Centrally Administered Nociceptin/Orphanin FQ (N/OFQ) Evokes Bradycardia, Hypotension, and Diuresis in Mice via Activation of Central N/OFQ Peptide Receptors

ABSTRACT The present studies examined the cardiovascular and renal responses produced by activation of central nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors in conscious mice. To assess this, we examined changes in heart rate (HR), mean arterial pressure (MAP), urine output (V), urinary sodium excretion (UNaV), and free water clearance (CH

Implementation of a Rapid Assessment Unit (Intake Team): Impact on Emergency Department Length of Stay

Implementation of a Rapid Assessment Unit (Intake Team): Impact on Emergency Department Length of Stay Richard S. MacKenzie, MD, David B. Burmeister, DO, Jennifer A. Brown, RN, Melissa Teitsworth, RN, BSN, Christopher J. Kita, MEd, Megan J. Dambach, DO, Shaheen Shamji, DO, Anita Kurt, PhD, RN , Susan Friend, Marna Greenberg, DO, MPH Acknowledge: Clare M. Lenhart, PhD, MPH Objective: Emergency Department (ED) crowding is an on-going formidable issue for many EDs. A Rapid Assessment Unit (RAU) is a potential solution. This process involves the use of a team approach to convert the current “series” type evaluation to a more “parallel” evaluation and treatment of patients. The RAU concept of evaluating and treating ED patients radically changes the current methods utilized in today’s standard emergency care area. The RAU concept offers a process in which the patient walks into the ED and is seen in a unit by an intake team composed of a nurse, registrar, and provider (physician assistant, nurse practitioner, or physician) that provides evaluation and emergent treatment. This removes the redundancy of a patient giving the same information several times before they are treated. Simultaneously, the team decides whether the patient would be better served by remaining seated or requires a recumbent position. This is referred to as allowing “vertical flow” versus the default “horizontal flow” where all patients recline on a stretcher whether they need it or not. Certainly, having construction that specifically supports these processes is an innovation as well (having an area where patients can be seated and remain “vertical”). The team structure itself is unique. The nurses and providers are not assigned geographically by room but rather are defined by their function. We set out to determine if the addition of the RAU process would decreases the LOS of the discharged ambulatory arrival patient. Methods: After IRB approval, this retrospective, pre- and post intervention, observational comparison study was conducted from August 2011-March 2012 at a suburban teaching hospital in central Pennsylvania with an annual ED census of approximately 54,000. The inclusion criteria were all ambulatory discharged patients. The exclusion criteria were all patients that arrived by ambulance and admitted patients. Data points captured included: time of arrival in triage , time in triage to ED entry, time of ED entry until seen by a provider, time from ED entry to discharge, total length of stay (LOS). The data were uploaded to Horizon Business Insight™ (HBI), a cumulative data manager and exported to an Microsoft excel file for analysis. Mann-Whitney U tests were used to demonstrate differences in Median LOS. All statistical tests were 2-sided; probability values \u3c0.05 were considered significant. Results: 11, 994 pre and 10814 post-RAU patients were included in analysis. Median LOS was shorter during the post-RAU period in each subcategory of LOS with the exception of the interval from being seen in the ER to discharge which is a result of provider seeing the patient earlier in the ED encounter. Results, Table 1. Conclusions: The RAU process decreases the LOS of the discharged ambulatory arrival patient and deserves further exploration as an innovative model in the ED that improves flow

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Using a Delphi process to determine optimal care for patients with pancreatic cancer

Aim Overall 5-year survival for pancreatic cancer is ~5%. Optimising the care that pancreatic cancer patients receive may be one way of improving outcomes. The objective of this study was to establish components of care which Australian health professionals believe important to optimally manage patients with pancreatic cancer. Methods Using a Delphi process, a multi-disciplinary panel of 250 health professionals were invited to provide a list of factors they considered important for optimal care of pancreatic cancer patients. They were then asked to score and then rescore (from one (no importance/disagree) to 10 (very important/agree) the factors. The mean and coefficient of variation scores were calculated and categorised into three levels of importance. Results Overall 63 (66% of those sent the final questionnaire; 25% of those initially invited) health professionals from 9 disciplines completed the final scoring of 55 statements/factors encompassing themes of presentation/staging, surgery and biliary obstruction, multi-disciplinary team details and oncology. Mean scores ranged from 3.7 to 9.7 with the highest related to communication and patient assessment. There was substantial intra- and inter- disciplinary variation in views about MDT membership and roles. Conclusion Overall the opinions of Australian health professionals reflect international guideline recommended care; however they identified a number of additional factors focusing on where patients should be treated, the importance of clear communication and the need for multi-disciplinary care which were not included in current clinical practice guidelines. Differences in priorities between specialty groups were also identified

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Funder: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)Funder: Dalio Foundation; doi: https://doi.org/10.13039/100009834Funder: Wayne and Gladys Valley Foundation; doi: https://doi.org/10.13039/100001370Funder: Robert Wood Johnson Foundation (RWJF); doi: https://doi.org/10.13039/100000867Funder: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)Funder: The Dalio FoundationBipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP