The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gß5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.

Specific regulation of mechanical nociception by Gß5 involves GABA-B receptors.

Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gß5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gß5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gß5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gß5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gß5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist ß-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gß5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.

Comparison of a formatted versus traditional sign out process for physicians in the emergency department.

INTRODUCTION: Frequent interruptions, critically ill patients, and high patient turnover can make Emergency Department (ED) physician transitions of care (TOCs) challenging. Currently, there is no strict format for TOC in the ED. We structured a formatted ED TOC and evaluated the comparative effects from traditional TOC practice on the perceived quality of sign-out among physicians working in the ED. METHODS: We performed a prospective pre/post-interventional study utilizing convenience sampling in an urban community teaching hospital. The primary outcome was perceived quality of sign-out, as evaluated by the incoming physician one-hour after TOC, using the handoff-Clinical Evaluation Exercise (h-CEX) score with a 9-point scale for each category: Organized/Efficient, Communications Skills, Included Pertinent Information, Clinical Judgment, Patient Focused, Setting, and Overall Sign-Out Quality. Additional evaluation of unexpected tasks and errors from TOC w performed. RESULTS: We included 344 patient TOC observed, of which 147 (43%) were formatted interventions while 197 (57%) were standard TOCs. After analysis in a random effects model, statistically significant improvements among resident physicians were seen for the formatted TOC: patient focused (mean difference 0.40), setting (mean difference 1.05), and overall (mean difference 0.68). The rate of unexpected tasks and errors were higher in the standard TOC, though not statistically significant. CONCLUSION: Resident physicians saw improvement in several h-CEX categories with a formatted TOC. Consistent with prior studies, a formatted TOC for emergency medicine should be strongly considered, especially among learners.

Manual Palpation vs. Femoral Arterial Doppler Ultrasound for Comparison of Pulse Check Time During Cardiopulmonary Resuscitation in the Emergency Department: A Pilot Study.

BACKGROUND: Manual palpation (MP) is frequently employed for pulse checks, but studies have shown that trained medical personnel have difficulty accurately identifying pulselessness or return of spontaneous circulation (ROSC) using MP. Any delays in identifying pulselessness can lead to significant delays in starting or resuming high-quality chest compressions. OBJECTIVES: This study explored whether femoral arterial Doppler ultrasound (FADU) decreases pulse check duration during cardiopulmonary resuscitation (CPR) compared with MP among patients in the emergency department (ED) receiving CPR directed by emergency medicine physicians who had received minimal additional didactic ultrasound training. METHODS: We performed a prospective observational cohort study from October 2018 to May 2019 at an urban community ED. Using convenience sampling, we enrolled patients arriving at our ED or who decompensated during their ED stay and received CPR. For continuous data, median (interquartile range [IQR]) were calculated, and medians were compared using Kruskal-Wallis test. RESULTS: Fifty-two eligible patients were enrolled and 135 pulse checks via MP and 35 via FADU were recorded. MP observations had a median (IQR) of 11.00 (7.36-15.48) s, whereas FADU had a median (IQR) of 8.98 (5.45-13.85) s. There was a difference between the two medians of 2.02 s (p = 0.05). CONCLUSIONS: In this study, the use of FADU was superior to MP in achieving shorter pulse check times. Further research is needed to confirm the accuracy of FADU for identifying ROSC as well as to determine whether FADU can improve clinical outcomes.