17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

Dysfunction among Families of Children with Intellectual Disability in India Using Systems Model: Prevalence, Pattern, and Severity of Impairment.

OBJECTIVES: Family dysfunction is observed in families with children with intellectual disability (ID). We study the prevalence, pattern of dysfunction, and severity of impairment in these special families using Systems approach. METHODS: Sixty-two special families (a child with ID) and 62 typical families (all children with typical development) were included in the present study. The presence of ID was confirmed and quantified with the Binet-Kamat Scale of intelligence or Gesell's Developmental Schedule and Vineland Social Maturity Scales among the special families. In the typical families, brief ID scale was used to rule out ID. Prevalence, pattern, and severity of family dysfunction were assessed using Family Apgar Scale, Chicago Youth Development Study Family Assessment Scale and Global Assessment of Relational Functioning Scale, respectively. Appropriate bivariate analyses were used. RESULTS: About 53% of special families and 19% of typical families had family dysfunction. About 21% of special families and 71% of typical families had the satisfactory relational unit. Areas of adaptability, partnership, growth, affection, resolve, beliefs about family, beliefs about development, beliefs about purpose, cohesion, deviant beliefs, support, organization, and communication were significantly different between special and typical families. The functional impairment was significantly more in the special families. CONCLUSION: Family dysfunction is more prevalent among special families in India using systems approach. These families should be screened for dysfunction, and family therapy be prescribed when required.

Predictors of disability: a 5-year cohort study of first-episode schizophrenia.

BACKGROUND: There is a dearth of information about the predictors of disability in schizophrenia from low and middle-income countries. This study attempted to investigate the impact of socio-demographic and clinical variables on disability in a cohort of first episode schizophrenia. METHOD: Patients diagnosed to have DSM IV schizophrenia (n=131) were assessed prospectively for psychopathology, functioning, insight and explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Disability was assessed at 5 years. Multiple linear regression was employed to adjust for common confounders. RESULTS: We could follow-up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. Disability scores at 5 years were associated negatively with episodic nature of illness at baseline, functional assessments at 6 and 12 months and return to pre-morbid level function. Disability correlated positively with psychopathology at 6 and 12 months and time spent in psychotic episodes. It was also associated with psychopathology, remission, insight and patient perspectives at the 5th year cross-sectional evaluation. While employment status at recruitment was not associated with disability, it was associated with unemployment at follow-up. CONCLUSIONS: Disability at 5 years was associated with illness variables - episodic nature of illness at baseline, psychopathology and functioning, duration in psychotic episode and return to pre-morbid function. Patient perspectives about their illness (insight and patient explanatory models) were only associated cross-sectionally at 60 months but not earlier and are more suggestive of a coping response rather than being predictive of outcome. The relationship between unemployment and disability suggests that they are products of the same disease process.

Predictors of insight in first-episode schizophrenia: a 5-year cohort study from India.

BACKGROUND AND AIMS: There is a dearth of data on the predictors of insight in schizophrenia. This study attempted to assess the predictors of insight in a cohort of first-episode schizophrenia followed up over 5 years. METHODS: Patients diagnosed to have Diagnostic and statistical manual of mental disorders (4th ed.; DSM-IV) schizophrenia (n = 131) were assessed prospectively for insight, psychopathology and explanatory models of illness over a 5-year period using standard instruments. Multiple linear regression and generalized estimating equations (GEE) were employed to assess predictors of insight. RESULTS: We could follow up 95 (72.5%) patients, 5 years after recruitment. A total of 65 of these patients interviewed at 60 months (68.4%) achieved remission. Cross-sectional evaluations suggest a relationship between insight, psychosis rating and explanatory models of illness with good insight and medical models associated with good outcome. However, baseline and early illness data do not predict insight scores at 5 years. Serial longitudinal assessment of insight is negatively associated with Brief Psychiatric Rating Scale (BPRS) scores and positively associated with the number of nonmedical explanatory models of illness held by patients. CONCLUSION: These findings argue that insight and explanatory models of illness are secondary to psychopathology, course and outcome. They are dependent on the trajectory of the person's illness, are not independent of the condition and call for multifaceted understanding of the issues.

ADad 8: School Phobia and Anxiety Disorders among adolescents in a rural community population in India.

