Search

Introduction: Intraoperative neuromonitoring (IONM) is commonly used during surgery of the spine and spinal cord for early surveillance of iatrogenic injury to the central and peripheral nervous system. However, for infants and young children under 3 years of age, the use of IONM is challenging due to incomplete central and peripheral myelination. Case Presentation: We report a case of a T4-T6 dermal sinus tract (DST) that was resected on day of life 23, with the successful use of IONM. Conclusion: To our knowledge, this is the youngest reported case of the use of IONM in the surgical correction of a DST in a neonatal patient. This case demonstrates the potential efficacy of IONM in neonatal spine surgery and the techniques used to adapt the technology to an immature nervous system.

The electrode fabrication stage is a crucial step in the design of supercapacitors. The latter involves the binder generally for adhesive purposes. The binder is electrochemically dormant and has weak interactions, leading to isolating the active material and conductive additive and then compromising the electrochemical performance. Designing binder-free electrodes is a practical way to improve the electrochemical performance of supercapacitors. However, most of the methods developed for the fabrication of binder-free LDH electrodes do not accommodate LDH materials prepared via the co-precipitation or ions exchange routes. Herein, we developed a novel method to fabricate binder-free LDH electrodes which accommodates LDH materials from other synthesis routes. The induced impacts of various physical parameters such as the temperature and time applied during the fabrication process on the crystalline domain and electrochemical performances of all the binder-free LDH electrodes were studied. The electrochemical analysis showed that the electrode prepared at 200 °C-1 h exhibited the best electrochemical performance compared to its counterparts. A specific capacitance of 3050.95 Fg−1 at 10 mVs−1 was achieved by it, while its Rct value was 0.68 Ω. Moreover, it retained 97% of capacitance after 5000 cycles at 120 mVs−1. The XRD and FTIR studies demonstrated that its excellent electrochemical performance was due to its crystalline domain which had held an important amount of water than other electrodes. The as-developed method proved to be reliable and advantageous due to its simplicity and cost-effectiveness.

Subjective confidence reports are used in numerous research paradigms to examine the extent to which participants are aware of their performance in a task. By examining the discrepancy between objective performance and subjective confidence ratings, inferences can be made about the conditions in which participants have greater explicit knowledge of the representations and processes used to complete a task. In the current study, we examined the effects of prior knowledge on subjective assessments of performance using a categorisation task wherein lists of features that defined exemplars shared latent feature associations on the basis of prior knowledge or had no prior associations. Using 2 methods for computing confidence, we demonstrate the strengths and limitations of these measures of subjective awareness. Whereas our findings replicated the effect of prior knowledge on learning, our results challenge the role of explicit and implicit knowledge suggested by previous research using a similar paradigm. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

In 2017, the third American Society of Regional Anesthesia and Pain Medicine (ASRA) practice advisory on local anesthetic systemic toxicity (LAST)[1][1] revised[2][2] its 2012 LAST checklist[3][3] to enhance the user experience. By comparing the readability (content and presentation) and

Brodifacoum (BDF) is a potent, long-acting anticoagulant rodenticide that can cause fatal poisoning in humans. The chemical structure of BDF includes 2 chiral carbons, resulting in 2 pairs of diastereomers, BDF-cis (R/S and S/R) and BDF-trans (R/R and S/S). However, the relative potency of these molecules is not known. The purpose of this study was to compare the in vitro and in vivo toxic effects of the 2 BDF diastereomer pairs. In adult Sprague-Dawley rats BDF-cis was significantly more toxic than BDF-trans (LD50 values of 219 versus 316 μg/kg, respectively) while racemic BDF had intermediate potency (266 μg/kg). In adult New Zealand white rabbits, BDF-cis had a longer half-life than BDF-trans which could contribute to its observed increased toxicity. Lastly, BDF-cis (10 μM), but not BDF-trans, damaged cultured SH-SY5Y human neuroblastoma cells by attenuating mitochondrial reductive capacity. Taken together, these data suggest that different toxic manifestations of BDF poisoning in mammals could be attributed, in part, to differences in relative enantiomer concentrations present in racemic formulations of this commercially-available toxicant.

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p &lt, 0.01), blocking pathological increases in systemic extracellular water (p &lt, 0.001) and prolonging median survival (15%, p &lt, 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1–7) levels, promoting nitric oxide bioavailability and stimulating 3′-5′-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1–7) levels, nitric oxide bioavailability and cGMP production.

