie. The field of cancer metabolism has evolved greatly over the last 100 years, from the seminal discovery of aerobic glycolysis in tumours to more recent evidence that respiration is not inconsequential and is frequently enhanced in cancer. More specifically, as dependencies on oxidative phosphorylation (OXPHOS) appear prevalent in a variety of aggressive cancer types, the development of OXPHOS inhibitors through targeting the electron transport chain has shown promising pre-clinical efficacy –4.IACS-010759 was developed as a highly potent complex I inhibitor and demonstrated promising anti-cancer efficacy in multiple animal models within a moderate safety window. However, Yap et al. have carefully reported the results of two phase I clinical trials of IACS-010759 in patients with advanced solid tumours (23 patients), some with OXPHOS sensitive mutations, and refractory acute myeloid leukaemia (AML) (17 patients). IACS-010759 had unacceptable toxicities including elevated blood lactate, lactic acidosis, vomiting, and peripheral neuropathy; resulting in early trial termination . Dose-reThe extremely narrow, if any, therapeutic window of IACS-010759, is likely attributed to its highly potent, on-target complex I inhibition, which operates on a nanomolar range in vitro, similar to toxins targeting complex I e.g., rotenone. Excessive inhibition of mitochondrial respiration is clearly associated with a glycolytic shift towards increased lactate production and lactic acidosis, a common adverse event with IACS-010759. However, other less potent OXPHOS inhibitors such as metformin, nitric oxide and arsenic trioxide, have been widely used in clinics for decades for indications outside of oncology and have established safety profiles . Many moThe clinical applications of OXPHOS inhibitors can extend beyond anti-proliferative chemotherapies. Tumour hypoxia, which results from an imbalance between oxygen demand and delivery within the chaotic vasculature of solid malignancies, is strongly implicated in radiation therapy resistance. Modest reductions in cellular oxygen consumption, modelled to be approximately 30% can increase local oxygen availability in tumours to alleviate hypoxia and improve radiosensitivity . ReducinIncreasing the differential biological effect a drug has on its target tissue is another strategy that can improve therapeutic benefit without exacerbating healthy tissue toxicity. Drug design strategies to mitigate this can include the addition of mitochondria targeting moieties, such as triphenylphosphine (TPP+). TPP+ is a lipophilic molecule that possesses delocalised cations enabling its accumulation in the mitochondria matrix according to the charge differential across the plasma and mitochondria membranes – see Fig. While the early termination of IACS-010759 comes as disappointing news in the development of metabolism targeting therapies, there are several ways ahead for selectively targeting mitochondria in cancer. Preclinical toxicology highlights the problems of using different species which have subtle differences in the susceptibility of their mitochondria at a target and tissue level. Considerations for the impact of OXPHOS inhibition on the tumour microenvironment, including proliferation of different types of T-cells, should also be evaluated carefully in the development of new inhibitors. Additional approaches may include organotypic tissue cultures of normal susceptible tissues, tumour organoids, and immunocompetent in vivo models such as genetically engineered mouse models.


