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The charge or, so it would seem, the plaudit of being a liberal - somehow, vaguely on account of Hegel - seems nonetheless to be the focus of Alexander H. Shapiro's book on, of all Wagner's works, I Götterdämmerung i . Shapiro has stern words for Wagner scholars who see Bakunin, Schopenhauer, or even both ( I mea culpa i ) in the final conflagration or, indeed, in anything leading up to it. "Was Hegel a liberal?". [Extracted from the article]

With the objective of trying to understand the adaptability of agriculture across the Canadian Prairies under climate change, simple‐to‐use agroclimatic indices were calculated for the base climate period of 1981 to 2010 and for both the medium (RCP4.5) and high (RCP8.5) emission projections extending to the distant future (2071–2100). The agroclimatic indices included the Effective Growing Degree Days (EGDDs), Growing Season Length (GSL), the Climate Moisture Index (CMI), and the Temperature Humidity Index (THI). For climate change in 30‐year periods, these indices were calculated as multi‐model ensembles of six Global Climate Models recommended under the Coupled Model Intercomparison Project Phase 5 (CMIP5) for the study area. We found that the GSL, EGDDs, CMI, and THI were amplified above the values of the base climate period in the order of 40–50 days, 600–1200 heat units, −100 to −120 mm and 3–4 THI units by the close of the distant future (2071–2100) under the RCP4.5 and RCP8.5, respectively. This amplification has implications on where crop and livestock production could become more suitable or riskier in future. Opportunities include expanding crop and livestock production to more northerly regions which currently have insufficient heat units, a short growing season and unfavourable temperature humidity thresholds for livestock production. Moisture deficits will continue to be the greatest risk during the growing season under climate change scenarios but options exist to implement adaptive measures such as staggering seeding times to take advantage of moisture availability in the spring and autumn seasons and crop substitution. This study has relevance for policy and program formulation and implementation in Canada's agricultural regions and potentially, other areas of the world with similar climate change outcomes. [ABSTRACT FROM AUTHOR]

The article presents the text of the speech by barrister Dr. Mark Berry delivered to the Law and Economics Association of New Zealand in Auckland on March 10, 2020, and in Wellington on March 11, 2020. Among the issues he discussed include a reflection on his time as Chairman of New Zealand Commerce Commission (NZCC) from 2009-2019, the institutional design issues facing the NZCC, and the central policy issue arising from the NZME Ltd. v. Commerce Commission (NZME/Fairfax) merger decision.

Introduction: The use of debating as an educational tool is increasing in popularity. Students who take part in debates can develop a range of skills such as confidence and communication as well as gaining a greater understanding of the topic discussed. Within this study we have evaluated an antibiotic-resistant debate kit, assessing the ability of the debate lesson to improve student knowledge and awareness around antibiotics. Methods: The debate lesson was delivered in seven schools across South West England to 235 students aged 13-16 years. Change in student knowledge was measured using before and after knowledge questionnaires. Student and teacher feedback and suggestions for improvements for the lesson were also collected through questionnaires and interviews. Results: Quantitative questionnaires found a significant improvement in knowledge for most areas covered in the debate, particularly around the use of antibiotics to treat colds and bacteria developing resistance. Teachers felt their students engaged well with the debate session and made suggestions for minor modifications that could improve the lesson. Conclusions: The results suggest that the e-Bug antibiotic resistant debate kit is able to improve knowledge in young people around antibiotics and antibiotic resistance. Furthermore, the lesson was enjoyed by students and therefore this resource should be promoted more widely to teachers and schools. [ABSTRACT FROM AUTHOR]

When evaluating the real-world treatment effect, the analysis based on randomized clinical trials (RCTs) often introduces generalizability bias due to the difference in risk factors between the trial participants and the real-world patient population. This problem of lack of generalizability associated with the RCT-only analysis can be addressed by leveraging observational studies with large sample sizes that are representative of the real-world population. A set of novel statistical methods, termed “genRCT”, for improving the generalizability of the trial has been developed using calibration weighting, which enforces the covariates balance between the RCT and observational study. This paper aims to review statistical methods for generalizing the RCT findings by harnessing information from large observational studies that represent real-world patients. Specifically, we discuss the choices of data sources and variables to meet key theoretical assumptions and principles. We introduce and compare estimation methods for continuous, binary, and survival endpoints. We showcase the use of the $R$R package $genRCT$genRCT through a case study that estimates the average treatment effect of adjuvant chemotherapy for the stage 1B non-small cell lung patients represented by a large cancer registry. [ABSTRACT FROM AUTHOR]

The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders. [ABSTRACT FROM AUTHOR]

The use of physiological response endpoints in environmental monitoring represents an opportunity to provide an integrated picture of health status and ecological fitness of individuals, and may provide an indication of potential longer term effects on aquatic organisms in the environment. The feeding behavior response sensitivity of blue mussels (Mytilus edulis) of differing size to dispersed crude oil (DCO) was investigated in a lab exposure experiment. The ability of mussels to recover following a single exposure was also investigated, as well as the response to consecutive exposures, in order to assess the utility of employing the same individuals in chronic environmental monitoring. Feeding physiology was assessed by measuring retention efficiency and filtration rate of individual mussels in a live-algae feeding assay. In addition, the percentage of mussels actively filtering during testing was calculated. The feeding physiology parameters were sensitive and able to discriminate exposed mussels from controls. Further, data indicated that larger mussels appear more suitable in environmental monitoring, as these animals showed both sensitivity and an ability to adapt and recover from exposure while remaining sensitive to subsequent treatments. Smaller mussels were also sensitive to the measured endpoints, even if these animals suffered higher rates of mortality during the exposure. Finally, when exposed to the high concentration of DCO, mussels displayed a tendency to close the valves and terminate filtration. [ABSTRACT FROM PUBLISHER]

