Risk Factor For Psychiatric Disorders Research Articles

Risk of severe mood and anxiety disorders in the adult children of parents with alcohol use disorder: a nationwide cohort study

BackgroundGrowing up with parental alcohol use disorder (AUD) is a risk factor for psychiatric disorders. This study investigated the risk of mood disorders and of anxiety disorders in the adult...

The Psychiatric Disorders and Cannabis Use

Introduction: Cannabis is the most widely used of illicit substances. It is a public health problem for the most vulnerable populations, and in particular; adolescents. Cannabis is the subject of much debate in its links with psychiatric disorders where it appears to be a risk factor and a worsening factor, as all psychoactive substances. Objective: Determine the hospital prevalence of psychiatric disorders among patients who use cannabis and establish a correlation between cannabis use and psychiatric disorders. Method: This is a prospective study of 100 patients, consuming or having consumed cannabis, hospitalized at Ibn NAFISS hospital over a 6-month period from February 24, 2021 to August 24, 2021. The statistical study was carried out with the SPSS software version 25.0 and in bivariate analysis, and the comparison of the qualitative variables appealed to the statistical test of Chi2. Results: The average age of our patients is 32 years old, a clear predominance of men (95%), 73% of patients are single, 85% of patients have a low socio-economic level and 40% have a secondary education level. Psychiatric evaluation of our patients revealed that psychotic disorders (schizophrenia, acute psychotic attack, etc.) are found with a rate of 85% followed by bipolar (34%) and anxiety disorders (34%) and lastly depressive disorders (13%). The correlation between psychiatric disorders and the cannabis behaviour of our patients has objected that an early age of onset of use, heavy use, regular use and an unfavourable socio-economic level are all risk factors for psychiatric disorders in patients of cannabis users, especially psychotic disorders (schizophrenia, acute psychotic attack, etc...) Conclusion: The association between cannabis and psychiatric disorders is reported in numerous studies. These results found that cannabis-dependent subjects more frequently presented with psychiatric disorders and personality disorders than in the general population. This high .........

Increased risk of psychiatric disorder in patients with hearing loss: a nationwide population-based cohort study

BackgroundHearing loss has been shown to be a risk factor for psychiatric disorders. In addition, long-term hearing loss is associated with increased hospitalization and mortality rates; however, the increased risk and duration of effect of hearing loss in combination with other chronic diseases on each psychiatric disorder are still not clearly defined. The purpose of this article is to clarify the risk of hearing loss for each disorder over time.MethodsThis was a retrospective cohort study, and a national health insurance research database in Taiwan was utilized. All (n = 1,949,101) Taiwanese residents who had a medical visit between 2000 and 2015 were included. Patients with hearing loss and a comparative retrospective cohort were analyzed. Every subject was tracked individually from their index date to identify the subjects who later received a diagnosis of a psychiatric disorder. The Kaplan‒Meier method was used to analyze the cumulative incidence of psychiatric disorders. Cox regression analysis was performed to identify the risk of psychiatric disorders.ResultsA total of 13,341 (15.42%) and 31,250 (9.03%) patients with and without hearing loss, respectively, were diagnosed with psychiatric disorders (P < 0.001). Multivariate analysis indicated that hearing loss significantly elevated the risk of psychiatric disorders (adjusted HR = 2.587, 95% CI 1.723–3.346, p < 0.001).ConclusionOur findings indicate that patients with hearing loss are more likely to develop psychiatric disorders. Furthermore, the various psychiatric disorders are more likely to occur at different times. Our findings have important clinical implications, including a need for clinicians to implement early intervention for hearing loss and to pay close attention to patients’ psychological status.Trial registration TSGHIRB No. E202216036.

Prefrontal-Limbic Circuitry Is Associated With Reward Sensitivity in Nonhuman Primates

BackgroundAbnormal reward sensitivity is a risk factor for psychiatric disorders, including eating disorders such as overeating and binge-eating disorder, but the brain structural mechanisms that underlie it are not completely understood. Here, we sought to investigate the relationship between multimodal whole-brain structural features and reward sensitivity in nonhuman primates. MethodsReward sensitivity was evaluated through behavioral economic analysis in which monkeys (adult rhesus macaques; 7 female, 5 male) responded for sweetened condensed milk (10%, 30%, 56%), Gatorade, or water using an operant procedure in which the response requirement increased incrementally across sessions (i.e., fixed ratio 1, 3, 10). Animals were divided into high (n = 6) or low (n = 6) reward sensitivity groups based on essential value for 30% milk. Multimodal magnetic resonance imaging was used to measure gray matter volume and white matter microstructure. Brain structural features were compared between groups, and their correlations with reward sensitivity for various stimuli was investigated. ResultsAnimals in the high sensitivity group had greater dorsolateral prefrontal cortex, centromedial amygdaloid complex, and middle cingulate cortex volumes than animals in the low sensitivity group. Furthermore, compared with monkeys in the low sensitivity group, high sensitivity monkeys had lower fractional anisotropy in the left dorsal cingulate bundle connecting the centromedial amygdaloid complex and middle cingulate cortex to the dorsolateral prefrontal cortex, and in the left superior longitudinal fasciculus 1 connecting the middle cingulate cortex to the dorsolateral prefrontal cortex. ConclusionsThese results suggest that neuroanatomical variation in prefrontal-limbic circuitry is associated with reward sensitivity. These brain structural features may serve as predictive biomarkers for vulnerability to food-based and other reward-related disorders.