Multiple studies have shown that extracellular vesicles (EVs) play a key role in the process of information transfer and material transport between cells. EVs are classified into different types according to their sizes, which includes the class of exosomes. In comparison to normal EVs, tumor-derived EVs (TDEs) have both altered components and quantities of contents. TDEs have been shown to help facilitate an environment conducive to the occurrence and development of tumor by regulation of glucose, lipids and amino acids. Furthermore, TDEs can also affect the host metabolism and immune system. EVs have been shown to have multiple clinically useful properties, including the use of TDEs as biomarkers for the early diagnosis of diseases and using the transport properties of exosomes for drug delivery. Targeting the key bioactive cargoes of exosomes could be applied to provide new strategies for the treatment of tumors. In this review, we summarize the finding of studies focused on measuring the effects of TDE on tumor-related microenvironment and systemic metabolism.Video AbstractThe online version contains supplementary material available at 10.1186/s12964-023-01111-6. In the last few years, there has been increased interest in the roles and biological functions of extracellular vesicles (EVs). Exosomes are one type of EVs and are 30-100 nm in diameter . ExosomeThe formation process of exosomes is thought to begin with the establishment of intraluminal vesicles (ILVs), which accumulate in the lumen and then lead to the formation of multivesicular bodies (MVBs). While a proportion of MVBs are degraded by lysosomal fusion, MVBs could also bind to the plasma membrane and could be secreted extracellularly . ExosomeExosomes act on receptor cells in three main ways: first, proteins on the exosome membrane directly contact with proteins on the receptor cell membrane to trigger intracellular signaling cascades; second, the contents of the exosome membrane are delivered to the receptor cells after fusion with the receptor cell membrane; and third, the target cells directly engulf exosomes . Uptake In comparison to the normal cell, the tumor cell have an increased consumption of glucose and also undergo metabolism alterations required to sustain growth and reproduction in a limited nutritional environment. Even under oxygen-rich conditions, cancer cells have a much higher rate of glycolysis than tricarboxylic acid (TCA) cycle-mediated oxidative phosphorylation (OXPHOS), a phenomenon known as the “Warburg effect” . IncreasStudies have shown that in order to survive in the complex tumor microenvironment (TME), tumor cells increase the number of secreted exosomes to actively construct conditions suitable for their growth . Tumor cMultiple cell types, including tumor cells, can secret exosomes. The exosomes secreted by tumor cells are called tumor-derived exosomes (TDEs). Studies have estimated that the blood from cancer patients contains twice as many exosomes as the blood from healthy individuals . TDE canSelective protein sorting, controlled by posttranslational modifications, results in the enrichment of certain molecules in specific exosomes . Exosome. found that platinum nanoparticles (PtNPs) infused with lutein stimulate the release of exosomes in human lung epithelial adenoma cells (A549) by inducing oxidative stress and the ceramides pathway. The function of PtNPs to promote exosome release provides a new therapeutic target for tumor [The biogenesis and exocytosis pathways of TDEs are also regulated by specific intracellular mechanisms. The composition, function and possible targeting of exosomes are determined by modulation. Cellular and environmental signals such as inflammation, stress, or cell-cycle events could alter the specific cargo loaded into exosomes or regulate the whole process of exosome release . For exaor tumor .In addition to inducing tumorigenesis, TDEs may trigger a parenthetical signaling response at the site of metastasis. It has been proposed that TDEs may induce pre-metastatic niche formation, and thus enhance the progression of cancer metastasis . Some stTumor development is dependent on the surrounding environment for nutrients, which often requires the cooperation between cells in TME. TME is a highly heterogeneous and complex ecosystem incorporating both tumor and non-tumor cells. These non-tumor cells include immune and inflammatory cells, bone marrow derived cells, cancer associated fibroblasts (CAFs), adipocytes, endothelial cells and pericytes composing tumor vasculature, and the extracellular matrix (ECM) establishing a complex cross-talk with the tumor . VariousGlucose metabolism could be divided into anabolism and catabolism. Anabolism refers to the synthesis of glycogen macromolecules from monosaccharides, which requires energy consumption. After a series of decomposition reactions, glucose can release large amounts of energy to the organism. Simultaneously, intermediates formed in the decomposition process can be used as raw materials for the synthesis of biological macromolecules such as proteins, lipids and nucleic acids . Glucose13C metabolic flux analysis, cancer cells rapidly internalize