We study here the permeability of the hydrophobic O2 molecule through a model DPPC bilayer at 323K and 350K, and of the trace amine p-tyramine through PC bilayers at 310K. The tyramine results are compared to previous experimental work at 298K. Nonequilibrium work methods were used in conjunction to simultaneously obtain both the potential of mean force (PMF) and the position dependent transmembrane diffusion coefficient, D(z), from the simulations. These in turn were used to calculate the permeability coefficient, P, through the inhomogeneous solubility-diffusion model. The results for O2 are consistent with previous simulations, and agree with experimentally measured P values for PC bilayers. A temperature dependence in the permeability of O2 through DPPC was obtained, with P decreasing at higher temperatures. Two relevant species of p-tyramine were simulated, from which the PMF and D(z) were calculated. The charged species had a large energetic barrier to crossing the bilayer of ~ 21 kcal/mol, while the uncharged, deprotonated species had a much lower barrier of ~ 7 kcal/mol. The effective in silico permeability for p-tyramine was calculated by applying three approximations, all of which gave nearly identical results (presented here as a function of the pKa). As the permeability value calculated from simulation was highly dependent on the pKa of the amine group, a further pKa study was performed that also varied the fraction of the uncharged and zwitterionic p-tyramine species. Using the experimental P value together with the simulated results, we were able to label the phenolic group as responsible for the pKa 1 and the amine for the pKa 2, that together represent all of the experimentally measured pKa values for p-tyramine. This agrees with older experimental results, in contrast to more recent work that has suggested there is a strong ambiguity in the pKa values. [ABSTRACT FROM AUTHOR]

The article reviews the operas "Tannhäuser und der Sängerkrieg auf Wartburg," performed by Peter Seiffert, Ann Petersen and Peter Mattei, and "Parsifal," performed by Stefan Vinke, Evelyn Herlitzius and Bo Skovhus.

The article reviews the opera "Das Liebesverbot," composed by Richard Wagner, performed by the Leipzig Opera company in Germany on October 13, 2013.

The article examines a critical essay done by German sociologist Theodor W. Adorno concerning German composer Richard Wagner and its relation to German philosopher Friedrich Nietzsche. Topics discussed include the special responsibility of Wagner with respect to musical fatalism according to Adorno, Wagner's Romantic organicism, and the views of Adorno that Wagner's own linguistic usage was more sophisticated compared to his aesthetics of unmediated unity.

ABSTRACT Both pre- and post-synaptic effects of trace amines have been demonstrated. The putative intracellular location of Trace Amine-Associated Receptors necessitate that membrane transport processes be present in order for post-synaptic effects to occur. Here we examine the ability of trace amines to cross synthetic (Fluorosomes) and native (synaptosomes) lipid bilayer membranes. Trace amines readily crossed Fluorosome membranes by simple diffusion, p-tyramine ( P = 0.01) and tryptamine ( P = 0.0004) showing significantly faster diffusion than dopamine and 5-HT, respectively, with diffusion half-lives of 13.5 ± 4.1 ( p-tyramine) and 6.8 ± 0.7 seconds (tryptamine). Similarly, release of [3H] p-tyramine and [3H]2-phenylethylamine from pre-loaded synaptosomes occurred significantly quicker than did [3H]dopamine ( P = 0.0001), with half lives of 38.9 ( p-tyramine), 7.8 (2-phenylethylamine) and 133.6 seconds (dopamine). This was, however, significantly slower than the diffusion mediated passage across Fluorosome membranes ( P = 0.0001), suggesting a role for transporters in mediating trace amine release. Further, a pronounced shoulder region was observed in the synaptosome [3H] p-tyramine release curve, suggesting that multiple processes regulate release. No such shoulder region was present for [3H]dopamine release. Surprisingly, both [3H] p-tyramine ( P = 0.001) and [3H]2-phenylethylamine ( P = 0.0001) release from synaptosomes was significantly decreased under depolarizing conditions. As expected, depolarization significantly increased [3H]dopamine release. The data presented indicate that the release of p-tyramine and 2-phenylethylamine from neuronal terminals occurs by a different mechanism than dopamine, and does not involve classical exocytosis. The data are consistent with an initial release of trace amines by simple diffusion, followed by an activity-dependent regulation of synaptic levels via one or more transporter proteins. Synapse 67:656-667, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: Men who have sex with men (MSM) are at high risk for HIV infection. MSM in Central Asia, however, are not adequately studied to assess their risk of HIV transmission. Methods: This study used respondent driven sampling methods to recruit 400 MSM in Almaty, the largest city in Kazakhstan, into a cross-sectional study. Participation involved a one-time interviewer- administered questionnaire and rapid HIV screening test. Prevalence data were adjusted for respondent network size and recruitment patterns. Multivariate logistic regression was used to investigate the association between HIV and selected risk factors, and unprotected anal intercourse (UAI) and selected risk factors. Results: After respondent driven sampling (RDS) weighted analysis, 20.2% of MSM were HIV-positive, and 69.0% had unprotected sex with at least one male partner in the last 12 months. Regression analysis showed that HIV infection was associated with unprotected receptive anal sex (AOR: 2.00; 95% CI: 1.04-3.84). Having unprotected anal intercourse with male partners, a measure of HIV risk behaviors, was associated with being single (AOR: 0.38; 95% CI: 0.23- 0.64); very difficult access to lubricants (AOR: 11.08; 95% CI: 4.93-24.91); STI symptoms (AOR: 3.45; 95% CI: 1.42-8.40); transactional sex (AOR: 3.21; 95% CI: 1.66-6.22); and non-injection drug use (AOR: 3.10; 95% CI: 1.51-6.36). Conclusions: This study found a high HIV prevalence among MSM in Almaty, and a population of MSM engaging in multiple high-risk behavior in Almaty. Greater access to HIV education and prevention interventions is needed to limit the HIV epidemic among MSM in Almaty. [ABSTRACT FROM AUTHOR]

