Prolonged cognitive effort can be considered one of the core determinants of mental fatigue and may negatively affect the efficacy and efficiency of cognitive performance. Metacognition—understood as a multi-componential set of skills concerning awareness and control of one’s own cognition—might reduce such negative outcomes. This study aimed to explore the relation between metacognitive skills, neurocognitive performance, and the level of mental effort as mirrored by electrophysiological (EEG) markers of cognitive load and task demand. A challenging cognitive task was used to prompt and collect metacognition reports, performance data (accuracy and response times—RTs), and physiological markers of mental effort  via wearable EEG. Data analysis highlighted that different aspects of metacognitive skills are associated with performance as measured by, respectively, accuracy and RTs. Furthermore, specific aspects of metacognitive skills were found to be consistently correlated with EEG markers of cognitive effort, regardless of increasing task demands. Finally, behavioral metrics mirroring the efficiency of information processing were found to be associated with different EEG markers of cognitive effort depending on the low or high demand imposed by the task. Mental fatigue is a state characterized by a decline in cognitive performance and increased subjective feelings of exhaustion. It can result from prolonged periods of cognitive activity and is often associated with tasks that require sustained attention and effort. Mental effort is linked and follows the allocation of cognitive resources to complete a task, with the level of effort varying based on task demands , individual factors , and situational circumstances  ,3,4,5,6.Studies investigating neurofunctional correlates of executive control and strategic management of neurocognitive resources have shown that the dorsolateral prefrontal cortex (dlPFC) plays a central role in their allocation and in the regulation of mental effort . ConsistCognitive strategies such as goal setting and time management techniques, besides higher cognitive functions such as strategic planning, situated reasoning, and decision-making, support and mediate the efficiency of mental operations needed to face and solve challenging tasks as expressions of an intentional and goal-directed regulation of mental effort .Relevantly for this discussion, such manifestation of the self-regulation meta-function is a core constituent of metacognitive skills, contributing to cognitive achievement and performance notwithstanding increasing mental effort and fatigue via its association with motivational factors and processes ,14,15. IRegarding, the above-introduced second facet of metacognition, attention regulation can be considered a pervasive and overarching higher-order process that results from the interactions of complex dynamic modalities that are functionally connected by a single cognitive activity . TherefoGiven the relevance and potential for optimizing human performance, developing reliable methods to assess mental effort and metacognitive control skills, as well as understanding the relationship between those two constructs, represent highly valuable challenges. Therefore, several tasks based on shifting or maintaining focus as well as blocking automatic behaviors were developed to try and investigate an individual’s capacity for cognitive control and attention regulation . FurtherThe increasing diffusion of wearable technologies is furthering applied research and will likely offer novel insights into understanding and mitigating mental fatigue and optimizing mental effort in various contexts. As an example, wearable EEG devices now allow for measuring brain electrical activity noninvasively and easily, providing real-time data on neural markers of mental fatigue and effort, such as on changes in brainwave patterns . Yet, suTo begin filling this gap, this study aimed to explore the relation between metacognitive skills, neurocognitive performance, and level of mental effort as mirrored by EEG markers of cognitive load and task demand, and to investigate whether greater metacognition is associated with better performance. To achieve this goal, a neuroscientific approach was adopted based not only on the administration of a revisited attentional switching task but also on the continuous detection of neurophysiological parameters via wearable EEG.Based on the above-introduced background knowledge, we expected to observe a positive correlation between metacognitive skills and performance at the challenging task. Also, even though this investigation is still explorative given the lack of previous evidence, we expected to observe significant correlation coefficients even between metacognitive skills and EEG task-related markers of cognitive load, mirroring the pervasive modulatory role of metacognitive processes not only on behavior but also on neurofunctional correlates of performance. Finally, we expected to observe consistent profiles when looking at physiological and behavioral markers of performance and mental fatigue, with worse performance  associated with increased EEG markers of cognitive load .age = 35.3, SDage = 11.7). None of the recruited participants had neurocognitive impairments, a history of psychiatric or neurological illnesses, or were currently receiving pharmacological therapy that could alter neurofunctional responses or impair cognition or judgment. Additionally, participants reported normal or corrected-to-normal vision, normal global cognitive functioning, and no habitual drug taking. Also, participants were asked to refrain from smoking and drinking coffee in the two hours before testing, in order to limit potential effects on cognitive performance related to such habits (should they have them). Any of these requirements that failed to be satisfied led to exclusion from the study.This study involved a sample of 24 participants .The experiment took approximately 20 min and was conducted in a dedicated quiet room, where the participants were invited to sit in a comfortable chair in front of a monitor (distance: approximately 80 cm). After filling and signing the written informed consent, the experimental procedures and the task were presented to the participants. Specifically, before beginning the experimental task, participants were asked to wear a non-invasive EEG recording band, to detect neurofunctional activity at rest and during task performance.The experimental task was administered via a web-based experiment-management platform  and conIn the task performance phase, participants performed a digitalized challenging dual-task, in which they had to respond to two different tasks depending on whether stimuli were presented at the top or bottom of the screen. Specifically, if the stimulus appeared at the top of the screen the response had to be given based on its shape, whereas if it was presented at the bottom of the screen the response had to be given based on the number of dots depicted within the stimulus. In both situations, to correctly perform the task, it is necessary to ignore the feature of the stimulus  that is not relevant for such trial and orient cognitive resources to process the relevant one, depending on the part of the screen where the stimulus is presented. If the stimulus was presented at the top of the screen, thus making shape information relevant, participants had to discriminate between squared and diamond shapes by using two different buttons. When the stimulus appeared at the bottom of the screen, thus making information concerning the number of dots relevant, the same two buttons had to be used to discriminate between two- or three-dot patterns. During the task, participants were also asked to try and metacognitively focus on their performance and cognitive strategies (if any) used during the task.The task included a total of 84 trials, in which the stimulus was presented until a response was given and up to a maximum duration equal to 4000 ms, with 1000 ms of interstimulus interval see . Also, tWere you able to apply some kind of strategy during the game?”); (ii) the awareness of employing a strategy while performing the task (question: “Were you aware of using this strategy during the game?”); (iii) the occurrence of online self-monitoring and change in strategy while performing the task (question: “Did you change your strategy during the game?”); (iv) the perception of the effectiveness of the adopted strategy (question: “Do you think you used an effective strategy?”); and (v) the evaluation of the used strategy and of the opportunity to modify it (question: “Would you make changes to the strategy used?”). For each item, participants provided a response on a 5-point Likert scale, where 1 corresponds to “totally disagree” and 5 to “totally agree”.The metacognition assessment phase consisted of the administration of a post-experiment quantitative questionnaire devised to assess metacognition and, specifically, participants’ awareness, use, and evaluation of strategies employed to complete the challenging digitalized task (adapted from: ). The meTM headband  was employed in the resting-state recording and during the task to monitor and collect variations in EEG spectral activity . This wearable EEG band included seven dry electrodes, three of which were used as references while the remaining four electrodes were used to collect the EEG signal from frontal  and temporoparietal  sites  via Fast Fourier Transformation, then mean PSD values were computed for each standard frequency band: delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), and gamma (30–44 Hz). Then, the average PSD for each frequency band was extracted for both baseline  and task-related conditions . Finally, task-related changes in power spectral values were computed separately for the basic and mixed conditions, as follows:The relations between metacognitive skills as measured via the items of the metacognitive questionnaire, neurocognitive performance in basic and mixed conditions as measured via accuracy and RTs metrics, and level of mental effort in basic and mixed conditions as measured via EEG markers of cognitive load and task demand  were explored by computing Pearson correlation coefficients.Data analyses in this study were planned according to two sequential steps: the first one was focused on metacognition, while the second one was focused on performance. Specifically, in the first step, participants’ responses to the items of the metacognitive questionnaire were correlated with behavioral measures of neurocognitive performance (accuracy and RTs in basic and mixed conditions) and task-related changes of power spectral values for EEG bands . In the second step, Pearson correlation coefficients were computed between performance metrics (accuracy and RTs) in each condition of the task (basic and mixed) and task-related changes of power spectral values for EEG bands . The outcomes of correlation analyses were checked against the false discovery rate by applying the Benjamini–Hochberg procedure , so to mp = 0.050; p = 0.004, p = 0.008; p = 0.002; Correlation analyses computed on the items of the metacognitive questionnaire and performance indices (accuracy and RTs) for basic and mixed conditions of the task highlighted: a significant negative correlation, between scores at item 5 and accuracy in the mixed condition ; and a positive significant correlation between RTs and beta TRPSD in AF8 for the mixed condition . No other correlation coefficient was found to reach the statistical threshold.Correlation analyses computed between performance indices (accuracy and RTs) and EEG data for basic and mixed conditions of the task highlighted: a negative significant correlation between RTs and theta TRThe rationale of the present study was built on the potential of metacognitive skills and strategic regulation of mental effort for preserving performance in case of increasingly challenging conditions. Also, given the lack of systematic investigation of the relationship between metacognition and behavioral/neurophysiological markers of mental effort, we aimed to explore the relation between individual propensity towards metacognitive awareness and control, neurocognitive performance, and neurofunctional correlates of cognitive load and effort. Specifically, a challenging digitalized dual-task was used to prompt and collect metacognition reports concerning performance at the task and strategies used to complete the task, behavioral performance data, and electrophysiological markers of mental effort via wearable EEG.Analysis of data highlighted three main findings: (i) metacognitive reports on the post-performance evaluation of the used strategy and of the opportunity to modify it, on intentional implementation and awareness of used task-solving strategies, and on their perceived efficacy correlated with performance as measured by accuracy and RTs; (ii) specific aspects of metacognitive skills we explored, such as online self-monitoring and adaptation of task-solving strategies and perception of the effectiveness of the adopted strategy, consistently correlated with EEG markers of cognitive effort (beta and gamma power modulations) as measured throughout the dual-task; and (iii) RTs correlated with different EEG markers of cognitive effort—namely, task-related changes in theta and beta power over frontal areas—depending on the low vs. high demand imposed by the task.reviewing their own performance after its completion and towards changing the used task-solving strategy was linked to limited efficacy in responding to the task, as mirrored by lower accuracy scores. At the same time, individual propensity towards actually using a task-solving strategy, online awareness of implementing it, and evaluation of efficacy for the implemented strategy were linked to greater efficiency of information processing in responding to task demands, as mirrored by lower RTs. Such observations, taken together, seem consistent with a twofold organization of metacognitive skills paralleling the distinction between self-regulation and self-awareness metacognitive dimensions, in keeping with multicomponential accounts of metacognition  or cognitive styles  as potential mediators of the relationship between metacognitive skills, performance, and mental effort. Again, further depth into the discussion could be reached by integrating data on task-related metacognitive skills with qualitative reports on the actual strategy that participants have planned to use or used to solve the task. This could enrich data interpretation and give the opportunity to begin exploring even the potential role of logical/practical soundness of such strategy in influencing performance, awareness, and regulation. Finally, future applied studies should test the efficacy of empowerment protocols targeting metacognitive skills in improving the effective management of mental effort and fatigue.This work is, to the best of our knowledge, among the first ones to focus on the relationship between metacognitive skills, performance, executive control of cognitive resources, and task-related neurofunctional markers of neurocognitive effort. Practical implications of a deeper understanding of the relationship between metacognitive awareness and regulation of performance, efficacy and efficiency of performance, and mental effort—as well as of the potentially protective role of metacognitive skills against cognitive fatigue—hint at the potential of the study.