Local anesthetic systemic toxicity (LAST) is a life-threatening crisis, and many cognitive aids have been developed including three versions from the American Society of Regional Anesthesia and Pain Medicine (ASRA).[1–3][1] Eye tracking has applications in medical education[4][2] and has been

The American Society of Regional Anesthesia and Pain Medicine (ASRA) periodically updates its practice advisories and associated cognitive aids. The 2020 version of the ASRA Local Anesthetic Systemic Toxicity checklist was created in response to user feedback, simulation studies and advances in medical knowledge. This report presents the 2020 version and discusses the rationale for its update.

Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about the safety and effects of sexual interactions in patients with HF. We tested whether a lack of sexual interactions affected pathophysiological outcomes in a pre-clinical mouse model of dilated cardiomyopathy that recapitulates the progressive stages of human HF. Male mice were randomly given access to, or deprived from, sexual interactions with female mice, which were confirmed by videography and generation of offspring. Cohousing with access to sexual interactions markedly prolonged survival, while cohousing without access to sexual activity did not. Sexual interactions improved systolic function, reduced HF-associated edema, altered transcription of heart contractile protein genes and decreased plasma testosterone levels. To determine whether testosterone levels contributed to survival, testosterone levels were experimentally reduced. Reduction of testosterone levels significantly prolonged survival. Taken together, in mice with dilated cardiomyopathy, sexual activity altered cardiac contractile gene transcription, improved systolic function, reduced edema and prolonged survival which may be in part due to lower testosterone levels.

Altered expression of corin, a cardiac transmembrane serine protease, has been linked to dilated and ischemic cardiomyopathy. However, the potential role of corin in myocardial infarction (MI) is lacking. This study examined the outcomes of MI in wild-type vs. cardiac-specific overexpressed corin transgenic (Corin-Tg) mice during pre-MI, early phase (3, 24, 72 h), and late phase (1, 4 weeks) post-MI. Corin overexpression significantly reduced cardiac cell apoptosis (p &lt, 0.001), infarct size (p &lt, 0.001), and inhibited cleavage of procaspases 3, 9, and 8 (p &lt, 0.05 to p &lt, 0.01), as well as altered the expression of Bcl2 family proteins, Bcl-xl, Bcl2 and Bak (p &lt, 0.001) at 24 h post-MI. Overexpressed cardiac corin also significantly modulated heart function (ejection fraction, p &lt, 0.0001), lung congestion (lung weight to body weight ratio, p &lt, 0.0001), and systemic extracellular water (edema, p &lt, 0.05) during late phase post-MI. Overall, cardiac corin overexpression significantly reduced apoptosis, infarct size, and modulated cardiac expression of key members of the apoptotic pathway in early phase post-MI, and led to significant improvement in heart function and reduced congestion in late phase post-MI. These findings suggest that corin may be a useful target to protect the heart from ischemic injury and subsequent post-infarction remodeling.

Background Epinephrine is recommended in contemporary educational efforts by the American Heart Association (AHA) as central to adult Advanced Cardiac Life Support (ACLS). However, the International Liaison Committee on Resuscitation (ILCOR) 2019 recommendations update describes large evidentiary gaps for epinephrine use in cardiopulmonary resuscitation, highlighting that clinical and experimental evidence do not support the current AHA recommendations. Objective This controversies article was written as a response to updated AHA and ILCOR adult ACLS recommendations in late 2019. This report summarizes and evaluates the evidence surrounding epinephrine for cardiac arrest with a focus on the historical perspective of epinephrine research. Discussion According to the 2019 AHA ACLS guidelines, epinephrine is an integral component of adult out-of-hospital cardiac arrest resuscitation. Epinephrine improves rates of return of spontaneous circulation and might provide benefit at different doses or in select resuscitation scenarios, such asystole as an initial rhythm at onset of resuscitation efforts. However, evidence indicates potential harms with routine use of standard dose epinephrine (1 mg/10 mL), with no improvement in neurologic or long-term outcomes. Conclusions Despite years of use and inclusion in resuscitation guidelines, epinephrine is not associated with improved neurologic outcomes. The AHA Emergency Cardiovascular Care committee should revise ACLS guidelines reflecting evidence that standard-dose epinephrine offers little benefit to successful patient recovery including neurologic outcomes. Future resuscitation guidelines should reflect this important consideration.

ContextPostoperative recovery rooms have existed since 1847, however, there is sparse literature investigating interventions undertaken in recovery, and their impact on patients after recovery room discharge.ObjectiveThis review aimed to investigate the organisation of care delivery in postoperative recovery rooms; and its effect on patient outcomes; including mortality, morbidity, unplanned intensive care unit (ICU) admission and length of hospital stay.Data sourcesNCBI PubMed, EMBASE and Cumulative Index to Nursing and Allied Health Literature.Study selectionStudies published since 1990, investigating health system initiatives undertaken in postoperative recovery rooms. One author screened titles and abstracts, with two authors completing full-text reviews to determine inclusion based on predetermined criteria. A total of 3288 unique studies were identified, with 14 selected for full-text reviews, and 8 included in the review.Data extractionEndNote V.8 (Clarivate Analytics) was used to manage references. One author extracted data from each study using a data extraction form adapted from the Cochrane Data Extraction Template, with all data checked by a second author.Data synthesisNarrative synthesis of data was the primary outcome measure, with all data of individual studies also presented in the summary results table.ResultsFour studies investigated the use of the postanaesthesia care unit (PACU) as a non-ICU pathway for postoperative patients. Two investigated the implementation of physiotherapy in PACU, one evaluated the use of a new nursing scoring tool for detecting patient deterioration, and one evaluated the implementation of a two-track clinical pathway in PACU.ConclusionsManaging selected postoperative patients in a PACU, instead of ICU, does not appear to be associated with worse patient outcomes, however, due to the high risk of bias within studies, the strength of evidence is only moderate. Four of eight studies also examined hospital length of stay; two found the intervention was associated with decreased length of stay and two found no association.PROSPERO registration numberThis protocol is registered on the International Prospective Register of Systematic Reviews (PROSPERO) database, registration numberNCT42018106093.

The incidence of inappropriate cardiac catheterization lab activation for treatment of a false ST-segment elevation myocardial infarction (STEMI) has been reported to be 2.6%-36%. Excessive inappropriate catheterization lab activation may be associated with risks to patients, provider fatigue and improper resource usage. Hypothesis: To derive and validate a prediction score to more accurately classify patients with STEMI. Methods and results: We conducted a retrospective cohort analysis of 1144 consecutive patients initially diagnosed with STEMI between September 2008 and January 2013. The incidence of catheterization laboratory activation for false STEMI was 21.4%. Multiple logistic regression identified 8 factors as important for prediction of false STEMI. Using a prediction rule derived from these factors, the area under the curve for differentiating false from true STEMI patients was 0.80 (95% CI: 0.75-0.84). Using objective standards, criteria were defined that had 95% specificity for detecting patients with an incorrect diagnosis of STEMI. In conclusion: A prediction rule has been derived and validated in a large, racially diverse group to identify false STEMI patients with an incorrect classification rate of 5%, which is an improvement over current clinical practice. Prediction rules may be particularly useful in patients with atypical presentations in which emergent catheterization cannot be achieved rapidly or carries significant patient risk.

Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p &lt, 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p &lt, 0.01), lung edema (p &lt, 0.05), systemic extracellular free water (p &lt, 0.01), and heart weight were decreased (p &lt, 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p &lt, 0.01), while ventricular dilation decreased (p &lt, 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3&beta, (pSer9-GSK3&beta, ) levels were increased in corin(i)-Tg/DCM mice (p &lt, 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3&beta, activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.

The American Society of Regional Anesthesia and Pain Medicine's Third Practice Advisory on local anesthetic systemic toxicity is an interim update from its 2010 advisory. The advisory focuses on new information regarding the mechanisms of lipid resuscitation, updated frequency estimates, the preventative role of ultrasound guidance, changes to case presentation patterns, and limited information related to local infiltration anesthesia and liposomal bupivacaine. In addition to emerging information, the advisory updates recommendations pertaining to prevention, recognition, and treatment of local anesthetic systemic toxicity. WHAT'S NEW IN THIS UPDATE?: This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists.

