Retrospective evaluation of ketamine versus droperidol on time to restraint removal in agitated emergency department patients.

PURPOSE: Acute agitation and violent behavior in the emergency department (ED) can lead to significant patient morbidity and contribute to the growing problem of workplace violence against health care providers. To our knowledge, there is no available literature directly comparing intramuscular ketamine to intramuscular droperidol in ED patients presenting with undifferentiated agitation. The purpose of this investigation was to compare the effectiveness and safety of these agents for acute agitation in the ED. METHODS: This was a retrospective observational study conducted at an urban, academic ED. The primary endpoint was time from the first dose of study medication to restraint removal. Safety endpoints included incidence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure. RESULTS: An initial 189 patients were screened, of which, 92 met inclusion criteria. The median time from initial drug administration to restraint removal was 49 min (IQR 30, 168) in the ketamine group and 43 min (IQR 30, 80) in the droperidol group (Median difference 6 min; 95% CI [-7, 26]). There was no significant difference in rates of bradycardia (3% vs 3%, 95% CI [-7%, 8%]), hypotension (0% vs 2%, 95% CI [-5%, 2%]), or hypoxia (7% vs 10%, 95% CI [-15%, 9%]) in the ketamine versus droperidol groups respectively. One patient in the ketamine group was intubated for ongoing agitation, and one patient in the droperidol group was intubated for respiratory failure. CONCLUSIONS: Intramuscular droperidol and intramuscular ketamine were associated with similar times from drug administration to restraint removal in patients presenting to the ED with undifferentiated agitation. Prospective studies are warranted to evaluate IM droperidol and IM ketamine head-to-head as first line agents for acute agitation in the ED.

Medication Profiles at Hospital Discharge Predict Poor Outcomes After Acute Ischemic Stroke.

Objectives: To examine the relationship between medications prescribed during the first 6-months post-stroke and functional outcome. Materials and Methods: A retrospective analysis of ischemic stroke survivors enrolled in an observational stroke recovery study from June-2017 to July-2019 was performed. Survivors with favorable outcomes (modified rankin scale (mRS) score 0-2) were compared to those with unfavorable outcomes (mRS ≥3) 6-months after stroke on the following: discharge medication classes prescribed, achievement of recommended targets for blood pressure control, glycemic control, and LDL ≤70 mg/dL, medication changes, medication interactions, and medication list discrepancies. Results: Unfavorable 6-month outcomes occurred in 36/78 (46.2%) of survivors. Survivors with unfavorable outcomes were more likely to be prescribed a central nervous system-acting agent (97.2% vs 71.4%; P = .0022) and/or an anti-hyperglycemic agent (25.0% vs 9.5%; P = .009) at discharge. After adjustment of baseline covariates, total number of medications prescribed was associated with unfavorable 6-month outcomes (OR 1.13, 95% CI 1.0-1.28). Secondary stroke prevention measures were not achieved in a high proportion of survivors. Medication changes during 6-month follow up were common and survivors with unfavorable outcomes were more likely to have clinically significant drug-drug interactions. Discussion: At 6-months, survivors with unfavorable outcomes were found to be prescribed more medications, particularly central nervous system-acting and anti-hyperglycemic agents. There were also more drug-drug interactions in the medications prescribed compared to those with favorable outcomes. Together, these data suggest the need for enhanced screening of high-risk stroke survivors focused on close monitoring of polypharmacy, drug-drug interactions, and adverse events with pharmacotherapy.

Continuation of outpatient buprenorphine therapy after dispensing Buprenorphine-Naloxone from the emergency department.

BACKGROUND: Patients with opioid use disorder (OUD) are frequently seen in the ED for opioid-related reasons, which creates an opportunity for ED providers to discuss medications for OUD with their patients. Buprenorphine is a partial mu-opioid agonist that is FDA approved to treat OUD and may be initiated in the ED. Traditionally, buprenorphine therapy was initiated under healthcare provider observation; however, other strategies such as at-home induction have also emerged. METHODS: This was a retrospective descriptive analysis of patients aged 18 years or older who received a take-home supply of buprenorphine-naloxone from an urban, academic ED between March 2018 and March 2020. The primary outcome was the proportion of patients who filled a prescription for buprenorphine at three months after index ED visit. The proportion of patients that filled a prescription for buprenorphine at six months was also evaluated. The primary safety endpoint was the proportion of patients with return ED visit within six months related to opioid overdose. RESULTS: There were 242 patient records reviewed with 155 patients included in final analysis. Seventy (45.2%) patients filled buprenorphine prescriptions at three months, with 64 (41.3%) who filled buprenorphine prescriptions at six months. Seventeen (11%) patients had a return ED visit related to opioid overdose within six months. CONCLUSION: Dispensing buprenorphine take-home kits from the ED resulted in continuation of outpatient buprenorphine in almost 50% of patients. Further studies are warranted to define the role of ED-dispensed buprenorphine.