Helicobacter pylori infection. However, the damaging effect of anticoagulants and corticosteroids or oral iron therapy on the gastric mucosa is controversial. At the same time, the increased use of new antineoplastic drugs, such as checkpoint inhibitors, has opened up a new area of gastrointestinal damage that will be seen more frequently in the near future. We conclude that there is a need to expand and understand drug-induced gastrointestinal damage to prevent and recognize drug-associated gastropathy in a timely manner.Drugs are widely used to treat different diseases in modern medicine, but they are often associated with adverse events. Those located in the gastrointestinal tract are common and often mild, but they can be serious or life-threatening and determine the continuation of treatment. The stomach is often affected not only by drugs taken orally but also by those administered parenterally. Here, we review the mechanisms of damage, risk factors and specific endoscopic, histopathological and clinical features of those drugs more often involved in gastric damage, namely NSAIDs, aspirin, anticoagulants, glucocorticosteroids, anticancer drugs, oral iron preparations and proton pump inhibitors. NSAID- and aspirin-associated forms of gastric damage are widely studied and have specific features, although they are often hidden by the coexistence of  Drug therapy is one of the key elements of the armamentarium employed to treat many different diseases. Clinical trials and real changes in the mucous membrane are associated with the actions of various etiological factors, while drug-induced gastritis is characterized by various structural changes in the gastric mucosa with minimal signs of inflammation, which has led to the more frequent use of the collective term “gastropathy” as a synonym for drug-induced gastritis. In this case, damage to the gastric mucosa can be acute or chronic.This publication was prepared in order to systematize the available data on modern diagnostic criteria for drug-induced gastropathy (DIG)—lesions of the gastric mucosa associated with a negative manifestation of either a drug or its metabolites.The diagnosis of DIG should be based on the identification of gastric damage chronologically caused by the use of the drugs followed by recovery or a pronounced decrease in the signs of gastropathy after discontinuation of the medication. In this regard, thorough history taking, including medical history, with a clarification of previous signs is one of the first reasons for a diagnostic search in the case of DIG .Clinical symptoms of DIG are variable. Often, patients with DIG may be asymptomatic or have mild symptoms which can be overshadowed by the presence of symptoms of the underlying disease, which means that it is difficult to assess or detect the presence of DIG in a timely manner. Some patients, however, may have dyspepsia, as well as clinical symptoms showing that other parts of the digestive tract are concerned. Finally, patients with DIG may have more severe symptoms, including severe pain or a complicated course with anemia, or overt bleeding and perforation associated with ulceration.The clinical signs of DIG upon physical examination are not specific and often reveal only signs of the underlying disease treated with the drug inducing the gastroduodenal damage. In some cases, epigastric tenderness can be present, and in cases of a complicated course, pallor of the skin and the presence of visible mucous membranes, hypotension and compensatory tachycardia are common.Non-invasive tests have low informative value but may have diagnostic value, either for detecting a complicated course of the disease  or when conducting a differential diagnosis with other types of gastritis .The next step in the diagnostic process of DIG is an endoscopic examination with the collection of gastric biopsy specimens. It should be taken into account that the majority of endoscopic and histopathological changes in the gastric mucosa caused by taking drugs are nonspecific and reflect inflammation, erosions or uncomplicated or complicated ulcers. Biopsies of the gastric mucosa, however, may show morphological changes in the so-called reactive gastropathy pattern, most clearly represented as damage induced by non-steroidal anti-inflammatory drugs (see below). However, the coexistence of H. pylori-associated gastritis often hides these features linked to DIG. Nevertheless, there are individual characteristic features of the morphological picture associated with the action of a particular drug agent, which may be specific. These features are reviewed in this article.The first description of the endoscopic picture of the damage to the gastric mucosa associated with the use of aspirin was published by A. Douthwait and J. Lintoff in 1938 .NSAIDs are one of the most commonly prescribed classes of medication with a wide range of indications and availability in over-the-counter forms. According to some studies, the prevalence of NSAID and aspirin use among older people is 24.7% . GastricAccording to two large cohort studies, ESTHER (N = 7737) and British Biobank N = 213,598), taking low doses of aspirin is an independent risk factor for the development of gastric and duodenal ulcers in the early period after the start of treatment [98, takinAccording to data from Spain, the mortality rate associated with the use of NSAIDs or aspirin is 5.6%, which is equivalent to 15.3 cases of death per 100,000 users [H. pylori infection [Risk factors for the development of NSAID/aspirin-associated gastropathy include >60-year-olds , high-dose NSAID treatment, a previous history of peptic ulcers with or without complications, co-therapy with low-dose aspirin, anticoagulants, serotonin re-uptake inhibitors or steroids and nfection ,9.Gastrointestinal-associated NSAID/aspirin damage is based on the blockade of the enzyme cyclooxygenase (COX), which regulates the synthesis of prostaglandins from arachidonic acid. COX exists in two isoforms: structural COX-1 and induced COX-2. The COX-2 isoform is not detected in normal tissues. Its expression is induced by inflammatory mediators  and causes all the clinical manifestations of inflammatory processes: soreness, fever, swelling and dysfunction. Therefore, it is the blockade of COX-2 that causes the main targeted pharmacological effects of NSAIDs/aspirin, including the anti-inflammatory, analgesic and antipyretic. At the same time, COX-1 blockade induces a systemic decrease in the synthesis of prostaglandins (PGs), which have cytoprotective effects.It has been established that PGE2 inhibits the formation of H+ ions and pepsinogen in the stomach, reducing the volume of gastric secretion and its acid and peptic activity; however, the main effect is the increase in the production of mucus and bicarbonates, stimulation of the processes of cell proliferation and physiological regeneration of the epitheliocytes of the gastric mucosa . Thus, aThe direct  interaction between NSAIDs and phospholipids and the uncoupling of oxidative phosphorylation in mitochondria cause cell membrane damage, with a disruption of the phospholipid layer and tight junctions. This action increases transcellular permeability. The inhibition of COX, as a systemic effect, reduces microvascular blood flow, and luminal aggressive factors modify and amplify this reaction, leading to inflammation, erosions and ulcers .Depending on their blockade of one COX isoform or another, NSAIDs are divided into those that are selective (inhibiting only COX-2) and non-selective (inhibiting both COX-1 and COX-2). Selective drugs, called “coxibs”, have a less damaging effect on the gastric and duodenal mucosa and were initially used to prevent NSAID-associated damage to the digestive tract. However, it was later discovered that as gastrointestinal risks decrease when taking selective NSAIDs, the risk of fatal cardiovascular events increases ,16,17. CThe mechanism of development of NSAID-associated gastropathy is shown in As a rule, most patients taking NSAIDs have no gastrointestinal symptoms. However, dyspeptic symptoms may occur in a significant number of patients, including epigastric pain (17–20%) and nausea (22%). In some cases, there might be symptoms such as heartburn, sour belching, constipation (19.3%) or diarrhea (9.2%) showing that other parts of the digestive tract are concerned .A rare but clinically important feature of NSAID/aspirin-associated gastropathy is the development of complications, mainly gastrointestinal bleeding ,20, withIt is important to note that damage to the digestive tract while taking NSAIDs/aspirin is not limited to the mucous membrane of the stomach and duodenum but can also affect the small and large intestines, as has been shown in a number of large, randomized clinical trials ,24. MostA typical localization of erosive and ulcerative lesions is the antrum of the stomach, but all areas of the gastroduodenal tract can be affected. This condition is characterized by damage of a multifarious nature, which can be both acute and chronic. Signs of bleeding and subepithelial hemorrhages are often noted . During Helicobacter pylori (H. pylori) [Microscopic signs comprise the picture of the so-called reactive gastropathy, which is not strictly specific to NSAIDs. There is a weak–diffuse, predominantly mononuclear inflammatory infiltration of the lamina propria, often revealing erosive and/or ulcerative defects, pronounced regenerative changes in the epithelium , mucosal edema with vascular ectasia in the lamina propria and lamina propria expansion with fibromuscular proliferation. Subnuclear vacuolated mucous cells may be an additional criterion, which is associated with operated stomach syndrome. Interestingly, the nature of the necrotic masses at the bottom of the defect may be the starting point for the differential diagnosis between NSAID-associated lesions with a homogeneous eosinophilic zone of necrotic masses and a defect caused by  pylori)  with theAnticoagulants are among the most commonly prescribed drugs worldwide. Over the past few decades, new second-generation oral anticoagulants (NOACs) that directly inhibit factor Xa  or