ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy.

Background:Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions. Methods:Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures. Results:A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients. Conclusion:Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied. ClinicalTrialsgov identifier:NCT02656875

A new strain-based finite element for plane elasticity problems

Purpose The purpose of this paper is to develop a new quadrilateral strain-based element. The element has five nodes, four at the corners as well as an internal node. Design/methodology/approach Through the introduction of the internal node, the numerical performance of the element proved to be superior to existing elements in the literature, even though a static condensation is required. Findings From several numerical examples, it is shown that convergence can be achieved with the use of only a small number of finite elements. The proposed element can be used to solve general plane linear elasticity problems resulting in excellent results. Originality/value The results obtained are comparable with those given by the robust element Q8

The effect of surveillance and appreciative inquiry on puerperal infections : a longitudinal cohort study in India

Peer reviewedPublisher PD

Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine.

Dialysis patients with chronic renal failure receiving deferoxamine for treating iron overload are uniquely predisposed for mucormycosis, which is most often caused by Rhizopus oryzae. Although the deferoxamine siderophore is not secreted by Mucorales, previous studies established that Rhizopus species utilize iron from ferrioxamine (iron-rich form of deferoxamine). Here we determined that the CBS domain proteins of Fob1 and Fob2 act as receptors on the cell surface of R. oryzae during iron uptake from ferrioxamine. Fob1 and Fob2 cell surface expression was induced in the presence of ferrioxamine and bound radiolabeled ferrioxamine. A R. oryzae strain with targeted reduced Fob1/Fob2 expression was impaired for iron uptake, germinating, and growing on medium with ferrioxamine as the sole source of iron. This strain also exhibited reduced virulence in a deferoxamine-treated, but not the diabetic ketoacidotic (DKA), mouse model of mucormycosis. The mechanism by which R. oryzae obtains iron from ferrioxamine involves the reductase/permease uptake system since the growth on ferrioxamine supplemented medium is associated with elevated reductase activity and the use of the ferrous chelator bathophenanthroline disulfonate abrogates iron uptake and growth on medium supplemented with ferrioxamine as a sole source of iron. Finally, R. oryzae mutants with reduced copies of the high affinity iron permease (FTR1) or with decreased FTR1 expression had an impaired iron uptake from ferrioxamine in vitro and reduced virulence in the deferoxamine-treated mouse model of mucormycosis. These two receptors appear to be conserved in Mucorales, and can be the subject of future novel therapy to maintain the use of deferoxamine for treating iron-overload

Repeating adrenal vein sampling when neither aldosterone/cortisol ratio exceeds peripheral yields a high incidence of aldosterone-producing adenoma

Objectives:In primary aldosteronism, adrenal vein sampling (AVS) suggests unilateral aldosterone-producing adenoma (APA) when the aldosterone/cortisol (A/F) ratio is less than or equal to peripheral on one side and at least two times peripheral on the other. When A/F ratios are lower bilaterally than peripheral despite adequate samples (adrenal venous cortisol 3 times peripheral), we recommend repeat AVS. This study aimed to determine the frequency of this occurrence and outcomes in such cases.Methods:We performed a retrospective observational study of all cases of primary aldosteronism undergoing initial AVS over a 34-year period.Results:Initial AVS in 1397 patients returned satisfactory and discriminatory results in 1066 (76.3%) but 37 patients (2.6%) had adequate samples but bilateral A/F ratios no higher than peripheral. Of the 22 of these 37 who agreed to repeat AVS, 10 demonstrated unilateral aldosterone production, and eight of these had unilateral adrenalectomy disclosing APAs and resulting in cure (3) or improvement (5) in hypertension. Eight had bilateral aldosterone production. Four studies were inconclusive. Patients with initial unsatisfactory AVS because of bilaterally low A/F ratios had significantly (P=0.023) more unilateral disease [10 of 18 satisfactory repeat studies (55.6%) vs. 326 of 1066 satisfactory initial studies (30.6%)] and a significantly higher (67.6 vs. 49.9%, P=0.034) percentage of males.Conclusion:As the incidence of APAs was high in a subgroup with low A/F bilaterally on initial AVS, these patients should be offered repeat AVS. This might reflect both a greater dependence of aldosterone production on adrenocorticotrophic hormone (ACTH) in APAs and the pulsatile nature of ACTH secretion