OBJECTIVES Lobectomy with an en-bloc chest wall resection is an effective but potentially morbid treatment of lung cancer invading the chest wall. Minimally invasive approaches to lobectomy have reduced morbidity compared with thoracotomy for early stage lung cancer, but there is insufficient evidence regarding the feasibility of hybrid thoracoscopic lobectomy chest wall resection. We reviewed our experience with an en-bloc chest wall resection and lobectomy to evaluate the outcomes of a hybrid approach using thoracoscopic lobectomy combined with the chest wall resection where rib spreading is avoided. METHODS All patients who underwent lobectomy and en-bloc chest wall resection with ribs for primary non-small cell lung cancer from January 2000 to July 2010 were reviewed. Starting in April 2003, a hybrid approach was introduced where thoracoscopic techniques were utilized to accomplish the pulmonary resection and a limited counter incision was used to perform the en-bloc resection of the chest wall, avoiding scapular mobilization and rib spreading. Preoperative, perioperative and outcome variables were assessed using the standard descriptive statistics. RESULTS During the study period, 105 patients underwent en-bloc lobectomy and chest wall resection, including 93 patients with resection via thoracotomy and 12 patients with resection via the hybrid thoracoscopic approach. Complete resection was achieved in all patients in both groups. Tumour size and the extent of resection were similar in the two groups. There were no conversions and no perioperative mortality in the hybrid group. Post-operative outcomes were similar, although patients who underwent the hybrid approach had a shorter length of stay (P = 0.03). CONCLUSIONS A hybrid approach that combines thoracoscopic lobectomy and chest wall resection is feasible and effective in selected patients. The use of a limited counter incision without rib spreading does not compromise oncologic efficacy. Further experience is needed to determine if this approach provides any advantage in outcomes, including post-operative morbidity. [ABSTRACT FROM AUTHOR]

2-Phenylethylamine (PE) potentiates neuronal responses to dopamine by an unknown post-synaptic mechanism. Here, whether PE modifies D1-like receptor binding was examined. An unexpected effect of the monoamine oxidase inhibitor pargyline was observed, which did not involve competition for ligand binding. PE did not affect ligand binding in the presence or absence of pargyline. It is concluded that the effect of pargyline does not involve elevation of endogenous PE, and PE effects on dopaminergic neurotransmission are not due to altered D1-like receptor binding. [ABSTRACT FROM AUTHOR]

Trace amines are endogenous compounds, typified by 2-phenylethylamine (PE) and p-tyramine (TA), found in the vertebrate central nervous system. Although synthesized in pre-synaptic terminals, trace amines do not appear to act as neurotransmitters, but rather modulate responsivity to co-existing neurotransmitters. Trace amines are neither actively accumulated in synaptic vesicles, nor released in an activity-dependent manner. Further, Trace Amine-Associated Receptor 1 (TAAR1), which is selectively activated by PE and TA, is intracellular. As such, PE and TA need to cross cell membranes in order to exert their effects. This has been assumed to occur by simple diffusion, but has not previously been systematically examined. Experimental data were obtained using Fluorosome technology. A permeability coefficient of 25.3 ± 3.8 Å/s ( n = 6) was obtained for TA which was not significantly different from that obtained for the monoamine neurotransmitter noradrenaline (20.3 ± 3.8 Å/s, n = 8). PE was unsuitable for use with this system. We have also used molecular dynamics computer simulation techniques to determine the potential of mean force (PMF) associated with trace amine passage across lipid bilayers. A PMF peak barrier of 25 ± 6 kcal/mol (protonated) and 13 ± 1 kcal/mol (deprotonated) was obtained for PE. Protonated TA peak energy barriers were even greater at 31 ± 1 kcal/mol. Application of a homogeneous solubility-diffusion model combining the measured permeability coefficients and simulated PMF allows fitting of the diffusion coefficient for trace amines in the hydrophobic region of the lipid bilayer. The diffusion coefficients in other regions of the membrane were found to make negligible contributions to the permeability coefficient for the calculated PMF. The fit obtained a value for the diffusion coefficient of (163 ± 25) × 10 m/s for TA in the hydrophobic core region. The diffusion coefficient for TA in the aqueous compartment was also calculated directly by simulation yielding a value of (0.62 ± 0.26) × 10 m/s. The adopted simulation methods failed to yield diffusion coefficients in the core region indicating that further work will be required to accurately predict permeability coefficients for trace amines passing through membranes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Age is an important risk factor for morbidity after lung resection. This study was performed to identify specific risk factors for complications after lung resection in octogenarians. Methods: A prospective database containing patients aged 80 years or older, who underwent lung resection at a single institution between January 2000 and June 2009, was reviewed. Preoperative, histopathologic, perioperative, and outcome variables were assessed. Morbidity was measured as a patient having any perioperative event as defined by the Society of Thoracic Surgeons General Thoracic Surgery Database. A multivariable risk model for morbidity was developed using a panel of established preoperative and operative variables. Survival was calculated using the Kaplan–Meier method. Results: During the study period, 193 patients aged 80 years or older (median age 82 years) underwent lung resection: wedge resection in 77, segmentectomy in 13, lobectomy in 96, bilobectomy in four, and pneumonectomy in three. Resection was accomplished via thoracoscopy in 149 patients (77%). Operative mortality was 3.6% (seven patients) and morbidity was 46% (89 patients). A total of 181 (94%) patients were discharged directly home. Postoperative events included atrial arrhythmia in 38 patients (20%), prolonged air leak in 24 patients (12%), postoperative transfusion in 22 patients (11%), delirium in 16 patients (8%), need for bronchoscopy in 14 patients (7%), and pneumonia in 10 patients (5%). Significant predictors of morbidity by multivariable analysis included resection greater than wedge (odds ratio 2.98, p =0.006), thoracotomy as operative approach (odds ratio 2.6, p =0.03), and % predicted forced expiratory volume in 1s (odds ratio 1.28 for each 10% decrement, p =0.01). Conclusions: Octogenarians can undergo lung resection with low mortality. Extent of resection, use of a thoracotomy, and impaired lung function increase the risk of complications. Careful evaluation is necessary to select the most appropriate approach in octogenarians being considered for lung resection. [Copyright &y& Elsevier]