thrombin (dabigatran) have been introduced into a wide range of areas of clinical practice. They can be prescribed in fixed doses, without the need for laboratory monitoring, for the treatment and prevention of venous thrombosis and thromboembolism, including stroke, in non-valvular atrial fibrillation, while gastrointestinal bleeding is the “Achilles’ heel” affecting the application of this class of drugs .The possible negative risks of gastric mucosal damage in the establishment of anticoagulant therapy have been studied in numerous clinical trials, followed by evaluations in meta-analyses. At the same time, only the risk of upper digestive tract bleeding was studied as a phenomenon of interest without any assessment of its possible links with gastritis or gastropathy. In the latest review published in January 2023, which examined pharmacovigilance data registered with EudraVigilance , adversep = 0.95). In any case, there are multiple meta-analyses of either clinical trials or observational studies concerning the risk of gastrointestinal bleeding associated with NOACs and vitamin K inhibitors published in the last decade. All highlight an increased risk of gastrointestinal bleeding with the use of these agents with some differences between them, but these differences are of uncertain clinical significance.An analysis of 16 RCTs showed that the greatest number of refusals to pursue further therapy occurred while taking dabigatran, while warfarin and factor Xa inhibitors slightly increased the incidence of adverse events involving the digestive tract . A syste-A history of gastrointestinal bleeding;-A history of gastric and/or duodenal ulcers;-Gastroesophageal reflux disease, reflux esophagitis;-Chronic H. pylori-associated gastritis;-Other pathologies of the gastrointestinal tract: inflammatory bowel disease, diverticula, hemorrhoids and angiodysplasia;-Neoplasms of the gastrointestinal tract in history;-Age > 65 years;-Concomitant use of NSAIDs (including LDA) or other drugs that affect blood coagulation or have a contact damaging effect on the gastrointestinal tract;-Impaired renal function: glomerular filtration rate (GFR) < 50 mL/min;-Use of high doses of NOACs .The major risk factors for gastrointestinal bleeding with NOACs are designated as follows :-A histoHowever, some of the presented factors require further assessment and study. Thus, the consensus on H. pylori Maastricht VI, published in August 2022, states that there is no evidence to suggest that anticoagulants  increase the risk of bleeding in patients with H. pylori infection  . The potIt is assumed that anticoagulants may increase the risk of bleeding from the gastrointestinal tract through several mechanisms or their combinations: (1) a systemic anticoagulant effect; (2) local anticoagulant effect; (3) local irritant effect; and (4) a local action of the drug not that is not associated with coagulation  ,36,37.The local and systemic anticoagulant effect is associated with the drug’s bioavailability. Thus, NOACs are characterized by low bioavailability ; that is, a significant amount of the drug turns into an active anticoagulant during its passage through the gastrointestinal tract under the action of the intestinal esterases and, theoretically, can potentiate bleeding from vulnerable foci of pre-existing lesions (in combination with systemic action). In contrast, warfarin is absorbed at a level of more than 95%; thus, the increase in major gastrointestinal bleeding in patients taking warfarin probably reflects the systemic anticoagulant effect of the drug. The hypothesis that the tartaric acid in dabigatran may contribute to gastrointestinal bleeding due to a direct damaging effect seems unlikely.The clinical manifestations of DIG resulting from the use of anticoagulants are highly controversial. On the one hand, anticoagulants, including aspirin, as well as NSAIDs are often taken simultaneously with anticoagulants. This situation highlights the need to study the risk of gastropathy development against the background of joint administration of anticoagulants with other potentially ulcerogenic drugs ,39,40. OAn upper endoscopy reveals changes ranging from erythema and petechiae to hemorrhagic gastropathy, Cameron’s lesions, erosion and stomach ulcers. The risks of peptic ulcers and bleeding from the upper gastrointestinal tract against the background of the use of NSAIDs and anticoagulants are presented in Cytostatics comprise a group of antitumor drugs that are relatively heterogeneous in terms of their chemical structure and pharmacokinetic properties; therefore, data on the incidence of DIG and its development mechanisms, clinical course and endoscopic and morphological patterns are different for individual drugs in this group. In the literature, the greatest amount of data concerns DIG associated with the use of mycophenolate mofetil (MMF).Gastropathy and erosive and ulcerative lesions of the mucous membrane of the stomach and duodenum occur in 40–50% of patients taking MMF, while perforation and bleeding occur in 3–8% of cases, usually during the first 6 months after the start of MMF therapy ,46.p = 0.043), while the risk increases with combination therapy based on MMF with other cytostatics and/or glucocorticosteroids [MMF intake is an independent risk factor for erosive and ulcerative lesions of the gastric mucosa, with an odds ratio of 1.83  is described ,51.Characteristic morphological changes in the gastric mucosa against the background of cytostatic consumption include hyaline degeneration of cells in the submucosal and muscle layers and, in the case of large doses, cell vacuolization, necrotic changes and desquamation of the epithelium ,55.MMF-associated gastropathy is characterized by impaired mucosal architectonics with inflammatory infiltration and edema of the lamina propria of the gastric mucosa, the enlargement of the glands and increased apoptotic activity of the epithelium, less often resulting in changes resembling those observed in Crohn’s disease .Immune checkpoint inhibitors are a relatively new class of anticancer drugs; hence, data on the incidence of side effects resulting from their use are still limited. The first representative of this class, ipilimumab, was approved for the treatment of melanoma in 2011 . It has H. pylori infection [The risk of developing unwanted side effects affecting the digestive tract is determined primarily by the types of immune response checkpoint inhibitors used, among which are the inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1). Separate observational studies have shown that the incidence of gastric injury is higher for CTLA-4 than PD-1/PD-L1 and increases significantly with combination therapy ,59,60. Tnfection .It is assumed that the risk of developing severe lesions of the stomach is increased in genetically predisposed individuals. Thus, a severe gastric lesion was described in a patient homozygous for the rs2241880 gene variant of the autophagy-related 16-like protein (ATG16L1), which is associated with Crohn’s disease .The mechanism underlying the negative effects of inhibitors of immune response checkpoints on the gastric mucosa is not fully understood. It is assumed that during the use of this group of drugs, together with an increase in the antitumor activity of lymphocytes, an autoreactive immune response is activated against healthy tissues. A larger number of T- and B-lymphocytes are formed with the release of pro-inflammatory cytokines tropic to the gastric mucosa ,64,65.The complaints of patients taking immune response checkpoint inhibitors are nonspecific and correspond to dyspepsia syndrome. The main complaints include nausea, vomiting, abdominal pain and loss of appetite .Endoscopic examination reveals erythematous and edematous gastric mucosa without obvious manifestations. The mucous membrane of the stomach is covered with a whitish fibrin-like film. When examining the body of the stomach with the applied magnification in narrow-spectrum imaging, the destruction of the glandular structure is visible. With air infusion, oozing hemorrhages are often noted, which indicates the friability of the mucous membrane .DIG associated with immune checkpoint inhibitor therapy exhibits two distinct patterns of damage . The patData on the prevalence of gastropathy during GCS consumption are contradictory. Despite the generally accepted view that the use of corticosteroids increases the risk of developing peptic ulcers, large meta-analyses of randomized controlled trials have not shown a significant association between the use of corticosteroids and gastric ulcers . Hence, H. pylori infection [The main risk factor for peptic ulcer bleeding in patients taking glucocorticosteroids is the concomitant use of NSAIDs/ASA. Recently, another study also reported an increased risk with the concomitant use of glucocorticosteroids and serotonin re-uptake inhibitors. Other risk factors for damage to the gastric mucosa while taking GCSs include older age (65 years and older), long-term use (a month or more) with a total intake of high doses (more than 1000 mg in regard to prednisone) and erosive and ulcerative lesions of the stomach and duodenum intestines, including those complicated by a history of gastrointestinal bleeding and nfection ,69.In the meta-analysis conducted by Narum S. et al., which combined data from 159 studies involving 33,253 patients, it was shown that an increased risk of gastrointestinal bleeding and ulcer perforation while taking corticosteroids is typical of only hospitalized patients, compared with outpatients receiving corticosteroids (40% versus 0.13% of cases) . At the 2O2 levels being responsible for mucosal damage [GCSs inhibit the production of prostaglandin by regulating the activity of prostaglandin synthesis and the expression of type 2 cyclooxygenase . It has l damage .There are no specific clinical manifestations of this condition. The most common manifestations of dyspepsia syndrome are epigastric pain, nausea and a feeling of heaviness in the epigastrium. It is possible that the affected parents will be asymptomatic. The most severe manifestations include hemorrhagic gastropathy