Warfare, Fiscal Capacity, and Performance

We exploit differences in casualties sustained in pre-modern wars to estimate the impact of fiscal capacity on economic performance. In the past, states fought different amounts of external conflicts, of various lengths and magnitudes. To raise the revenues to wage wars, states made fiscal innovations, which persisted and helped to shape current fiscal institutions. Economic historians claim that greater fiscal capacity was the key long-run institutional change brought about by historical conflicts. Using casualties sustained in pre-modern wars to instrument for current fiscal institutions, we estimate substantial impacts of fiscal capacity on GDP per worker. The results are robust to a broad range of specifications, controls, and sub-samples

Perspectives for a mixed two-qubit system with binomial quantum states

The problem of the relationship between entanglement and two-qubit systems in which it is embedded is central to the quantum information theory. This paper suggests that the concurrence hierarchy as an entanglement measure provides an alternative view of how to think about this problem. We consider mixed states of two qubits and obtain an exact solution of the time-dependent master equation that describes the evolution of two two-level qubits (or atoms) within a perfect cavity for the case of multiphoton transition. We consider the situation for which the field may start from a binomial state. Employing this solution, the significant features of the entanglement when a second qubit is weakly coupled to the field and becomes entangled with the first qubit, is investigated. We also describe the response of the atomic system as it varies between the Rabi oscillations and the collapse-revival mode and investigate the atomic inversion and the Q-function. We identify and numerically demonstrate the region of parameters where significantly large entanglement can be obtained. Most interestingly, it is shown that features of the entanglement is influenced significantly when the multi-photon process is involved. Finally, we obtain illustrative examples of some novel aspects of this system and show how the off-resonant case can sensitize entanglement to the role of initial state setting.Comment: 18 pages, 9 figure

Finite-Element Model for Pretensioned Prestressed Concrete Girders

This paper presents a nonlinear model for pretensioned prestressed concrete girders. The model consists of three main components: a beam-column element that describes the behavior of concrete, a truss element that describes the behavior of prestressing tendons, and a bond element that describes the transfer of stresses between the prestressing tendons and the concrete. The model is based on a two-field mixed formulation, where forces and deformations are both approximated within the element. The nonlinear response of the concrete and tendon components is based on the section discretization into fibers with uniaxial hysteretic material models. The stress transfer mechanism is modeled with a distributed interface element with special bond stress-slip relation. A method for accurately simulating the prestressing operation is presented. Accordingly, a complete nonlinear analysis is performed at the different stages of prestressing. Correlation studies of the proposed model with experimental results of pretensioned specimens are conducted. These studies confirmed the accuracy and efficiency of the model

The intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time

Ascaris lumbricoides remains the most common endoparasite in humans, yet there is still very little information available about the immunological principles of protection, especially those directed against larval stages. Due to the natural host-parasite relationship, pigs infected with A. suum make an excellent model to study the mechanisms of protection against this nematode. In pigs, a self-cure reaction eliminates most larvae from the small intestine between 14 and 21 days post infection. In this study, we investigated the mucosal immune response leading to the expulsion of A. suum and the contribution of the hepato-tracheal migration. Self-cure was independent of previous passage through the liver or lungs, as infection with lung stage larvae did not impair self-cure. When animals were infected with 14-day-old intestinal larvae, the larvae were being driven distally in the small intestine around 7 days post infection but by 18 days post infection they re-inhabited the proximal part of the small intestine, indicating that more developed larvae can counter the expulsion mechanism. Self-cure was consistently associated with eosinophilia and intra-epithelial T cells in the jejunum. Furthermore, we identified increased gut movement as a possible mechanism of self-cure as the small intestinal transit time was markedly decreased at the time of expulsion of the worms. Taken together, these results shed new light on the mechanisms of self-cure that occur during A. suum infections