Retrospective Study of Midazolam Protocol for Prehospital Behavioral Emergencies

Introduction: Agitated patients in the prehospital setting pose challenges for both patient care and emergency medical services (EMS) provider safety. Midazolam is frequently used to control agitation in the emergency department setting; however, limited data exist in the prehospital setting. We describe our experience treating patients with midazolam for behavioral emergencies in a large urban EMS system. We hypothesized that using midazolam for acute agitation leads to improved clinical conditions without causing significant clinical deterioration.Methods: We performed a retrospective review of EMS patient care reports following implementation of a behavioral emergencies protocol in a large urban EMS system from February 2014–June 2016. For acute agitation, paramedics administered midazolam 1 milligram (mg) intravenous (IV), 5 mg intramuscular (IM), or 5 mg intranasal (IN). Results were analyzed using descriptive statistics, Levene’s test for assessing variance among study groups, and t-test to evaluate effectiveness based on route.Results: In total, midazolam was administered 294 times to 257 patients. Median age was 30 (interquartile range 24–42) years, and 66.5% were male. Doses administered were 1 mg (7.1%) and 5 mg (92.9%). Routes were IM (52.0%), IN (40.8%), and IV (7.1%). A second dose was administered to 37 patients. In the majority of administrations, midazolam improved the patient’s condition (73.5%) with infrequent adverse events (3.4%). There was no significant difference between the effectiveness of IM and IN midazolam (71.0% vs 75.4%; p = 0.24).Conclusion: A midazolam protocol for prehospital agitation was associated with reduced agitation and a low rate of adverse events

976-14 Immediate Heart Rate Response to Orthostatic Stress During β-blocker Therapy for Vasodepressor Syncope

Although β-blockers are preferred agents for therapy of vasodepressor syncope (VDS), they are not uniformly effective and their mechanism of action is incompletely understood. Since we have previously shown a differential therapeutic response to β-blocker therapy between pts with isoproterenol-independent [iso(-)] and isoproterenol-dependent [iso(+)] VDS during tilt table testing we sought to determine whether this was due to a differential heart rate (HR) response to orthostasis during β-blockade. We therefore examined immediate HR and blood pressure responses to upright tilt before and after initiation of therapy with atenolol (12.5–50mg daily) in 62 pts with VDS and positive tilt tests. The protocol comprised upright tilt (60°) for up to 60min followed by repeat tilt for 15min during isoproterenol (iso) infusion. Supine HR, mean arterial pressure (MAP) and pulse pressure (PP) were determined as the mean of 3 consecutive 1-min samples during supine rest; orthostatic HR, MAP, and PP were the mean of the samples recorded in the first 3min after upright tilt (before infusion of iso). Response to atenolol required completion of tilt with and without infusion of iso. There were 15 iso(-) pts and 47 iso(+) pts. The groups did not differ significantly in blood pressure response (MAP, PP) to orthostasis. Supine HR fell and the ΔHR in response to orthostasis was blunted during therapy in both groups:Baseline (Mean ± SD)Rx (Mean ± SD)Iso(+)Iso(-)pIso(+)Iso(-)pSupine HR69±1368±9NS57±958±8NSOrthostatic ΔHR8±712±9NS3±53±4NS11 iso(-) pts (73%) had a therapeutic response to β-blockade compared with 46 iso(+) pts (98%, p=0.01); the orthostatic ΔHR in the iso(-) pts who failed β-blocker therapy was no different from the response in the patients with a therapeutic response.ConclusionsThe HR response to orthostasis is comparably blunted after β-blockade in pts with iso(-) and iso(+) VDS, indicating that failure to respond is not due to inadequate β-blockade and suggests that in some pts iso-independent VDS may be independent of a cardiac β1 receptor mediated mechanism

Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2−/− mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes

Predicting impact of freshwater exotic species on native biodiversity: Challenges in spatial scaling

