The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences.

Neurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12-26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3-7 Hz) and alpha (7-12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15-19 (B: 0.15-0.21, p < 10-4). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.

Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Economic burden of diagnosed pertussis among individuals with asthma or chronic obstructive pulmonary disease in the USA: an analysis of administrative claims.

Individuals with chronic respiratory conditions may be at increased risk for pertussis. We conducted a retrospective administrative claims analysis to examine the incidence and economic burden of diagnosed pertussis among adolescents and adults in the USA with chronic obstructive pulmonary disease (COPD) or asthma. Patients aged ⩾11 years with diagnosed pertussis and pre-existing COPD (n = 343) or asthma (n = 1041) were matched 1:1 to patients with diagnosed pertussis but without COPD or asthma. Differences in all-cause costs ('excess' costs) during the 45-day and 3-month and 6-month periods before and after the pertussis index date were calculated; adjusted excess costs were estimated via multivariate regressions. The incidence of diagnosed pertussis was higher among patients with COPD or asthma than among matched patients. Compared with matched patients, patients with pertussis and pre-existing COPD or asthma accrued greater all-cause adjusted costs across study periods ($3694 and $1193 more, respectively, in the 45-day period; $4173 and $1301 more in the 3-month period; and $6154 and $1639 more in the 6-month period; all P < 0·0001). Patients with pre-existing COPD or asthma experience an increased economic burden after diagnosed pertussis and may especially benefit from targeted tetanus, diphtheria, and acellular pertussis vaccination strategies.

An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10-8. The most significantly associated SNP, rs11720469 (ß: -0.124; P<4.5 × 10-9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Religiosity, race/ethnicity, and alcohol use behaviors in the United States.

BACKGROUND: Religiosity is a protective factor against many health problems, including alcohol use disorders (AUD). Studies suggest that religiosity has greater buffering effects on mental health problems among US Blacks and Hispanics than Whites. However, whether race/ethnic differences exist in the associations of religiosity, alcohol consumption and AUD is unclear. METHOD: Using 2004-2005 NESARC data (analytic n = 21 965), we examined the relationship of public religiosity (i.e. frequency of service attendance, religious social group size), and intrinsic religiosity (i.e. importance of religious/spiritual beliefs) to frequency of alcohol use and DSM-IV AUD in non-Hispanic (NH) Blacks, Hispanics and NH Whites, and whether associations differed by self-identified race/ethnicity. RESULTS: Only public religiosity was related to AUD. Frequency of religious service attendance was inversely associated with AUD (NH Whites ß: -0.103, p 0.05) or Hispanics (ß: -0.002, p > 0.05). CONCLUSIONS: US adults reporting greater public religiosity were at lower risk for AUD. Public religiosity may be particularly important among NH Blacks, while intrinsic religiosity may be particularly important among NH Whites, and among Hispanics who frequently attend religious services. Findings may be explained by variation in drinking-related norms observed among these groups generally, and in the context of specific religious institutions.

Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways.

Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.

Health care resource utilization and costs during episodes of care for type 2 diabetes mellitus-related comorbidities.

AIMS: To obtain costs of episodes of care for type 2 diabetes mellitus (T2DM)-related comorbidities. METHODS: Data from the MarketScan Commercial Claims and Encounters Database were analyzed with the Medical Episode Grouper software, which uses proprietary algorithms to identify episodes of care. Episodes relevant to the T2DM population were examined, including: coronary artery disease with acute myocardial infarction, ventricular fibrillation, shock, and/or cardiac arrest (CAD episodes); cerebrovascular disease with stroke (CVD episodes); hypoglycemia; T2DM with complications (complication episodes); and renal failure. RESULTS: 45,350 CAD; 85,287 CVD; 29,886 hypoglycemia; 40,339 complication; and 211,673 renal failure episodes were identified. Mean (SD) episode durations were 15.2 (39.1), 25.5 (55.0), 5.9 (24.0), 21.2 (54.6), and 364.0 (0.0) days, respectively. Inpatient visits were the largest component of unadjusted costs for CAD, CVD, and complication episodes (93.4%, 78.3%, and 91.9%, respectively). Other ancillary care represented the largest component of unadjusted costs for hypoglycemia (53.3%) and renal failure (80.5%) episodes. Mean adjusted total costs were $16,435; $4558; $445; $5675; and $8765 for CAD, CVD, hypoglycemia, complication, and renal failure episodes, respectively. CONCLUSIONS: This study adds important information to the literature regarding costs of episodes of care for patients with T2DM in the US.

Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit Neighborhood Health Study.

Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene-environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 × 10(-7)) genetic variants from a recent meta-analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ~3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene-environment interaction, for smoking behaviors. In addition, this study indicates that environmental determinants have the potential to both exacerbate (traumatic events) and diminish (neighborhood social cohesion) genetic influences on smoking behaviors.

Improving the availability of emergency obstetric care in conflict-affected settings.

This paper describes an emergency obstetric care (EmOC) project implemented by the Reproductive Health Response in Conflict (RHRC) Consortium in 12 conflict-affected settings in nine countries from 2000-2005 with funding and technical support from Columbia University's Mailman School of Public Health Averting Maternal Death and Disability (AMDD) programme. The overall goal of the project was to reduce maternal morbidity and mortality in select conflict-affected settings by improving the availability of EmOC. Another aim of the project was to institutionalize EmOC within RHRC Consortium agencies by modelling how to improve the availability of basic and comprehensive EmOC at clinics and hospitals. The specific project purpose was to increase the availability of EmOC in select conflict-affected settings. The project demonstrated that a great deal more can and should be done by humanitarian workers to improve the availability of basic and comprehensive emergency obstetric services in conflict-affected settings.

Catch-up growth is associated with delayed senescence of the growth plate in rabbits.

In mammals, release from growth-inhibiting conditions results in catch-up growth. To explain this phenomenon, we proposed the following model: 1) The normal senescent decline in growth plate function depends not on age per se, but on the cumulative number of replications that growth plate chondrocytes have undergone. 2) Conditions that suppress growth plate chondrocyte proliferation therefore slow senescence. 3) After transient growth inhibition, growth plates are thus less senescent and hence show a greater growth rate than expected for age, resulting in catch-up growth. To test this model, we administered dexamethasone to growing rabbits to suppress linear growth. After stopping dexamethasone, catch-up growth occurred. In distal femoral growth plates of untreated controls, we observed a senescent decline in the growth rate and in the heights of the proliferative zone, hypertrophic zone, and total growth plate. During the period of catch-up growth, in the animals previously treated with dexamethasone, the senescent decline in all these variables was delayed. Prior treatment with dexamethasone also delayed epiphyseal fusion. These findings support our model that linear catch-up growth is caused, at least in part, by a delay in growth plate senescence.

The relationships between family primary caregiver characteristics and satisfaction with hospice care, quality of life, and burden.

PURPOSE/OBJECTIVES: To examine relationships between family primary caregiver characteristics and satisfaction with hospice care, quality of life (QOL), and burden. DESIGN: Exploratory, quantitative. SETTING: Five hospice organizations in Eastern Washington and Northern Idaho. SAMPLE: 44 primary caregivers of patients enrolled in hospice for more than two weeks. METHODS: Telephone surveys measured primary caregivers' satisfaction with hospice care, QOL, and burden. Demographic, personal, and situational characteristics were compiled. Multivariate regression techniques were used to identify caregiver characteristics that explained the most variation in satisfaction with hospice care, QOL, and burden. MAIN RESEARCH VARIABLES: Satisfaction with hospice care, QOL, and burden. FINDINGS: Being retired, being a wife or daughter, patient diagnosis, per diem rate paid to the hospice organization, county population and density, length of time in hospice, and length of time as a caregiver were significantly related to satisfaction with hospice care, QOL, and burden. Age, sex, education level, occupation, income, patient functional status, and social support were not related to these variables. CONCLUSION: Although caregivers reported satisfaction with hospice care, the caregiver role negatively affects their QOL and they are burdened. "At-risk" caregivers are still working, have been providing care for a long time, and live in a rural locale. IMPLICATIONS FOR NURSING PRACTICE: These findings create a profile of "typical" and "at-risk" primary caregivers and support the role of hospice to care for family caregivers.