Function learning research has shown that people tend to underestimate positive linear functions when extrapolating Y for X-values below the training range. Kwantes and Neal (2006) proposed that this underestimation occurs because people anchor their Y-estimates at zero. It is equally plausible, however, that people are biased to make Y-estimates similar to the presented X-value. To differentiate these 2 explanations, 135 participants extrapolated positive linear functions with a y-intercept either greater than or less than zero. In line with the anchoring hypothesis, participants underestimated in the lower extrapolation region when the y-intercept was positive, but overestimated when the y-intercept was negative. These results are consistent with a version of the extrapolation association model (EXAM; Delosh, Busemeyer, & McDaniel, 1997), which proposes that people interpolate linearly between the training exemplars and zero in the lower extrapolation region. (PsycINFO Database Record

We examine the role of heterogenous organizational attributes of firms and environmental activists in determining the likelihood of them cooperating. We argue that insofar as heterogeneity in their...

Non-ST elevation-acute coronary syndrome (NSTE-ACS) includes NSTE myocardial infarction and unstable angina. This patient population forms approximately two-thirds of all hospital admissions for ACS in the United States each year and is associated with an in-hospital mortality of 5%. NSTE-ACS is primarily due to an acute change in the supply and demand balance of coronary perfusion and myocardial oxygen consumption, because of the significant coronary artery obstruction presenting as plaque rupture or erosion. Nevertheless, nonobstructive causes may lead to that same phenomenon by excessive myocardial oxygen demand or reduced coronary supply from hypotension, anemia, or sepsis, including transient coronary vasospasm and endocardial dysfunction. The recent clinical application of high-sensitivity troponin biomarker assays and computer tomography angiography shows promise for improving the diagnosis and the risk stratification of patients with angina symptoms. Implementation of recent updates to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on NSTE-ACS, especially regarding the selection and duration of antiplatelet therapy, have led to improvement in management and outcomes of this disease. Additionally, new adjunctive therapies and approaches to diagnosis and treatment are discussed. Despite the progress made in recent years in the diagnosis and management of NSTE-ACS, morbidity remains high and mortality is significant. Such a fact suggests that future research targeting prevention, early diagnosis, and intervention in these patients is warranted. This article provides a detailed overview of the most recent information on the pathophysiology, diagnosis, treatment, and prognosis of NSTE-ACS.

Background Accurate identification of patients at risk of early postoperative deterioration allows needs-based allocation of patients to appropriate levels of care. This study aimed to record the incidence of early postoperative deterioration and identify factors predictive of at-risk patients. Doing so may assist future evidence-based perioperative planning and allocation of patients to high-acuity facilities. Methods With ethical approval, data from elective non-cardiac surgical patients were collected between May and August 2013. Patient and surgical factors potentially related to postoperative deterioration were collected from preoperative assessment records. Data on deterioration in the postanaesthesia care unit (PACU), and on the wards were collected prospectively for a period of 72 h postoperatively. Patient factors, surgical factors and PACU events were compared with ward events using binomial logistic regression analysis. Results Of the 747 patients, postoperative deterioration was common both in PACU (155 (20.1%) patients) and on the wards (125 (16.7%)). Common ward events included hypotension (64 (8.2%)) and desaturation (59 (6.2%)). A rapid response team call occurred for 33 (4.4%) patients and an unplanned ICU admission for seven (0.9%) patients. A history of atrial fibrillation and chronic liver disease, duration of surgery and excessive sedation in PACU, among others, were strongly associated with subsequent ward deterioration. However, measures of surgical complexity were not. Conclusions Patient factors, duration of surgery and events in PACU can be predictive of subsequent early postoperative ward clinical deterioration. Such information may aid appropriate perioperative decision-making with respect to postoperative utilization of high-acuity facilities.

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin–angiotensin–aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.

INTRODUCTION: Every year, more than 500,000 US Emergency Department visits are associated with cocaine use. People who use cocaine tend to have a lower incidence of true ST-elevation myocardial infarction (STEMI). OBJECTIVE: To identify the factors associated with true STEMI in patients with cocaine-positive (CPos) findings. METHODS: We retrospectively analyzed 1144 consecutive patients with STEMI between 2008 and 2013. True STEMI was defined as having a culprit lesion on coronary angiogram. Multivariate and univariate analyses were used to identify risk factors and create a predictive model. RESULTS: A total of 64 patients with suspected STEMI were CPos (mean age 53.1 ± 11.2 years; male = 80%). True STEMI was diagnosed in 34 patients. Patients with CPos true STEMI were more likely to be uninsured than those with false STEMI (61.8% vs 34.5%, p = 0.03) and have higher peak troponin levels (21.1 ng/mL vs 2.12 ng/mL, p = < 0.01) with no difference in mean age between the 2 groups (p = 0.24). In multivariate analyses, independent predictors of true STEMI in patients with CPos findings included age older than 65 years (odds ratio [OR] = 19.3, 95% confidence iterval [CI] = 1.2–318.3), lack of health insurance (OR = 4.9, 95% CI = 1.2–19.6), and troponin level higher than 0.05 (OR = 24.0, 95% CI = 2.6–216.8) (all p < 0.05). A multivariate risk score created with a C-statistic of 82% (95% CI = 71–93) significantly improved the identification of patients with true STEMI. CONCLUSION: Among those with suspected STEMI, patients with CPos findings had a higher incidence of false STEMI. Older age, lack of health insurance, and troponin levels outside of defined limits were associated with true STEMI in this group.

