Team Strategies and Dynamics During Resuscitation.

Resuscitations are complex events that require teamwork to succeed. In addition to the technical skills involved, a host of nontechnical skills are critical for optimal medical care delivery. These skills include mental preparation; planning for tasks and roles; leadership to guide resuscitation progress; and clear, closed-loop communication. Concerns and error detection should be escalated in an established format. Debriefing after the event helps identify learning points to carry forward for the next resuscitation. Support of the team providing this intense form of care is crucial to protect the mental health and function of providers.

Clinical profile of injection drug users presenting to the ED.

BACKGROUND: Injection drug users (IDUs) commonly use the emergency department (ED) as their primary health care access point. OBJECTIVE: We sought to characterize infectious disease clinical presentations and laboratory results of IDUs admitted to the hospital from the ED and contrast them with those of non-IDUs. METHODS: We enrolled all admitted adult patients with infectious disease-related diagnoses at a county level 1 trauma center from June 2010 to January 2011 and used a structured chart abstraction tool to record patient characteristics and clinical outcomes. We compared clinical presenting features, laboratory data, and microbiological culture results of IDUs with concomitantly enrolled non-IDUs. RESULTS: Of 603 total participants, 189 were IDUs, and 414 were non-IDUs. Injection drug users had higher rates of skin and soft tissue infection admission but had similar hospital length of stay (7.5 vs 6.1 days) and mortality (2.1% vs 2.9%). Compared with non-IDUs, IDUs more commonly had hyponatremia, 38.1% vs 27.1% (mean difference, 11.4%; 95% confidence intervals [CIs], 3.4%-19.6%) and thrombocytopenia, 18.5% vs 11.0% (mean difference, 7.5%; 95% CI, 1.5%-14.2%) but less frequently had leukocytosis, 36.0% vs 52.7% (mean difference, 16.7%; 95% CI, 8.2%-24.8%). Injection drug users and non-IDUs had similar rates of positive ED-derived blood cultures, 16.5% vs 22.6% (mean difference, 6.1%; 95% CI, -13.3 to 1.7%). CONCLUSIONS: When admitted from the ED for infectious disease-related diagnoses, IDUs had similar rates of fever, higher rates of hyponatremia and thrombocytopenia, and lower rates of leukocytosis than non-IDUs. Although they had similar rates of bacteremia, only IDUs were positive for methicillin-resistant Staphylococcus aureus.

Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB-siRNA conjugates.

Delivery of siRNA is a key hurdle to realizing the therapeutic promise of RNAi. By targeting internalizing cell surface antigens, antibody-siRNA complexes provide a possible solution. However, initial reports of antibody-siRNA complexes relied on non-specific charged interactions and have not been broadly applicable. To assess and improve this delivery method, we built on an industrial platform of therapeutic antibodies called THIOMABs, engineered to enable precise covalent coupling of siRNAs. We report that such coupling generates monomeric antibody-siRNA conjugates (ARCs) that retain antibody and siRNA activities. To broadly assess this technology, we generated a battery of THIOMABs against seven targets that use multiple internalization routes, enabling systematic manipulation of multiple parameters that impact delivery. We identify ARCs that induce targeted silencing in vitro and extend tests to target prostate carcinoma cells following systemic administration in mouse models. However, optimal silencing was restricted to specific conditions and only observed using a subset of ARCs. Trafficking studies point to ARC entrapment in endocytic compartments as a limiting factor, independent of the route of antigen internalization. Our broad characterization of multiple parameters using therapeutic-grade conjugate technology provides a thorough assessment of this delivery technology, highlighting both examples of success as well as remaining challenges.

Alk is a transcriptional target of LMO4 and ERα that promotes cocaine sensitization and reward.

Previously, we showed that the mouse LIM-domain only 4 (Lmo4) gene, which encodes a protein containing two zinc-finger LIM domains that interact with various DNA-binding transcription factors, attenuates behavioral sensitivity to repeated cocaine administration. Here we show that transcription of anaplastic lymphoma kinase (Alk) is repressed by LMO4 in the striatum and that Alk promotes the development of cocaine sensitization and conditioned place preference, a measure of cocaine reward. Since LMO4 is known to interact with estrogen receptor α (ERα) at the promoters of target genes, we investigated whether Alk expression might be controlled by a similar mechanism. We found that LMO4 and ERα are associated with the Alk promoter by chromatin immunoprecipitation and that Alk is an estrogen-responsive gene in the striatum. Moreover, we show that ERα knock-out mice exhibit enhanced cocaine sensitization and conditioned place preference and an increase in Alk expression in the nucleus accumbens. These data define a novel regulatory network involved in behavioral responses to cocaine. Interestingly, sex differences in several behavioral responses to cocaine in humans and rodents have been described, and estrogen is thought to mediate some of these differences. Our data suggest that estrogen regulation of Alk may be one mechanism responsible for sexually dimorphic responses to cocaine.

Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors.

The consequences of alcohol use disorders (AUDs) are devastating to individuals and society, yet few treatments are currently available. To identify genes regulating the behavioral effects of ethanol, we conducted a genetic screen in Drosophila and identified a mutant, happyhour (hppy), due to its increased resistance to the sedative effects of ethanol. Hppy protein shows strong homology to mammalian Ste20 family kinases of the GCK-1 subfamily. Genetic and biochemical experiments revealed that the epidermal growth factor (EGF)-signaling pathway regulates ethanol sensitivity in Drosophila and that Hppy functions as an inhibitor of the pathway. Acute pharmacological inhibition of the EGF receptor (EGFR) in adult animals altered acute ethanol sensitivity in both flies and mice and reduced ethanol consumption in a preclinical rat model of alcoholism. Inhibitors of the EGFR or components of its signaling pathway are thus potential pharmacotherapies for AUDs.