The continuity psychiatric nursing care model to enhance medication adherence in schizophrenia patients in Indonesia: Participatory action research.

OBJECTIVE: To develop a continuity of psychiatric nursing care model to enhance medication adherence in schizophrenia patients. METHODS: The Participatory Action Research study was conducted from 2017 to 2018 in Pekanbaru, Riau, Indonesia, after approval form the ethics review committee of the Faculty of Nursing, Prince of Songkla University, Thailand. The sample included schizophrenia inpatients at a mental hospital, their family members and nursing staff. Qualitative data were gathered through in-depth interviews, observations, field notes, and photo records. Data was subjected to content analysis, while trustworthiness of the model was also determined. RESULTS: Of the 57 subjects, 22(38.6%) were schizophrenia patients, 22(38.6%) were family members, and 13(22.8%) were nurses. The continuity of psychiatric nursing care model consisted of three components: preparing for readiness to live a normal way of life; creating a supportive environment; and, sustaining the continuity of care until the community level care. CONCLUSIONS: The continuity of psychiatric nursing care model facilitated holistic nursing care aspects.

Randomized open-label study of second-generation antipsychotics for the treatment of schizophrenia: 104-week final results of the JUMPs study assessing treatment discontinuation, remission, and social functioning.

BACKGROUND: We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study. METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension). RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation. CONCLUSIONS: The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment. CLINICAL TRIAL REGISTRATION: UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012).

Functioning Management and Recovery, a psychoeducational intervention for psychiatric residential facilities: a multicenter follow-up study.

AIM: Functional Management and Recovery is a standardized Psychoeducational Intervention, derived from "Integro", an effective salutogenic-psychoeducational intervention for people in recovery journey, designed to improve recovery and functioning of individuals with psychotic disorders in Psychiatric Residential Facilities (PRFs). The aim of this study is to evaluate the primary and secondary outcomes of this intervention elaborated specifically for PRFs where evidence based structured interventions seem rare and desirable. METHODS: 66 individuals with psychotic disorders were recruited in 9 PRFs dislocated in the North, Center and South Italy and 63 underwent a multicenter follow-up study with a two time-point evaluation (t0, pre-treatment and t1, 6 months; ). At each time point, social functioning was assessed as primary outcome by the Personal and Social Performance scale (PSP); furthermore, psychopathological status was assessed by Brief Psychiatric Rating Scale (BPRS), Recovery by Recovery Assessment Scale (RAS), Cognitive Functioning by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Stress management by Stress-Scale, Cognitive Flexibility by Modified Five-Point Test (M-FPT), Emotional Intelligence by Emotional Intelligence Index (EI-I), the PRF Atmosphere and the Opinion of users about the PFR by an ad hoc questionnaire. The Abilities Knowledge, the Utility and Pleasantness of sessions were measured by an ad hoc list of items. RESULTS: 63 individuals out of 66, 52 (82,5%) affected by schizophrenia and 11 (17,5%) by bipolar I disorder with psychotic symptoms according to DSM-5-TR completed the study. At the end of the study, 43 (68,3%) were male, 57 (90.5%) were single, 5 (7.9%) engaged, 1 (1.6%) married; 45 (71.4%) unemployed. The total scores of PSP, RAS, BPRS, BANS, Stress management, Abilities Knowledge, Utility and Pleasantness of sessions showed a statistically significant improvement at t1 vs. t0. Two sub-scales out of 5 of M-FPT showed a statistically significant improvement. The Emotional Intelligence, the Unit Atmosphere and the Opinion of Users about PFR improved without statistical significance. Six months after the end of the follow-up study 22 individuals of the sample were dismissed with a very high turnover. CONCLUSIONS: After a six-month follow-up (a short period of time), these results showed improvement in functioning, the primary outcome, as well as in the following secondary outcome variables: RAS, BPRS, BANS, Stress management, Abilities Knowledge, two sub-scales out of 5 of M-FPT, Utility and Pleasantness of sessions. Overall, a remarkable impact of psychoeducational structured intervention on the key Recovery variables is observed. Further studies are needed to address extent and duration of these improvements.

Psychological interventions for early-phase schizophrenia: protocol for a systematic review and network meta-analysis.