CDEs, leading to depletion of extracellular exosomes within 24 h. Metabolites regulate glycolytic pathway flux through lactate supply and significantly alter intracellular metabolism within 24 h [CAFs are important components of TME. The dynamic interaction between CAFs and tumor cells plays a crucial role in tumorigenesis and progression. Tumor cells could promote glycolysis of CAFs, and alternatively, the CAFs could provide tumor cells with metabolites, such as pyruvate and lactate, through the OXPHOS and TCA cycle to fuel neighboring cancer cells. This phenomenon is known as the “Reverse Warburg Effect” , 44. In hin 24 h . Thus, e. found that hypoxia-induced tumor cells could secrete more exosomes, affecting the recruitment of macrophages and promoting the polarization of M2 macrophages. This effect is achieved by TDEs that enhance oxidative phosphorylation of bone marrow-derived macrophages by transferring let-7a miRNA and inhibit the insulin-Akt-mTOR signaling pathway to affect macrophage metabolism [TDE not only regulate the metabolism of CAFs, but also affect glucose metabolism of tumor-associated macrophages (TAM). Macrophages are one of the most abundant innate immune cells in TME and are associated with tumor growth, angiogenesis, metastasis, and poor prognosis. According to the surface markers of polarized macrophages and their functions, the polarized macrophages could be divided into two types: classically activated macrophages (M1) and alternatively activated macrophages (M2) . The poltabolism . In additabolism . These c. found that exosomal miR-122 secreted by breast cancer cells could inhibit glucose uptake by niche cells by down-regulating GLUT1 and PKM2. Inhibition of miR-122 in vivo can lower the glucose metabolism of distal organs such as brain and lung, and reduce the incidence of metastasis. This suggests that exosomal miR-122 can reshape whole-body energy metabolism and promote tumor progression [Tumor cells can systematically inhibit the use of nutrients by other cells to gain an advantage in growth and metastasis. For example, tumor cells secrete exosomes carrying high levels of miR-122 to inhibit glucose uptake by non-tumor cells in pre-metastatic sites . Taken ugression .. showed that exosomes secreted by acute myeloid leukemia (AML) cells, which contain VEGF/VEGFR, promote glycolysis in endothelial cells (ECs) [Besides solid tumors, Wang et alls (ECs) . Neovascls (ECs) .Exosome mediated metabolic changes have been shown to affect the immune response to the tumor. For example, exosomes secreted by Pancreatic Ductal Adenocarcinoma (PDAC) cells which do not express SMAD can increase calcium flux and glycolysis by transferring differentially expressed proteins and miRNA associated with SMAD4. This transfer of exosomes has been shown to generate an immunosuppressive background . It has . have demonstrated that ABCG1-mediated cholesterol efflux promotes exosome release, while SRB1-mediated cholesterol efflux inhibits exosome uptake by recipient cells [Exosome-mediated disruption of lipid metabolism is increasingly recognized as a feature of tumor cells and may be a key factor in the progression and metastatic behavior of malignant tumors . Studiesnt cells .The role of lipids in cell communication is an interesting emerging topic of research and is worth further investigation. Exosomes are known to carry bioactive lipids, such as prostaglandins and leukotrienes, which have been shown to promote the development of tumors . FurtherIt has been shown that tumor derived signaling molecules trigger lipolysis in cancer-associated adipocytes (CAAs), which results in lipoatrophy in humans , a form . found that overexpression of FASN (Fatty Acid Synthase) in ovarian cancer led to lipid accumulation in TME, resulting in T cell dysfunction, and then impaired anti-tumor immune responses [Lipids in TDEs have also been shown to alter immune responses. For example, Jiang et alesponses . It has esponses .. found that CAFs mainly regulated amino acid metabolism in an exosome-dependent manner in lung adenocarcinoma (LUAD) cells. Stimulated by tumor-derived proinflammatory cytokines, the specific long noncoding RNA LINC01614 secreted from CAFs, was up-regulated. CAF-derived exosomes could promote NF-κB activation through transport of LINC01614 to LUAD cells, which then interacted with ANXA2 and p65, leading to upregulation of glutamine transporters SLC7A5 and SLC38A2. Ultimately, LINC01614 enhanced glutamine uptake in LUAD cells [Studies on exosomes and amino acid metabolism mainly focus on tumor cells and CAFs and provides evidence that TDEs could induce CAFs production . Liu et AD cells . MoreoveAD cells . The aboAD cells  TDEs eff. found that inhibition of exosomal miR-122 could normalize glucose metabolism of the brain, lung and other distal organs and reduce the incidence of tumor metastasis, indicating that exosomal miR-122 could reshape the whole body energy metabolism and promote tumor progression [The normal state of the body is one of equilibrium and homeostasis. The development of neoplasms can upset this balance, for example emaciation is considered to be a manifestation of tumor cachexia. It has been shown that TDEs from