Symptoms Of Schizophrenia Research Articles

The Potential Effects of the Ketogenic Diet in the Prevention and Co-Treatment of Stress, Anxiety, Depression, Schizophrenia, and Bipolar Disorder: From the Basic Research to the Clinical Practice.

The ketogenic diet (KD) has been highly developed in the past for the treatment of epileptic pathological states in children and adults. Recently, the current re-emergence in its popularity mainly focuses on the therapy of cardiometabolic diseases. The KD can also have anti-inflammatory and neuroprotective activities which may be applied to the prevention and/or co-treatment of a diverse range of psychiatric disorders. This is a comprehensive literature review that intends to critically collect and scrutinize the pre-existing research basis and clinical data of the potential advantageous impacts of a KD on stress, anxiety, depression, schizophrenia and bipolar disorder. This literature review was performed to thoroughly represent the existing research in this topic, as well as to find gaps in the international scientific community. In this aspect, we carefully investigated the ultimate scientific web databases, e.g., PubMed, Scopus, and Web of Science, to derive the currently available animal and clinical human surveys by using efficient and representative keywords. Just in recent years, an increasing amount of animal and clinical human surveys have focused on investigating the possible impacts of the KD in the prevention and co-treatment of depression, anxiety, stress, schizophrenia, and bipolar disorder. Pre-existing basic research with animal studies has consistently demonstrated promising results of the KD, showing a propensity to ameliorate symptoms of depression, anxiety, stress, schizophrenia, and bipolar disorder. However, the translation of these findings to clinical settings presents a more complex issue. The majority of the currently available clinical surveys seem to be moderate, usually not controlled, and have mainly assessed the short-term effects of a KD. In addition, some clinical surveys appear to be characterized by enormous dropout rates and significant absence of compliance measurement, as well as an elevated amount of heterogeneity in their methodological design. Although the currently available evidence seems promising, it is highly recommended to accomplish larger, long-term, randomized, double-blind, controlled clinical trials with a prospective design, in order to derive conclusive results as to whether KD could act as a potential preventative factor or even a co-treatment agent against stress, anxiety, depression, schizophrenia, and bipolar disorder. Basic research with animal studies is also recommended to examine the molecular mechanisms of KD against the above psychiatric diseases.

Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia.

Cognitive reserve (CR) and the catechol-O-methyltransferase (COMT) Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia. However, the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined. To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism. In a cross-sectional study, 54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype, CR, and negative symptoms. CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale. COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes. In the total sample, significant negative correlations were found between negative symptoms and information, similarities. Associations between information, similarities and negative symptoms were observed in Val homozygotes only, with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms (information, β = -0.282, 95%CI: -0.552 to -0.011, P = 0.042; similarities, β = -0.250, 95%CI: -0.495 to -0.004, P = 0.046). This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

The contribution of prosody to machine classification of schizophrenia

We show how acoustic prosodic features, such as pitch and gaps, can be used computationally for detecting symptoms of schizophrenia from a single spoken response. We compare the individual contributions of acoustic and previously-employed text modalities to the algorithmic determination whether the speaker has schizophrenia. Our classification results clearly show that we can extract relevant acoustic features better than those textual ones. We find that, when combined with those acoustic features, textual features improve classification only slightly.

Formulation and Characterization of Clozapine Nanosuspension as a Sublingual Film

Background: Clozapine (CLZ) is a potent antipsychotic drug that suppresses the symptoms of schizophrenia and mania. Clozapine falls into Class II (BCS); its poor bioavailability is attributed to low water solubility and an extensive first-pass effect. Objective: To prepare CLZ as a nanosuspension (NS) to improve its low water solubility and load it into a sublingual film to enhance oral bioavailability. Methods: CLZ nanosuspensions are prepared by the “solvent anti-solvent precipitation” method using Soluplus as a stabilizing agent. We evaluated the polydispersity index (PDI) and the particle size of the CLZ nanosuspension formulations. The optimized formula of CLZ nanosuspension is loaded directly onto a sublingual thin film, eliminating the need for freeze-drying for solidification by the solvent casting approach. The sublingual films were characterized by thickness, surface pH, folding endurance, disintegration time, and in vitro dissolution rate. Results: We selected the formula F1 sublingual film as the best, as it demonstrated a uniform thickness of 0.087mm, good flexibility, and a surface pH of 6.7. It disintegrated quickly in 13 seconds and had a faster in vitro dissolution rate (3 min) compared to the CLZ ordinary films. Conclusions: The results confirmed the success of CLZ NS as a sublingual thin film for dissolution rate enhancement, which may improve oral bioavailability.

