Increase in brain-derived neurotrophic factor expression in early crack cocaine withdrawal.

Recent reports suggest that brain-derived neurotrophic factor (BDNF) could be a biomarker for relapse, drug craving and withdrawal severity. In particular, elevated BDNF levels among former cocaine users have been associated with higher rates of relapse in 90 d. However, no data are available on BDNF levels at baseline and during crack cocaine withdrawal. This study evaluated BDNF among crack cocaine users during inpatient treatment, before and after withdrawal, vs. healthy controls. Clinical correlates with changes in BDNF levels were also assessed. Serum BDNF was evaluated in 49 male crack users on the first and last days of hospitalization and in 97 healthy controls. Serum BDNF was assayed using a sandwich ELISA kit. BDNF levels were significantly lower upon admission when compared to controls, even after adjustment for age, length of inpatient treatment, number of crack rocks used in the last 30 d, years of crack use and interaction between the latter two variables. At discharge, BDNF levels between patients and controls were similar. Number of crack rocks used in the last 30 d and years of crack use were inversely correlated with the outcome. Our findings show that BDNF levels increase during early crack cocaine withdrawal, at an inverse correlation with number of crack rocks used in the last 30 d and years of crack use.

Measurement methods of BDNF levels in major depression: a qualitative systematic review of clinical trials.

There is evidence that the brain-derived neurotrophic factor (BDNF) has implications for the pathophysiology of major depressive disorders (MDD). Measures of BDNF levels are highly dependent on the methodologies used and these vary among different studies. Therefore, the aim of this study was to carry out a descriptive analysis of the methodologies used to measure BDNF in clinical trials (CT) in patients with the diagnosis of major depression. We conducted a qualitative systematic review of CT that included samples of subjects diagnosed with major depression and evaluated the BDNF levels as an outcome. The search was performed on Pubmed, Scielo, Psychinfo and Lilacs. The selected articles were analyzed according to the CONSORT Statement and their methods of BDNF collection and analysis were described. Twenty-eight studies were included in the final analysis. Of those, 6 trials (21.4%) involved non-pharmacological interventions and only half had the MDD diagnosis based on structured interview. Trials used different methods to evaluate BDNF levels: most of them verified serum BDNF levels, 17 (60.7%) trials mentioned that measured BDNF levels in duplicate and 9 (32.1%) collected blood in fasting. A variety of methods for BDNF collection and analysis was used in the different studies, making it difficult to compare results. However, despite of the methodology, BDNF seems to increase after treatment for major depression.

Early discharge predictors among inpatients crack cocaine users.

INTRODUCTION: High rates of early hospital discharge are often observed in crack cocaine users and are related to adverse outcomes and increased public spending. This study evaluated clinical and sociodemographic factors associated with early treatment discharge among crack users. METHODS: The sample comprised 308 men diagnosed with crack cocaine use disorder (crack only), aged 18 to 65 years, admitted between 2013 and 2017 to a male-only hospital unit to treat substance use disorders. Sociodemographic and clinical data were obtained using the Addiction Severity Index, 6th version, and a Sociodemographic Questionnaire. RESULTS: Early discharge (within 7 days) was significantly associated with lack of own income, insufficient family support, being single, and recent homelessness. Regarding drug use, lower treatment retention was related to younger age of crack use onset, recent alcohol use, and nicotine use. Factors such as age, skin color, and educational level showed no relation to the outcome. CONCLUSION: Our findings suggest that presence of characteristics verifiable at the time of admission may be related to crack users' treatment retention. Identification of these factors can contribute to target interventions in order to improve treatment adherence in crack cocaine users.

Serum BDNF levels increase during early drug withdrawal in alcohol and crack cocaine addiction.

Brain-derived neurotrophic factor (BDNF) is involved in several drug-induced brain neuroadaptations. The impact of withdrawal from substances that have different neurological mechanisms on BDNF levels is unclear. Our goal was to compare serum BDNF levels in inpatients with alcohol or crack cocaine use disorders during the early withdrawal period, and to evaluate the association with substance-related outcomes. We performed a follow-up study with 101 men under detoxification treatment (drug preference: alcohol [n = 37] and crack cocaine [n = 64]). Blood samples were collected on the 1st and 15th days of hospitalization to measure serum BDNF levels. Serum BDNF levels increased during the early stage of withdrawal (28.2 ± 10.0 vs. 32.6 ± 13.3, p < 0.001), similarly in individuals with alcohol and crack cocaine use. In the alcohol group, BDNF levels on the 15th day of hospitalization were negatively correlated with age (r = -0.394, p = 0.023). Delta BDNF levels were also negatively correlated with BDNF on the 1st day of hospitalization (p = 0.011). No significant correlation was found regarding substance-related outcomes. This is the first study to compare BDNF levels in alcohol and crack cocaine users undergoing similar treatment conditions. These findings could be related to clinical improvement after abstinence or even to drug withdrawal itself, decreasing neuronal injury. Furthermore, age may be a crucial factor, hindering the recovery of neuroplasticity in alcohol users.