Local anesthetic toxicity is a rare but serious complication of local anesthetic administration. Although lidocaine has a safety profile superior to other amide local anesthetics, we report a case of cardiac arrest after intranasal injection of lidocaine. The case involves a 22-year-old healthy woman who experienced pulseless electrical activity shortly after a submucosal injection of 2.2 mg/kg of lidocaine with epinephrine. Resuscitative efforts were unsuccessful until a bolus of intralipid was given. This case emphasizes that even a "low" dose of a less lipophilic drug has the potential for severe toxicity.

Technological innovations by digital platform-based firms have led to public debates about the legitimacy of new entrants’ business strategies in a range of industries, prompting governments to rev...

Mutation of the gene encoding dystrophin leads to Duchenne and Becker muscular dystrophy (DMD and BMD). Currently, dystrophin is thought to function primarily as a structural protein, connecting the muscle cell actin cytoskeleton to the extra-cellular matrix. In addition to this structural role, dystrophin also plays an important role as a scaffold that organizes an array of signaling proteins including sodium, potassium, and calcium channels, kinases, and nitric oxide synthase (nNOS). Many of these signaling proteins are linked to dystrophin via syntrophin, an adapter protein that is known to bind directly to two sites in the carboxyl terminal region of dystrophin. A search of the dystrophin sequence revealed three additional potential syntrophin binding sites (SBSs) within the spectrin-like repeat (SLR) region of dystrophin. Binding assays revealed that the site at SLR 17 bound specifically to the α isoform of syntrophin while the site at SLR 22 bound specifically to the β-syntrophins. The SLR 17 α-SBS contained the core sequence known to be required for nNOS-dystrophin interaction. In vitro and in vivo assays indicate that α-syntrophin facilitates the nNOS-dystrophin interaction at this site rather than nNOS binding directly to dystrophin as previously reported. The identification of multiple SBSs within the SLR region of dystrophin demonstrates that this region functions as a signaling scaffold. The signaling role of the SLR region of dystrophin will need to be considered for effective gene replacement or exon skipping based DMD/BMD therapies.

Background. In patients with reduced systolic function, the natriuretic peptide system affects heart failure (HF) progression, but the expression of key activating (corin) and degrading enzymes (neprilysin) is not well understood. Methods and Results. This pilot study (n=48) compared plasma levels of corin, neprilysin, ANP, BNP, and cGMP in control patients with normal ejection fractions (mean EF 63±3%) versus patients with systolic dysfunction, with (EF 24±8%) and without (EF 27±7%) decompensated HF (dHF), as defined by Framingham and BNP criteria. Mean ages, use of beta blockers, and ACE-inhibitors-angiotensin receptor blockers were similar between the groups. Corin levels were depressed in systolic dysfunction patients (797±346 pg/ml) versus controls (1188±549, p Conclusions. Levels of neprilysin, ANP, BNP, and cGMP increased in patients with reduced systolic function and were the highest in dHF patients. Conversely, corin levels were low in patients with reduced EF with or without dHF. This pattern suggests possible enzymatic downregulation of natriuretic peptide activity in patients with reduced EF, which may have diagnostic and prognostic implications.

The experimental use of lipid emulsion for local anesthetic toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than local anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.