Risk Factors for Psychiatric Disorders in Patients with Multiple Sclerosis-A Single-Center Study in the Polish Population.

Aim: The aim of this study was to determine the prevalence of mental disorders in a group of patients with multiple sclerosis (MS) during outpatient treatment. Additionally, an attempt was made to assess the influence of parameters related to patients and their clinical status on the prevalence of mental disorders. Materials and Methods: This study was conducted between 2017 and 2018 in a group of 103 patients with MS who underwent treatment at the Outpatient Clinic of Neurology at the Clinical Hospital No. 1 in Zabrze, Poland. Sociodemographic data were collected, and the course of the underlying disease and comorbidities underwent assessment. The Mini International Neuropsychiatric Interview (MINI) and psychiatric examination were used to assess the occurrence of mental disorders. Results: In this study, female subjects accounted for 67.96% of patients (mean age: 43 years). Of all patients, 67% of subjects were clinically diagnosed with mental disorders during their lifetime. The results of the MINI Questionnaire showed that 33% of MS patients had a history of a major depressive episode, while 8.7% of patients met the criteria for a depressive episode. The same number of patients were treated for recurrent depressive disorders. Generalized anxiety disorder was diagnosed in 10.7% of patients, agoraphobia in 8.7% and panic disorder in 7.8%. Most patients (94.2%) had a low risk of suicide, according to the MINI Questionnaire. This study did not show a significant influence of age, sex, duration of MS symptoms or severity of symptoms as expressed by the Expanded Disability Status Score (EDSS) on the prevalence of mental disorders (p = 0.05). However, a significantly higher median EDSS score was found in patients with a history of mental disorders (p = 0.03). Additionally, a significant negative correlation was found between having a family and a psychiatric diagnosis (p = 0.01). A statistically significant negative correlation was found between the level of education and the suicide risk as assessed by the MINI Questionnaire (p = 0.03). Conclusions: This study showed a high prevalence of mental disorders in patients with MS, of which depressive episodes and anxiety disorders were the most commonly reported. There may exist a relationship between the degree of disability of MS patients and a higher prevalence of mental disorders. Patients with MS who do not have a family may be more susceptible to mental disorders. In turn, patients with a lower level of education may show a higher risk of suicide. This suggests the need for psychological and psychiatric support for patients with MS, with particular consideration given to those who are alone, those with more severe disability and patients with a lower level of education.

Sleep inertia, not chronotype, is a marker of circadian misalignment and a risk factor for psychiatric disorders: genetic and epidemiological evidence

Sleep inertia, not chronotype, is a marker of circadian misalignment and a risk factor for psychiatric disorders: genetic and epidemiological evidence

Prevalence, severity and risk factors of psychiatric disorders amongst sexual and gender diverse young people during the COVID-19 pandemic: A systematic review.

Before the COVID-19 pandemic, the prevalence and severity of psychiatric disorders among sexual and gender diverse (SGD) young people was greater than in their heterosexual/cisgender peers. We systematically reviewed literature examining the prevalence, severity, and risk factors for psychiatric disorders among SGD young people aged 25 and under during the pandemic. Four databases (MEDLINE, PsycInfo, Scopus and Web of Science) were searched. Eligibility criteria were studies assessing prevalence rates, mean symptomology scores and risk factors of psychiatric disorders using contemporaneous screening measures or diagnosis. Thirteen studies of mixed quality were identified. Most studies indicated SGD young people were at high risk of experiencing several psychiatric disorders including depressive and generalised anxiety disorder compared to the general population. This group also experienced more severe symptomology of various psychiatric disorders compared to their heterosexual/cisgender peers. Risk factors included those specific to the pandemic along with factors that led to greater risk before the pandemic. This systematic review has indicated evidence of heightened risk of psychiatric disorders among SGD young people during the COVID-19 pandemic. It is important for clinicians to acknowledge the needs of SGD young people, working with them to co-develop more inclusive care as they deal with the pandemic's fallout.

Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice

Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

EPH237 Incidence and Risk Factors for Psychiatric Disorders Across Different Health Insurance Systems in Japan

EPH237 Incidence and Risk Factors for Psychiatric Disorders Across Different Health Insurance Systems in Japan

Childhood abuse v. neglect and risk for major psychiatric disorders.

Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders. Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473). Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24). Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies.

Early traumatic experiences and the hypothalamus-pituitary-adrenal axis in people with eating disorders: A narrative review

Exposure to trauma during childhood is a non-specific risk factor for psychiatric disorders, including eating disorders (EDs), over the life course. Moreover, an association between stressful life events and the onset/maintenance of EDs has been documented. Therefore, the hypothalamus-pituitary-adrenal (HPA) axis, namely the main component of the endogenous stress response system, has been proposed to be implicated in the pathophysiology of EDs. In this narrative review the current knowledge concerning the effects of early trauma exposure on the HPA axis activity and their putative role in the pathophysiology of EDs will be illustrated. Research findings corroborate the idea that childhood trauma exposure has long-lasting dysregulating effects on the activity of the HPA axis, which may contribute to the biological background of the early trauma-related risk for the development of EDs across the life span. Moreover, literature data support the existence of a “maltreated ecophenotype” in EDs characterized by specific clinic and neuroendocrine features, which may have important implications in treatment programming for such a type of patients.

Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to adverse effect of cannabis exposure in genetically vulnerable individuals.

Maternal Perinatal Stress Trajectories and Negative Affect and Amygdala Development in Offspring.

Maternal psychological stress during pregnancy is a common risk factor for psychiatric disorders in offspring, but little is known about how heterogeneity of stress trajectories during pregnancy affect brain systems and behavioral phenotypes in infancy. This study was designed to address this gap in knowledge. Maternal anxiety, stress, and depression were assessed at multiple time points during pregnancy in two independent low-risk mother-infant cohorts (N=115 and N=2,156). Trajectories in maternal stress levels in relation to infant negative affect were examined in both cohorts. Neonatal amygdala resting-state functional connectivity MRI was examined in a subset of one cohort (N=60) to explore the potential relationship between maternal stress trajectories and brain systems in infants relevant to negative affect. Four distinct trajectory clusters, characterized by changing patterns of stress over time, and two magnitude clusters, characterized by severity of stress, were identified in the original mother-infant cohort (N=115). The magnitude clusters were not associated with infant outcomes. The trajectory characterized by increasing stress in late pregnancy was associated with blunted development of infant negative affect. This relationship was replicated in the second, larger cohort (N=2,156). In addition, the trajectories that included increasing or peak maternal stress in late pregnancy were related to stronger neonatal amygdala functional connectivity to the anterior insula and the ventromedial prefrontal cortex in the exploratory analysis. The trajectory of maternal stress appears to be important for offspring brain and behavioral development. Understanding heterogeneity in trajectories of maternal stress and their influence on infant brain and behavioral development is critical to developing targeted interventions.

A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females

Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.

A stable and replicable neural signature of lifespan adversity in the adult brain

Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years (n = 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years (n = 114) and in an independent sample at 22 years (n = 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology.

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation.

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain.

The perceived effects of migration on the mental health of Afro-Caribbean immigrants: A narrative synthesis of qualitative studies.

INTRODUCTION: There is evidence to support migration as a significant risk factor for psychiatric disorders in immigrants. Unfortunately, as an immigrant group, little is known about the mental health of Afro-Caribbean immigrants and the factors that threaten their mental health. To explore the perceived effects of migration on the mental health of Afro-Caribbean immigrants. A qualitative narrative synthesis was employed to interpretively integrate 13 primary qualitative research findings. Eleven of the primary studies were conducted in the U.K., one in the U.S. and one in Canada. The themes gleaned: (1) experiences of racism, (2) generational conflicts, (3) feelings of powerlessness, (4) limited socioeconomic resources, (5) unfulfilled expectations, (6) fragmented family and community and (7) ignoring cultural/ethnic identity. The findings broadened the understanding and experiences of Afro-Caribbean immigrants and their mental health vulnerabilities as they navigate through migration and acculturation. Addressing the mental health of Afro-Caribbeans will require health care providers to: (1) be cognizant of their immigrant status; (2) understand how migration and acculturation influence the mental health of immigrants; (3) be aware of the ethnocultural differences among Black subgroups.

Stress, microRNAs, and stress-related psychiatric disorders: an overview.

Stress is a major risk factor for psychiatric disorders. During and after exposure to stressors, the stress response may have pro- or maladaptive consequences, depending on several factors related to the individual response and nature of the stressor. However, the mechanisms mediating the long-term effects of exposure to stress, which may ultimately lead to the development of stress-related disorders, are still largely unknown. Epigenetic mechanisms have been shown to mediate the effects of the environment on brain gene expression and behavior. MicroRNAs, small non-coding RNAs estimated to control the expression of about 60% of all genes by post-transcriptional regulation, are a fundamental epigenetic mechanism. Many microRNAs are expressed in the brain, where they work as fine-tuners of gene expression, with a key role in the regulation of homeostatic balance, and a likely influence on pro- or maladaptive brain changes. Here we have selected a number of microRNAs, which have been strongly implicated as mediators of the effects of stress in the brain and in the development of stress-related psychiatric disorders. For all of them recent evidence is reported, obtained from rodent stress models, manipulation of microRNAs levels with related behavioral changes, and clinical studies of stress-related psychiatric disorders. Moreover, we have performed a bioinformatic analysis of the predicted brain-expressed target genes of the microRNAs discussed, and found a central role for mechanisms involved in the regulation of synaptic function. The complex regulatory role of microRNAs has suggested their use as biomarkers for diagnosis and treatment response, as well as possible therapeutic drugs. While, microRNA-based diagnostics have registered advancements, particularly in oncology and other fields, and many biotech companies have launched miRNA therapeutics in their development pipeline, the development of microRNA-based tests and drugs for brain disorders is comparatively slower.

Interactions between early adversity and the serotonin system determine lifespan immune responses in the hippocampus

Early Life Adversity (ELA) is a major risk factor for psychiatric disorders, but the neurobiological mechanisms that mediate the long-lasting effects of ELA are largely unknown. One candidate process implicated in stress-induced psychiatric disorders that is also increased by ELA, is neuroinflammation. Reducing neuroinflammation may thus be a promising new strategy to rescue the impact of ELA on brain function and mental health. To test this hypothesis, we exposed mice to ELA (limited bedding and nesting material from postnatal day (PND)3 to PND10). We then tested their behavior in a fear discrimination task and collected brains at PND35 (adolescence), PND56 (adulthood), and at 18 months of age (old age). While ELA did not alter adolescent behavior, we find that ELA causes fear discrimination deficits in female mice from adulthood (PND56; n=12, p=0.009) that last into old age (18 months; n=5, p=0.02). At the neurobiological level, we used immunohistochemistry for CD68+/Iba1+ to determine the number of activated microglia. We found a strong and long-lasting increase in the number of activated microglia in the hippocampus of ELA-exposed mice in adulthood and in old age (n=6; p<0.001). We then used a transgenic mouse line to increase hippocampal serotonin (5-HT) by knockdown of the 5-HT1A autoreceptor, and found that adolescent 5-HT1A knockdown can rescue ELA effects on fear discrimination and neuroinflammation later on. Our findings provide new insight into the potential of targeting the 5-HT system to prevent the neuroinflammatory and behavioral deficits resulting from ELA.

The burden of psychiatric disorders associated with orofacial cleft pathology among children in Ontario, Canada

Individuals with orofacial cleft (OFC) may be at a higher risk of developing psychiatric disorders (PD) than the general population. We determined the risk of psychiatric diagnoses in children with OFC in Canada. This population-based retrospective cohort study used health administrative data from the province of Ontario, Canada. Children with OFC who were born between April 1, 1994, and March 31, 2017, in Ontario were matched to five non-OFC children based on sex, date of birth, and mother's age. We determined the rate of events and time-to-event for first diagnosis of PD in children aged ≥3 years (y), and for intellectual developmental delay (IDD) from birth. Risk factors for PD and IDD were assessed using 1-way ANOVA for means, Kruskal-Wallis for medians, and the χ2 test for categorical variables. There were 3051 children with OFC (matched to 15,255 controls), of whom 2515 patients with OFC (12,575 controls) had a complete follow-up to the third birthday. Children with OFC were more likely to have PD than controls (54.90 vs. 43.28 per 1000 patient-years, P<.001), with a mean age to first diagnosis of 8.6±4.2y. The cleft palate group had the highest risk (HR 1.33, 95% CI 1.18-1.49). Children with OFC also had a higher risk of IDD than non-OFC children (27.78 vs. 3.46 per 1000 patient-years, p<.001). Children born with OFC in Ontario had a higher risk of psychiatric diagnosis and IDD compared to controls. Further research is also required to better understand the predictors of variation in risk, including geographic location and the presence of congenital abnormalities, and identify potential areas for intervention. Level II.