Global homogenization of biota is underway through worldwide introduction and establishment of nonindigenous (exotic) species. Freshwater ecologists should devote more attention to exotic species for two reasons. First, exotics provide an opportunity to test hypotheses about what characteristics of species or habitats are related to successful establishment or invasibility, respectively. Second, predicting which species will cause large ecological change is an important challenge for natural resource managers. Rigorous statistical relationships linking species characteristics to probability of establishment or of causing ecological impacts are needed. In addition, it is important to know how reliable different sorts of experiments are in guiding predictions. We address this issue with different spatial scales of experiments testing the impact of two predators on native snail assemblages in northern Wisconsin USA lakes: an exotic crayfish, the rusty crayfish (Orconectes rusticus); and a native fish predator, the pumpkinseed sunfish (Lepomis gibossus). For the crayfish, laboratory experiments, a field cage experiment, and a snapshot survey of 21 lakes gave consistent results: the crayfish reduced abundance and species richness of native snails. Laboratory and field experiments suggested that pumpkinseed sunfish should have a similar impact, but the lake survey suggested little impact. Unfortunately, no algorithms exist to guide scaling up from small-scale experiments to the whole-lake, long-term management scale. To protect native biodiversity, management of freshwater exotic species should be targeted on lakes or drainages that are both vulnerable to colonization by an exotic, and that harbour endemic species. Management should focus on preventing introduction because eradication after establishment is usually not possible.The following grants funded our research: NSFBSR85-00775, NSFBSR89-07407, EPA CR820290-0T -0 (to DML)

Association of alcohol consumption after development of heart failure with survival among older adults in the Cardiovascular Health Study

Importance: More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown. Objective: To determine whether alcohol use is associated with increased survival among older adults with incident heart failure. Design, Setting, and Participants: This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of follow-up through June 2013. The study analysis was performed between January 19, 2016, and September 22, 2016. Exposures: Alcohol consumption was divided into 4 categories: abstainers (never drinkers), former drinkers, 7 or fewer alcoholic drinks per week, and more than 7 drinks per week. Primary Outcomes and Measures: Participant survival after the diagnosis of incident heart failure. Results: Among the 393 adults diagnosed with incident heart failure, 213 (54.2%) were female, 339 (86.3%) were white, and the mean (SD) age was 78.7 (6.0) years. Alcohol consumption after diagnosis was reported in 129 (32.8%) of the participants. Across alcohol consumption categories of long-term abstainers, former drinkers, consumers of 1-7 drinks weekly and consumers of more than 7 drinks weekly, the percentage of men (32.1%, 49.0%, 58.0%, and 82.4%, respectively; P \u3c .001 for trend), white individuals (78.0%, 92.7%, 92.0%, and 94.1%, respectively, P \u3c. 001 for trend), and high-income participants (22.0%, 43.8%, 47.3%, and 64.7%, respectively; P \u3c .001 for trend) increased with increasing alcohol consumption. Across the 4 categories, participants who consumed more alcohol had more years of education (mean, 12 years [interquartile range (IQR), 8.0-10.0 years], 12 years [IQR, 11.0-14.0 years], 13 years [IQR, 12.0-15.0 years], and 13 years [IQR, 12.0-14.0 years]; P \u3c .001 for trend). Diabetes was less common across the alcohol consumption categories (32.1%, 26.0%, 22.3%, and 5.9%, respectively; P = .01 for trend). Across alcohol consumption categories, there were fewer never smokers (58.3%, 44.8%, 35.7%, and 29.4%, respectively; P \u3c .001 for trend) and more former smokers (34.5%, 38.5%, 50.0%, and 52.9%, respectively; P = .006 for trend). After controlling for other factors, consumption of 7 or fewer alcoholic drinks per week was associated with additional mean survival of 383 days (95% CI, 17-748 days; P = .04) compared with abstinence from alcohol. Although the robustness was limited by the small number of individuals who consumed more than 7 drinks per week, a significant inverted U-shaped association between alcohol consumption and survival was observed. Multivariable model estimates of mean time from heart failure diagnosis to death were 2640 days (95% CI, 1967-3313 days) for never drinkers, 3046 days (95% CI, 2372-3719 days) for consumers of 0 to 7 drinks per week, and 2806 (95% CI, 1879-3734 days) for consumers of more than 7 drinks per week (P = .02). Consumption of 10 drinks per week was associated with the longest survival, a mean of 3381 days (95% CI, 2806-3956 days) after heart failure diagnosis. Conclusions and Relevance: These findings suggest that limited alcohol consumption among older adults with incident heart failure is associated with survival benefit compared with long-term abstinence. These findings suggest that older adults who develop heart failure may not need to abstain from moderate levels of alcohol consumption