Background: Patients with a family history of coronary artery disease (FHxCAD) are at increased risk for development of myocardial infarction (MI). However, the data on the influence of FHxCAD on in-hospital clinical outcomes post ST-segment myocardial infarction (STEMI) is limited. Hence, we evaluated the impact of FHxCAD on in-hospital clinical outcomes post STEMI in an unselected nationwide cohort. Methods: Nationwide Inpatient Sample (NIS) database [2003–2011] was used to compare differences in all-cause in-hospital mortality and adverse clinical events (cardiogenic shock, acute cerebrovascular events and use of intra-aortic balloon pump) between patients with and without FHxCAD. Results: A total of 2,123,492 STEMI admissions were identified, of which 7.4% (n=158,079) patients were with FHxCAD and 92.6% (n=1,965,413) were without FHxCAD. The FHxCAD group had lower inhospital mortality [1.4% vs. 8.1%; adjusted odds ratio (OR): 0.42, 95% confidence interval (CI): 0.41–0.44; P Conclusions: This large sample size study demonstrates that STEMI patients with FHxCAD had lower in-hospital mortality and adverse clinical events in comparison to patients with no-FHxCAD. Further research is warranted to determine whether the superior outcomes in FHxCAD patients with STEMI are related to differences in strategies related to diet, exercise, use of medications or coronary interventions.

Background: The paradox that smokers have better clinical outcomes in cardiovascular diseases remains controversial. No literature exists studying impact of smoking on outcomes following transcatheter aortic valve replacement (TAVR). Methods: We performed an electronic search of the 2011–2012 National Inpatient Sample (NIS) database to identify all TAVR hospitalizations. Outcomes were measured comparing smokers to non-smokers. Results: A total of 8,345 TAVR hospitalizations were identified with 24% being smokers. Compared to non-smokers, smokers were younger (80.4±8.8 vs. 81.4±9.2 years, P

Background Local anesthetic systemic toxicity (LAST) is a rare and potentially devastating complication of regional anesthesia. Single-institution registries have reported a decreasing incidence, but these results have limited broad applicability. A recent study using a US database found a relatively high incidence of LAST. We used the National Inpatient Sample, a US database of inpatient admissions, to identify the national incidence and associated risk factors for LAST in total joint arthroplasties. Methods In this retrospective study, we studied patients undergoing hip, knee, or shoulder arthroplasty, from 1998 to 2013, with an adjunct peripheral nerve blockade. We used a multivariable logistic regression to identify patient conditions, hospital level variables, and procedure sites associated with LAST. Results A total of 710,327 discharges met inclusion criteria. The average adjusted incidence was 1.04 per 1000 peripheral nerve blocks, with decreasing trend over the 15-year study period (odds ratio [OR], 0.90; P = 0.002). Shoulder arthroplasty (OR, 4.35; P = 0.0001) compared with knee or hip arthroplasty and medium-size (OR, 3.34; P = 0.003) and large-size (OR, 2.40; P = 0.025) hospitals as compared with small hospitals were associated with increased odds of LAST. Conclusions The incidence of LAST nationally in total joint arthroplasty with adjunct nerve blocks is similar to recent estimates from academic centers, with a small decreasing trend through the study period. Despite an overall low incidence rate, practitioners should continue to maintain vigilance for manifestations of LAST, especially as the use of regional anesthesia continues to increase.

Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC). The most common and severe form among children is Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, with an average life expectancy around 25 years of age. Another group of MD's referred to as the limb-girdle muscular dystrophies (LGMDs) can affect boys or girls, with different types caused by mutations in different genes. Mutation of the α-sarcoglycan gene, also a DGC component, causes LGMD2D and represents the most common form of LGMD. Early preclinical and clinical trial findings support the feasibility of gene therapy via recombinant adeno-associated viral vectors as a viable treatment approach for many MDs. In this mini-review, we present an overview of recent progress in clinical gene therapy trials of the MD's and touch upon promising preclinical advances.