Assessment of cognitive functioning using the Mini Mental State Examination in men with Alcohol and Crack Cocaine Use Disorder.

INTRODUCTION: Consumption of substances has been associated with cognitive impairment. The Mini Mental State Examination (MMSE) is an easy-to-apply screening tool used to assess cognitive functions. OBJECTIVES: To evaluate the cognitive performance of individuals with alcohol (AUD) and/or crack cocaine use disorder (CUD) and polysubstance use using the MMSE and to investigate the impact of substance use profile and the moderation effect of educational level on MMSE performance. METHODS: Cross-sectional study with 508 adult male inpatients diagnosed with substance use disorders (245 with AUD, 85 with CUD, and 178 with polysubstance use). Cognitive performance was assessed using the MMSE scale (total and composite scores). RESULTS: Individuals with AUD had worse total MMSE scores and scored worse for all three MMSE components compared to individuals with polysubstance use (p < 0.001, oral/written language comprehension, p < 0.001, attention/memory, and p = 0.007, motor functions). MMSE scores were positively correlated with educational level (p < 0.017), but were not associated with age, recent drug use, or years of drug use. Educational level moderated the impact of substance use on MMSE performance, especially total score and composite language comprehension score. Individuals with a low educational level (≤ 8 years) had worse performance than those with a high educational level (≥ 9 years), mainly in individuals with AUD (p < 0.001). DISCUSSION: Individuals with a low educational level and alcohol use are more prone to present cognitive impairment than crack cocaine users, especially involving language aspects. Better-preserved cognitive function could impact treatment adherence and might guide the decision of therapeutic strategies.

Proposing an integrative, dynamic and transdiagnostic model for addictions: dysregulation phenomena of the three main modes of the predostatic mind.

Several theories have been proposed to explain the complex diagnostic aspects related to addiction disorders and their development. Recent frameworks tend to focus on dimensional perspectives of symptoms rather than categorical systems, since substance use disorders are frequently comorbid with other psychiatric and especially personality disorders. However, useful transdiagnostic models that could integrate clinical evaluation derived from neuroscientific theories are lacking. In the present manuscript, the authors propose a model based on a new paradigm, in an attempt to better explain this complex, multifaceted phenomenon. The new paradigm presupposes that emotions and behavior are a response to risk prediction. Individuals make choices and engage in actions to manage potential risks/rewards in order to seek or maintain homeostasis in their internal and external environments - a mechanism that the authors call predostatic (predictive mechanism with homeostatic purpose). The model considers three main modes of the predostatic mind: (1) Alarm Mode, activated by high and/or imminent risk prediction; (2) Seek Mode, activated by long-term risk or reward prediction; and (3) Balance Mode, a self-regulating state of mind related to low risk prediction, a soothing system and a calm state. Addiction is seen as a chronic dysregulation of organism systems leading to internalizing or externalizing phenomena mainly related to the Seek and Alarm Modes, which are persistently activated by reward and risk prediction, respectively, thus hindering Balance. Addiction neuroscience research has shown that chronic drug use or engagement in addictive behaviors can lead to neuroadaptations in the brain reward circuitry, disrupting normal balance and the regulation of reward processes. This dysregulation can contribute to persistent drug-seeking/addictive behaviors despite negative consequences. This newly proposed dynamic and integrative model, named dysregulation based on externalizing and internalizing phenomena of the three main modes of the predostatic mind (DREXI3), proposes six dysregulation dimensions with basic emotional and behavioral symptoms, such as neurophysiological alterations, impulsivity, compulsion, cognitive impairment/psychosis, mood, and anxiety/anger. In this paper, the authors explain the rationale behind DREXI3 and present some hypothetical clinical examples to better illustrate the use of the model in clinical practice. The development of this innovative model could possibly guide tailored treatment interventions in the addiction field.

Differential impact on suicide mortality during the COVID-19 pandemic in Brazil.

