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Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

Background Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. Methods We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. Findings From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0middot48, 95% CI 0middot38-0middot61; p

Purpose: Previous research demonstrates the relevance of childhood trauma and attachment to communication development. This study aimed to understand speech-language pathology (SLP) practitioners' knowledge, beliefs, training, and current practices regarding developmental trauma and attachment. Method: An online survey was administered to SLP practitioners ( N = 97) who work primarily with children from birth to age 6 years in Canada. Quantitative (univariate and bivariate) analysis was performed with SPSS. Qualitative responses were coded by two reviewers using thematic analysis to identify key themes. Results: SLP practitioners are working with children who have experienced trauma and adapt their practice when they are aware of this history. Practitioners also indicated, however, that they lack training with respect to trauma and attachment, their understanding of the concepts is narrow, they do not have standardized practices for obtaining trauma history, and they do not adapt their practice in consistent ways. The results show there is interest in understanding how trauma affects communication development, the relevance to their work, and that additional training is needed to support practitioners to identify and respond to trauma in early childhood. Conclusions: Findings from this study support SLP practitioners' involvement in early identification of trauma and the development of best practices regarding trauma-informed SLP assessment and intervention. The results also inform how systems and areas of service need to be adjusted to be more accessible, flexible, and collaborative in order to support children and families whose lives have been impacted by trauma and indicate additional areas of research in the area. Supplemental Material: https://doi.org/10.23641/asha.16968097

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.

Two reactive metabolites were identified in vivo for the dual A2A/A1 receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.

The relationship between economic interdependence and international conflict is a burgeoning research topic. Previous research has examined the role of interstate conflict on bilateral total trade. Civil wars also have severe consequences on society and are not uncommon. This article seeks to shed light on this relationship by examining the impact of civil war in one country on the total bilateral trade between the afflicted state and its trade partners. The repercussions of civil war participation on a militarily intervening third party’s trade also receive scrutiny. Furthermore, the outcome of the civil war is investigated to determine whether all war terminations have the same effects on trade. Finally, this article questions whether the effects of civil wars can be mitigated by security partnerships. One key finding from analyses of 120 countries between 1950 and 1992 is that civil wars decrease bilateral trade between states by one-third. In addition, the findings indicate that the effects of civil wars on trade are not limited to countries where the civil wars are occurring but also affect joiners. Furthermore, the outcome types of civil wars have repercussions for future bilateral trade and, under certain situations, their effects can be alleviated.

A new class of chiral indenes (verbenindenes), in which a verbenone moiety is annulated to an indene core, is prepared by a sequence of Shapiro lithiation and Nazarov cyclization reactions. Since the initial indenes are resistant to deprotonation, they are isomerized via [1,5]-sigmatropic shifts to obtain indenes that are readily deprotonated with n-butyllithium. Reaction of the indenide anions with chloro(1,5-cycloctadiene)rhodium dimer produces verbenindenyl transition-metal complexes. Coordination of the indenyl ligand may occur with the gem-dimethyl bridge of the verbenone moiety syn or anti to the metal. Selectivity favors the less hindered anti complexes, and a crystal structure of a member of this series is presented.

Animal feeding operations are experiencing increasing pressure from neighbors, regulators, and legislative authorities to improve air and water quality. One of the most popular tools used in legislation and regulations is the placement of buffers between odor emitting sites and property lines and between potential water pollution sources and water bodies. This study was done to demonstrate how a GIS system can be used to study the effects of placing such buffers around surface water bodies and setbacks from property lines where confined animal feeding operations and their associated waste application fields would be banned. Data from three counties in southern Georgia were analyzed to determine how much land would be made unavailable by the placement of various buffers. “Available land” after restrictions ranged from 63% of total land for 30.5 m (100 ft) buffers and setbacks, to 7% of total land with 152.5 m (500 ft) buffers and setbacks. “Available land” was based strictly on the size of properties after restrictions were placed and did not include consideration of whether the property owner was interested in starting an animal feeding operation or selling the land. The possibility of combining properties to make larger tracts was also not analyzed. Although it did not provide answers to all questions that need to be asked, the GIS system was demonstrated as a useful tool in obtaining some objective data on the cost to society of placing protective buffers.

The MAP kinase p38 plays a key role in the biosynthesis of the inflammatory cytokines TNF-alpha and IL-1. We have developed a novel series of potent p38 inhibitors that could lead to new methods of treatment for inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

Incorporation of 13C-labelled acetates and methionine indicate that andibenin B (1) and andilesin A (5), C25 metabolites of Aspergillus variecolor, are biosynthesised via a mixed polyketide-terpenoid pathway. 18O2-Labelling studies, and incorporation of aromatic precursors and mevalonic acids variously labelled with 13C, 2H and 18O provide evidence for the extensive oxidative and other modifications involved in the elaboration of the highly oxygenated polycyclic structures found in these metabolites. The biosynthetic interrelationships among these and other complex meroterpenoid metabolites are discussed.