Abstract: The combined thermal load created by exercise and a hot environment is associated with an exaggerated core temperature response. The elevated core temperature is believed to increase the total stress of the exercise. Increased stress during exercise has been associated with increased levels of cortisol. The association of cortisol with increased inflammatory responses following exercise in the heat is equivocal. Thus, the purpose of the current investigation was to explore the relationship between increases in rectal temperature (T re) and TNFα and cortisol. To induce T re changes, 8 male subjects (mean±SD, age=23.6±2yr, VO2max=52.8±3.7mL/kg/min, BMI=24.2±1.9) participated in two 40min trials of cycle ergometry at 65% of VO2peak immersed to chest level in cool (25°C) and warm (38.5°C) water. T re was monitored throughout each trial, with blood samples taken immediately pre and post of each trial. Neither cortisol nor TNFα changed significantly during exercise in the cool water; however, in the warm trial, both cortisol and TNFα significantly increased (p<0.004). Concordance correlations (R c) between Δcortisol and ΔTNFα indicated a strong but non-significant correlation (R c=0.833, p=0.135). In conclusion, changes in core temperature may be impacting the relationship between exercise induced changes in cortisol and TNFα. Therefore, acute moderate-intensity exercise (40min or less) in warm water impacts the stress and inflammatory response. Understanding this is important because exercise load may need to be adjusted in warm and hot environments to avoid the negative effects of elevated stress and inflammation response. [ABSTRACT FROM AUTHOR]

The article discusses the transcendental aspect of the opera "Parsifal," by Richard Wagner. It states that the opera represents a climax of ideology with concern on Christianity and allows exploration of cyclical and teleological aspects. It also notes that the opera's Hegelian characterization remains helpful in considering the conflict between time and eternity. It mentions the developing idea of the opera.

The article focuses on the composers who write romantic modernism music. In various ways, Wilhelm Furtwängler and Theodor W. Adorno both stand as two of the twentienth century's most important and controversial musicians. As composers, their understanding of composition has enabled them to understand musical works from the inside. Adorno has become the preeminent theorist of musical modernism and its dialectical adversary known as the culture industry.

This essay follows Schoenberg's path from Die Jakobsleiter to Moses und Aron, with particular reference to these works and to his spoken drama, Der biblische Weg. Schoenberg's development may be summarized in general terms as leading from the religious syncretism of Die Jakobsleiter, via Zionism (Der biblische Weg), to the 'negative monotheism' of Moses und Aron. It is a journey strongly influenced by Schoenberg's German, Lutheran inheritance, his Judaism, and, most importantly, the problematical yet productive interplay between these influences. An alternative understanding of this path, centred on the compositional and philosophical dialectic between freedom and organization, is also examined, in the context of the claim that these are ultimately two formulations of the same problem. These dialectics are played out in an arena that is theological, political, and aesthetic, questioning the acceptability and indeed possibility of artistic representation and 'effect'. Such questioning is in turn related to broader issues concerning modernism. [ABSTRACT FROM AUTHOR]

Abstract: A general multivariate procedure for assessing the similarity of dissolution and drug release profiles was developed. A mathematical model is fit to the data, and Hotelling''s T 2 test is used to calculate the joint confidence region around the vector of differences between least-squares estimates of the parameters in the model. The method of Lagrange multipliers is used to determine if this confidence region is enclosed within a predetermined similarity region, and profile similarity is claimed if this is the case. The first-order, Gompertz, logistic, second-order, and Weibull models were fit to the in vitro extended-release profile of pseudoephedrine HCl from an asymmetric membrane (AM) film-coated osmotic tablet. The first-order model was selected because of its simplicity and because it was the best-fitting model according to a modified form of Akaike''s Information Criterion. A nonlinear response surface model was also developed so that the formulator could calculate how much of the AM film coat should be applied in order to obtain the desired drug release profile. The usefulness of this model-dependent procedure was further demonstrated during an analytical method transfer exercise, where it was used to compare the drug release profiles obtained by two independent laboratories; additional research is required, however, before the appropriate acceptance criteria for demonstrating profile similarity can be recommended. [Copyright &y& Elsevier]

Abstract: Background: Recurrent incisional hernia repair is associated with high recurrence and wound complication rates. Methods: The clinical courses of patients who underwent recurrent incisional hernia repair via retromuscular mesh placement with concomitant panniculectomy at a university teaching hospital from 1999 to 2004 were reviewed retrospectively. Postoperative evaluation included a quality of life survey. Results: Forty-seven patients (13 male, 34 female) with an average body mass index of 34.4 kg/m2, an average midline hernia defect of 31.4 cm, and at least 1 and on average 2.5 previous repair attempts underwent hernia repair. Wound infections occurred in 4 patients (8%) and seromas requiring aspiration occurred in 1 patient (2%). Four patients (8%) had re-recurrences of their hernias. All patients rated the postoperative appearance of their abdomen as at least satisfactory. Conclusions: Recurrent incisional hernia repair with a retromuscular mesh and panniculectomy has low recurrence and wound complication rates and excellent patient satisfaction. [Copyright &y& Elsevier]

Abstract: During development of solid dosage products, a pharmaceutical manufacturer is typically required to propose dissolution acceptance criteria unless the product falls into Biopharmaceutics Classification System (BCS) class I, in which case a disintegration test may be used. At the time of filing the new drug application (NDA) or common technical document (CTD), the manufacturer has already met with regulatory agencies to discuss and refine dissolution strategy. The dissolution acceptance criteria are based on stability and batch history data and are often arrived at by considering the percentage of batches that pass United States Pharmacopeia (USP) criteria at Stage 1 (S1), when in fact, the product is deemed unacceptable only when a batch fails USP criteria at Stage 3 (S3) [H. Saranadasa, Disso. Technol. 7 (2000) 6–7, 18 ]. Calculating the probability of passing (or failing) dissolution criteria at S1, S2, or S3 can assist a manufacturer in determining appropriate acceptance criteria. This article discusses a general statistical method that was developed to assess the probability of passing the multistage USP test for dissolution and how it was applied to an immediate release tablet formulation. In this case, acceptance criteria were set and the analysis was conducted to assess the probabilities of passing or failing based on this acceptance criterion. Whether the acceptance criteria were relevant to the product was also considered. This mathematical approach uses a Monte Carlo simulation and considers a range of values for standard deviation and mean of historical data. [Copyright &y& Elsevier]