and erosive and ulcerative lesions of the stomach and/or duodenum, with the development of bleeding and posthemorrhagic iron deficiency anemia.Single and multiple erosions with foci of hemorrhage and gastric or duodenal ulcers can be detected . Ulcers The main possible manifestation of the action of GCSs on the gastric mucosa is the formation of erosive and ulcerative defects. This effect is most pronounced in combination therapy with NSAIDs ,80.A similar situation involving an increase in the effect of GCSs in combination with NSAIDs is reflected in the publications on gastric bleeding . This relationship has been demonstrated with particular clarity in patients with a history of previous bleeding . In animThe accumulation of iron in the gastric mucosa is known as gastric siderosis and was first described in the literature in the 1980s .The prevalence of iron-associated DIG is 0.7% in the adult population . HoweverStudies have not been conducted on the search for risk factors for the development of gastritis induced by iron preparations. Based on the pathogenetic mechanisms underlying the effect of iron on the gastric mucosa, it can be assumed that concomitant diseases of the gastroduodenal zone may be predictors of more severe damage to the gastric mucosa while taking iron tablets.Our knowledge of the pathogenesis of iron-associated DIG is limited. There are two hypotheses for the mechanism of damage. Firstly, iron can cause local effects in the gastric mucosa, mimicking a chemical burn. This is due to the fact that ferrous and ferric iron ions are catalysts for the formation of reactive oxygen species and highly toxic radicals, which can damage the components of the epithelial cells of the gastric mucosa ,87,88. IThe symptoms are nonspecific and may present as nausea, vomiting, abdominal pain or, in complicated cases, upper gastrointestinal bleeding .Typical manifestations of iron-induced DIG are erythema, mucosal discoloration  and erosions .For the differential diagnosis of the side effects of iron tablets and other sideropenic conditions, a classification was proposed by Marginean et al., consisting of three models of iron deposition in the stomach. In the scheme of these authors, the most common pattern of gastric siderosis is the deposition of iron in the stroma and macrophages, mainly due to inflammation of the stomach, ulceration and previous bleeding and rarely due to iron supplementation. The second type is represented by extracellular iron deposition and is most often associated with the consumption of iron supplements. The third type is associated with iron overload and/or portal hypertension/cirrhosis, in which gastric cells are exposed to high concentrations of iron, possibly as a result of porto-caval shunting .When staining biopsy specimens of the gastric mucosa with hematoxylin and eosin, characteristic features are chronic inflammation, the presence of superficial edema and a layer of brown granular pigment that covers the surface of the epithelium, spreads into the gastric pits, and may be present in macrophages localized in the lamina propria. By carrying out a histochemical reaction for iron (using Perls’ Prussian blue), it is possible to identify the substrate based on the appearance of a diffuse bluish color of the macrophage cytoplasm and the mucosal lamina propria .The key features of DIG associated with different groups of drugs are presented in Regarding DIG, it is necessary to make a few remarks about possible changes in the structure of the gastric mucosa in people who have undergone long-term PPI treatment. On the one hand, as part of the safety assessment of long-term PPI use, the risk of possible structural changes in the gastric mucosa is being actively studied and critically analyzed. On the other hand, these changes are difficult to interpret as either gastritis or gastropathy.H. pylori colonization, namely a change in the topography of gastritis with an increase in the likelihood of atrophy of the gastric mucosa. In this regard, eradication is necessary for all patients with H. pylori infection undergoing long-term PPI therapy. However, these changes are probably related to the pro-carcinogenic potential of H. pylori rather than the independent effects of PPIs.Undoubtedly, the most important changes have been described in relation to long-term acid suppression under the conditions of However, the long-term use of PPIs is associated with hyperplasia of enterochromaffin-like cells (ECL cells) and can provoke the formation of gastric fundus polyps  with speThe expansion of opportunities for the management of both infectious and, above all, chronic non-communicable diseases is accompanied by an increase in the duration and number of drugs used by patients. The undoubted success of such treatment is accompanied by risks of drug damage to the digestive tract, including the stomach. For some of the drugs , sufficient experience has already been gained with regard to the possible manifestations, while for other, new groups of drugs , we are only at the beginning of the journey towards the acquisition of scientific evidence. It is important to expand and understand not only the mechanism of damage and the risk factors but also the specific features of drug-induced gastrointestinal damage in order to prevent and recognize DIG in a timely manner.


Eating disorders (ED) usually first appear between the ages of 13 and 25. They continue to be of clinical concern by virtue of increasing incidence in younger populations and in boys, earlier onset, and risk of chronicity.The COVID-19 pandemic saw an increase in new and relapsing cases of ED, with surges of referrals to both pediatric and adult general hospitals and to community services . CurrentIn this context, and to counterbalance potential therapeutic nihilism, our Research Topic addressing updated research in ED disorders is timely. Papers included cover biological, family and cultural components on individual illness development and trajectories.Historically adverse family interactions were seen as significant contributing factors to the origins and maintenance of these disorders in adolescents, with systemic family therapy advocated as the treatment of choice. Subsequent clinical work and research has enlightened us to the complex bio-psycho-social nature of ED, genetically mediated and with significant personal, cognitive and social components. These areas, including the role of parents, culture and attachments, are further scrutinized in this issue.Izydorczyk et al. in their paper. Attachment experiences during early childhood provide an essential basis for future resilience, including self-acceptance and confidence, with both positive and potentially adverse effects.An overall review highlighting the potential protective role of parental relationships is well described by Izydorczyk et al. dare to suggest an approach that promotes understanding between the child's perception of parental bonding, sociocultural influences on appearance, body image and ED risk. Key messages here remind us of the perils of maternal overprotection and emphasizing the importance of paternal care. The import of socio-cultural influence is exposed, with the knowledge that these internalized standards, including lower clarity of self-concept and identity confusion, are formed early and are more often perceived as egosyntonic , hence providing treatment opportunities.Starting from here, Verschueren et al. in their large longitudinal cohort of adolescents, mostly females. They identified cognitive emotional dysregulation—namely “rumination, catastrophizing, and less positive reappraisal”—as an indirect factor paving the way to development of an ED . They proffer that the distressing key symptom of body image disturbance, the nature of the self-perception of the mirroring self, may emanate from a dissociation between the psycho-physiological reactivity and the subjective response to body exposure . Another irritation-prone developmental step is the subjective search for identity . Transitional and stepped care approaches are also described in this issue and when linked with motivational work have been found effective .Given that ED onset typically occurs over a broad developmental period, it is important to ensure seamless transitional pathways exist between child and adult services. Prior transition specific research has highlighted that youth with ED have been found to be least likely to transition to adult service . The egoThere has been a wealth of research examining the link between the gut-brain axis and the role of the microbiome in our general health and wellbeing and genesis of specific diseases.Ghenciulescu et al. argue for a broader recognition of a potential contributory role of the microbiome in the etiology and maintenance of ED. They highlight he potential adverse effects of standard nutritional rehabilitation and rapid refeeding, such as severe GI distress. Additionally, they suggest the development and possible therapeutic advantages of microbiome-based therapies for patients with AN, such as fecal microbiota transplants and probiotic adjunctive treatments.In addition to genetic factors, the type and quantity of food eaten contributes to the diversity of the millions of micro-organisms lining our digestive track and changes in food consumption and preparation has been reflected in significant deviations in our microbial flora. Both beneficial and harmful microbes exist, inducing those with anti or pro inflammatory immune function, either promoting or hindering physical and mental health. The changed microbial flora among those with AN compared to healthy controls remind us of the perils regarding the limitations of conceptualizing AN as a purely psychiatric or “brain centric” condition . GhenciuBased on this collection of papers, we can be optimistic of continued developments in search of a clearer understanding of the origins of the various ED and optimizing treatment outcomes in this vulnerable group.FM and US created the first draft. JC-F and DN extended with additions and suggestions for corrections. All authors finally contributed and agreed on the final version.


Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression. Tumors are formed by proliferating malignant cells caused by a range of oncogenic processes, including the accumulation of mutations and the abnormal proliferation of stem cells or specific tissues , 2. ChanLiquid biopsy approaches enable the noninvasive assessment of tumor biomarkers in a range of biofluids including blood, saliva, cerebrospinal fluid (CSF), urine, bile, or breast milk –17. ExosTumors of the central nervous system (CNS) are relatively rare but are associated with very high mortality rates . GliomasThe present review summarizes the clinical application of exosomal circRNAs in the context of the early diagnosis, treatment, and prognostic evaluation of glioma patients through liquid biopsy-based approaches, with a particular focus on the relevance of exosomal circRNAs to the dynamic monitoring of disease progression with the goal of providing a robust foundation for future efforts to improve patient prognostic outcomes and to expand the clinical potential of liquid biopsy.The increased understanding of disease mechanisms together with technological development have led to significant advances in the diagnosis and treatment of a variety of diseases. Techniques such as blood or CSF analysis, tissue biopsy, MRI, and other imaging techniques have been widely used in clinical work. Analysis of blood and CSF are most commonly used; however, the tests tend to have poor specificity and often need to be combined with other tests for comprehensive judgment. Although more intuitive understanding of some diseases can be achieved through MRI and other optical techniques, they can only reflect the disease state at a specific stage. Tissue biopsy is the gold standard for disease diagnosis. However, although tissue biopsy is an accurate indicator of tumor diagnosis, it nevertheless has limitations. The use of exosome based-liquid biopsy is gradually achieving recognition. Liquid biopsies represent a convenient and minimally invasive alternative to traditional tissue biopsy techniques, enabling analyses of blood as well as other biofluids of interest such as the CSF, urine, bile, breast milk, or saliva. Notably, these approaches allow for the dynamic monitoring of tumors over the course of disease progression , 31. BeyThe production of CTCs, ctDNA, ctRNA, exosomes, and exosomal contents is highly heterogeneous over the course of tumor development and progression. Accordingly, the most appropriate methods for detecting these tumor-related biomarkers and their clinical significance when detected can vary substantially over the course of disease.Initially identified in blood samples as early as 1860 , CTCs arFirst described in 1940, ctDNA is DNA derived from tumor cells that circulates systemically, comprising a small fraction of the total cell-free DNA (cfDNA) . CtDNA iAny RNA derived from tumor cells, including messenger RNAs (mRNAs), miRNAs, circRNAs, and lncRNAs, is classified as a form of ctRNA when released into the systemic circulation. Reports of the detection of circulating mRNA in tumor patients were first published in the 1990s, and many more recent studies have similarly documented high levels of circulating miRNAs in tumor patient biofluids, with over 70 such miRNAs having been proposed as candidate HCC-related biomarkers . Higher Exosomes are small lipid bilayer-enclosed vesicles derived from the endocytic pathway . They arin vitro and in vivo experimental models (Exosomes are a type of extracellular vesicles (EVs) associated with both normal and diseased cells and have multiple biological functions. Exosome release is significantly increased in various diseases, including cancer. Various drugs that inhibit the release or uptake of pro-oncogenic exosomes in the tumor microenvironment (TME) have been proposed as novel cancer therapeutics , 66. Thel models , 68. TheWestern blotting (WB), nanoparticle tracking analysis (NTA), dynamic light scattering analysis (DLSA), zeta potential analysis (ZPA), tunable resistive pulse sensing (TRPS), size exclusion chromatography (SEC), and other techniques can be used for the detection and characterization of EVs , 70. NTAin vivo and in vitro. The source of the exosomes can affect the drug-loading capacity  of exosomes sustains their stability, allowing the transfer of information between cells. Exosomes are released into the TME, leading to protein-protein and protein-lipid interactions and reducing the expenditure of energy. ATP produced by mitochondria and lactate accumulation may facilitate the entry of exosomes into cancer cells to promote metastasis and contribute to the targeting of cancer cells to the TME . Exosomecapacity . Exosomecapacity .High levels of circRNAs in serum exosomes were first reported in RNA-Seq analyses conducted in 2015, and they have since emerged as promising tumor-related biomarkers with the potential to guide diagnostic or related efforts . MechaniGlioma is the most common CNS tumor and is characterized by rapid progression, aggressive growth, substantial heterogeneity, resistance to treatment, and poor prognostic outcomes , 84–86. GBM is the most aggressive glioma subtype and accounts for roughly half of all cases. GBM patients exhibit lower levels of exosomal circSMARCA5 and circHIPK3 in their plasma samples, and researchers have reported improvements in GBM diagnostic accuracy when assessing these two exosomal circRNA biomarkers in combination with three traditional prognostic and diagnostic biomarkers associated with this tumor type including the preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) , 110. GBCircMMP1 can promote the proliferation of tumor cells while inhibiting apoptosis, and high levels of exosomal circMMP1 are evident in the glioma where it promotes oncogenesis via the circMMP1/miR-433/HMGB3 axis, indicating that this pathway may be amenable to patient treatment . In glioHigh serum exosomal circMMP1 (circ_0024108) levels have been potentially linked to poor glioma patient prognosis . While hGiven their noninvasive nature and amenability to convenient sample collection and analysis, liquid biopsy-based testing strategies have developed rapidly in recent years and are used in a range of advanced clinical tests assessing particular biomarkers relevant to specific disease states. Liquid biopsy strategies can be used for early cancer screening and diagnosis, while also enabling the prediction of therapeutic targets, therapeutic resistance, post-treatment follow-up outcomes, and disease recurrence. Many recent studies have explored the molecular basis for the pathogenesis of glioma, spurring the increased application of liquid biopsy-based analyses in this oncogenic context. Exosomal circRNAs have emerged as particularly promising biomarkers in the context of liquid biopsy analyses, offering higher levels of sensitivity and specificity compared with more traditional biomarkers, thereby providing clinicians with better guidance for the timely diagnosis, prognostic assessment, and monitoring of treatment resistance in individuals affected by glioma. At present, the methods for detecting exosomes are increasing, together with improved specificity and credibility, leading to potential for borad clinical application. Through the discussion of the formation, action mechanism, clinical application and detection means of exosomes, we have gained a deeper understanding of the role of exosomes in disease. CircRNAs in exosomes can play a role in both the physiological and pathological state of the body, especially in tumors. The deepening understanding of the roles of exosomal circRNAs in glioma has led to the proposal of novel clinical applications. Exosomal circRNA is a small molecule present in body fluids where it can be accurately detected by liquid biopsy technology, allowing its precise analysis.Liquid biopsy strategies are still subject to a range of challenges and necessitate further validation before they can enter into routine clinical use. For one, it is important that appropriate biofluids be selected when conducting these analyses, and whether a given biomarker is the most appropriate target in that biofluid sample also warrants consideration. One must also consider whether the source of a given biomarker detected in a particular biofluid is unique to primary or metastatic tumor-derived sources or whether it may also arise from other tissues or cell populations in the body. Given the relatively low levels of particular molecular biomarkers in samples of different body fluids, this can place substantial demands on the volume of available body fluids, and highly sensitive assay instruments must be capable of detecting even small changes in these biomarker concentrations. As they are a relatively new type of tumor marker, there also remain several barriers to the clinical application of exosomal circRNAs, and new detection instruments with higher levels of sensitivity will be essential to facilitate their routine detection. It is also important that the molecular basis of glioma pathogenesis be better understood, so that exosomal circRNAs can be more reliably applied to guide the diagnosis and treatment of patients suffering from this devastating form of cancer. We believe exosomal circRNAs can be used as liquid biopsies and noninvasive biomarkers for the early detection, diagnosis, and treatment of cancer and other diseases in the nearly future.YL and HZ provided direction and guidance throughout the preparation of this manuscript. XW wrote and edited the manuscript. MS reviewed and made significant revisions to the manuscript. All authors contributed to the article and approved the submitted version.


The current opioid pandemic is a major public health crisis in the United States, affecting millions of people and imposing significant health and socioeconomic burdens. Preclinical and clinical research over the past few decades has delineated certain molecular mechanisms and identified various genetic, epigenetic, and environmental factors responsible for the pathophysiology and comorbidities associated with opioid use. Opioid use-induced epigenetic modifications have been identified as one of the important factors that mediate genetic changes in brain regions that control reward and drug-seeking behavior and are also implicated in the development of tolerance. Recently, it has been shown that opioid use results in microbial dysbiosis, leading to gut barrier disruption, which drives systemic inflammation, impacting the perception of pain, the development of analgesic tolerance, and behavioral outcomes. In this review, we highlight the potential role of microbiota and microbial metabolites in mediating the epigenetic modifications induced by opioid use. Opioids are highly effective analgesics for the treatment of perioperative and postoperative pain. However, their use is limited by the development of analgesic tolerance, dependence, opioid use disorders, addiction, and comorbidities associated with opioid use. The present opioid crisis is multifactorial, arising from increased use, misuse, and abuse of prescription opioids as well as the recreational use of opioids. The rate of opioid overdoses, mainly involving synthetic opioids such as fentanyl, is on the rise, and in the year 2020, ~68,630 overdose deaths involving opioids  homeostasis by impairing gut motility, barrier function, and microbial composition. Opioid use-associated gut microbial dysbiosis  is emerging as a key factor in modulating opioid function and comorbidities associated with opioid use . Their combined genetic materials, metabolites, and bioactive compounds are collectively termed the microbiome. Under homeostatic conditions, the host and the microbiome maintain a symbiotic relationship, and the gut microbes are known to impact the host's physiology through the production and modulation of epigenetically active compounds , neurotransmitters, bile acids, vitamins, and nutrients  and Bifidobacterium pseudocatenulatum (MB 237) are high folate producers. Folate production by bacteria is independent of host folate levels  to tetrahydrofolic acid (THF) in the folate cycle is coupled with the conversion of homocysteine (hCYS) to methionine, which is subsequently converted to SAM, the universal methyl donor . Thus, fLactobacillus and Bifidobacterium are potent producers of these vitamins , niacin (B3), pantothenate (B5), pyridoxine (B6), folate (B9), and cobalamin (B12) and contribute to the host's vitamin B supply, thus affecting the host epigenome. Probiotic bacteria belonging to the species Gut microbial colonization has been shown to affect the DNA methylation and expression of inflammation-associated genes in neonates  results in inhibition of TET enzymes  of Caucasian heroin addicts on methadone maintenance , encoded by the OPRM1 gene, is a receptor for morphine and morphine derivatives and plays an important role in mediating morphine's analgesic properties and the development of tolerance. Considering the crucial role of μ-opioid receptor signaling, a large number of studies have focused on studying opioid-induced epigenetic modifications that affect the OPRM1 promoter was observed in cancer patients taking opioids for pain management, and the extent of methylation was dose-dependent and associated with the lack of inadequate pain relief  at position +188 of the Lactobacillus acidophilus was shown to attenuate abdominal pain by mediating the expression of OPRM1 and cannabinoid receptors (CB2) in the intestinal epithelial cells in an Nf-kb-dependent mechanism , and the acetyl group from the lysine present on histone N-terminal tails is removed by the action of enzymes termed histone deacetylases (HDACs). Class I  and class II HDACs  are zinc-dependent, and class III HDACs belong to the family of NAD+ dependent sirtuins (Sirt1–7)  was observed with morphine treatment in the dorsal horn neurons of the spinal cord, contributing to the development of OIH; treatment with the HDAC inhibitor SAHA led to prolonged OIH , neuropathic pain  encoding for postsynaptic density protein (PSD-95) mediated by pCREB in the ventral tegmental area (VTA) contributed to morphine-induced CPP and rewarding behavior . For example, pretreatment with HDAC inhibitor trichostatin A (TSA) was shown to facilitate memory formation during the acquisition and extinction of morphine-induced CPP in the basolateral amygdala through increased H3K14 acetylation and a concomitant increase in BDNF, Delta FOSB, and CREB activation  is a dynamic, evolutionarily conserved acyl modification that is regulated by the action of acylases, which add the modification, and deacylases, which remove the modification  and cofactors  of the one-carbon metabolism and folate cycle  The gut microbiome modulates the epigenome through the production of epigenetically active metabolites and the regulating expression of epigenetic enzymes; (2) the gut microbiome has been shown to play an important role in modulating opioid functions, such as analgesia, and contribute to comorbidities associated with chronic opioid use, including behavioral outcomes such as anxiety and depression; and (3) opioid use causes persistent, stable epigenetic alterations that change gene expression and behavioral outcomes. In this review, we have described the possible ways in which opioid-induced microbial dysbiosis, through the production of epigenetically active metabolites, may influence the epigenetic changes observed with morphine. Currently, direct evidence linking morphine-induced changes in the microbiome and microbial metabolism to the production of epigenetically active metabolites and subsequent epigenetic changes responsible for altered behavioral responses to opioids is sparse. In addition, studies aimed at understanding the role of the microbiome in mediating the epigenetic changes associated with opioid use have heavily relied on the use of pharmacological inhibitors of epigenetic enzymes, supplementation of SCFAs, and strategies based on candidate genes. To fully understand the crosstalk between the microbiome and epigenetics in modulating the pathophysiology, molecular, and behavioral changes associated with morphine use, it will be necessary to comprehend opioid and opioid microbiome-induced changes in metabolites, including choline, methionine, SAM, SAH, folate, SCFAs, and vitamins, which serve as cofactors in one-carbon metabolism and the folate cycle, by sampling the serum and fecal samples in gnotobiotic and germ-free mice.Future studies should investigate epigenetic modifications  in combination with the altered microbiome and epigenetically active metabolites to obtain a better understanding of the role of the microbiome in modulating opioid-induced changes in the epigenome.UK drafted the manuscript. SR provided critical revisions, approved the manuscript, and provided funding and resources. All authors contributed to the article and approved the submitted version.