OBJECTIVES: To compare suicide rates observed in Brazil after the onset of the COVID-19 pandemic with the estimated rate based on suicide deaths between 2010 and 2020, and identify sociodemographic variables associated with this outcome. METHODS: Ecological time-series study. Data were obtained from Brazilian Unified Health System Department of Information Technology (DATASUS), with the structural break of the data set in March 2020. The number of actual suicides observed and the number of expected suicides if there were no COVID-19 pandemic were analyzed through bayesian structural time series modeling. RESULTS: The overall incidence of suicides in Brazil remained stable after the start of the COVID-19 pandemic compared to what would be expected. However, there was a significant increase in suicide deaths among women (6.9%) and older adult (9.1%). Analysis by macro-regions of the country showed significant increases in suicide deaths in the Center-West (7.4%), Northeast (5.7%), and Southeast (10%). Stratified analyses revealed differences according to age, sex, education, and skin color. CONCLUSIONS: Despite stability in the overall number of suicides, this phenomenon occurs heterogeneously among different population groups and regions of Brazil. Rates have increased in populations with a history of poor access to health, which may have been more severely impacted by the pandemic.

Anger and substance abuse: a systematic review and meta-analysis.

OBJECTIVE: Conduct a systematic review and meta-analysis to evaluate levels of anger among substance users compared to non-user controls and to analyze the possible association between anger and psychoactive substance use (PSU). METHODS: The procedures of this review followed the Meta-Analyzes of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four electronic databases (MEDLINE, EMBASE, BIREME, PsycINFO) were searched. RESULTS: Twelve studies were included in the meta-analysis; 10 used the State-Trait Anger Expression Inventory (STAXI) anger trait subscale and two used the Buss-Perry-Aggression Questionnaire (BPAQ) anger subscale. The sample included 2,294 users of psychoactive substances and 2,143 non-users, all male. The mean difference in anger scale scores between users and non-users was 2.151 (95%CI 1.166-3.134, p ≤ 0.00, inconsistency index [I2] = 98.83) standard deviations. Age and abstinence duration did not moderate the difference in anger between substance users and non-users. CONCLUSION: Users of psychoactive substances had elevated anger scores compared to non-users, which represents a high risk of relapse. It is suggested that PSU treatment programs include intensive anger management modules, focusing on factors such as dealing with daily stressors, family conflicts, frustrations, and problems.

Clinical vulnerability for severity and mortality by COVID-19 among users of alcohol and other substances.

The COVID-19 pandemic is a public health emergency. Individuals with substance use disorder have a higher risk of infection and may suffer from more severe forms of the disease. Our goal is to investigate the prevalence of risk factors for COVID-19 severity in individuals with different substance use and explore whether specific types of substance are potentially associated with more clinical risk factors which could increase morbimortality in this population. The sample included 821 men hospitalized at an inpatient Addiction unit (305 alcohol users, 233 cocaine/crack users, and 283 multiusers). Data were collected using the Addiction Severity Index version 6. The most prevalent risk factors for COVID-19 severity observed in our sample were: smoking (82.5%), arterial hypertension (26.6%), respiratory problems (23.4%), and history of homelessness (25.1%). Arterial hypertension and cirrhosis occurred more frequently among alcohol users. Multiusers lived in the streets longer and had a higher prevalence of HIV than alcohol users. Overall, 28% of the sample had three or more risk factors. The frequency of risk factors was high and this scenario suggests that these individuals could be more susceptible to worse COVID-19 prognosis. Therefore, prevention strategies directed at specific characteristics of substance users merit attention during the pandemic.

Association between childhood trauma, parental bonding and antisocial personality disorder in adulthood: A machine learning approach.

Childhood trauma (CT) and parental bonding (PB) have been correlated with later antisocial personality disorder (ASPD). Aiming to better understand this complex interaction we analyzed the data from a cross-sectional study that evaluated 346 male inpatient cocaine users, using both traditional statistical analysis and machine learning (ML) approaches. Childhood Trauma Questionnaire (CTQ), Parental Bonding Instrument (PBI), and Mini International Neuropsychiatric Interview (MINI) were applied. We found a markedly higher prevalence of mental illness in the ASPD group. The ML method and the traditional analysis showed that emotional and physical abuse were the factors with the strongest relationship with ASPD. Also, there were discrepancies between the findings of both methods regarding physical neglect and paternal care. Although this study does not allow definitive answers in this matter, we do propose that these two methods can aid in better comprehending how multiple variables interact with each other in the development of psychological disorders.

The next pandemic: impact of COVID-19 in mental healthcare assistance in a nationwide epidemiological study.