Background: Heart failure occurs predominantly due to coronary artery disease and may be amenable to novel revascularization therapies. This study evaluated the effects of placental growth factor (PlGF), a potent angiogenic agent, in a rat model of ischemic cardiomyopathy. Methods: Wistar rats underwent high proximal ligation of the left anterior descending coronary artery and direct injection of PlGF (n = 10) or saline as a control (n = 10) into the myocardium bordering the ischemic area. After 2 weeks, the following parameters were evaluated: ventricular function with an aortic flow probe and a pressure/volume conductance catheter, left ventricular (LV) geometry by histology, and angiogenesis by immunofluorescence. Results: PlGF animals had increased angiogenesis compared to controls (22.8 ± 3.5 vs. 12.4 ± 3.2 endothelial cells/high-powered field, p < 0.03). PlGF animals had less ventricular cavity dilation (LV diameter 8.4 ± 0.2 vs. 9.2 ± 0.2 mm, p < 0.03) and increased border zone wall thickness (1.85 ± 0.1 vs. 1.38 ± 0.2 mm, p < 0.03). PlGF animals had improved cardiac function as measured by maximum LV pressure (95.7 ± 4 vs. 73.7 ± 2 mmHg, p = 0.001), maximum dP/dt (4206 ± 362 vs. 2978 ± 236 mmHg/sec, p = 0.007), and ejection fraction (25.7 ± 2 vs. 18.6 ± 1%, p = 0.02). Conclusions: Intramyocardial delivery of PlGF following a large myocardial infarction enhanced border zone angiogenesis, attenuated adverse ventricular remodeling, and preserved cardiac function. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure. [ABSTRACT FROM AUTHOR]

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) causes myocardial extracellular matrix remodeling and fibrosis in myocardial infarction and chronic heart failure models. Pre-clinical and clinical trials of TNF inhibition in chronic heart failure have shown conflicting results. This study examined the effects of the administration of a TNF inhibitor immediately after myocardial infarction on the development of heart failure.Lewis rats underwent coronary artery ligation and then received either intravenous etanercept (n = 14), a soluble dimerized TNF receptor that inhibits TNF, or saline as control (n = 13). Leukocyte infiltration into the infarct borderzone was evaluated 4 days post-ligation in 7 animals (etanercept = 4, control = 3). After 6 weeks, the following parameters were evaluated in the remaining animals: cardiac function with a pressure-volume conductance catheter, left ventricular (LV) geometry, and borderzone collagenase activity.Etanercept rats had significantly less borderzone leukocyte infiltration 4 days post-infarction than controls (10.7 ± 0.5 vs 18.0, ±2.0 cells/high power field; p < 0.05). At 6 weeks, TNF inhibition resulted in significantly reduced borderzone collagenase activity (110 ± 30 vs 470 ± 140 activity units; p < 0.05) and increased LV wall thickness (2.1 ± 0.1 vs 1.8 ± 0.1 mm, p < 0.05). Etanercept rats had better systolic function as measured by maximum LV pressure (84 ± 3 mm Hg vs 68 ± 5 mm Hg, p < 0.05) and the maximum change in left ventricular pressure over time (maximum dP/dt) (3,110 ± 230 vs 2,260 ± 190 mm Hg/sec, p < 0.05), and better diastolic function as measured by minimum dP/dt (−3,060 ± 240 vs −1,860 ± 230 mm Hg/sec; p < 0.05) and the relaxation time constant (14.6 ± 0.6 vs 17.9 ± 1.2 msec; p < 0.05).TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function. [Copyright &y& Elsevier]

This article outlines Richard Wagner's conception of music-drama during the period in which he formulated his intentions for composition of the epic Ring of the Nibelung. Attempting to renew rather than to restore the communal, political nature of Attic tragedy, he wished to transform that model from celebration of the Athenian political order into a savage critique of the contemporary political order, indeed into an incitement to and celebration of revolution. Wagner was determined to restore the dignity of art, a dignity he believed to have been lost in the pursuit of base, commercial considerations; but this determination should not be confused with the idea of art for art's sake. Instead, he wished to renew art in a socialist, even communist, sense as the paradigm of free, productive activity. The direct revolutionary experience of participation in the Dresden uprising of 1849 bolstered his conviction of the necessity of such a transformation. With his magnum opus, Wagner wrote, he intended to ‘make clear to the men of the Revolution the meaning of that Revolution, in its noblest sense’. [ABSTRACT FROM AUTHOR]

Recent articles have highlighted numerous additional functions of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that are independent of its well-documented glycolytic function. One of the most intriguing of these functions is as an initiator of programmed cell death cascades. This activity involves a nuclear appearance of GAPDH, a considerable proportion of which requires synthesis of new GAPDH protein and has characteristics suggesting the involvement of a novel isozyme. The relevance of such findings to human neurodegenerative conditions is emphasized by the increased nuclear GAPDH observed in post- mortem samples from patients with Parkinson's disease, Alzheimer's disease, Huntington's disease and glaucoma, among others. A number of small-molecule compounds have now been identified that show anti-apoptotic activity because of their ability to interact with GAPDH and prevent its nuclear accumulation. These compounds, one of which is currently being tested in late-stage Phase II clinical trials as a disease-modifying therapy for Parkinson's disease, have potential utility in the treatment of human neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter. [ABSTRACT FROM AUTHOR]

Many inhibitors of monoamine oxidase, particularly those developed during the past three decades, are often referred to as being “selective” for one or other isoform of the enzyme. However true this may be, selectivity within the EC 1.4.3.4 family does not preclude the possibility of interactions of these drugs with other proteins unrelated to monoamine oxidase. Indeed, evidence exists which either suggests or demonstrates directly that many of these inhibitors do interact with, and affect the behaviour of, other enzymes, receptor systems and uptake pumps, with potentially interesting consequences, desirable or otherwise, for the patient or the pharmacologist. An overview of many such interactions, and speculation upon some of the possible consequences, are provided in this review. [Copyright &y& Elsevier]

Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged or unnecessary cells, such as those resulting from DNA damage or during development. There are many factors that contribute to this process, each demonstrating specificity of function, regulation, and pathway involvement. The aim of this brief overview is to provide an introduction to a number of these factors as well as the various apoptotic pathways that have been identified. [Copyright &y& Elsevier]