Impact of psychopathology on day-to-day living in patients with schizophrenia: A network analysis

Although the relationship between schizophrenia and disability is well established, the association between the symptoms of the disorder and functional domains remains unclear. The current study explored the nuances of the relationship between symptoms and domains of functioning in a sample of 1127 patients with schizophrenia. We assessed the symptoms of schizophrenia with the Positive and Negative Syndrome Scale (PANSS) and psychosocial functioning with the mini-ICF-APP (mini-International Classification of Functioning Rating for Limitations of Activities and Participation in Psychological Disorders). The mean PANSS score was 94.28 (27.20), and the mean mini-ICF-APP score was 25.25 (8.96), both of which are indicative of severe symptom load and impairment. We were able to show a strong relationship and overlap between symptoms and disability in patients with schizophrenia. We identified several symptoms related to functional impairment. Deficits in judgment and abstract thinking contribute to impairment through poor adherence (to routines and compliance with rules) and difficulties in planning and organizing. We believe that in schizophrenia, symptoms and their interactions constitute a disorder beyond any single manifestation. Furthermore, we suggest that cognitive testing and cognitive treatment should become part of the standard of care for patients with schizophrenia.

"RNSP (Rannasangpei)" Rescued MK-801-induced Schizophrenia-like Behaviors in Mice via Oxidative Stress and BDNF-TrkB/Akt Pathway.

Schizophrenia (SCZ) is a complex, severe psychotic disorder that is highly persistent. Patients often cannot control their emotions and have delusions of victimization, world-weariness, and even suicide. Therefore, safer and more effective drugs are urgently needed. Rannasangpei (RNSP) from "the four medicine tantras" was used as a neuroprotective agent. The objective of this study was to investigate the effect and mechanism of RNSP on MK-801-induced SCZ in mice. Fifty C57BL/6J mice were randomly divided into a normal group, a model group, an RNSP group, a crocin (CRO) group, and an olanzapine (OLA) group, except for the normal group. The remaining mice were used to establish the MK-801-induced SCZ model. Changes in positive symptoms and cognitive impairment in mice before and after drug intervention were assessed by using the prepulse inhibition (PPI) test, Y-maze test (YMT), and open-field test (OFT). Intragastric administration of RNSP alleviated the symptoms of SCZ in SCZ mice, as demonstrated by the PPI, YMT, and OFT results. Compared with the model group, the first-line antipsychotic olanzapine reversed the anxiety-like phenotypes, hypermotility, and PPI deficits in the SCZ model mice. Further analysis revealed that RNSP reduced oxidative stress in SCZ model mice, as evidenced by increased superoxide dismutase (SOD) levels and decreased malondialdehyde (MDA) levels in the hippocampus, cortex, and blood of SCZ model mice. In our study, RNSP treatment restored the expression of brain-derived neurotrophic factor (BDNF), dopamine D2 receptor, p-Trkb, Akt/p-Akt, and doublecortin and inhibited the expression of IBA1 and Bax in the hippocampus of SCZ model mice. The polymerase chain reaction data indicated that RNSP treatment increased the expression of Bcl-2 and TGF-β and decreased the expression of Bax, IL-1β, and TNF-α in the brains of the model mice. Our results are the first to show that RNSP reverses SCZ-like behaviors in rodents (both positive symptoms and cognitive deficits) by reducing oxidative stress and activating the BDNF-TrkB/Akt pathway, suggesting that RNSP is a novel approach for treating SCZ.

Emotional anticipation for dynamic emotional faces is not modulated by schizotypal traits: A Representational Momentum study.