BACKGROUND: Studies have reported the worsening of psychiatric symptoms during the COVID-19 pandemic. However, few studies have evaluated the impact on the access to mental health services during COVID-19. Our aim was to analyze temporal trends and prediction of appointments held in Brazil's public health system, to compare the observed and expected number of mental healthcare appointments during the COVID-19 pandemics. METHODS: An ecological time-series study was performed, analyzing mental health appointments before and during the pandemic (from 2016 and 2020) from the Brazilian governmental database. The structural break in the data series was assessed using the Chow test, with the break considered in March 2020. Bayesian structural time-series models were used to estimate current average appointments and the predicted expectation if there was no pandemic. FINDINGS: Compared to the expected, between March and August 2020 about 28% less outpatient appointments in mental health were observed, totaling 471,448 individuals with suspended assistance. Group appointments and psychiatric hospitalizations were also severely impacted by the pandemic (decreased of 68% and 33%, respectively). On the other hand, mental health emergency consultations and home care increased during this period (36% and 52%, respectively). INTERPRETATION: Our findings demonstrate a dramatic change in mental health assistance during the COVID-19 pandemic, which corroborates a recent WHO survey. This phenomenon can aggravate the mental health crisis and generate a parallel pandemic that may last for a longer time than the COVID-19 pandemic. FUNDING: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

Modulation of neuropeptide Y levels is impaired in crack withdrawal patients.

Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal.

OBJECTIVE: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. METHOD: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. RESULTS: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. CONCLUSION: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Sex-based differences in multidimensional clinical assessments of early-abstinence crack cocaine users.

Crack cocaine use disorder (CUD) has been related to sex differences. This work aimed to compare the severity of drug use and the severity of other negative related outcomes in males and females with CUD. A total of 1344 inpatients (798 males and 546 females) with crack cocaine use disorder (CUD) were evaluated by a detailed multidimensional clinical assessment, including addiction severity and trauma exposure. Linear regression predicted higher drug use severity (ß = 0.273, p < 0.001) and more problems in domains related to childcare issues (ß = 0.321), criminal involvement (ß = 0.108), work-related problems (ß = 0.281) and social support impairments (ß = 0.142) for females, all with p < 0.001. Alcohol problems were predicted to be higher in males (ß = -0.206, P < 0.001). Females had higher rates of other mental disorders, particularly trauma and stress-related disorders (OR: 3.206, CI: 2.22, 4.61). Important sex differences also emerged in trauma history and HIV infection prevalence. CUD has a more severe clinical presentation among females facing early abstinence. Sex differences in the CUD course indicate the need for consideration of sex-specific interventions and research.

Mental states as part of countertransference responses in psychotherapists facing reports of traumatic events of mourning and sexual violence.

The study aims to compare the mental states and countertransference responses of 92 psychodynamically oriented psychotherapists, male and female, experienced and inexperienced, facing written reports of real patients who experienced traumatic events. Two vignettes were presented: one of a sexual violence, the other the sudden death of a significant person. The Mental States Rating System (MSRS; Bouchard, Picard, Audet, Brisson, & Carrier, 1998), the MSRS Self-Report (Goldfeld & Bouchard, 2004), and the Inventory of Countertransference Behavior (ICB; Friedman & Gelso, 2000) were used. Results showed that the mourning vignette led to more reflective responses (MSRS) and the rape case was associated with more negative countertransference reactions (ICB). Female participants were more reflective (MSRS); male therapists used less mentalized states (MSRS Self-Report) and expressed more negative reactions (ICB) for both scenarios. Experienced therapists showed more positive reactions on the ICB. The construct validity of the instruments is discussed in relation to the findings.

Combined physical training associated with multidisciplinary intervention in the treatment of alcohol use disorder: a study with n of 1 / O treinamento físico combinado associado à intervenção multiprofissional no tratamento do transtorno por uso de álcool: um estudo com n de 1

ABSTRACT Objective: Substance misuse can lead to several consequences for physical and mental health. Physical exercise is an important ally to pharmacological and psychotherapeutic treatment for substance use. However, the literature is still scarce regarding long-term interventions. Thus, this study aims to describe the acceptability and effects of combined physical training intervention (aerobic and strength). Methods: This study comprises an n-of-1 clinical trial that was performed with a 64-year-old male individual with alcohol use disorder. The treatment lasted 12 weeks and evaluated the association of multidisciplinary interventions on quality of life, depressive symptoms, cognitive impairment, and anxiety. Results: The participant improved general quality of life (12.5%), no alterations were found for depressive symptoms, there was an improvement in cognition (20%), as well a reduction in the trait (16.2%) and state (14.7%) anxiety symptoms of the participant. Conclusions: These findings allude to the importance of non-drug therapeutic resources such as structured physical exercise, associated with other offers in the treatment of alcohol use disorder.