Rapid buprenorphine microdosing for opioid use disorder in a hospitalized patient receiving very high doses of full agonist opioids for acute pain management: Titration, implementation barriers, and strategies to overcomes.

Background: Conventional buprenorphine inductions for OUD are clinically useful but require patients to experience mild to moderate opioid withdrawal symptoms to avoid precipitated withdrawal. This may be intolerable/unreasonable for some, which may have precluded successful buprenorphine treatment in the past. Microdosing buprenorphine, allowing for full agonist opioid overlap, has emerged as a clinically useful strategy for those unable to complete conventional buprenorphine induction. However, many questions remain such as preclusions regarding the amount of full agonist opioid overlap, speed of buprenorphine microdose titration, and overcoming implementation barriers in U.S. hospitals. Case presentation: A female between the ages of 30 and 40 with severe OUD admitted to the hospital for IDU-related osteomyelitis wished to begin buprenorphine for OUD. Her hospitalization was subject to premature discharge at any time due to competing interests of potential foreclosure on her home, so buprenorphine needed to be started rapidly for safety and improved outcomes. Due to her significant acute pain requirements managed with full agonist opioids, it was unreasonable to consider conventional buprenorphine induction. Buprenorphine microdose strategy was employed at more rapid titration and previously described in the literature, starting at 1 mg TDD on day 1, 3 mg TDD on day 2, and 8 mg TDD on day 3 with full agonist opioid overlap starting at 1,944 MME tapered down to 473 MME. The patient prematurely left the hospital, at which time buprenorphine 8 mg TDD was held at this dose for days 3-8 while full agonist opioid was tapered from 473 MME to 117 MME. BUP was then further titrated to 8 mg TID. This patient tolerated buprenorphine microdosing well, without any treatment-emergent opioid symptoms or worsening of baseline symptoms. Discussion: This case demonstrates the success of buprenorphine microdose induction despite very high doses of full agonist opioid overlap and demonstrates the ability to titrate buprenorphine microdoses faster than originally described. Strategies to overcoming implementation barriers are also discussed.

Assessment of clinical inertia in people with diabetes within primary care.

RATIONALE, AIMS AND OBJECTIVES: Clinical inertia, defined as a delay in treatment intensification, is prevalent in people with diabetes. Treatment intensification rates are as low as 37.1% in people with haemoglobin A1c (HbA1c) values >7%. Intensification by addition of medication therapy may take 1.6 to more than 7 years. Clinical inertia increases the risk of cardiovascular events. The primary objective was to evaluate rates of clinical inertia in people whose diabetes is managed by both pharmacists and primary care providers (PCPs). Secondary objectives included characterizing types of treatment intensification, HbA1c reduction, and time between treatment intensifications. METHOD: Retrospective chart review of persons with diabetes managed by pharmacists at an academic, safety-net institution. Eligible subjects were referred to a pharmacist-managed cardiovascular risk reduction clinic while continuing to see their PCP between October 1, 2016 and June 30, 2018. All progress notes were evaluated for treatment intensification, HbA1c value, and type of medication intensification. RESULTS: Three hundred sixty-three eligible patients were identified; baseline HbA1c 9.6% (7.9, 11.6) (median interquartile range [IQR]). One thousand one hundred ninety-two pharmacist and 1739 PCP visits were included in data analysis. Therapy was intensified at 60.5% (n = 721) pharmacist visits and 39.3% (n = 684) PCP visits (P < .001). The median (IQR) time between interventions was 49 (28, 92) days for pharmacists and 105 (38, 182) days for PCPs (P < .001). Pharmacists more frequently intensified treatment with glucagon-like peptide-1 agonists and sodium glucose cotransporter-2 inhibitors. CONCLUSION: Pharmacist involvement in diabetes management may reduce the clinical inertia patients may otherwise experience in the primary care setting.