Introduction: Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol: Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion: This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Feuerstein Instrumental Enrichment Program for People With Schizophrenia After the First Episode of Psychosis: Protocol for an Open-Label Intervention Study.

BACKGROUND: Schizophrenia is a disorder associated with neurocognitive deficits that adversely affect daily functioning and impose an economic burden. Cognitive rehabilitation interventions, particularly during the early phases of illness, have been shown to improve cognition, functionality, and quality of life. The Feuerstein Instrumental Enrichment (FIE) program, based on the Mediated Learning Experience and the Structural Cognitive Modifiability theory, has been applied in various disorders, but its applicability in schizophrenia has not yet been clarified. OBJECTIVE: This study aims to investigate the effects of the FIE program on the functionality of patients with first-episode schizophrenia. METHODS: In total, 17 patients will be recruited for an open-label intervention consisting of twice-weekly sessions for 10 weeks. The primary outcome measure will be changes in the Goal Achievement Scale score. Maze task performance from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery will serve as a secondary outcome measure. At the same time, changes in Positive and Negative Syndrome Scale scores and other MATRICS domains will be analyzed as exploratory outcomes. Assessments will be administered before and after the intervention, with a follow-up period of 6 months. RESULTS: This trial was preregistered in The Brazilian Registry of Clinical Trials (RBR-4gzhy4s). By February 2024, 11 participants were enrolled in the training. Recruitment is expected to be completed by May 2024. Data analysis will be conducted between May and September 2024. The results are expected to be published in January 2025. CONCLUSIONS: This study may establish a protocol for the FIE program that uses mediation techniques for individuals in the early stages of schizophrenia. The results will add to the knowledge about strategies to promote cognitive skills and functional impairment in daily life. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57031.

Patients with cancer and pre-existing severe mental disorder.

Patients with cancer and pre-existing severe mental disorder, which include moderate to severe depression, bipolar disorder and schizophrenia, are known to have reduced life expectancy and are less likely to get recommended cancer treatment. Barriers at patient-, provider- and system level have been identified, e.g. lack of identification of psychiatric comorbidity, shortage of stabilising psychiatric symptoms and fragmentation of the healthcare system. Patient-centered, interdisciplinary and cross-sectorial healthcare interventions have shown a high potential to improve the cancer care, as argued in this review.

Exploring the relationship between lipid metabolism and cognition in individuals living with stable-phase Schizophrenia: a small cross-sectional study using Olink proteomics analysis.

BACKGROUND: Cognitive impairment is a core symptom of schizophrenia. Metabolic abnormalities impact cognition, and although the influence of blood lipids on cognition has been documented, it remains unclear. We conducted a small cross-sectional study to investigate the relationship between blood lipids and cognition in patients with stable-phase schizophrenia. Using Olink proteomics, we explored the potential mechanisms through which blood lipids might affect cognition from an inflammatory perspective. METHODS: A total of 107 patients with stable-phase schizophrenia and cognitive impairment were strictly included. Comprehensive data collection included basic patient information, blood glucose, blood lipids, and body mass index. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB). After controlling for confounding factors, we identified differential metabolic indicators between patients with mild and severe cognitive impairment and conducted correlation and regression analyses. Furthermore, we matched two small sample groups of patients with lipid metabolism abnormalities and used Olink proteomics to analyze inflammation-related differential proteins, aiming to further explore the association between lipid metabolism abnormalities and cognition. RESULTS: The proportion of patients with severe cognitive impairment (SCI) was 34.58%. Compared to patients with mild cognitive impairment (MCI), those with SCI performed worse in the Attention/Alertness (t = 2.668, p = 0.009) and Working Memory (t = 2.496, p = 0.014) cognitive dimensions. Blood lipid metabolism indicators were correlated with cognitive function, specifically showing that higher levels of TG (r = -0.447, p < 0.001), TC (r = -0.307, p = 0.002), and LDL-C (r = -0.607, p < 0.001) were associated with poorer overall cognitive function. Further regression analysis indicated that TG (OR = 5.578, P = 0.003) and LDL-C (OR = 5.425, P = 0.001) may be risk factors for exacerbating cognitive impairment in individuals with stable-phase schizophrenia. Proteomics analysis revealed that, compared to individuals with stable-phase schizophrenia and normal lipid metabolism, those with hyperlipidemia had elevated levels of 10 inflammatory proteins and decreased levels of 2 inflammatory proteins in plasma, with these changes correlating with cognitive function. The differential proteins were primarily involved in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway. CONCLUSION: Blood lipids are associated with cognitive function in individuals with stable-phase schizophrenia, with higher levels of TG, TC, and LDL-C correlating with poorer overall cognitive performance. TG and LDL-C may be risk factors for exacerbating cognitive impairment in these patients. From an inflammatory perspective, lipid metabolism abnormalities might influence cognition by activating or downregulating related proteins, or through pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway.