Barley is a very important crop particularly in marginal dry areas, where it often serves as the most viable option for farmers. Additionally, barley carries great significance in the Western world, serving not only as a fundamental crop for animal feed and malting but also as a nutritious food source. The broad adaptability of barley and its ability to withstand various biotic and abiotic stresses often make this species the sole cereal that can be cultivated in arid regions. The collection and utilization of barley genetic resources are crucial for identifying valuable traits to enhance productivity and mitigate the adverse effects of climate change. This review aims to provide an overview of the management and exploitation of barley genetic resources. Furthermore, the review explores the relationship between gene banks and participatory breeding, offering insights into the diversity and utilization of barley genetic resources through some examples such as the initiatives undertaken by ICARDA. Finally, this contribution highlights the importance of these resources for boosting barley productivity, addressing climate change impacts, and meeting the growing food demands in a rapidly changing agriculture. The understanding and utilizing the rich genetic diversity of barley can contribute to sustainable agriculture and ensure the success of this vital crop for future generations globally. Hordeum vulgare L.) is one of the most adaptable crops belonging to the Poaceae family, serving as a vital source of food, feed, and malt for the brewing industry on a global scale [Hordeum. A high-quality genome sequence was achieved following the establishment of the International Barley Genome Sequencing Consortium (IBSC) in 2006. This endeavor was based on two main approaches: the BAC-by-BAC strategy, which exploited a large set of genetically mapped BAC clones, and whole-genome shotgun sequencing, synergized with deep RNA-Seq analysis [Barley  Asch. et Graebn.); hereinafter H. spontaneum). This classification is supported by phylogenetic analysis and the ability of these plants to interbreed [Barley has been cultivated and selectively bred for thousands of years, resulting in abundant genetic and morphological diversity ,8. Althoterbreed . A key mvrs1 (previously known as v for vulgare), which is recessive to the dominant allele responsible for the two-rowed spike (Vrs1). Throughout domestication, the Vrs1 gene has undergone independent mutations multiple times, resulting in the emergence of the six-rowed phenotype [vrs5, an allele that enhances lateral grain fill characteristics to modern six-row cultivars [Vrs1 to Vrs5), all involved in the regulation of the arrangement and development of spikelets [Among cultivated forms, various types are commonly distinguished. These distinctions are often based on characteristics such as growth habit, row type (two-rowed or six-rowed), and the presence/absence of hulls ,11. All henotype . This isultivars . Recent pikelets .Hordeum vulgare L. var. nudum Hook. f., lacks this outer layer. In relation to adaptability, winter barley is more suitable to colder climates and typically sown in the fall, while spring barley thrives in warmer climates and is usually sown in the spring in higher latitudes and in fall in the Mediterranean climate. Furthermore, variants can be classified based on agronomic characteristics. Finally, certain types of barley are particularly suitable for malting due to their content of amylase and proteins. Protein content in barley seeds ranges from 8% to 30% of the total seed mass [Coming to the different types of barley, hulled barley is encased in a tough outer layer, while hulless (naked) barley, scientifically known as eed mass ,16,17,18eed mass . These veed mass ,11. Avena sativa) and some other cereals. Beta glucans are known for their ability to lower cholesterol levels, regulate blood sugar levels, and promote digestive health. They have been linked to a reduced risk of heart disease, improved immune function, and enhanced weight management [Recently, barley has gained renewed attention as a food source particularly with the advancement of biofortified varieties that are enriched with beta glucans , a type nagement ,22. By inagement . The clanagement . Barley possesses extensive phenotypic and genetic diversity, due to its long history of cultivation and adaptation to diverse environments worldwide, which is preserved in governmental or international gene banks and germplasm collections in research institutions, universities, breeding companies, and agricultural organizations across the globe .The progress made in genomics and biotechnology has facilitated the identification and characterization of genes and molecular markers associated with essential agronomic traits in barley . These aThis review aims to provide an assessment of the genetic resources of barley, including its wild relatives and cultivated varieties. It will explore the management and exploitation of these genetic resources, highlighting the importance of strategies such as gene bank establishment and core collections’ development. The review will also delve into the management and exploitation of barley genetic resources, considering participatory breeding approaches and the importance and limitations of including local knowledge and perspectives. Finally, the historical contributions of the International Center for Agricultural Research in the Dry Areas (ICARDA) in the exploration and utilization of barley genetic resources will be highlighted. We conclude by discussing how advanced genomics and phenomics tools can be harnessed and exploited by institutions in an equitable manner, prioritizing principles of fairness and equal access among different institutions or organizations globally involved in the conservation of barley genetic resources.There is little doubt that environmental changes, agricultural intensification, urbanization, land degradation, and economic factors have significantly contributed to loss of traditional farming practices and, hence, crop diversity in barley, as well as in many other crop species ,29. To lIn situ conservation of genetic resources involves their preservation in their habitats . SpecifiBriefly, it is possible to identify the following main agro-ecological regions in which barley has thrived and adapted: the Near Eastern area , the European–Siberian area, the Ethiopian area, the East Asiatic area, and New World centers (Americas and Oceania). In each area, the combination of geographic isolation and significant climatic variations has led to the emergence of an ample set of agro-ecological groups of varieties that also include further subdivisions .The Fertile Crescent, which is considered the area where barley was domesticated, is home to a diverse range of wild and cultivated varieties of barley . This reHordeum genus, wild barley is the sole wild representative in the primary gene pool, and it is the only wild species utilized for genetic improvement in cultivated barley [H. spontaneum) is normally considered a weed in barley and wheat fields, but it can also be used as forage for livestock. This plant presents a significant amount of genetic variation related to various traits such as biomass, yield, nitrogen content, drought and salinity tolerance, and resistance to diseases [It is also worth adding the widespread occurrence of wild barley, which can be found across a vast geographic range spanning from Morocco to China ,36. Amond barley ,37. Wilddiseases . Mlo gene (mlo-11), most likely present in landraces from the highlands in the southwest region of Ethiopia collected during German expeditions in the 1930s [The Ethiopian highlands are another important region for in situ conservation, with several barley landraces that are considered important for food security and livelihoods in the region . In Ethihe 1930s . Hordeum agriocrithon Åberg, a wild species discovered by Åberg in 1938 known because of its resistance to abiotic and abiotic stress [In the East Asiatic area, the Himalaya is another important center of diversity for barley, and the region is home to several wild and cultivated varieties of the crop. Among the former, it is necessary to cite c stress . Among cc stress ,45,46,47c stress ,45,46,47c stress . Hordeum vulgare var. coeleste, is well suited to the high altitude and cool temperatures of the region [H. chilense Roem. et Schult., a wild species of barley, known for its crossability with the genera Triticum and Secale [The Americas and Oceania have a relatively recent history of barley development compared to other regions and are dominated by six-row types. In South America, barley is a valuable staple crop and even today represents an important source of food and income for local communities. Although introduced, this crop is embedded in some traditional cultures, playing a role in traditional festivals and rituals. For example, the Puno region (Peru) is home to the Feast of the Virgen de la Candelaria, a festival that includes drinking of chicha, a traditional fermented beverage made from the two-rowed Andean barley . The Ande region . The sixd Secale ,51. Ex situ conservation of barley includes establishment of gene banks, botanical gardens, and other facilities that store plant genetic resources. http://www.fao.org/3/i1500e/i1500e.pdf; accessed on 1 May 2023), there are a total of 466,531 barley accessions  in ex situ collections, and this genus ranks third following Triticum and Oryza. Nonetheless, as for many other plant species, the level of duplication is not well defined, with estimates indicating that around 120,000 accessions could be distinct . Barley is well-represented in gene banks, evidenced by the considerable number of accessions available. The species is considered among the 14 most important crops for food security by the International Union for Conservation of Nature (IUCN) Red List of Threatened Species, a comprehensive inventory of the conservation status of plant and animal species worldwide. However, more diversity can be collected targeting more wild relative species and populations with adaptive traits to climate change. According to the Second State of the World’s Plant Genetic Resources for Food and Agriculture report published by the Food and Agriculture Organization of the United Nations (FAO) . The inventory revealed that there are 47 major barley gene banks (holding more than 500 accessions), with a total of 402,000 accessions [A global inventory of barley genetic resources in ex situ collections was performed through the development of the Global Strategy for the Ex Situ Conservation and Use of Barley Germplasm. This collaborative approach was led by the ICARDA, the Global Crop Diversity Trust, and the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) , with the support of CGIAR and FAO, and the contribution from international barley experts  refers to a breeding approach that involves farmers and other stakeholders by actively engaging them in variety