An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and ß-blocker Overdose.

Both calcium channel blockers (CCBs) and ß blockers (BBs) are associated with fatal substance exposures within the United States. Cases of overdose with these agents have the potential to be both complex and difficult to manage. A variety of pharmacologic treatment options are available for clinicians to use to help mitigate harm from these poisonings. Hyperinsulinemic-euglycemic therapy (HIET) was once regarded as a last-ditch effort to treat patients in highly refractory cases. In recent years, this therapy has become a routine therapy in the treatment of CCB/BB overdose. This article provides a literature review regarding HIET in cases of overdose with CCB and BB agents. Relevant literature articles from 1997-2018 were identified and reviewed using the PubMed and Embase databases. The following search terms were used to identify potential articles: "hyperinsulinemic-euglycemic therapy," "overdose," "calcium channel blocker," "beta blocker," and "insulin." Articles published in the English language were included in this review. A manual search of reference lists was also conducted. Much of the literature is limited to case reports, series, retrospective chart reviews, and small prospective studies. The success rate observed in published case series ranged from 80.4-100%. Regular insulin is most commonly dosed at an initial bolus of 1 unit/kg followed by a regular insulin infusion of 0.5-1 unit/kg/hour. Euglycemia is often maintained using intravenous fluids containing dextrose. Hyperinsulinemic-euglycemic therapy exhibited a promising safety profile, provided close monitoring is conducted. More research is needed to determine optimal strategies for maintaining euglycemia, ideal monitoring parameters, and consistent efficacy goals.

Genome-wide patterns of gene flow across a house mouse hybrid zone.

Hybrid zones between closely related species or subspecies provide useful settings for studying the genetic architecture of speciation. Using markers distributed throughout the mouse genome, we use a hybrid zone between two recently diverged species of house mice (Mus musculus and Mus domesticus) as a natural mapping experiment to identify genomic regions that may be involved in reproductive isolation. Using cline analysis we document a nearly 50-fold variation in level of introgression among markers. Some markers have extremely narrow cline widths; these genomic regions may contribute to reproductive isolation. Biological processes associated with these narrow clines include physiological and immune responses to the environment as well as physiological and behavioral aspects of reproduction. Other autosomal markers exhibit asymmetrically broad clines, usually with high frequencies of M. domesticus alleles on the M. musculus side of the hybrid zone. These markers identify genome regions likely housing genes with alleles that are spreading from one species to the other. Biological processes associated with these wide clines include cell signaling, olfaction, and pheromone response. These processes play important roles in survival and reproduction, and associated genes are likely targets of selection. Patterns of linkage disequilibrium in the center of the hybrid zone suggest that isolation may be caused by multiple epistatic interactions between sets of genes. These data highlight the complex genetic architecture underlying speciation even at early stages of divergence and point to some of the biological processes that may govern this architecture.

Molecular phylogenetics and evolution of turtles.

Turtles are one of Earth's most instantly recognizable life forms, distinguished for over 200 million years in the fossil record. Even so, key nodes in the phylogeny of turtles remain uncertain. To address this issue, we sequenced >90% of the nuclear recombination activase gene 1 (RAG-1) for 24 species representing all modern turtle families. RAG-1 exhibited negligible saturation and base composition bias, and extensive base composition homogeneity. Most of the relationships suggested by prior phylogenetic analyses were also supported by RAG-1 and, for at least two critical nodes, with a much higher level of support. RAG-1 also indicates that the enigmatic Platysternidae and Chelydridae, often considered sister taxa based on morphological evidence, are not closely related, although their precise phylogenetic placement in the turtle tree is still unresolved. Although RAG-1 is phylogenetically informative, our research revealed fundamental conflicts among analytical methods for estimating phylogenetic hypotheses. Maximum parsimony analyses of RAG-1 alone and in combination with two mitochondrial genes suggest the earliest phylogenetic splits separating into three basal branches, the pig-nosed turtles (Carettochelyidae), the softshell turtles (Trionychidae), and a clade comprising all remaining extant turtles. Maximum likelihood and Bayesian analyses group Carettochelyidae and Trionychidae (=Trionychoidae) in their more traditional location as the sister taxon to all other hidden-necked turtles, collectively forming the Cryptodira. Our research highlights the utility of molecular data in identifying issues of character homology in morphological datasets, while shedding valuable light on the biodiversity of a globally imperiled taxon.