The preferred management option for intraoperative splenic injuries is organ repair and preservation rather than splenectomy given the important immunologic function of the spleen. Wrapping the injured spleen with a Dexon mesh has been shown to be an effective alternative to splenectomy for significant splenic bleeding. However, this technique uses a foreign body that carries a theoretical infectious risk particularly in cases in which the alimentary tract has been opened. This study was undertaken to evaluate whether Dexon mesh splenorrhaphy when used for intraoperative splenic injuries was associated with significant infectious complications. The clinical courses of 23 patients who had Dexon mesh splenorrhaphy performed at a university teaching hospital for intraoperative splenic injury from 1991 to 1999 were reviewed. Eleven patients (48%) had their gastrointestinal tract opened during the surgery. No patients developed an intra-abdominal abscess or required reoperation for bleeding. The most common postoperative complications were left lower lobe atelectasis (18 patients, 78%), postoperative fever (13 patients, 56%), and left pleural effusion (12 patients, 52%). Dexon mesh splenorrhaphy effectively controls splenic bleeding due to intraoperative injury without significant infectious complications. [ABSTRACT FROM AUTHOR]

Aromatic l-amino acid decarboxylase (AAAD), an enzyme required for the synthesis of catecholamines, indoleamines, and trace amines, is rapidly activated by cyclic AMP-dependent pathways in striatum and midbrain in vivo, suggesting enzyme phosphorylation. We now report that the catalytic subunit of cyclic AMP-dependent protein kinase (PKA) directly phosphorylated AAAD immunoprecipitated from homogenates prepared from the mouse striatum and midbrain in vitro. Under the same phosphorylation conditions, the catalytic subunit of PKA also phosphorylated a recombinant AAAD protein expressed in Escherichia coli transfected with an AAAD cDNA isolated from the bovine adrenal gland. The PKA-induced AAAD phosphorylation of immunoprecipitates from striatum and midbrain was time and concentration dependent and blocked by a specific PKA peptide inhibitor. Incubation of the catalytic subunit of PKA with striatal homogenates increased enzyme activity by ~20% in a time- and concentration-dependent manner. Moreover, incubation of the catalytic subunit of PKA with recombinant AAAD increased activity by ~70%. A direct phosphorylation of AAAD protein by PKA might underlie the cyclic AMP-induced rapid and transient activation of AAAD in vivo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study evaluated the impact of local treatment modalities in the management of large non-small cell lung cancer (NSCLC) tumors using a nationwide population-based dataset. MATERIAL AND METHODS: Patients with NSCLC tumors >7 cm that were cN0-1M0 in the Surveillance, Epidemiology, and End Results (SEER) registry from 2010 to 2015 were stratified by local management strategy (surgery, radiation therapy, no local treatment) and evaluated using Kaplan–Meier survival analyses, Cox proportional-hazard methods, and propensity-matched analysis. RESULTS: A total of 3156 patients were identified, of which 1580 (50.1%) underwent surgical resection, 920 (29.2%) received radiation only, 655 (20.7%) received no local treatment. Overall, the 5-year survival of patients undergoing surgical resection was 40.7%, compared to 14.7% and 5.3% for the radiation only and no local treatment groups, respectively (P < .001). Surgery with or without radiation continued to have an independent association with improved survival in multivariable analysis (HR 0.23, P < .0001). Other factors associated with improved survival included younger age, negative nodal disease, and chemotherapy use. In propensity-matched sub-analyses, 5-year survival remained significantly better after surgery alone compared to radiation alone (38.5% vs. 13.6%, P < .001), while survival after radiation alone was better than no local treatment, though both were largely poor (12.4% vs. 7.5%, P < .001). CONCLUSIONS: Survival of patients with large NSCLC managed non-surgically is very poor. Despite the significant long-term survival benefit with surgical intervention, nearly half of the study cohort did not undergo surgery. Patients and clinicians can use these results to estimate specific potential benefits when considering possible treatment strategies for large NSCLC tumors. [ABSTRACT FROM AUTHOR]

Background Remdesivir has demonstrated benefit in some hospitalized patients with coronavirus disease 2019 (COVID-19) on supplemental oxygen and in nonhospitalized patients breathing room air. The durability of this benefit across time periods with different circulating severe acute respiratory syndrome coronavirus 2 variants of concern (VOC) is unknown. This comparative effectiveness study in patients hospitalized for COVID-19 and not receiving supplemental oxygen at admission compared those starting remdesivir treatment in the first 2 days of admission with those receiving no remdesivir during their hospitalization across different VOC periods. Method Using a large, multicenter US hospital database, in-hospital mortality rates were compared among patients hospitalized for COVID-19 but not requiring supplemental oxygen at admission between December 2020 and April 2022. Patients receiving remdesivir at hospital admission were matched 1:1 to those not receiving remdesivir during hospitalization, using propensity score matching. Cox proportional hazards models were used to assess 14- and 28-day in-hospital mortality rates or discharge to hospice. Results Among the 121 336 eligible patients, 58 188 remdesivir-treated patients were matched to 17 574 unique patients not receiving remdesivir. Overall, 5.4% of remdesivir-treated and 7.3% in the non-remdesivir group died within 14 days, and 8.0% and 9.8%, respectively, died within 28 days. Remdesivir treatment was associated with a statistically significant reduction in the in-hospital mortality rate compared with non-remdesivir treatment (14-day and 28-day adjusted hazard ratios [95% confidence interval], 0.75 [0.68–0.83] and 0.83 [0.76–0.90], respectively). This significant mortality benefit endured across the different VOC periods. Conclusions Remdesivir initiation in patients hospitalized for COVID-19 and not requiring supplemental oxygen at admission was associated with a significantly reduced in-hospital mortality rate. These findings highlight a potential survival benefit when clinicians initiated remdesivir on admission across the dominant variant eras of the evolving pandemic. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that p -tyramine (TYR), an endogenous trace amine-associated receptor 1 agonist, passage across neuronal membranes involves a transporter exhibiting the pharmacological profile of Organic Cation Transporter 2 (OCT2). Since TYR is also a constituent of foodstuffs and produced by the intestinal microbiota, here we have investigated whether similar processes are involved in the passage of 100 nM TYR across apical and basolateral membranes of the Caco-2 human intestinal epithelial cell line. 3H]TYR transport across apical and basolateral membranes of Caco-2 cell monolayers was measured in the presence of inhibitors of TYR metabolizing enzymes. Cellular, apical, and basolateral compartments were collected at various timepoints, TYR concentrations calculated, and transport properties pharmacologically characterized. Apical transport resulted in equimolar accumulation of TYR within cells. Pentamidine (OCT1/OCT2 inhibitor) decreased apical transport (P = 0.001) while atropine (OCT1 inhibitor) had no effect, suggesting apical transport involved OCT2. In contrast, basolateral transport resulted in 500–1000 nM cellular concentrations (P < 0.0001) indicating the presence of an active transporter. Replacement of Na+ on an equimolar basis with choline resulted in loss of TYR transport (P = 0.017). Unexpectedly, this active transport was also atropine-sensitive (P = 0.020). Kinetic analysis of the active transporter revealed V max = 43.0 nM/s with a K t = 33.1 nM. We have demonstrated for the first time that TYR is transported across Caco-2 apical membranes via facilitated diffusion by OCT2, whereas transport across basolateral membranes is by a Na+-dependent, atropine-sensitive, active transporter. Unlabelled Image • p -Tyramine passage across Caco-2 cell membranes involves multiple transporters. • Transport across apical membranes involves Organic Cation Transporter 2. • Basolateral transport occurs via a novel Na+-dependent active transporter. • This suggests plasma p -tyramine levels are tightly regulated to maintain health. [ABSTRACT FROM AUTHOR]

