Conspectus There exists a special kind of perfectionin symmetry, simplicity, and stabilityattainable for structures generated from precisely 60 ligands (all of a single type) that protect 145 ...metal-atom sites. The symmetry in question is icosahedral (Ih ), generally, and chiral icosahedral (I) in particular. A 60-fold equivalence of the ligands is the smallest number to allow this kind of perfection. Known cluster compounds that approximate this structural ideal include palladium-carbonyls, Ih -Pd145(CO)60; gold-thiolates, I-Au144(SR)60; and gold-alkynyls, I-Au144(C2R)60. Many other variants are suspected. The Pd145 compound established the basic achiral structure-type. However, the Au144-thiolate archetype is prominent, historically in its abundance and ease of preparation and handling, in its proliferation in many laboratories and application areas, and ultimately in the intrinsic chirality of its geometrical structure and organization of its bonding network or connectivity. As discovered by mass spectrometry (the “30-k anomaly”) in 1995, it appeared as a broad single peak, as solitary and symmetrical as Mount Fuji, centered near 30 kDa (∼150 Au atoms), provoking these thoughts: Surely this phenomenon requires a unique explanation. It appears to be the Buckminsterfullerene (carbon-60) of gold-cluster chemistry. Herein we provide an elementary account of the unexpected discovery, in which the Pd145-structure played a critical role, that led to the identification and prediction, in 2008, of a fascinating new molecular structure-type, evidently the first one of chiral icosahedral symmetry. Rigorous confirmation of this prediction occurred in early spring 2018, when two single-crystal X-ray crystallography reports were submitted, each one distinguishing both enantiomeric structures and noting profound chirality for the surface (ligand) layer. The emphasis here is on the structure and bonding principles and how these have been elucidated. Our aim has been to present this story in simplest terms, consistent with the radical simplicity of the structure itself. Because it combines intrinsic profound chirality, at several levels, with the highest possible symmetry-type (icosahedral), the structure may attract broader interest also from educators, especially if studied in tandem with the analysis of hollow (shell) metallic systems that exhibit the same chirality and symmetry. Because the shortest (stiffest) bonds follow the chiral 3-way weave pattern of the traditional South-Asian reed football, this cultural artifact may be used to introduce chiral-icosahedral symmetry in a pleasant and memorable way. One may also appreciate easily the bonding and excitations in I-symmetry metallic nanostructures via the golden fullerenes, that is, the proposed hollow Au60,72 spheres. Beyond any aesthetic or pedagogical value, we aim that our Account may provide a firm foundation upon which others may address open questions and the opportunities they present. This Account can scarcely hint at the prospects for further fundamental understanding of these compounds, as well as a widening sphere of applications (chemical, electronic, imaging). The compounds remain crucial to a wider field presently under intense development.
Here we report on the identification and applications of an aqueous 29-atom silver cluster stabilized with 12 lipoate ligands, i.e. Ag29(R-α–LA)12 or (29,12), wherein R-α–LA = R-α-lipoic acid, a ...natural dithiolate. Its uniformity is checked by HPLC-ESI-MS and analytical ultracentrifugation, which confirms its small dimension (∼3 nm hydrodynamic diameter). For the first time, this cluster has been detected intact via electrospray ionization mass spectrometry, allowing one to confirm its composition, its 3- charge-state, and the 8-electron shell configuration of its metallic silver core. Its electronic structure and bonding, including T-symmetry and profound chirality in the outer shell, have been analyzed by DFT quantum-chemical calculations, starting from the known structure of a nonaqueous homologue. The cluster is effective against Methicillin-Resistant Staphylococcus aureus bacteria (MRSA) at a minimum inhibitory concentration (MIC) of 0.6 mg-Ag/mL. A preformed Candida albicans fungal biofilm, impermeable to other antifungal agents, was also inhibited by aqueous solutions of this cluster, in a dose–response manner, with a half-maximal inhibitory concentration (IC50) of 0.94 mg-Ag/mL. Scanning electron micrographs showed the post-treatment ultrastructural changes on both MRSA and C. albicans that are characteristic of those displayed after treatment by larger silver nanoparticles.
We report stable, high capacity cycling performance over 2500 deep cycles at variable C-rates (1C, 5C and 10C) for slurry-cast Li-ion battery anodes made using commercially-available germanium ...nanopowder. The determining factor in cycling performance was the use of fluoroethylene carbonate (FEC) rather than ethylene carbonate (EC) as a co-solvent in the electrolyte. Cycling tests for the FEC-based electrode showed stable performance close to 700 mAh g−1 through 500 cycles at 10C with near 100% Coulombic efficiency. These results show that a Ge-based slurry-cast electrode using active material structured only as a simple particle can be used to create an electrode system which is a candidate for optimization and scale-up. These cycling improvements obtained using the FEC-based electrolyte complements recent progress in Ge-based electrode research which has focused on improving performance through tailored structural and chemical modifications to the active material structure. The effect of the electrolyte on Li-ion transport, electrode stability toward oxidation, and electrode and SEI structural stability was studied using electrochemical impedance spectroscopy, differential capacity profiles, SEM and cross-sectional TEM imaging where we characterize the evolution of the electrode structure cycled with the FEC-based electrolyte considering the type and extent of SEI growth, particle agglomeration and fracturing.
► Ge-based slurry cast Li-ion anode performs stably at high C-rates for 2500 cycles. ► Fluoroethylene carbonate (FEC) based electrolyte critical to anode performance. ► Stable performance and near 100% Coulombic efficiency at 10C for 500 cycles. ► dq/dV show thermodynamic reversibility of FEC- but not EC-based electrode. ► Cross-sectional TEM with SEM show structure of cycled anode and SEI.