Differential patterns of introgression across the X chromosome in a hybrid zone between two species of house mice.

A complete understanding of the speciation process requires the identification of genomic regions and genes that confer reproductive barriers between species. Empirical and theoretical research has revealed two important patterns in the evolution of reproductive isolation in animals: isolation typically arises as a result of disrupted epistatic interactions between multiple loci and these disruptions map disproportionately to the X chromosome. These patterns suggest that a targeted examination of natural gene flow between closely related species at X-linked markers with known positions would provide insight into the genetic basis of speciation. We take advantage of the existence of genomic data and a well-documented European zone of hybridization between two species of house mice, Mus domesticus and M. musculus, to conduct such a survey. We evaluate patterns of introgression across the hybrid zone for 13 diagnostic X-linked loci with known chromosomal positions using a maximum likelihood model. Interlocus comparisons clearly identify one locus with reduced introgression across the center of the hybrid zone, pinpointing a candidate region for reproductive isolation. Results also reveal one locus with high frequencies of M. domesticus alleles in populations on the M. musculus side of the zone, suggesting the possibility that positive selection may act to drive the spread of alleles from one species on to the genomic background of the other species. Finally, cline width and cline center are strongly positively correlated across the X chromosome, indicating that gene flow of the X chromosome may be asymmetrical. This study highlights the utility of natural populations of hybrids for mapping speciation genes and suggests that the middle of the X chromosome may be important for reproductive isolation between species of house mice.

Heterogeneous patterns of variation among multiple human x-linked Loci: the possible role of diversity-reducing selection in non-africans.

Studies of human DNA sequence polymorphism reveal a range of diversity patterns throughout the genome. This variation among loci may be due to natural selection, demographic influences, and/or different sampling strategies. Here we build on a continuing study of noncoding regions on the X chromosome in a panel of 41 globally sampled humans representing African and non-African populations by examining patterns of DNA sequence variation at four loci (APXL, AMELX, TNFSF5, and RRM2P4) and comparing these patterns with those previously reported at six loci in the same panel of 41 individuals. We also include comparisons with patterns of noncoding variation seen at five additional X-linked loci that were sequenced in similar global panels. We find that, while almost all loci show a reduction in non-African diversity, the magnitude of the reduction varies substantially across loci. The large observed variance in non-African levels of diversity results in the rejection of a neutral model of molecular evolution with a multi-locus HKA test under both a constant size and a bottleneck model. In non-Africans, some loci harbor an excess of rare mutations over neutral equilibrium predictions, while other loci show no such deviation in the distribution of mutation frequencies. We also observe a positive relationship between recombination rate and frequency spectra in our non-African, but not in our African, sample. These results indicate that a simple out-of-Africa bottleneck model is not sufficient to explain the observed patterns of sequence variation and that diversity-reducing selection acting at a subset of loci and/or a more complex neutral model must be invoked.

Molecular phylogeography of common garter snakes (Thamnophis sirtalis) in western North America: implications for regional historical forces.

Complete ND2 and partial ND4 and cytochrome b mitochondrial DNA (mtDNA) sequences were analysed to evaluate the phylogeographic patterns of common garter snakes (Thamnophis sirtalis) in western North America. This species is widely distributed throughout North America, and exhibits extensive phenotypic variation in the westernmost part of its range. The overall phylogeographic pattern based on mtDNA sequences is concordant with results from studies of other species in this region, implicating historical vicariant processes during the Pleistocene and indicating bottleneck effects of recent dispersal into postglacial habitat. Indeed, the topology is statistically consistent with the hypothesis of both southern (Great Basin and California) and northern (Haida Gwaii) refugia. Specifically, we identified genetic breaks among three major clades: Northwest Coastal populations, Intermountain populations, and all California populations. The California clade contained the only other well-supported branching patterns detected; relationships among populations within the two northern clades were indistinguishable. These molecular splits contrast sharply with all prior geographical analyses of phenotypic variation in T. sirtalis in this region. Our results suggest that the extensive phenotypic variation in western T. sirtalis has been shaped more by local evolutionary forces than by shared common ancestry. Consequently, we consider all morphologically based subspecies designations of T. sirtalis in this region invalid because they do not reflect reciprocal monophyly of the mtDNA sequences.