Background: A Medicare effect has been described to account for increased health care utilization occurring at the age of 65 years. The existence of such an effect in cancer care, where it would be most likely to reduce mortality, has been unclear.Methods: Patients aged 61 to 69 years who were diagnosed with lung, breast, colon, or prostate cancer from 2004 to 2016 were identified with the Surveillance, Epidemiology, and End Results database and were dichotomized on the basis of eligibility for Medicare (61-64 vs 65-69 years). With age-over-age (AoA) percent change calculations, trends in cancer diagnoses and staging were characterized. After matching, uninsured patients who were 61 to 64 years old (pre-Medicare group) were compared with insured patients who were 65 to 69 years old (post-Medicare group) with respect to cancer-specific mortality.Results: In all, 134,991 patients were identified with lung cancer, 175,558 were identified with breast cancer, 62,721 were identified with colon cancer, and 238,823 were identified with prostate cancer. The AoA growth in the number of cancer diagnoses was highest at the age of 65 years in comparison with all other ages within the decade for all 4 cancers (P < .01, P < .001, P < .01, and P < .001, respectively). In a comparison of diagnoses at the age of 65 years with those in the 61- to 64-year-old cohort, the greatest difference for all 4 cancers was seen in stage I. In matched analyses, the 5-year cancer-specific mortality was worse for lung (86.3% vs 78.5%; P < .001), breast (32.7% vs 11.0%; P < .001), colon (57.1% vs 35.6%; P < .001), and prostate cancer (16.9% vs 4.8%; P < .001) in the uninsured pre-Medicare group than the insured post-Medicare group.Conclusions: The age threshold of 65 years for Medicare eligibility is associated with more cancer diagnoses (particularly stage I), and this results in lower long-term cancer-specific mortality for all cancers studied.Lay Summary: Contributing to the current debate regarding Medicare for all, this study shows that the expansion of Medicare would improve cancer outcomes for the near elderly. [ABSTRACT FROM AUTHOR]

Background Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods. Methods Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods. Results A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval,.62–.78) and 28 days (HR, 0.75; 95% CI,.68–.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods. Conclusions Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population. [ABSTRACT FROM AUTHOR]

Background: Wixela™ Inhub™ is a fluticasone propionate/salmeterol dry powder inhaler developed as a generic equivalent of Advair Diskus® for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Wixela Inhub and Advair Diskus are comparable in terms of functionality, user interface, and device resistance. The primary objectives of the studies were to evaluate in vitro dose delivery with Wixela Inhub compared with Advair Diskus at relevant flow rates and to explore inhalation profiles generated by patients with asthma or COPD. Methods:In vitro studies: Emitted dose (ED) and individual dose aerodynamic particle size distribution (APSD) were measured at flow rates ranging from 30 to 90 L min−1. Patient inhalation study: Inhalation profile recording was conducted three times in each patient (40 children with asthma, 14 adults with asthma, and 14 adults with severe-to-very-severe COPD) with an empty Inhub in an open-label study. The primary endpoint was peak inhaled flow rate (PIFR). An additional endpoint was peak pressure drop. Results:In vitro studies: ED and APSD delivered from Wixela Inhub showed low flow dependency across the patient-relevant flow-rate range. Wixela Inhub gave in vitro performance comparable with Advair Diskus for all strengths and flow rates. Patient inhalation study: For Inhub, mean PIFR was lowest for children with asthma ages 4 to 7 years (50.6 L min−1) and highest for adults with asthma (74.8 L min−1). For adults with severe-to-very-severe COPD, mean PIFR was 69.5 L min−1 with Inhub. The PIFRs observed with Diskus were higher than those with Inhub, consistent with slightly higher resistance measured in vitro. The difference in resistance did not impact demonstration of bioequivalence and does not impact substitutability of the product. Peak pressure drop values were comparable between Diskus and Inhub. Conclusions: Comparable in vitro performance of Wixela Inhub to Advair Diskus confirmed that Wixela Inhub is a generic equivalent to Advair Diskus across all patient groups. [ABSTRACT FROM AUTHOR]

