pinecone/core-2020-05-10-deduplication huggingface dataset:
Rapid Response Systems 20 Years Later: New Approaches, Old Challenges

Following the embargo period the above license applies.In 1990, Schein and colleagues changed the paradigm\ud
of in-hospital cardiopulmonary arrest. Their report,\ud
“Clinical Antecedents to In-Hospital Cardiopulmonary\ud
Arrest,” provided evidence from adults suggesting\ud
that many arrests could have been prevented if existing\ud
signs of deterioration were identified, interpreted,\ud
communicated, and responded to appropriately.1 Five\ud
years later, Liverpool Hospital published the first report\ud
of a rapid response system.2 This marked the start\ud
of a patient safety movement that spread quickly to\ud
children’s hospitals.3\ud
Rapid response systems aim to improve the detection\ud
and management of deterioration in hospitalized\ud
patients. They combine tools to help clinicians identify\ud
deterioration with medical emergency teams that can\ud
be summoned to the bedsides of ill patients. Rapid response\ud
system implementation was associated with\ud
reductions in cardiopulmonary arrests (relative risk [RR],\ud
0.62 [95% CI, 0.46-0.84]) and mortality (RR, 0.79\ud
[95%CI,0.63-0.98]) in a recentmeta-analysis,4 and reversed\ud
a trend of increasing critical deterioration events\ud
(a more proximate outcome) in a quasi-experimental\ud
study.5Duein part tomountingevidence,commonsense\ud
appeal, and their inclusion in major initiatives like the\ud
Institute for Healthcare Improvement’s 5 Million Lives\ud
Campaign, rapid response systems are now nearly universally\ud
present in hospitals worldwide.\ud
Unfortunately, rapid responsesystemshavenotfully\ud
solved the problem they targeted 20years ago, and, despite\ud
progress, the challenges in pediatrics remain complex.\ud
Children still deteriorate on hospital wards, and\ud
40% or more of these events may be preventable.6\ud
There is an opportunity to renew the enthusiasm that\ud
surrounded the first generation of rapid response systemwork,\ud
which focused primarilyonthe medicalemergency\ud
team response, to pursue the more difficultwork\ud
of optimizing the identification of deteriorating children.\ud
Below we propose a set of recommendations for\ud
a research agenda aimed at addressing this challenge. [Introduction]Peer-reviewedPost-prin
Influence of CRTC1 Polymorphisms on Body Mass Index and Fat Mass in Psychiatric Patients and the General Adult Population.

IMPORTANCE There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown. OBJECTIVE To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population. DESIGN, SETTING, AND PARTICIPANTS Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123 865). INTERVENTION Noninterventional studies. MAIN OUTCOME AND MEASURE Difference in BMI and/or fat mass between CRTC1 genotype groups. RESULTS Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A&gt;G was associated with BMI (Padjusted = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m2 lower BMI than noncarriers (n = 226; P &lt; .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m2 lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P &lt; .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C&gt;T (a proxy of the rs3746266 G allele; r2 = 0.7) was associated with lower BMI (sample 5, n = 123 865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02). CONCLUSIONS AND RELEVANCE These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry
ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure

Context: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. Objective: To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs)with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations. Design: Case-control genetic association study that included 2 control groups (lacking an established optimal control group). Setting: Semistructured psychiatric interviews. Participants: A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample. Main Outcome Measure: Lifetime heroin dependence. Results: Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P≥.01); a similar comparison with neighborhood controls revealed greater differences (P≥1.8×10-4). Comparing cases (n=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n=340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio=1.59; 95% CI, 1.32-1.92; P=9.7×10-7), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n=191) and nondependent (n=340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P=2.7×10-9 for the risk-associated linear trend). Conclusions: Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence
A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders

Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320 543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489 006 persons were censored owing to death; and 69 987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES Age and sex. MAIN OUTCOMES AND MEASURES Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS During the course of life, 37.66%of females (95%CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research
Identification of pathways for bipolar disorder: a meta-analysis

IMPORTANCE:

Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders.

OBJECTIVE:

To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS).

DATA SOURCES:

Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data.

STUDY SELECTION:

The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample.

DATA EXTRACTION AND SYNTHESIS:

We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12,127 [5253 cases, 6874 controls]). Simulations using 10,000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex.
MAIN OUTCOMES AND MEASURES:

Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3.

CONCLUSIONS AND RELEVANCE:

Pathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention
Depression with atypical features and increase in obesity, body mass index, waist circumference, and fat mass: a prospective, population-based study.

IMPORTANCE: Depression and obesity are 2 prevalent disorders that have been repeatedly shown to be associated. However, the mechanisms and temporal sequence underlying this association are poorly understood.
OBJECTIVE: To determine whether the subtypes of major depressive disorder (MDD; melancholic, atypical, combined, or unspecified) are predictive of adiposity in terms of the incidence of obesity and changes in body mass index (calculated as weight in kilograms divided by height in meters squared), waist circumference, and fat mass.
DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based cohort study, CoLaus (Cohorte Lausannoise)/PsyCoLaus (Psychiatric arm of the CoLaus Study), with 5.5 years of follow-up included 3054 randomly selected residents (mean age, 49.7 years; 53.1% were women) of the city of Lausanne, Switzerland (according to the civil register), aged 35 to 66 years in 2003, who accepted the physical and psychiatric baseline and physical follow-up evaluations.
EXPOSURES: Depression subtypes according to the DSM-IV. Diagnostic criteria at baseline and follow-up, as well as sociodemographic characteristics, lifestyle (alcohol and tobacco use and physical activity), and medication, were elicited using the semistructured Diagnostic Interview for Genetic Studies.
MAIN OUTCOMES AND MEASURES: Changes in body mass index, waist circumference, and fat mass during the follow-up period, in percentage of the baseline value, and the incidence of obesity during the follow-up period among nonobese participants at baseline. Weight, height, waist circumference, and body fat (bioimpedance) were measured at baseline and follow-up by trained field interviewers.
RESULTS: Only participants with the atypical subtype of MDD at baseline revealed a higher increase in adiposity during follow-up than participants without MDD. The associations between this MDD subtype and body mass index (β = 3.19; 95% CI, 1.50-4.88), incidence of obesity (odds ratio, 3.75; 95% CI, 1.24-11.35), waist circumference in both sexes (β = 2.44; 95% CI, 0.21-4.66), and fat mass in men (β = 16.36; 95% CI, 4.81-27.92) remained significant after adjustments for a wide range of possible cofounding.
CONCLUSIONS AND RELEVANCE: The atypical subtype of MDD is a strong predictor of obesity. This emphasizes the need to identify individuals with this subtype of MDD in both clinical and research settings. Therapeutic measures to diminish the consequences of increased appetite during depressive episodes with atypical features are advocated
Generational increase in young women\u27s drinking: A prospective analysis of mother-daughter dyads

IMPORTANCE Increases in alcohol use in young women over recent decades are shown by national survey data but have yet to be replicated using prospective data. OBJECTIVE To compare change in alcohol use over a generation of young women born in Australia from 1981 to 1983 at 21 years with that of their mothers at the same age. DESIGN, SETTING, AND PARTICIPANTS Data came from the Mater University Study of Pregnancy, a prospective prebirth cohort study that recruited all pregnant mothers attending a hospital in Brisbane, Australia, from 1981 to 1983. The analyses were restricted to 1053 mothers who were aged 18 to 25 years of age at the baseline measurement and their daughters who were between the same ages when assessed 21 years later. MAIN OUTCOME AND MEASURE Assessing the increase in the same prospective measures of 4 levels of alcohol use between mothers and daughters. RESULTS Multinomial logistic regression for clustered data indicated daughters were at greater odds of consuming high (odds ratio [OR] = 5.68 [95%CI, 4.24-7.57]) and moderate (OR = 2.81 [95%CI, 2.18-3.63]) levels of alcohol than their mothers. Not having a dependent child roughly doubled the odds of all levels of drinking in both cohorts. Undertaking or completing tertiary education had no effect on consumption. There was an interaction between mothers\u27 or daughters\u27 drinking and partner status (?2 3 = 12.56; P = .007); having a partner doubled the daughters\u27 odds of consuming high levels of alcohol (no partner: OR = 0.51 [95%CI, 0.31-0.80]) while the odds of drinking at the highest level were more than 5 times for mothers who were single (OR = 5.65 [95%CI, 2.99-12.35]). CONCLUSIONS AND RELEVANCE To our knowledge, we provide the first longitudinal evidence confirming that female alcohol use has dramatically increased over a generation, especially at higher levels of drinking. Later age at child bearing contributed to this increase and the relationship between alcohol use and having a partner was found to reverse alcohol consumption across the 2 generations. Copyrigh
Variability inworking memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score
Consistent etiology of severe, frequent psychotic experiences and milder, less frequent manifestations: a twin study of specific psychotic experiences in adolescence

- Importance: The onset of psychosis is usually preceded by psychotic experiences (PE). Little is known about the etiology of PE and whether the degree of genetic and environmental influences varies across different levels of severity. A recognized challenge is to identify individuals at high risk of developing psychotic disorders prior to disease onset.\ud
\ud
- Objectives: To investigate the degree of genetic and environmental influences on specific PE, assessed dimensionally, in adolescents in the community and in those who have many, frequent experiences (defined using quantitative cutoffs). We also assessed the degree of overlap in etiological influences between specific PE.\ud
\ud
- Design, Setting, and Participants: Structural equation model-fitting, including univariate and bivariate twin models, liability threshold models, DeFries-Fulker extremes analysis, and the Cherny method, was used to analyze a representative community sample of 5059 adolescent twin pairs (mean [SD] age, 16.31 [0.68] years) from England and Wales.\ud
\ud
- Main Outcomes and Measures: Psychotic experiences assessed as quantitative traits (self-rated paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia, as well as parent-rated negative symptoms).\ud
\ud
- Results: Genetic influences were apparent for all PE (15%-59%), with modest shared environment for hallucinations and negative symptoms (17%-24%) and significant nonshared environment (49%-64%) for the self-rated scales and 17% for parent-rated negative symptoms. Three empirical approaches converged to suggest that the etiology in extreme-scoring groups (most extreme scoring: 5%, 10%, and 15%) did not differ significantly from that of the whole distribution. There was no linear change in heritability across the distribution of PE, with the exception of a modest increase in heritability for increasing severity of parent-rated negative symptoms. Of the PE that showed covariation, this appeared to be due to shared genetic influences (bivariate heritabilities, 0.54-0.71).\ud
\ud
- Conclusions and Relevance: These findings are consistent with the concept of a psychosis continuum, suggesting that the same genetic and environmental factors influence both extreme, frequent PE and milder, less frequent manifestations in adolescents. Individual PE in adolescence, assessed quantitatively, have lower heritability estimates and higher estimates of nonshared environment than those for the liability to schizophrenia. Heritability varies by type of PE, being highest for paranoia and parent-rated negative symptoms and lowest for hallucinations