Schizotypy, a personality structure that resembles schizophrenia symptoms, is often associated with abnormal facial emotion perception. Based on the prevailing sense of threat in psychotic experiences, and the immediate perceptual history of seeing others' facial expressions, individuals with high schizotypal traits may exhibit a heightened tendency to anticipate anger. To test this, we used insights from Representational Momentum (RM), a perceptual phenomenon in which the endpoint of a dynamic event is systematically displaced forward, into the immediate future. Angry-to-ambiguous and happy-to-ambiguous avatar faces were presented, each followed by a probe with the same (ambiguous) expression as the endpoint, or one slightly changed to express greater happiness/anger. Participants judged if the probe was "equal" to the endpoint and rated how confident they were. The sample was divided into high (N = 46) and low (N = 49) schizotypal traits using the Schizotypal Personality Questionnaire (SPQ). First, a forward bias was found in happy-to-ambiguous faces, suggesting emotional anticipation solely for dynamic faces changing towards a potential threat (anger). This may reflect an adaptative mechanism, as it is safer to anticipate any hostility from a conspecific than the opposite. Second, contrary to our hypothesis, high schizotypal traits did not heighten RM for happy-to-ambiguous faces, nor did they lead to overconfidence in biased judgements. This may suggest a typical pattern of emotional anticipation in non-clinical schizotypy, but caution is needed due to the use of self-report questionnaires, university students, and a modest sample size. Future studies should also investigate if the same holds for clinical manifestations of schizophrenia.

EVALUATION OF SUICIDAL BEHAVIOR AND DEPRESSION, INSIGHT AND DISEASE CHARACTERISTICS IN SCHIZOPHRENIA

Introduction: Suicide is a severe public health issue with high rates of morbidity and mortality. Schizophrenia also has a high suicide incidence, which is one of the main factors contributing to rising morbidity and mortality. For strategies to lower suicide rates, it is essential to understand the risk factors for suicide in people with schizophrenia. By evaluating the relationship between the risk of suicidal behavior and demographic factors, disease characteristics, depression, and insight in schizophrenia patients, in the light of literature information, this study aimed at preventing suicide in schizophrenia and set an example for future studies. Method: This study included 103 schizophrenia patients who underwent follow-up for at least 4 years in a community mental health center (CMHC). The study included patients who had the mental capacity to understand and complete the questionnaires, were not experiencing an acute psychotic attack, and gave their consent to participate. The patients were given the Three Components of Insight Scale (TCIS), Scale for Evaluation of Positive Symptoms in Schizophrenia (SAPS), Scale for Evaluation of Negative Symptoms in Schizophrenia (SANS), Calgary Depression Inventory in Schizophrenia (CDIS), and Suicide Behavior Scale (SBS). Results: 47% of patients demonstrated suicidal behavior, and 69% of patients were men. 46% of the group demonstrating suicidal behavior had severe or very severe suicidal ideation. Age and disease duration were revealed to be significant risk factors for suicidal behavior (p=0.033 and p=0.004, respectively), but gender, SBS, CDIS, SANS, SAPS, and TCIS scores had no significant effect. Age and suicidal behavior risk were found to be inversely correlated, with each unit of age increase reducing the risk of suicidal behavior by 0.929 times. The risk of suicidal behavior rises along with the duration of disease. With every one unit increase in the duration of disease, the risk of suicidal behavior increases by 1.133 times. Additionally, the group with severe-very severe suicidal ideation had significantly more severe depression scores than the group with mild-moderate (p=0.01). Discussion: More than half of the patients with schizophrenia who were followed up showed suicidal behavior, and approximately half of the group who had suicidal ideation showed severe suicidal ideation. Suicidal behavior was found to be correlated with age and duration of illness. While suicidal behavior increases age decreases and duration of illness increases.There was no significant correlation between insight, depression, gender, symptom severity and suicidal behavior in this population. In addition, depression scores were found to be statistically significantly higher in the group with severe-very severe suicidal ideation. According to the research, in individuals with schizophrenia who were being monitored, the frequency of suicidal behavior increased along with the severity of depression. Conclusion: It is crucial to identify the risk factors and protective factors for suicide in schizophrenia patients in order to develop interventions for them. Because suicidal behavior is a significant morbidity and mortality factor in schizophrenia.

In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18–Labeled THK5351

ImportanceIn vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation.ObjectiveTo investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)–binding fluorine 18 ([18F])–labeled THK5351 positron emission tomography (PET).Design, Setting, and ParticipantsIn this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals.Main Outcomes and MeasuresStandardized uptake value ratios (SUVrs) of [18F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores.ResultsA total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [18F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)–corrected P = .04]; right, F = 5.977 [FDR-corrected P = .04]) and left hippocampus (F = 4.834 [FDR-corrected P = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [P = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r = 0.423 [FDR-corrected P = .03]; right, r = 0.406 [FDR-corrected P = .03]) in patients with schizophrenia.Conclusions and RelevanceThis case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.