Diabetes mellitus (DM) is a pro-thrombotic state with enhanced thrombin generation and platelet reactivity. For most patients undergoing percutaneous coronary intervention (PCI), bivalirudin demonstrates efficacy comparable with that of heparin and glycoprotein IIb/IIIa inhibitors (GPIs). Yet, because of their pro-thrombotic condition, we hypothesized that patients with DM may benefit from more aggressive dual antithrombin and antiplatelet therapy. The aim of this paper was to provide a systematic review comparing outcomes of PCI with bivalirudin versus heparin plus GPI in patients with DM using meta-analytical techniques. Eligible studies needed to have reported a subgroup analysis of outcomes among diabetic patients. Six trials comprising 5924 diabetic patients were eligible. At 30 days, bivalirudin was associated with a reduction in net adverse cardiac events [relative risk (RR) 0.81, 95 % confidence interval (CI) 0.70-0.93, p = 0.002] and major bleeds (RR 0.68, 95 % CI 0.49-0.95; p = 0.02), with no difference in composite ischemia (RR 0.92, 95 % CI 0.74-1.14; p = 0.43) or mortality (RR 0.71, 95 % CI 0.45-1.13; p = 0.15). At 1 year, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.73, 95 % CI 0.54-1.00, p = 0.05) despite similar composite ischemia (RR 1.02, 95 % CI 0.56-1.21, p = 0.811). In conclusion, thrombin inhibition with bivalirudin alone was associated with reduced 30-day major bleeding and 1-year all-cause mortality compared with heparin plus GPI in diabetic patients undergoing PCI.

Local anesthetic systemic toxicity (LAST) occurrence may cross several medical specialties. In 2010, the American Society of Regional Anesthesia and Pain Medicine (ASRA) published the first algorithm on LAST management, introducing the use of lipid emulsion (ILE) treatment. In the present study, we retrieved the cases of LAST published between ASRA guidelines dissemination and March 2014. We analyzed the reported clinical manifestations of LAST, characteristics of affected patients, onset time of toxicity, and clinical setting. We also focused on the treatment measures that were applied in the different cases, especially on the use of ILE and adherence to ASRA recommendations. Despite the limits of a review of case reports, the present study calls attention to the insidious nature of LAST, especially its atypical manifestations, and shows that ILE may currently be underadministered in daily clinical practice, especially in nonanesthesiology practice.

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A&ndash, D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p &lt, 0.001) and neprilysin levels (p &lt, 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p &lt, 0.05, cardiac output, p &lt, 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p &lt, 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p &lt, 0.001) and prolonged survival (p &lt, 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.

Object The authors hypothesized that cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury and, if so, further hypothesized that hypothermia induction before or soon after craniotomy should be associated with improved outcomes. Methods The National Acute Brain Injury Study: Hypothermia I (NABIS:H I) was a randomized multicenter clinical trial of 392 patients with severe brain injury treated using normothermia or hypothermia for 48 hours with patients reaching 33°C at 8.4 ± 3 hours after injury. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) was a randomized, multicenter clinical trial of 97 patients with severe brain injury treated with normothermia or hypothermia for 48 hours with patients reaching 35°C within 2.6 ± 1.2 hours and 33°C within 4.4 ± 1.5 hours of injury. Entry and exclusion criteria, management, and outcome measures in the 2 trials were similar. Results In NABIS:H II among the patients with evacuated intracranial hematomas, outcome was poor (severe disability, vegetative state, or death) in 5 of 15 patients in the hypothermia group and in 9 of 13 patients in the normothermia group (relative risk 0.44, 95% CI 0.22–0.88; p = 0.02). All patients randomized to hypothermia reached 35°C within 1.5 hours after surgery start and 33°C within 5.55 hours. Applying these criteria to NABIS:H I, 31 of 54 hypothermia-treated patients reached a temperature of 35°C or lower within 1.5 hours after surgery start time, and the remaining 23 patients reached 35°C at later time points. Outcome was poor in 14 (45%) of 31 patients reaching 35°C within 1.5 hours of surgery, in 14 (61%) of 23 patients reaching 35°C more than 1.5 hours of surgery, and in 35 (60%) of 58 patients in the normothermia group (relative risk 0.74, 95%, CI 0.49–1.13; p = 0.16). A meta-analysis of 46 patients with hematomas in both trials who reached 35°C within 1.5 hours of surgery start showed a significantly reduced rate of poor outcomes (41%) compared with 94 patients treated with hypothermia who did not reach 35°C within that time and patients treated at normothermia (62%, p = 0.009). Conclusions Induction of hypothermia to 35°C before or soon after craniotomy with maintenance at 33°C for 48 hours thereafter may improve outcome of patients with hematomas and severe traumatic brain injury. Clinical trial registration no.: NCT00178711.