Increased Ventricular Premature Contraction Frequency During REM Sleep in Patients with Coronary Artery Disease and Obstructive Sleep Apnea

Background Patients with obstructive sleep apnea are reported to have a peak of sudden cardiac death at night, in contrast to patients without apnea whose peak is in the morning. We hypothesized that ventricular premature contraction (VPC) frequency would correlate with measures of apnea and sympathetic activity.Methods Electrocardiograms from a sleep study of 125 patients with coronary artery disease were evaluated. Patients were categorized by apnea-hypopnea index (AHI) into Moderate (AHI <15) or Severe (AHI>15) apnea groups. Sleep stages studied were Wake, S1, S2, S34, and rapid eye movement (REM). Parameters of a potent autonomically-based risk predictor for sudden cardiac death called heart rate turbulence were calculated.Results There were 74 Moderate and 51 Severe obstructive sleep apnea patients. VPC frequency was affected significantly by sleep stage (Wake, S2 and REM, F=5.8, p<.005) and by AHI (F=8.7, p<.005). In Severe apnea patients, VPC frequency was higher in REM than in Wake (p=.011). In contrast, patients with Moderate apnea had fewer VPCs and exhibited no sleep stage dependence (p=.19). Oxygen desaturation duration per apnea episode correlated positively with AHI (r2=.71, p<.0001), and was longer in REM than in non-REM (p<.0001). The heart rate turbulence parameter TS correlated negatively with oxygen desaturation duration in REM (r2=.06, p=.014).Conclusions Higher VPC frequency coupled with higher sympathetic activity caused by longer apnea episodes in REM sleep may be one reason for increased nocturnal death in apneic patients

Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39–43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1KO mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1KO mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ1–42 was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Combining left atrial appendage closure and catheter ablation for atrial fibrillation: 2-year outcomes from a multinational registry

AIMS: Clinical practice guidelines do not recommend discontinuation of long-term oral anticoagulation in patients with a high stroke risk after catheter ablation for atrial fibrillation (AF). Left atrial appendage closure (LAAC) with Watchman has emerged as an alternative to long-term anticoagulation for patients accepting of the procedural risks. We report on the long-term outcomes of combining catheter ablation procedures for AF and LAAC from multicentre registries. METHODS AND RESULTS: Data were pooled from two prospective, real-world

A Path Algorithm for Constrained Estimation

Many least squares problems involve affine equality and inequality constraints. Although there are variety of methods for solving such problems, most statisticians find constrained estimation challenging. The current paper proposes a new path following algorithm for quadratic programming based on exact penalization. Similar penalties arise in $l_1$ regularization in model selection. Classical penalty methods solve a sequence of unconstrained problems that put greater and greater stress on meeting the constraints. In the limit as the penalty constant tends to $\infty$, one recovers the constrained solution. In the exact penalty method, squared penalties are replaced by absolute value penalties, and the solution is recovered for a finite value of the penalty constant. The exact path following method starts at the unconstrained solution and follows the solution path as the penalty constant increases. In the process, the solution path hits, slides along, and exits from the various constraints. Path following in lasso penalized regression, in contrast, starts with a large value of the penalty constant and works its way downward. In both settings, inspection of the entire solution path is revealing. Just as with the lasso and generalized lasso, it is possible to plot the effective degrees of freedom along the solution path. For a strictly convex quadratic program, the exact penalty algorithm can be framed entirely in terms of the sweep operator of regression analysis. A few well chosen examples illustrate the mechanics and potential of path following.Comment: 26 pages, 5 figure