Daidzin enhances memory and the antischizophrenia drug olanzapine's effects, possibly through the 5-HT2A and D2 receptor interaction pathways.

Schizophrenia affects identification and disturbs our thinking and motivational capacity. Long-term use of daidzin (DZN) is evident to enhance attention and memory in experimental animals. This study aimed to investigate the effect of DZN on Swiss mice. To check animals' attention, identification, thinking, and motivational ability, we performed behavioral studies using marble burying, dust removal, and trained swimming protocols. For this, a total of 36 male Swiss albino mice were randomly divided into six groups, consisting of 6 animals in each group, as follows: control (vehicle), DZN-1.25, DZN-2.5, DZN-5 mg/kg, olanzapine (OLN)-2, and a combination of DZN-1.25 with OLN-2. Additionally, in silico studies are also performed to understand the possible molecular mechanisms behind this neurological effect. Findings suggest that DZN dose-dependently and significantly (p < .05) increased marble burying and removed dust while reducing the time to reach the target point. DZN-1.25 was found to enhance OLN's effect significantly (p < .05), possibly via agonizing its activity in animals. In silico findings suggest that DZN has strong binding affinities of -10.1 and -10.4 kcal/mol against human serotonin 2 A (5-HT2A) and dopamine 2 (D2) receptors, respectively. Additionally, DZN exhibits favorable pharmacokinetic and toxicity properties. We suppose that DZN may exert its attention- and memory-enhancing abilities by interacting with 5-HT2A and D2 receptors. It may exert a synergistic antischizophrenia-like effect with the standard drug, OLN. Further studies are required to discover the exact molecular mechanism for this neurological function in animals.

Burden in caregivers of patients with schizophrenia, depression, dementia, and stroke in Japan: comparative analysis of quality of life, work productivity, and qualitative caregiving burden.

BACKGROUND: The main objective of this study was to examine the burden of schizophrenia, depression, Alzheimer's disease/dementia, and stroke on caregivers and non-caregivers in Japan. This study also aimed to provide a comparative landscape on the burden of caregiving for each disorder. METHODS: The Japan National Health and Wellness Survey database, 2016 and 2018 was used in this study. Health-related quality of life (HRQoL), work productivity, and health care utilization were assessed using a self-administered, Internet-based questionnaire. The burden of caregiving experienced by each group of caregivers was compared with background-matched non-caregivers (controls) as well as with caregivers of patients with each disorder. RESULTS: Caregivers of patients with schizophrenia, depression, Alzheimer's disease/dementia, or stroke had lower HRQoL, higher healthcare costs and work productivity impairment than non-caregivers. Furthermore, caregivers of patients with psychiatric disorders such as schizophrenia and depression had lower HRQoL and work productivity than caregivers of patients with Alzheimer's disease/dementia and stroke. In addition, according to the Caregiver Reaction Assessment (CRA), caregivers of patients with schizophrenia and depression were more inclined to perceive a loss in physical strength and financial burden to the same extent as their self-esteem. CONCLUSIONS: This study indicated a substantial caregiving burden among caregivers of patients with psychiatric and neurological diseases in Japan. The caregiver burden of psychiatric disorders (schizophrenia and depression) was greater than that of neurological disorders (Alzheimer's disease/dementia and stroke), suggesting a need to provide support to caregivers of patients with psychiatric disorders to be better able to care for their patients. TRIAL REGISTRATION: None.

Klingsor Syndrome: Genital Self-Mutilation in a Psychotic Patient. / Klingsor Sendromu: Psikotik Hastada Genital Self Mutilasyon.

