Off-label use of bevacizumab in the treatment of retinal disease: ethical implications.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of a variety of ophthalmic conditions and has become the first-line therapy for a range of retinal diseases. Bevacizumab, a VEGF inhibitor first approved for the treatment of colorectal cancer, has been shown to be nearly or virtually as effective and safe as other anti-VEGF therapies in the treatment of certain retinal diseases but is not approved or registered by the Food and Drug Administration or European Medicines Agency. While other anti-VEGF options are approved and registered, they are generally more expensive and less accessible. Accordingly, despite its off-label status, bevacizumab is frequently used for a variety of disabling retinal diseases. Indeed, bevacizumab is included on the World Health Organization's list of essential medicines. However, its use in some parts of the world remains restricted due to its off-label status. How, then, should healthcare authorities approach this situation? What are the ethical and societal implications of adhering to a standard and generally effective evaluation and approval system while restricting access to a potentially cost-saving therapy? In countries where its use is not restricted, how should providers approach off-label treatment with bevacizumab? By examining the evidence behind bevacizumab's efficacy and safety and evaluating the individual and societal implications of off-label use and restriction, this paper illustrates the ethical factors providers and policy makers must consider in the off-label use of bevacizumab and ultimately argues for increased access to bevacizumab in the treatment of retinal disease.

Spray-Coated Multiwalled Carbon Nanotube Composite Electrodes for Thermal Energy Scavenging Electrochemical Cells.

Spray-coated multiwalled carbon nanotube/poly(vinylidene fluoride) (MWCNT/PVDF) composite electrodes, scCNTs, with varying CNT compositions (2 to 70 wt %) are presented for use in a simple thermal energy-scavenging cell (thermocell) based on the ferro/ferricyanide redox couple. Their utility for direct thermal-to-electrical energy conversion is explored at various temperature differentials and cell orientations. Performance is compared to that of buckypaper, a 100% CNT sheet material used as a benchmark electrode in thermocell research. The 30 to 70 wt % scCNT composites give the highest power output by electrode area-seven times greater than buckypaper at ΔT = 50 °C. CNT utilization is drastically enhanced in our electrodes, reaching 1 W gCNT(-1) compared to 0.036 W gCNT(-1) for buckypaper. Superior performance of our spray-coated electrodes is attributed to both wettability with better use of a large portion of electrochemically active CNTs and minimization of ohmic and thermal contact resistances. Even composites with as low as 2 wt % CNTs are still competitive with prior art. The MWCNT/PVDF composites developed herein are inexpensive, scalable, and serve a general need for CNT electrode optimization in next-generation devices.

Enhanced Salt Removal in an Inverted Capacitive Deionization Cell Using Amine Modified Microporous Carbon Cathodes.

Microporous SpectraCarb carbon cloth was treated using nitric acid to enhance negative surface charges of COO(-) in a neutral solution. This acid-treated carbon was further modified by ethylenediamine to attach -NH2 surface functional groups, resulting in positive surface charges of -NH3(+) via pronation in a neutral solution. Through multiple characterizations, in comparison to pristine SpectraCarb carbon, amine-treated SpectraCarb carbon displays a decreased potential of zero charge but an increased point of zero charge, which is opposed to the effect obtained for acid-treated SpectraCarb carbon. An inverted capacitive deionization cell was constructed using amine-treated cathodes and acid-treated anodes, where the cathode is the negatively polarized electrode and the anode is the positively polarized electrode. Constant-voltage switching operation using NaCl solution showed that the salt removal capacity was approximately 5.3 mg g(-1) at a maximum working voltage of 1.1/0 V, which is an expansion in both the salt capacity and potential window from previous i-CDI results demonstrated for carbon xerogel materials. This improved performance is accounted for by the enlarged cathodic working voltage window through ethylenediamine-derived functional groups, and the enhanced microporosity of the SpectraCarb electrodes for salt adsorption. These results expand the use of i-CDI for efficient desalination applications.

Continuous operation of membrane capacitive deionization cells assembled with dissimilar potential of zero charge electrode pairs.