OBJECTIVE: School Phobia (SP), although is not a formal psychiatric diagnosis, is widely prevalent debilitating phenomenon with a gamut of underlying psychiatric conditions in an overwhelming majority of cases. This study documents the prevalence, symptom presentation and the relationship between the various subtypes of Anxiety Disorders (AD) and School Phobia. METHODS: In a prospective community survey of 500 adolescents, independent raters administered the Screen for Child Anxiety Related Emotional Disorders and Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime to identify SP and subtype of AD respectively. Descriptive statistics for the prevalence and symptom presentation, Spearman's Correlation test, Independent t tests, on-way ANOVA and Chi-square tests were done to compare the prevalence and severity of School Phobia among various age groups and gender. Univariate and multivariate analyses were done for documenting the relationship between the School Phobia and Anxiety Disorders. RESULTS: School Phobia was noted in 4.8% of adolescents. Although age was related to SP, gender, school grade the adolescent was attending and family structure were not related to SP. Somatic symptoms were more often noted than cognitive-emotional symptoms among adolescents with SP. Panic Disorder (OR = 8.62), Social Anxiety Disorder (OR = 8.63), and Separation Anxiety Disorder (OR = 6.26), were significantly related to SP. CONCLUSIONS: School Phobia is noted in a significant proportion of adolescents in the community. Anxiety Disorder is a major underlying factor resulting in SP. Community and clinical intervention and service models should include anxiety alleviation methods in adolescents with School Phobia.

Insight, psychopathology, explanatory models and outcome of schizophrenia in India: a prospective 5-year cohort study.

BACKGROUND: The sole focus of models of insight on bio-medical perspectives to the complete exclusion of local, non-medical and cultural constructs mandates review. This study attempted to investigate the impact of insight, psychopathology, explanatory models of illness on outcome of first episode schizophrenia. METHOD: Patients diagnosed to have DSM IV schizophrenia (n = 131) were assessed prospectively for insight, psychopathology, explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Multiple linear and logistic regression and generalized estimating equations (GEE) were employed to assess predictors of outcome. RESULTS: We could follow up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. There was a negative relationship between psychosis rating and insight scores. Urban residence, fluctuating course of the initial illness, and improvement in global functioning at 6 months and lower psychosis rating at 12 months were significantly related to remission at 5 years. Insight scores, number of non-medical explanatory models and individual explanatory models held during the later course of the illness were significantly associated with outcome. Analysis of longitudinal data using GEE showed that women, rural residence, insight scores and number of non-medical explanatory models of illness held were significantly associated with BPRS scores during the study period. CONCLUSIONS: Insight, the disease model and the number of non-medical model positively correlated with improvement in psychosis arguing for a complex interaction between the culture, context and illness variables. These finding argue that insight and explanatory models are secondary to psychopathology, course and outcome of the illness. The awareness of mental illness is a narrative act in which people make personal sense of the many challenges they face. The course and outcome of the illness, cultural context, acceptable cultural explanations and the prevalent social stigma interact to produce a complex and multifaceted understanding of the issues. This complexity calls for a nuanced framing of insight.

Perceptions about suicide: a qualitative study from southern India.

BACKGROUND: Studies from India have reported high rates of suicide. We aimed to understand the social and cultural factors that modulate the risks related to suicide. METHODS: Focus group discussions were conducted with community health workers (1 group) and members of the public (6 groups). In-depth interviews were also conducted with 5 people who had attempted suicide and survived. The interviews were tape-recorded and transcribed verbatim. The results were summarized and analysed using standard procedures. RESULTS: The most common causes for suicide were interpersonal and family problems, and financial difficulties. Mental illness was also reported as causal. All 5 subjects who had attempted suicide mentioned marital and family discord as the cause. The majority of the general population and all the subjects who had attempted suicide were not aware of any community and support services for the prevention of suicide. CONCLUSION: Our study reveals that people perceived suicide as an option to overcome interpersonal, family and financial stress among normal individuals as well as those with mental illness. Healthcare providers should place greater emphasis on educating the general public regarding the policies and services available for suicide prevention.

Stigma and explanatory models among people with schizophrenia and their relatives in Vellore, south India.

BACKGROUND: Stigma associated with mental illness affects patients and their families. Diverse beliefs about the cause and treatment of schizophrenia are common among patients and their relatives. AIM: To study the association between stigma and beliefs about illness in patients and their relatives. METHOD: Standard instruments were used to assess beliefs about illness and about stigma among patients with schizophrenia and relatives in Vellore, south India. RESULTS: The majority of the patients and their relatives simultaneously held multiple and contradictory models of illness and its treatment. Stigma among patients with schizophrenia and their relatives is associated with specific beliefs about causes of mental illness. CONCLUSIONS: Beliefs may play a role in mitigating or may aggravate the effects of stigma. The cross-sectional study design precludes definitive conclusions on direction of the causal association.