Self-mutilation attempts are common in psychiatric practice. One form of self-harm, genital self-mutilation (GSM), is less common but may have severe consequences. GSM acts can occur in different diagnoses such as personality disorders, substance abuse disorders, obsessive-compulsive disorders, and psychotic disorders. When GSM is performed due to psychotic symptoms, the clinical picture is called Klingsor Syndrome. GSM is often associated with severe psychosis and often accompanied by religious delusions. In our article, we discussed a case of schizophrenia with penile autoamputation due to religious delusions. A 28-year-old male patient was admitted to our hospital after penile autoamputation. After surgical interventions, the patient's follow-up continued in our clinic. The patient had auditory hallucinations, delusions of persecution, and sinfulness. His symptoms improved after antipsychotic treatment. It is important to identify the risk factors of Klingsor Syndrome, which is a rare but serious condition, and to intervene early in these patients. Keywords: Self-mutilation, Psychosis, Self-injurious Behavior.

SCG2 mediates blood-brain barrier dysfunction and schizophrenia-like behaviors after traumatic brain injury.

Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single-cell RNA sequencing (scRNA-Seq). We adopted the gene expression omnibus and scRNA-Seq to identify the mediation by secretogranin II (SCG2) of TBI-induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2-triggered disruption of the blood-brain barrier (BBB) via the CypA-MMP-9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2-CypA-MMP-9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.

Borderlines of psychosis - nosological propositions of Polish psychiatrists of the interwar period. / Pogranicza psychozy ­ nozologiczne propozycje polskich psychiatrów dwudziestolecia miedzywojennego.

This paper examines nosological categories relating to borderlines between psychosis and other clinical categories, introduced by Polish psychiatrists in the interwar period. In the United States, the discussion about the borderline between neuroses and psychoses was urged by the 1938 article by psychoanalyst Adolph Stern. In Poland, nosological categories regarding the borderline between neuroses and psychoses were proposed by Adam Wizel, Maurycy Bornsztajn, Jan Nelken, and Wladyslaw Matecki. Wizel coined the term 'underdeveloped schizophrenia', Bornsztajn introduced 'schizothymia reactiva' and 'hypochondriac (somatopsychic) schizophrenia', Nelken described 'mild schizophrenia', first introduced by Moscow psychiatric school of Rosenstein, and Matecki presented the category of neurosis-like (pseudo-neurotic) schizophrenia. Additionally, Julian Dretler, after studying the borderline between schizophrenia and manic-depressive psychosis, coined the term 'mixed psychosis' and expressed conviction that it is an independent nosological entity. Like in the United States, the majority of Polish pioneers of the nosological studies of borderline cases were influenced by psychoanalysis. As a consequence of World War II and the new regime, which forced dialectical materialism and Pavlovism as an official ideology of psychiatry and condemned psychoanalysis, the categories presented in the article became forgotten and have not impacted Polish psychiatric nosology.

Challenging pharmacotherapy management of a psychotic disorder due to a delicate pharmacogenetic profile and drug-drug interactions: a case report and literature review.

This report presents challenging psychopharmacotherapy management of a psychotic disorder in a patient with a delicate pharmacogenetic profile and drug-drug interactions. A 31-year old woman diagnosed with schizophrenia in 2017 was referred by her psychiatrist to a clinical pharmacologist for interpretation of a pharmacogenetic test and advice regarding optimal psychopharmacotherapy. In spite of adherence to aripiprazole, olanzapine, risperidone, and levomepromazine, and rational anxiolytic therapy, she still experienced anxiety, anhedonia, loss of appetite, sleeping problems, and auditory hallucinations with commands to harm herself. Due to a lack of alternative therapeutic steps, low aripiprazole serum concentrations, and a lack of explanation for pharmacotherapy unresponsiveness, pharmacogenetic testing was performed. The patient was defined as CYP2D6 *1/*1, CYP1A2 *1F/*1F, CYP3A4 *1/*1B, CYP3A5 *1/*3, and having increased activity of the enzymes UGT1A4 and UGT2B7, intermediate activity of ABCB1 transporter, and low activity of COMT. Carbamazepine was discontinued, aripiprazole was increased to a maximum of 30 mg/day orally with long-acting injection (400 mg monthly), and olanzapine was increased to a daily dose of 35 mg orally. These changes led to an optimal therapeutic drug concentration and improved clinical status. At the last follow-up, the patient was without severe auditory hallucinations, became more engaged in daily life, had more interaction with others, had found a job, and even had started an emotional relationship. In psychiatry, pharmacogenetic testing is an important tool for guiding pharmacological therapy, particularly in patients with an unsatisfactory clinical response and a lack of alternative therapeutic steps for pharmacotherapy unresponsiveness.