pancreatic cancer could induce subcutaneous adipose tissue lipolysis through AM as a mediator, suggesting that TDEs induced lipolysis may be associated with weight loss in patients . In addigression . It has gression . And It gression . In summRecent studies have found that metabolism alterations caused by TDEs can affect the immune system which can aid in the ability of the tumor to escape the immune system. Studies have shown that TDEs can lead to increased glucose uptake by macrophages in the pre-metastasis niche through TLR2 and NF-κB signaling pathways, thus increasing the expression of PD-L1 and promoting the polarization of macrophages towards immunosuppressive phenotypes . In addiA large number of tumor markers carried by cancer cell exosomes have set off a boom in liquid biopsy. The application of TDEs was shown in Fig. Although the development of science and technology for exosome detection is growing, there are still many problems to be solved. First, each exosome assay technique is known to have its own bias in estimating exosome size. For example, Nanoparticle Tracking Analysis (NTA) is widely used for exosome size detection in bioparticle applications, and its detection limit for bioparticles is about 70 nm. NTA and Transmission Electron Microscopy are sensitive to different sizes . MoreoveThe exosome population is made up of exosomes of different internal and external carriers, different sizes, different cellular origins, different functional effects on the recipient cell, and resulting in uneven application functions . The con. showed the TDEs from MCF-7 cell line (estrogen receptor (ER +) breast cancer cell line) had increased levels of 27-OHC in compared with TDEs from the ER- breast cancer cell line (MDA-MB-231), providing evidence that TDEs may contain additional information of diagnostic value [Recent studies have shown that exosomes can be used as biomarkers to diagnose, identify the stage and the subtype of tumor cells. In 2015, Dr. Raghu Kallur’s team found that GPC1 protein contained in exosomes of pancreatic cancer cells could be used as a non-invasive method to diagnose and screen early pancreatic cancer at a stage suitable for surgical treatment. Most importantly, it can distinguish chronic pancreatitis from early or advanced pancreatic cancer, providing a new approach to the diagnosis of early pancreatic cancer, which is difficult to detect clinically . Moreoveic value .Exosomes are stable sources of miRNA in body fluids, which prevent the degradation of biomacromolecules under fluctuating body conditions . These hOne interesting therapeutic idea involves harnessing the functionality of exosomes, which transport proteins, lipids, and nucleic acids to mediate cell-to-cell communication between TMEs components, for anticancer therapy. Therefore, research focused on targeting exosome biogenesis and loading is required before the exosome could be used as a viable strategy to treat cancers.. found that reducing exosomes production with dimethyl amiloride enhanced the antitumor efficacy of the chemotherapy drug cyclophosphamide in vivo in three different mouse tumor models [Recent studies have investigated if manipulating the release of TDEs could be used for therapeutics. Inhibition of Rab27 with targeted shRNAs has been shown to reduce exosome release, but this manipulation also leads to a significant increase in smaller endosome-sized vesicles (50 nm), implying that Rab proteins have the ability to alter the size distribution of exosomes . Others r models . Anotherr models . For exar models .. loaded Hiltonol (TLR3 agonist) and the immunogenic cell death inducers human neutrophil elastase into α-LA -engineered breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos). HELA-Exos has been shown to exhibit potent antitumor activity in both mouse models and human breast cancer organoids, which improves subsequent tumor-reactive CD8 + T-cell response by promoting the activation of type one conventional dendritic cells in situ [. found that TDEs could be developed for combined delivery of AIEgen and proton pump inhibitors (PPI) for the combined treatment of gastric cancer [Exosomes have also been used to build cancer vaccines. For example, Huang et al in situ . Taking c cancer . In addic cancer . While tc cancer . Hypoxiac cancer .Tumor-derived exosomes play a key role in the development of tumors. By regulating the glucose and lipid metabolism of tumor cells and other cells in TME, TDEs promotes more suitable soil and materials for tumor growth. From this point of view, many researchers hope to provide new strategies for the diagnosis and treatment of cancer patients by improving the technology of exosomes detection and isolation, inhibiting the secretion of TDEs, or blocking the binding of TDEs with targeted cells. However, there are also problems that need attention, including how to quickly and effectively load drugs into exosomes, how to enhance the stability, and how to improve the specificity and targeting. It is believed that in the near future, with the progress of science and technology and the continuous efforts of researchers, these questions will get addressed, providing new benefits to patients.