Statins as an adjuvant therapy for patients with schizophrenia: An up-to-date systematic review and meta-analysis

BackgroundEvidence suggests that inflammatory processes play a role in the pathophysiology of schizophrenia. Statins exert anti-inflammatory and antioxidant effects and may be effective in improving the symptoms of schizophrenia. This study explored whether statins, as an adjunctive therapy, can alleviate the symptoms of schizophrenia. MethodsPubMed, EMBASE, and the Cochrane Library were searched for articles published up to March 2023. The risk-of-bias tool for randomized trials was used to assess study quality. Two researchers independently assessed the risks of bias and extracted data. Pooled data on Positive and Negative Syndrome Scale (PANSS) scores were analyzed. A random-effects model was employed to calculate pooled effect sizes. Statistical heterogeneity across studies was assessed using the I2 statistic. All analyses were performed using RevMan5 and Comprehensive Meta-Analysis software. ResultsNine trials enrolling 533 patients in total were included. Add-on statin therapy was found to be associated with a significantly better total PANSS score [standardized mean difference (SMD) = −0.42, 95% confidence interval (CI) −0.75 to −0.09, I2 = 72%; P = 0.01] and PANSS negative subscale score (SMD = −0.26, 95% CI −0.45 to −0.07, I2 = 0%; P = 0.009) in comparison with placebo. However, add-on statin therapy did not appear to improve scores for the PANSS positive and general subscales at the study-defined endpoint (6–24 weeks). ConclusionsOur meta-analysis indicates that adjunctive statin therapy may confer benefits in ameliorating PANSS negative and total scores. It needs more solid data to confirm the results are related to clinical improvement and functioning.

Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study.

The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Effects of transcranial direct current stimulation (tDCS) on positive and negative symptoms in patients with schizophrenia

Effects of transcranial direct current stimulation (tDCS) on positive and negative symptoms in patients with schizophrenia

Australian trial of behavioural activation for people with schizophrenia experiencing negative symptoms: a feasibility randomised controlled trial protocol

IntroductionNegative symptoms are frequently experienced by people with schizophrenia. People with negative symptoms often have impaired social functioning and reduced quality of life. There is some evidence that cognitive–behavioural therapy...

Aberrant salience mediates the interplay between emotional abuse and positive symptoms in schizophrenia

IntroductionChildhood trauma and adversities (CTA) and aberrant salience (AS) have a pivotal role in schizophrenia development, but their interplay with psychotic symptoms remains vague. We explored the mediation performed by AS between CTA and psychotic symptomatology in schizophrenia. MethodsWe approached 241 adults suffering from schizophrenia spectrum disorders (SSDs), who have been in the unit for at least 12 consecutive months, excluding the diagnosis of dementia, and recent substance abuse disorder, and cross-sectional evaluated through the Aberrant Salience Inventory (ASI), Childhood Trauma Questionnaire Short-Form (CTQ-SF), and Positive and Negative Symptom Scale (PANSS). We tested a path-diagram where AS mediated the relationship between CTA and psychosis, after verifying each measure one-dimensionality through confirmatory factor analysis. ResultsThe final sample comprised 222 patients (36.9% female), with a mean age of 42.4 (± 13.3) years and an average antipsychotic dose of 453.6 (± 184.2) mg/day (chlorpromazine equivalents). The mean duration of untreated psychosis was 1.8 (± 2.0) years while the mean onset age was 23.9 (± 8.2) years. Significant paths were found from emotional abuse to ASI total score (β = 0.39; p < .001) and from ASI total score to PANSS positive (β = 0.17; p = .019). Finally, a statistically significant indirect association was found from emotional abuse to PANSS positive mediated by ASI total score (β = 0.06; p = .041; CI 95% [0.01, 0.13]). ConclusionEmotional abuse has an AS-mediated effect on positive psychotic symptomatology. AS evaluation could allow a better characterization of psychosis as well as explain the presence of positive symptoms in adults with SSDs who experienced CTA.