[Pharmacotherapy of schizophrenia: clinical and some age-related aspects]. / Farmakoterapiya shizofrenii: klinicheskie i nekotorye vozrastnye aspekty.

The article discusses modern approaches to the rational choice of therapy for schizophrenia in accordance with the principles of personalized medicine. Clinical markers for determining the optimal treatment tactics are considered depending on the syndromic features and stereotype of the course of the disease, and the possibility of justified combination therapy with drugs of different pharmacological classes. The specifics of the treatment of schizophrenia in childhood/adolescence and adult are discussed, including the basic principles of choosing drug classes, daily doses and drug therapy tactics.

[Psychological concepts - design of clinical models of schizophrenia]. / Psikhologicheskie kontseptsii ­ konstrukt klinicheskikh modelei shizofrenii.

This publication presents an analysis of the psychological concepts, involved in the construction of clinical models of schizophrenia; in particular - the new clinical-biological paradigm of schizophrenia (reflecting the data of own psychometric studies). Based on the analysis, 3 modes of interaction between clinical and psychological constructs in the construction of models of schizophrenia were identified. The conceptualization of clinical models was carried out from the perspective of the contribution of psychological and psychometric constructs - allowing to expand theoretical ideas about the dynamics of views on the clinical construct of schizophrenia.

[Clinical systematics of chronic delusional psychoses in schizophrenia and schizophrenia-spectrum pathology]. / Klinicheskaya sistematika khronicheskikh bredovykh psikhozov pri shizofrenii i patologii shizofrenicheskogo spektra.

OBJECTIVE: To develop a systematics of chronic delusional psychoses in schizophrenia and pathology of the schizophrenic spectrum that takes into account psychopathological structure (the mechanism of delusional formation) and the trajectories of the disease course (the ratio of negative/positive dimensions). MATERIAL AND METHODS: The study sample was recruited from the large Moscow psychiatric hospital in 2019-2024 and included 126 patients (94 male, 32 female, mean age 36.5±12.1 years) hospitalized with ICD-10 diagnosis of paranoid schizophrenia (F20.00) or delusional disorder (F22). A clinical-psychopathological method was used. RESULTS: The study identifies three variants of paranoid domains, the typology of which takes into account both the psychopathological structure and the trajectories of their development, which determine the dominance of predominantly negative or positive symptoms throughout the disease: 1) psychosis with delusional interpretations and predominant orientation of symptoms towards the negative pole of the schizophrenia psychopathology (n=37, 29.4%); 2) psychosis with hallucinatory delusions and predominant direction of symptoms towards the positive pole of the schizophrenia psychopathology (n=50, 39.7%); and 3) «combined¼ hallucinatory-delusional psychosis with a simultaneous orientation of symptoms to the negative/positive poles of the schizophrenia psychopathology (n=39, 30.9%). Detailed phenomenological characteristics of each of the three presented variants are given. CONCLUSION: The developed three-component taxonomy confirms, on the model of chronic delusional psychoses appearing in schizophrenia and the pathology of the schizophrenia spectrum, the concept of simultaneous representation of two relatively independent domains determined by neurobiological processes in the schizophrenia psychopathology positive and negative disorders.

[Controversial issues of diagnosis and theoretical concepts of schizophrenia in childhood]. / Diskussionnye voprosy diagnostiki i teoreticheskie modeli shizofrenii v detskom vozraste.

The article presents modern approaches to classification, presents debatable diagnostic issues, including the differences between domestic approaches to the diagnosis of schizophrenia in childhood from foreign taxonomies. The modern hypothesis of the etiological continuum of schizophrenic and autistic spectrum disorders is discussed, as well as clinical models of manifest stages of schizophrenia in childhood, with an emphasis on the influence of the age factor on the clinic, dynamics and prognosis of diseases.