Background This comparative effectiveness study investigated the effect of remdesivir on in-hospital mortality among patients hospitalized for coronavirus disease 2019 (COVID-19) requiring supplemental oxygen including low-flow oxygen (LFO), high-flow oxygen/noninvasive ventilation (HFO/NIV), or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) across variant of concern (VOC) periods. Methods Patients hospitalized for COVID-19 between December 2020 and April 2022 and administered remdesivir upon admission were 1:1 propensity score matched to patients not administered remdesivir during their COVID-19 hospitalization. Analyses were stratified by supplemental oxygen requirement upon admission and VOC period. Cox proportional hazards models were used to derive adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for 14- and 28-day mortality. Results Patients treated with remdesivir (67 582 LFO, 34 857 HFO/NIV, and 4164 IMV/ECMO) were matched to non-remdesivir patients. Unadjusted mortality rates were significantly lower for remdesivir-treated patients at 14 days (LFO: 6.4% vs. 8.8%; HFO/NIV: 16.8% vs. 19.4%; IMV/ECMO: 27.8% vs. 35.3%) and 28 days (LFO: 9.8% vs. 12.3%; HFO/NIV: 25.8% vs. 28.3%; IMV/ECMO: 41.4% vs. 50.6%). After adjustment, remdesivir treatment was associated with a statistically significant reduction in in-hospital mortality at 14 days (LFO: aHR, 0.72; 95% CI, 0.66–0.79; HFO/NIV: aHR, 0.83; 95% CI, 0.77–0.89; IMV/ECMO: aHR, 0.73; 95% CI, 0.65–0.82) and 28 days (LFO: aHR, 0.79; 95% CI, 0.73–0.85; HFO/NIV: aHR, 0.88; 95% CI, 0.82–0.93; IMV/ECMO: aHR, 0.74; 95% CI, 0.67–0.82) compared with non-remdesivir treatment. Lower risk of mortality among remdesivir-treated patients was observed across VOC periods. Conclusions Remdesivir treatment is associated with significantly reduced mortality among patients hospitalized for COVID-19 requiring supplemental oxygen upon admission, including those requiring HFO/NIV or IMV/ECMO with severe or critical disease, across VOC periods. [ABSTRACT FROM AUTHOR]

Interruption of thoracic epidural analgesia may impact the postoperative course following esophagectomy. This study investigates the incidence and causes of epidural interruption in esophagectomy patients along with associated postoperative outcomes. This single-institution retrospective analysis examined patients undergoing esophagectomy who received a thoracic epidural catheter from 2016 to 2020. Patients were stratified according to whether epidural catheter infusion was interrupted or not postoperatively. Outcomes were compared between the two groups, and predictors of epidural interruption and postoperative complications were estimated using multivariable logistic regression. Of the 168 patients who received a thoracic epidural before esophagectomy, 60 (35.7%) required epidural interruption and 108 (64.3%) did not. Interruption commonly occurred on postoperative day 1 and was due to hypotension 80% of the time. Heart failure (10.0% versus 0.9%, P = 0.009), atrial fibrillation (20.0% versus 3.7%, P = 0.002), preoperative opioid use (30.0% versus 16.7%, P = 0.043), and higher American Society of Anesthesiology classification (88.4% versus 70.4%, P = 0.008) were more prevalent in the epidural interruption cohort. The female gender was associated with epidural interruption on multivariable logistic regression (adjusted odds ratio [AOR] 2.45, P = 0.039). Patients in the epidural interruption cohort had a higher incidence of delirium (30.5% versus 13.9%, P = 0.010), sepsis (13.6% versus 3.7%, P = 0.028), and severe anastomotic leak (18.3% versus 7.4%, P = 0.032). On adjusted analysis, heart disease (AOR 4.26, P = 0.027), BMI <18.5 (AOR 9.83, P = 0.031), and epidural interruption due to hypotension (AOR 3.51, P = 0.037) were associated with severe anastomotic leak. Early epidural interruption secondary to hypotension in esophagectomy patients may be a harbinger of postoperative complications such as sepsis and severe anastomotic leak. Patients requiring epidural interruption due to hypotension should have a low threshold for additional workup and early intervention. [ABSTRACT FROM AUTHOR]

Background: Esophageal perforations historically are associated with significant morbidity and mortality and generally require emergent intervention. The influence of improved diagnostic and therapeutic modalities available in recent years on management has not been examined. This study examined the surgical treatments and outcomes of a modern cohort. Methods: Patients with esophageal perforation management in the 2005-2020 American College of Surgeons National Surgical Quality Improvement Program database were stratified into three eras (2005-2009, 2010-2014, and 2015-2020). Surgical management was classified as primary repair, resection, diversion, or drainage alone based on procedure codes. The distribution of procedure use, morbidity, and mortality across eras was examined. Results: Surgical management of 378 identified patients was primary repair (n=193,51%), drainage (n=89,24%), resection (n=70,18%), and diversion (n=26,7%). Thirty-day mortality in the cohort was 9.5% (n=36/378) and 268 patients (71%) had at least one complication. The median length of stay was 15 days. Both morbidity (Era 1 65% [n=42/60] versus Era 2 69% [n=92/131] versus Era 3 72% [n=135/187], p=0.3) and mortality (Era 1 11% [n=7/65] versus Era 2 9% [n=12/131] versus Era 3 10% [n=19/187], p=0.9) did not change significantly over the three defined eras. Treatment over time evolved such that primary repair was more frequently utilized (43% in Era 1 to 51% in Era 3) while diversion was less often performed (13% in Era 1 to 7% in Era 3) (p=0.009). Conclusions: Esophageal perforation management in recent years uses diversion less often but remains associated with significant morbidity and mortality. [ABSTRACT FROM AUTHOR]

p-Tyramine is an archetypal member of the endogenous family of monoamines known as trace amines, and is one of the endogenous agonists for trace amine-associated receptor (TAAR)1. While much work has focused on the function of TAAR1, very little is known about the regulation of the endogenous agonists. We have previously reported that p-tyramine readily crosses lipid bilayers and that its release from synaptosomes is non-exocytotic. Such release, however, showed characteristics of modification by one or more transporters. Here we provide the first characterization of such a transporter. Using frontal cortical and striatal synaptosomes we show that p-tyramine passage across synaptosome membranes is not modified by selective inhibition of either the dopamine, noradrenaline or 5-HT transporters. In contrast, inhibition of uptake-2 transporters significantly slowed p-tyramine re-uptake. Using inhibitors of varying selectivity, we identify Organic Cation Transporter 2 (OCT2; SLC22A2) as mediating high affinity uptake of p-tyramine at physiologically relevant concentrations. Further, we confirm the presence of OCT2 protein in synaptosomes. These results provide the first identification of a high affinity neuronal transporter for p-tyramine, and also confirm the recently described localization of OCT2 in pre-synaptic terminals. [ABSTRACT FROM AUTHOR]