Study objective Copperhead snake ( Agkistrodon contortrix ) envenomation causes limb injury resulting in pain and disability. It is not known whether antivenom administration improves limb function. ...We determine whether administration of antivenom improves recovery from limb injury in patients envenomated by copperhead snakes. Methods From August 2013 through November 2015, we performed a multicenter, randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of ovine Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) antivenom therapy on recovery of limb function in patients with copperhead snake envenomation at 14 days postenvenomation. The study setting was 18 emergency departments in regions of the United States where copperhead snakes are endemic. Consecutive patients aged 12 years or older with mild- to moderate-severity envenomation received either FabAV or placebo. The primary outcome was limb function 14 days after envenomation, measured by the Patient-Specific Functional Scale. Additional outcomes included the Patient-Specific Functional Scale at other points; the Disorders of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and Patient’s Global Impression of Change instruments; grip strength; walking speed; quality of life (Patient-Reported Outcomes Measurement Information System Physical Fucntion-10); pain; and analgesic use. Results Seventy-four patients received study drug (45 FabAV, 29 placebo). Mean age was 43 years (range 12 to 86 years). Fifty-three percent were men, 62% had lower extremity envenomation, and 88% had mild initial severity. The primary outcome, the least square mean Patient-Specific Functional Scale score at 14 days postenvenomation, was 8.6 for FabAV-treated subjects and 7.4 for placebo recipients (difference 1.2; 95% confidence interval 0.1 to 2.3; P =.04). Additional outcome assessments generally favored FabAV. More FabAV-treated subjects experienced treatment-emergent adverse events (56% versus 28%), but few were serious (1 in each group). Conclusion Treatment with FabAV reduces limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation.
Abstract Objective There is growing recognition that a comprehensive economic assessment of a new health-care intervention at the time of launch requires both a cost-effectiveness analysis (CEA) and ...a budget impact analysis (BIA). National regulatory agencies such as the National Institute for Health and Clinical Excellence in England and Wales and the Pharmaceutical Benefits Advisory Committee in Australia, as well as managed care organizations in the United States, now require that companies submit estimates of both the cost-effectiveness and the likely impact of the new health-care interventions on national, regional, or local health plan budgets. Although standard methods for performing and presenting the results of CEAs are well accepted, the same progress has not been made for BIAs. The objective of this report is to present guidance on methodologies for those undertaking such analyses or for those reviewing the results of such analyses. Methods The Task Force was appointed with the advice and consent of the Board of Directors of ISPOR. Members were experienced developers or users of budget impact models, worked in academia, industry, and as advisors to governments, and came from several countries in North America, Oceana, Asia, and Europe. The Task Force met to develop core assumptions and an outline before preparing a draft report. They solicited comments on the outline and two drafts from a core group of external reviewers and more broadly from the membership of ISPOR at two ISPOR meetings and via the ISPOR web site. Results The Task Force recommends that the budget impact of a new health technology should consider the perspective of the specific health-care decision-maker. As such, the BIA should be performed using data that reflect, for a specific health condition, the size and characteristics of the population, the current and new treatment mix, the efficacy and safety of the new and current treatments, and the resourceuse and costs for the treatments and symptoms as would apply to the population of interest. The Task Force recommends that budget impact analyses be generated as a series of scenario analyses in the same manner that sensitivity analyses would be provided for CEAs. In particular, the input values for the calculation and the specific cost outcomes presented (a scenario) should be specific to a particular decision-maker's population and information needs. Sensitivity analysis should also be in the form of alternative scenarios chosen from the perspective of the decision-maker. The primary data sources for estimating the budget impact should be published clinical trial estimates and comparator studies for efficacy and safety of current and new technologies as well as, where possible, the decision-maker's own population for the other parameter estimates. Suggested default data sources also are recommended. These include the use of published data, well-recognized local or national statistical information and in special circumstances, expert opinion. Finally, the Task Force recommends that the analyst use the simplest design that will generate credible and transparent estimates. If a health condition model is needed for the BIA, it should reflect health outcomes and their related costs in the total affected population for each year after the new intervention is introduced into clinical practice. The model should be consistent with that used for the CEA with regard to clinical and economic assumptions. Conclusion The BIA is important, along with the CEA, as part of a comprehensive economic evaluation of a new health technology. We propose a framework for creating budget impact models, guidance about the acquisition and use of data to make budget projections and a common reporting format that will promote standardization and transparency. Adherence to these proposed good research practice principles would not necessarily supersede jurisdiction-specific budget impact guidelines, but may support and enhance localrecommendations or serve as a starting point for payers wishing to promulgate methodology guidelines.
Here we report simultaneous screening of bimetallic electrocatalyst candidates for the oxygen reduction reaction (ORR) using bipolar electrochemistry. The analysis is carried out by dispensing ...different bimetallic precursor compositions onto the cathodic poles of an array of bipolar electrodes (BPEs) and then heating them in a reducing atmosphere to yield the catalyst candidates. Because BPEs do not require a direct electrical connection for activation, up to 33 electrocatalysts can be screened simultaneously by applying a voltage to the electrolyte solution in which the BPE array is immersed. The screening of the electrocatalyst candidates can be achieved in about 10 min. The current required to drive the ORR arises from oxidation of Cr microbands present at the anodic poles of the BPEs. Therefore, the most effective electrocatalysts result in oxidation (dissolution) of the most microbands, and simply counting the microbands remaining at the end of the screen provides information about the onset potential required to reduce oxygen. Here, we evaluated three Pd–M (M = Au, Co, W) bimetallic electrocatalysts. In principle, arbitrarily large libraries of electrocatalysts can be screened using this approach.
Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic ...pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.
Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell ...lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19
or CD19
disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19
in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22
disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to ...enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 4H-thieno 3,2-bpyrrole-5-carboxylic acid and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.
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