RESUMO Objetivo: O uso de substâncias psicoativas pode levar a diversas consequências à saúde física e mental. O exercício físico é um importante aliado ao tratamento farmacológico e psicoterápico para o uso de substâncias. No entanto, a literatura ainda é escassa em relação às intervenções de longa duração. Dessa forma, este estudo objetiva descrever a aceitabilidade e os efeitos de uma intervenção de treinamento físico combinado (aeróbico e força). Métodos: Este estudo compreende um n-of-1 clinical trial que foi realizado com um indivíduo do sexo masculino, de 64 anos de idade, com transtorno por uso de álcool. O tratamento teve a duração de 12 semanas e avaliou a associação de intervenções multiprofissionais sobre a qualidade de vida, sintomas depressivos, comprometimento cognitivo e ansiedade. Resultados: O participante melhorou a qualidade de vida geral (12,5%), não foram encontradas alterações para sintomas depressivos, houve melhora na cognição (20%), bem como redução nos sintomas de ansiedade traço (16,2%) e estado (14,7%) do participante. Conclusões: Esses achados aludem à importância de recursos terapêuticos não medicamentosos como o exercício físico estruturado, associados às demais ofertas no tratamento para o transtorno por uso de álcool.

Early discharge predictors among inpatient crack cocaine users

Abstract Introduction High rates of early hospital discharge are often observed in crack cocaine users and are related to adverse outcomes and increased public spending. This study evaluated clinical and sociodemographic factors associated with early treatment discharge among crack users. Methods The sample comprised 308 men diagnosed with crack cocaine use disorder (crack only), aged 18 to 65 years, admitted between 2013 and 2017 to a male-only hospital unit to treat substance use disorders. Sociodemographic and clinical data were obtained using the Addiction Severity Index, 6th version, and a Sociodemographic Questionnaire. Results Early discharge (within 7 days) was significantly associated with lack of own income, insufficient family support, being single, and recent homelessness. Regarding drug use, lower treatment retention was related to younger age of crack use onset, recent alcohol use, and nicotine use. Factors such as age, skin color, and educational level showed no relation to the outcome. Conclusion Our findings suggest that presence of characteristics verifiable at the time of admission may be related to crack users' treatment retention. Identification of these factors can contribute to target interventions in order to improve treatment adherence in crack cocaine users.

Assessment of cognitive functioning using the Mini Mental State Examination in men with alcohol and crack cocaine use disorder

Abstract Introduction Consumption of substances has been associated with cognitive impairment. The Mini Mental State Examination (MMSE) is an easy-to-apply screening tool used to assess cognitive functions. Objectives To evaluate the cognitive performance of individuals with alcohol (AUD) and/or crack cocaine use disorder (CUD) and polysubstance use using the MMSE and to investigate the impact of substance use profile and the moderation effect of educational level on MMSE performance. Methods Cross-sectional study with 508 adult male inpatients diagnosed with substance use disorders (245 with AUD, 85 with CUD, and 178 with polysubstance use). Cognitive performance was assessed using the MMSE scale (total and composite scores). Results Individuals with AUD had worse total MMSE scores and scored worse for all three MMSE components compared to individuals with polysubstance use (p < 0.001, oral/written language comprehension, p < 0.001, attention/memory, and p = 0.007, motor functions). MMSE scores were positively correlated with educational level (p < 0.017), but were not associated with age, recent drug use, or years of drug use. Educational level moderated the impact of substance use on MMSE performance, especially total score and composite language comprehension score. Individuals with a low educational level (≤ 8 years) had worse performance than those with a high educational level (≥ 9 years), mainly in individuals with AUD (p < 0.001). Discussion Individuals with a low educational level and alcohol use are more prone to present cognitive impairment than crack cocaine users, especially involving language aspects. Better-preserved cognitive function could impact treatment adherence and might guide the decision of therapeutic strategies.

Identification and initial management of intoxication by alcohol and other drugs in the pediatric emergency room.

OBJECTIVE: To review the screening, diagnosis, evaluation, and treatment of intoxication by alcohol and other drugs in children and adolescents in the emergency scenario. DATA SOURCE: This was a narrative literature review. DATA SUMMARY: The detection of this problem in the emergency room can be a challenge, especially when its assessment is not standardized. The intentional and episodic use of large amounts of psychoactive substances by adolescents is a usual occurrence, and unintentional intoxication is more common in children younger than 12 years. The clinical picture in adolescents and children differs from that in adults and some particularities are important in the emergency scenario. After management of the acute condition, interventions targeting the adolescent at risk may be effective. CONCLUSION: The diagnosis and treatment of intoxication by alcohol and other drugs in adolescents and children in the emergency scenario requires a systematic evaluation of the use of these drugs. There are few specific treatments for intoxication, and the management comprehends support measures and management of related clinical complications.