Hypoactivation of the language network during auditory imagery contributes to hallucinations in Schizophrenia

Auditory verbal hallucinations (AVHs) involve perceptions, often voices, in the absence of external stimuli, and rank among the most common symptoms of schizophrenia. Metrical stress evaluation requires determination of the stronger syllable in words, and therefore requires auditory imagery, of interest for investigation of hallucinations in schizophrenia. The current functional magnetic resonance imaging study provides an updated whole-brain network analysis of a previously published study on metrical stress, which showed reduced directed connections between Broca's and Wernicke's regions of interest (ROIs) for hallucinations. Three functional brain networks were extracted, with the language network (LN) showing an earlier and shallower blood-oxygen-level dependent (BOLD) response for hallucinating patients, in the auditory imagery condition only (the reduced activation for hallucinations observed in the original ROI-based results were not specific to the imagery condition). This suggests that hypoactivation of the LN during internal auditory imagery may contribute to the propensity to hallucinate. This accords with cognitive accounts holding that an impaired balance between internal and external linguistic processes (underactivity in networks involved in internal auditory imagery and overactivity in networks involved in speech perception) contributes to our understanding of the biological underpinnings of hallucinations.

331. Disruption of Consciousness Depends on Insight in OCD and on Positive Symptoms in Schizophrenia

331. Disruption of Consciousness Depends on Insight in OCD and on Positive Symptoms in Schizophrenia

Fractional amplitude of low-frequency fluctuations in sensory-motor networks and limbic system as a potential predictor of treatment response in patients with schizophrenia

BackgroundPrevious investigations have revealed substantial differences in neuroimaging characteristics between healthy controls (HCs) and individuals diagnosed with schizophrenia (SCZ). However, we are not entirely sure how brain activity links to symptoms in schizophrenia, and there is a need for reliable brain imaging markers for treatment prediction. MethodsIn this longitudinal study, we examined 56 individuals diagnosed with 56 SCZ and 51 HCs. The SCZ patients underwent a three-month course of antipsychotic treatment. We employed resting-state functional magnetic resonance imaging (fMRI) along with fractional Amplitude of Low Frequency Fluctuations (fALFF) and support vector regression (SVR) methods for data acquisition and subsequent analysis. ResultsIn this study, we initially noted lower fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, coupled with higher fALFF values in the left hippocampus and right putamen in SCZ patients compared to the HCs at baseline. However, when comparing fALFF values in brain regions with abnormal baseline fALFF values for SCZ patients who completed the follow-up, no significant differences in fALFF values were observed after 3 months of treatment compared to baseline data. The fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, and the left postcentral gyrus were useful in predicting treatment effects. ConclusionOur findings suggest that reduced fALFF values in the sensory-motor networks and increased fALFF values in the limbic system may constitute distinctive neurobiological features in SCZ patients. These findings may serve as potential neuroimaging markers for the prognosis of SCZ patients.

412. Efficacy of Karxt on Negative Symptoms in Acute Schizophrenia: A Post Hoc Analysis of Participants With Prominent Negative Symptoms

412. Efficacy of Karxt on Negative Symptoms in Acute Schizophrenia: A Post Hoc Analysis of Participants With Prominent Negative Symptoms

Serum vitamin D in different schizophrenia groups and symptom severity

Serum vitamin D in different schizophrenia groups and symptom severity

Current State of Application of Formal Thought Disorder Screening Methods in First-Degree Relatives of Patients With Schizophrenia: A Narrative Review

Abstract: Historically, formal thought disorder (FTD) has been considered one of the distinctive key symptoms of schizophrenia and is still regarded as an important early warning sign and a marker of illness severity with solid predictive value. Recent studies are able to found that the presence of FTD is predictive of the subsequent diagnosis of schizophrenia and often precedes the frank clinical picture by several months. Much effort has been put into developing scales that can reliably detect FTD and can be readily applied in routine clinical practice. This narrative review investigated the use of FTD as a screening tool to assess risk in first-degree relatives of patients with schizophrenia. The results show that the use of these scales in firstdegree relatives of schizophrenic individuals during clinical contact and counseling is still an exception, despite their uniquely heightened vulnerability profile. To our knowledge, this is the first time that the application of FTD screening methods in first-degree relatives of schizophrenic individuals has been reviewed in a structured way.