cultivation, evaluation, and selection. In barley, PPB has long been an important complementary process within the broader context of preserving and exploiting biodiversity . A key fPPB, despite demonstrating its efficiency, has not been widely embraced mainly because of the reluctance in accepting the “implicit paradigm shift regarding seed sovereignty” . To addrThe improvement in landraces through participatory selection also encompasses the enhancement of seed quality through seed cleaning and treatment against seed-borne diseases, which have proven to be effective approaches for increasing yields of landraces and contribute to the on-farm conservation of landraces .Irrespective of the approach employed, the active involvement of farmers in the breeding process strongly decreased the risk of developing cultivars that do not meet their preferences or needs. Participatory plant breeding is crucial to preserve germplasm and sustain cultivation for indigenous communities in agroecological niches or marginal lands but also to address needs of specific stakeholders such as smallholder famers, local food processing and brewing industries, consumer groups and associations focused on food quality, safety, and nutrition, and more generally, of agricultural systems that do not rely heavily on off-farm input. To provide an example in cereals, Morocco has experienced a significant increase in wheat productivity through the replacement of local landraces with contemporary cultivars. However, the campaign to replace cultivars halted in the early 1990s, and therefore, most of the currently cultivated varieties were released decades ago. Although breeding programs have continuously released improved varieties, their adoption has been typically low , and onlParticipatory Variety Selection (PVS) is an approach that aims to expedite the adoption of new improved varieties in farmers’ fields by involving farmers in the selection process . PVS comHordeum species are part of the Multilateral System of the Plant Treaty, encompassing a total of 26 crops. Moreover, access to germplasm derived from breeding activities, categorized as “Material under Development,” is governed by the SMTA. However, when it comes to collecting additional accessions, two options are available: utilizing the SMTA or adhering to the requirements of the Nagoya Protocol, which involve Prior Informed Consent and Mutually Agreed Terms. The Nagoya Protocol is a supplementary agreement to the CBD for the implementation of measure to access GR and the fair and equitable sharing of benefits arising from their utilization [In response to the increasing concerns on the loss of diversity in barley and in other crops, international efforts are underway to promote the sustainable use and conservation of barley genetic resources. These frameworks provide guidelines, regulations, and incentives to promote the effective management of plant germplasm. They also facilitate access to genetic resources for research, breeding, and development purposes while ensuring fair benefits for all stakeholders involved. The Convention on Biological Diversity (CBD) established in 1992 and the International Treaty on Plant Genetic Resources for Food and Agriculture , adopted by FAO in 2001, are arguably the most important international agreements that aim to promote the conservation and sustainable use of biodiversity, including plant genetic resources. They recognize the sovereignty of countries over their genetic resources and are calling the parties to contribute to their conservation and sustainable use and for a fair and equitable sharing of the benefits arising from their use. These two binding agreements call for the development of national strategies and action plans and of national policies and legislations facilitating access to and exchange of genetic resources. An important component is the establishment of legal instruments to regulate access and benefit-sharing in a transparent and fair way. They involve the implementation of material transfer agreements, such as the Standard Material Transfer Agreement (SMTA). This is a private contract developed by the ITPGRFA that defines the terms and conditions for the exchange and use of genetic materials ensuring that countries and organizations that contribute genetic resources are recognized and rewarded for their efforts. Barley and its related lization . Just asCollaborative efforts between national and international organizations, research institutions, and farming communities are critical for the sustainable management and use of barley genetic resources. Key milestones in international initiatives for barley genetic resources management and exploitation include (i) the International Barley Genetics Symposium (IBGS) initiated in 1963, which can be considered among the first international platforms for researchers, breeders, and other stakeholders, to share knowledge and advancements in barley genetics and breeding, (ii) the International Barley Genetic Resources Network (IBGRNet), a global network of barley gene banks established in 1986, and (iii) the Barley Genome Project, launched in 2006 and coordinated by the International Barley Genome Sequencing Consortium (IBGS) ,74.https://www.agent-project.eu/; accessed on 1 July 2023).A prominent on-going initiative is currently the AGENT project (Access to Genetic Resources and Digitization of Plant Genetic Resources). AGENT aims to unleash the untapped potential of the vast biological material stored in gene banks worldwide by leveraging FAIR  international data standards and an open digital infrastructure dedicated to the management of plant genetic resources. The project aims to promote a more systematic effort to exploit Plant Genetic Resources (PGR) and advocate for generating extensive genotypic and phenotypic data for PGR stored in gene banks (GB), thus facilitating their educated selection and utilization in breeding and agriculture. AGENT consortium focuses on the following: (i) the establishment of an actively cooperating gene bank network, (ii) collecting new data and working on agreed standards and protocols for the use of passively stored GB information, (iii) generating new genotypic information for European barley and wheat collections in order to establish a roadmap and pave the way for a complete global wheat and barley biodiversity atlas, (iv) using this extensive genotypic information to evaluate the quality and redundancy of existing PGR collections as a basis for new quality control and management pathways, (v) establishing coordinated PGR training populations for phenotyping of independent collections as a foundation for a pan-European, genome-wide prediction, and (vi) mining new and historic genotypic and phenotypic information to drive the discovery of genes, traits, and knowledge for future missions. Furthermore, at a larger scale, the project aims to increase data density on collections and disseminate the societal impact of PGR to provide the community with a new database and novel data-mining tools to facilitate a well-informed selection of PGR for different purposes  and participatory research is BOLD-DIIVA-PR II project (Dissemination of ICARDA Varieties through Participatory Research). ICARDA breeding programs for durum wheat, barley, and lentil have successfully integrated the use of CWR that possess unique genetic traits that can enhance the adaptability and resilience of cultivated varieties to drought and other environmental stresses prevalent in the regions where ICARDA operates . BuildinFinally, although the activity of the following institutions is not limited to barley, it is worth acknowledging the efforts of the European Cooperative Programme for Plant Genetic Resources (ECPGR) Working Group on Barley and the U.S. National Plant Germplasm System (NPGS). The former plays a pivotal role in the conservation and sustainable utilization of barley genetic resources across Europe. This working group brings together experts, scientists, breeders, and stakeholders from various European countries who are dedicated to the conservation, evaluation, and improvement in barley diversity. Within the NPGS, a collaborative effort to preserve the genetic diversity of economically significant plant species, the Plant Genetic Resources Unit (PGRU) and its partners are responsible for collecting, preserving, and distributing barley genetic material worldwide. NPGS collections are managed by the Agricultural Research Service (ARS) of the United States Department of Agriculture (USDA).H. murinum L., adapted to saline environments and serving as genetic resource for studying and improving salt tolerance [H. bulbosum Sieber ex Kunth, a perennial species of applied interest as a source of traits to improve biotic stress resistance [H. marinum Huds., primarily found in coastal and maritime habitats, of interest to gain insights into the adaptation to saline environments [H. brevisubulatum Link and H. geniculatum All., two halophytes studied as a potential source of tolerance to drought and other abiotic stress such as alkalinity [H. turkestanicum R.E. Regel and H. hrasdanicum (part of H. murinum subsp. leporinum (Link) Arcang.) [ICARDA, a member of the CGIAR, was established in 1977 and holds the global mandate for the improvement in barley. This means that this non-profit agricultural research institute is recognized as the leading organization responsible for conducting research, developing strategies, and implementing programs aimed at enhancing the genetic potential and overall performance of barley crops worldwide, in addition to ensuring the conservation of barley genetic resources. olerance ; H. bulbronments ; H. brevkalinity ,80; and Arcang.)  