To optimize the reduction of the drag area coefficient of a speed skater, mannequins in static positions wearing suits were tested in the NRC 2m × 3m Wind Tunnel to find the lowest drag for a given range of speeds. The results obtained from this study can only be interpreted and applied to a speed skater if the aerodynamic drag coefficient is not affected significantly by the motion of the skater. It has been assumed that, for a representative cadence or frequency of oscillation of a speed skater lower than 1 Hz which is representative of the motion in a race, the aerodynamics could be considered quasi-stationary. The quasi-steady state is defined by the flow that developed around the body and the wake both governing the aerodynamic drag compared to the contribution of the low frequency of oscillation of the body. To verify this hypothesis and to determine to what extent the quasi-steady assumption is valid for a human body in a speed skating position, a study was carried out in a wind tunnel using a moving life-size mannequin. A mechanism was devised so that a mannequin in a sidepush position could be oscillated to mimic the sinusoidal path of a speed skater. The amplitude of motion was kept constant and the frequencies of oscillation and wind speeds were changed to cover the equivalent of 500 m to 10,000 m races. The experiments have revealed that the variations of the drag area coefficient with wind speed were similar for static positions and for cases where the mannequin was oscillating at frequencies lower than 0.67 Hz or for a period of rotation of 1.5 s. The drag reduction occurred at the same wind speeds for the static and dynamic cases. This paper presents details of the experiments and a summary of the main findings. © 2012 Published by Elsevier Ltd., 9th Conference of the International Sports Engineering Association, ISEA 2012, July 9-13, 2012, Lowell, MA

The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers.Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed.All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects.Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl.

In this paper, we theorize about nonmarket performance outcomes in contentious environments, i.e. in settings that are characterized by stakeholder disapproval targeting the firm and by social move...

The classic description of local anesthetic systemic toxicity (LAST) generally described in textbooks includes a series of progressively worsening neurologic symptoms and signs occurring shortly after the injection of local anesthetic and paralleling progressive increases in blood local anesthetic concentration, culminating in seizures and coma. In extreme cases, signs of hemodynamic instability follow and can lead to cardiovascular collapse. To characterize the clinical spectrum of LAST and compare it to the classic picture described above, we reviewed published reports of LAST during a 30-year period from 1979 to 2009. Ninety-three cases were identified and analyzed with respect to onset of toxicity and the spectrum of signs and symptoms. Sixty percent of cases followed the classic pattern of presentation. However, in the remainder of cases, symptoms were substantially delayed after the injection of local anesthetic, or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity. Although information gained from retrospective case review cannot establish incidence, outcomes, or comparative efficacies of treatment, it can improve awareness of the clinical spectrum of LAST and, theoretically, the diagnosis and treatment of affected patients. The analytic limitations of our method make a strong case for developing a prospective, global registry of LAST as a robust alternative for educating practitioners and optimizing management of LAST.

The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity.

Severe, systemic local anesthetic toxicity is arguably the most feared complication of regional anesthesia. A combination of old and new therapies is recommended to reduce the morbidity and mortality of symptomatic local anesthetic overdose. Prevention remains the criterion standard for improving patient safety during regional anesthesia. However, when local anesthetic toxicity occurs, considering the diagnosis is the doctor's first step to successful treatment. Preparing a plan of action ahead of time and having the necessary tools readily at hand will likewise contribute to saving the patient's life. Airway management, oxygenation, ventilation, and good basic life support are the sine qua non of successful resuscitation. Seizure suppression is key, and we recommend communicating with a perfusion team for possible cardiopulmonary bypass. Lipid infusion should be considered early, and the treating physician should be familiar with the method. We also recommend avoiding vasopressin and using epinephrine only in small doses. Vigilance, preparedness, and quick action will improve outcomes of this dreaded complication.

The purpose of this study was to investigate the effects of non-contact therapeutic touch on post-surgical pain in an elderly population receiving occupational therapy in an acute care hospital unit in the United States. Ninety participants were randomly assigned to three groups (experimental, control and placebo) using a three-group experimental pre-test-post-test design and a randomized clinical trial. The experimental group received the non-contact touch intervention, the control group received routine care and the placebo group received the sound of a metronome set at a steady slow pace. Objective measures included the Memorial Pain Scale, the Tellegen Absorption Scale, the Health Attribution Scale and measures of pulse rate and pupil size, which were performed as repeated measures. In the experimental group, 22 out of 30 (73%) demonstrated a statistically significant decrease in pain intensity scores from pre-test to post-test (t [7] = 7.24, p < 0.01) and were better able to participate in occupations. Further research is recommended to replicate this study.