High-Z, laser heated hohlraums can be made thick enough to contain thermal radiation, yet thin enough to let out x rays >∼6 keV produced by hot, relatively dense blow-off plasma. We use such “thin wall hohlraums” to observe the physical location of hot, dense, laser produced hohlraum plasmas. This technique has allowed us to come to some understanding of laser transport/deposition, plasma stagnation, and bulk plasma filling.

Co-gels of potato maltodextrin Paselli SA-6 with gelatin were prepared by rapid quenching of mixed solutions from 90°C. At fixed setting temperature and fixed concentration of gelatin, the time required to form a self-supporting network showed an initial steady decrease with increasing concentration of SA-6 (as expected from polymer exclusion), but then increased dramatically before again decreasing. The interpretation of this behaviour as phase inversion from a gelatin-continuous network with SA-6 inclusions to a (more slowly-forming) SA-6 network with gelatin inclusions was confirmed by differential scanning calorimetry (showing both components melting separately, with no evidence of specific interaction), mechanical spectroscopy (showing that the mixed gel network was destroyed completely by melting of the gelatin component at low concentrations of SA-6, but only weakened at SA-6 concentrations above the inversion point) and by light microscopy (showing the expected changes in distribution of the two polymers). In similar studies using the faster-gelling potato maltodextrin Paselli SA-2, microscopy and gel-melting profiles again showed phase-inversion from a gelatin-continuous network at low concentrations of SA-2 to a maltodextrin-continuous network at higher concentrations. Inversion, however, occurred at a lower concentration of maltodextrin than in the gelatin/SA-6 systems, and the accompanying change in gelation rate was confined to a sharp decrease in the dependence of gel-time on SA-2 concentration.

The MAP kinase p38 plays a key role in the biosynthesis of the inflammatory cytokines TNF-α and IL-1. We have developed a novel series of potent p38 inhibitors that could lead to new methods of treatment for inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

The incorporation of 13C, 2H and 18O labelled acetates and 18O2 gas into LL-D253α, a chromanone metabolite of Phoma pigmentivora and other fungi, and analysis of the enriched metabolites by 13C and 2H NMR spectroscopy and mass spectrometry indicates its formation via two preformed polyketide chains. Evidence is presented for the mechanism of formation of the chromanone ring and a cyclopropyl intermediate is proposed to account for the unexpected randomisation of label observed in the hydroxyethyl side chain. A pathway is proposed to explain the occurrence of the co-metabolites LL-D253β and γ.

The seal of the confessional was part of the canon law applied in England before the Reformation. It was also part of that law which was continued in force at the Reformation, as is confirmed by the proviso to canon 113 of the 1603 Canons. This proviso is still in force and proprio vigore binds the clergy of the Church of England. By the Act of Uniformity, 1662, the hearing of confessions was enjoined upon those clergy in certain circumstances; the law places no limit upon the frequency of their being heard. It is unsurprising that there are infrequent references to the seal of the confessional since the Reformation; such cases as there are are inconclusive. Nevertheless, although the seal of the confessional may be waived by the penitent, the refusal by an Anglican clergyman to disclose what was said within sacramental confession is based upon a duty imposed on him by the ecclesiastical law rather than upon an evidential privilege. An Anglican clergyman in breach of that duty would be in grave danger of censure by the ecclesiastical courts and such censure might well lead to his deprivation and possible deposition from Holy Orders. The ecclesiastical law is part of the general law of the land and must be applied in both the ecclesiastical and secular courts. Both courts must therefore enforce that clerical duty and uphold any refusal by an Anglican clergyman to answer questions in breach of the seal of the confessional.

Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.

The MAP kinase p38 is implicated in the release of the pro-inflammatory cytokines TNF-alpha and IL-1 beta. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn's disease. A novel series of imidazopyrimidines have been discovered that potently inhibit p38 and suppress the production of TNF-alpha in vivo.

The interaction of a single shock with a wavy interface results in the development of a Richtmyer-Meshkov instability. While in the case of a smoothly accelerated system, the growth of the perturbation has been shown to reach an asymptotic value, in the case of an impulsive acceleration, the growth rate has been postulated to depend on the variance of the initial perturbation. A systematic study of the sensitivity of mix to initial conditions using the LAM code does not support this assumption. Simulations performed in a 2D geometry also provide information on the Mach number dependence of mix and initial energy coupling between shock and instability.