thought Arcang.) ,83.The Genetic Resources Unit (GRU) was established in 1983 to safeguard the genetic resources of all the ICARDA mandate crops, through germplasm exploration, gathering, evaluation, and conservation . The GRUH. spontaneum and H. bulbosum, as sources of disease resistance, abiotic stress tolerance, and end-use quality. ICARDA’s work on landraces began in Syria in 1984 [H. spontaneum, due to its crossability with H. vulgare. In 2004, ICARDA released six barley cultivars with drought tolerance derived from H. spontaneum for use in Syria [H. spontaneum were also used to dissect complex traits such as drought stress [H. spontaneum consistently exhibited superior specific adaptation to the range of severe stress conditions employed [H. spontaneum from different origins, introgression lines derived from crosses between different barley cultivars , and lines derived from interspecific crosses with both H. spontaneum and H. bulbosum, was carried out in two cropping seasons at four experimental stations in Morocco [H. spontaneum showed high resistance levels to all four diseases, while 23 other accessions and 16 H. bulbosum-derived lines showed resistance to a combination of two to four diseases. Despite the good resistance levels found for individual diseases, the agronomic performance of all lines never surpassed that of the checks used, highlighting the importance of crossing selections from landraces and CWR derivatives with elite adapted materials [For barley, the routine pre-breeding activities at ICARDA focus on the identification and use of landraces and CWR, such as  in 1984 , at the  in 1984 ,86. The  in 1984 . The incin Syria ,88. Witht stress . For exat stress , and somemployed . Other semployed , drylandemployed , straw qemployed , powderyemployed , and leaemployed . In addi Morocco . The geraterials . H. spontaneum accessions [H. spontaneum accessions have higher beta-glucan content, while no substantial differences were found in microelements, except for a few H. spontaneum lines that showed higher combined contents of iron, zinc, and selenium. These accessions are currently being used in interspecific crosses to develop biofortified barley germplasm and eventually new varieties.The GRU is also working on the nutritional content of barley germplasm. For instance, the beta-glucan and microelement content  were recently assessed in a panel of cultivated barley and cessions . The resThe choice of accessions from ICARDA, as well as from other gene banks, has been typically carried out using random sampling or core collections. The former involves selecting accessions without any specific criteria, while core collections are designed to capture a significant proportion of the genetic diversity within 10% of the total accessions . To furtPyrenophora teres Drechs. f. teres), illustrating the potential of using freely available databases to enhance the efficiency of field screening trials [The Focused Identification of Germplasm Strategy (FIGS) is an approach developed by ICARDA in collaboration with the Vavilov Institute in Russia and GRDC-Australia to efficiently identify and prioritize crop germplasm collections based on specific target environments and traits . It was g trials . Recentlg trials . A furthg trials . The stuThe procedures and approaches for the conservation and use of barley genetic resources described here highlight some crucial aspects that need to be addressed, such as the need to align conservation strategies with continuous progress in cultivation practices, particularly in developing countries ,102. MorIn barley, the creation and distribution of improved varieties in various areas of the world is still one of the key goals of the breeding efforts of international institutions . While dWhile in situ conservation will always remain crucial for maintaining the dynamic interactions between barley and its natural environment, in the future, it will be necessary to strengthen policies to define and manage controlled environments where barley genetic material can be stored under specific conditions. It is also necessary to further recognize the importance of biodiversity hotspots worldwide. These should be given special attention, included in protected areas, and better managed for the conservation of biodiversity.Relevant advancements are expected to increase our understanding of the genetic variation of barley germplasm . BrieflyTo enhance the effectiveness of conservation efforts, it is also crucial to establish a strong connection between the conservation and utilization of barley genetic resources. As an example, an approach to achieve this is by improving the Focused Identification of Germplasm Strategy (FIGS) ,115. FurIn conclusion, now more than ever, it is an integrated approach that can ensure that genetic resources are not only preserved but also actively utilized to address the challenges of sustainable agriculture and food security . Therefo


Despite significant improvements of renal and obstetrical management, pregnancies in women with glomerular diseases and with lupus nephritis continue to be associated with increased complications both for the mother and the fetus as compared to those of pregnancies in healthy women. To reduce the risk of these complications, planning pregnancy in a phase of stable remission of the underlining disease is necessary. A kidney biopsy is an important event in any phase of pregnancy. A kidney biopsy can be of help during counselling before pregnancy in cases of incomplete remission of the renal manifestations. In these situations, histological data may differentiate active lesions that require the reinforcement of therapy from chronic irreversible lesions that may increase the risk of complications. In pregnant women, a kidney biopsy can identify new-onset systemic lupus erythematous (SLE) and necrotizing or primitive glomerular diseases and distinguish them from other, more common complications. Increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy may be either due to a reactivation of the underlying disease or to pre-eclampsia. The results of the kidney biopsy suggest the need to initiate an appropriate treatment, allowing the progression of the pregnancy and the fetal viability or the anticipation of delivery. Data from the literature suggest avoiding a kidney biopsy beyond 28 weeks of gestation to minimize the risks associated with the procedure vs. the risk of preterm delivery. In case of the persistence of renal manifestations after delivery in women with a diagnosis of pre-eclampsia, a renal kidney assessment allows the final diagnosis and guides the therapy. Pregnancy is no longer considered to be a contraindication in women with glomerular diseases. However, the risk for maternal and fetal complications is increased, particularly in patients with renal insufficiency, severe hypertension, proteinuria, lupus nephritis, or a type of glomerular disease ,2,3,4. OIn this invited mini review, we discuss the role of the kidney biopsy in clarifying the diagnosis and evaluating the prognosis and management of pregnant women with glomerular diseases, with a focus on lupus nephritis.We conducted a literature search from the 1990s to the present day in PubMed, Embase, and Medline and from a reference list of retrieved articles. During searching, we used these terms and keywords: pregnancy, glomerular diseases, chronic kidney disease, and kidney biopsy. The study quality and recommendations were assessed based on importance of the published studies.A kidney biopsy before planning a pregnancy may be indicated in women with an undiagnosed decline of kidney function, proteinuria, hypertension, or hematuria. An accurate histopathologic diagnosis may provide important prognostic and therapeutic information to facilitate appropriate counseling to prevent the risks of an unplanned pregnancy.Pregnancy in women with autoimmune diseases, such as SLE, may present several issues. SLE may influence the pregnancy outcome, being associated with a higher than expected rate of pre-eclampsia, miscarriage, and/or pre-term delivery ,11. PregAdditionally, among patients with primary glomerular disease, a quiescent disease and good kidney function are recommended before planning a pregnancy. In a retrospective study that included 360 patients with different histological forms of primary glomerulonephritis and normal renal function, the long-term end-stage kidney disease (ESKD)-free survival was not significantly different between patients who did and those who did not conceive after the diagnosis glomerulonephritis . The samDuring pregnancy, there are hemodynamic changes characterized by an increase in the blood flow in the kidney with a consequent increase in the vascular and interstitial size up to 30%. The mean arterial pressure and systemic vascular resistance are lower during pregnancy, resulting in an increased cardiac output, renal plasma flow (RPF), and glomerular filtration rate (GFR). These changes may continue after delivery and resolve 1-month post-partum. Tubular function is also altered, leading to mild increases in the proteinuria and glycosuria levels ,29 that Particularly difficult to recognize and differentiate from other complications are the rare cases of new-onset SLE, necrotizing or primitive glomerular diseases during pregnancy which usually develop in the first trimester ,32,33,34More frequently, pregnant women with a diagnosis of LN or of primary glomerular diseases may exhibit increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy. These complications may be due either to a reactivation of the underlying disease (more frequently in patients with LN) or to pre-eclampsia. From a clinical point of view, a flare of lupus nephritis is usually associated with a rapid increase in proteinuria (proteinuric flares) and/or of serum creatinine (nephritic flares) . In flarOld and recent reports outlined fair maternal and fetal outcomes in pregnant women with glomerular diseases when hypertension was controlled and GFR was stable ,57,58,59Many women who develop de novo proteinuria, exacerbation of the urinary findings, or hemolytic uremic syndrome do not receive a kidney biopsy during pregnancy either because of the fear of hemorrhagic complications or because of formal contraindications related to severe hypertension or coagulation disorders. If the clinical manifestations persist after delivery, a kidney biopsy should be conducted within few months. By definition, the manifestations of pre-eclampsia completely reverse within 12 weeks after delivery. The persistence of proteinuria or of hypertension after this period require careful evaluation . SeveralPregnancy is regarded by many clinicians as a relative contraindication for a kidney biopsy because of the underlying risk of major complications, such as perirenal hematomas requiring blood transfusions, perirenal abscess, and even sepsis ,78. HoweIn conclusion, pregnancy is associated with an increased risk of complications in patients with glomerular diseases, and often the differential diagnosis between the reactivation or onset of the glomerular disease and pregnancy complications, such as pre-eclampsia, may be difficult. A correct diagnosis is crucial for the outcome of both the mother and fetus. In this setting, a kidney biopsy is very helpful to obtain a prompt diagnosis to decide the management of these patients. According to the available literature data and our personal experience, performing a kidney biopsy in patients with urinary abnormalities or alteration of the renal function before planning a pregnancy can be useful to establish the ideal timing for conception. Pre-conception counselling and a planning pregnancy in patients with a quiescent disease, stable kidney function, and normal blood pressure may prevent complications. During pregnancy, we suggest that clinicians consider a kidney biopsy possibly before 25 weeks of gestational age to reduce the risk of complications in patients with active urinary sediment, significant proteinuria (>500 mg/day), or a reduction of GFR, in whom less invasive diagnostic tests have failed to elucidate the disease etiology. In addition, we recommend post-partum renal check-ups, including a kidney biopsy, in patients with alterations of the renal function or persistent proteinuria after delivery .