LAM is a two dimensional Eulerian hydro code with local adaption that uses a Van Leer limiter, artificial viscosity, and a staggered mesh (Crowley 1992). It differs from the Goduonov schemes used elsewhere (Colella and Graz 1985), but this formulation makes it easier to introduce additional physics to the code. Two distinct advantages of the present code are a conformal quadrilateral mesh option and a grow capability. The code is presently being extended to three dimensions.

In the last decade, the extension of the Rayleigh-Taylor instability problem to impulsive accelerations has generated much interest. The topic under study is that of the evolution of a slightly perturbed fluid interface towards a fully turbulent mixed region. Shock tubes are the natural experimental tool for furthering our understanding of the phenomena involved. They have been used by several researchers to probe, with an array of diagnostics, the mixed region which develops when an incident shock and subsequent reflected compression or expansion waves traverse a material interface. In most of the experimental techniques used so far, the turbulent region has been observed through the wall boundary layers. In such experiments care needs to be taken to separate the signature of these layers from that of the mixed region. Methods used to generate the interface also affect the phenomenon observed, so that experimental results are still the object of some controversy. Newer techniques strive to overcome these problems.

The alkali-catalysed rearrangement of (R)-[1-13C]-3-hydroxy-3-methylpentan-2-one has been studied. Rearrangement via a transition state having an anti arrangement of C–O bonds was preferred over that with a syn arrangement by a factor of 1.8:1. The result is of interest in relation to the mechanism of action of the enzymes reductoisomerase and acetolactate decarboxylase, both of which are involved in the metabolism of the branched-chain amino acids. The structure and relative configuration of the product 23 of bromolactonisation of N-methacrylolyl L-proline 22 were determined by X-ray crystallographic analysis.

We are developing a backlighter in the 4–10 keV energy range using K‐shell spectra from elements with Z≤30 and the L‐shell spectra from elements with Z≥58. Using one beam of the Nova laser yielded about 3.0 kJ of 0.53 μm wavelengths light in a 1.0 ns square pulse which was focused to a spot of less than 100 μm in diameter on 12.5 and 25.0‐μm‐thick foil targets. Our initial results include time‐resolved spectra from slab (2 mm×2 mm) and disk (100 μm diameter) targets of Ce (Z=58), Zn (Z=30), and Ti (Z=22). The Zn and Ti exhibit strong emission from the cold Kα line and satellite states, while the Ce spectra show prominent L‐band structure. By exploring the differences between disks matched to the beam focus and extended slabs we hope to obtain information on plasma cooling mechanisms.

Incorporation of 13C-labelled acetates and methionine, 14C and 2H-labelled ethyl 3,5-dimethylorsellinate into terretonin (5) by cultures of Aspergillus terreus indicated that its biosynthesis proceeds via a mixed polyketide-terpenoid (meroterpenoid) pathway. Incorporation of 18O2 gas and ethyl 3,5-dimethylorsellinate (7) doubly labelled with 13C and 18O in the carbonyl of the carboxyl group and at the C-6 position into terretonin (5) and observation of 18O isotope-induced shifts in the 13C n.m.r. spectra and GC/MS studies of the enriched metabolites determined the origin of all of the oxygen atoms in (5) and provided mechanistic insight into the biosynthetic pathway.

Parylene (C/sub 8/H/sub 8/) disks have been irradiated with a 1.06-..mu..m laser at fluxes of 10/sup 15/--10/sup 17/ W/cm/sup 2/. The spatial and temporal scattered light distributions, x-ray spatial and spectral emission properties, and ion spatial and energy distributions were measured. The results, together with two-dimensional magnetohydrodynamic code simulations, imply absorption via collective processes, laser generation of suprathermal electrons, and transport inhibition consistent with the presence of megagauss-level thermoelectric magnetic fields. (AIP)

Polymer-coated glass microspheres filled with DT fuel and argon seed gas were irradiated on the SHIVA 1.06-..mu..m laser using 4-kJ 200 ps (full width at half maximum), Gaussian pulses. Measured light absorption, x-ray spectrum, neutron yields, and x-ray continuum images compare favorably with detailed computer simulations. Pusher neutron activation and argon line imaging diagnostics were utilized to measure fuel density. Fuel densities of 1-3 g/cm/sup 3/ or 5-15 times liquid DT density were inferred.

The energy carried by particles and low‐energy x rays resulting from irradiation of laser fusion targets with 0.5–1‐TW 1.06‐μm lasers has been measured. The energy distributions were obtained from measurements at discrete locations using plasma calorimeters. The data have been integrated to obtain the absorbed energy, and these values compared to scattered‐light calorimetry and optical‐energy balance.