The performance of single stack membrane assisted capacitive deionization cells configured with pristine and nitric acid oxidized Zorflex (ZX) electrode pairs was evaluated. The potentials of zero charge for the pristine and oxidized electrodes were respectively -0.2V and 0.2V vs. SCE. Four cell combinations of the electrodes including a pristine anode-pristine cathode, oxidized anode-pristine cathode, pristine anode-oxidized cathode, and oxidized anode-oxidized cathode were investigated. When the PZC was located within the polarization window of the electrode, diminished performance was observed. The cells were operated at 1.2 V and based on potential distribution results, the effective working potentials were ∼0.9, 0.8, 1.2, and 1.1 V for the pristine anode-pristine cathode, oxidized anode-pristine cathode, pristine anode-oxidized cathode, and oxidized anode-oxidized cathode cells, respectively. The highest electrosorption capacity of 17 mg NaCl/g ZX was observed for the pristine anode-oxidized cathode cell, where both PZCs were outside of the polarization window.

Asymmetric electrode configuration for enhanced membrane capacitive deionization.

Long-term performance of capacitive deionization (CDI) and membrane-assisted capacitive deionization (MCDI) single cells equipped with the same pristine carbon xerogel (CX) electrodes configured as the anode and cathode was investigated. Unlike CDI, which was subject to performance degradation in a short period of time, MCDI showed performance preservation during the 50 h of operation due to its ability to mitigate charge leakage from parasitic electrochemical reactions that result in carbon oxidation. Differential capacitance measurements of the used CDI and MCDI electrodes revealed shifting of the potential of zero charge (EPZC) of the CDI anode from -0.1 to 0.4 V but only to 0.1 V for the MCDI anode. CDI and MCDI cells tested with electrodes having EPZCs at -0.1 and 0.5 V showed strongly contrasting results depending on the anode-cathode EPZC configuration. The MCDI cell configured with a 0.5 V EPZC cathode and -0.1 V EPZC anode displayed the best performance of all the tested cells, benefiting from increased counterion excess within the potential window, and the membrane was in-place to reject expelled co-ions from accessing the bulk.

Visualizing diastereomeric interactions of chiral amine-chiral copper salen adducts by EPR spectroscopy and DFT.

Single enantiomers of R/S-methylbenzylamine (MBA) were found to selectively form adducts with two chiral Cu-salen complexes, [Cu(II)(1)] (H(2)1 = N,N'-bis(3,5-ditert-butylsalicylidene)-1,2-diaminocyclohexane) and [Cu(II)(2)] (H(2)2 = N,N'-bis-salicylidene-1,2-cyclohexanediamino). The axial g/A spin Hamiltonian parameters of the Cu-MBA adducts were typical of 5-coordinate species. Enantiomer discrimination in the MBA binding was directly evidenced by W-band CW EPR, revealing an 86 ± 5% preference for formation of the R,R-[Cu(1)] + S-MBA adducts compared to R,R-[Cu(1)] + R-MBA; this was reduced to a 57 ± 5% preference for R,R-[Cu(2)] + S-MBA following removal of the tert-butyl groups. The structure of these diastereomeric adducts was further probed by different hyperfine techniques (ENDOR and HYSCORE), although no structural differences were detected between these adducts using these techniques. The diastereomeric adducts were found to possess lower symmetry, as evidenced by rhombic g tensors and inequivalent H(imine) couplings. This was caused by the selective binding mode of MBA onto one side of the chiral Cu(II) complex. DFT calculations were performed on the R,R-[Cu(1)] + S-MBA and R,R-[Cu(1)] + R-MBA adducts. A distinct difference in orientation and binding mode of the MBA was identified in both adducts, confirming the experimental results. The preferred heterochiral R,R-[Cu(1)] + S-MBA adduct was found to be 5 kJ mol(-1) lower in energy compared to the homochiral adduct. A delicate balance of steric repulsion between the α-proton (attached to the asymmetric carbon atom) of MBA and the methine proton (attached to the asymmetric carbon atom) of [Cu(1)] was crucial in the stereoselective binding.

Enantioselective binding of structural epoxide isomers by a chiral vanadyl salen complex: a pulsed EPR, cw-ENDOR and DFT investigation.

The mode of chiral interaction between a series of asymmetric epoxides (propylene oxide, butylene oxide, epifluorohydrin and epichlorohydrin) and a chiral vanadyl salen complex, N, N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-diamino-vanadium (iv) oxide, [VO()], was investigated by a range of electron magnetic resonance techniques (EPR, ENDOR, HYSCORE) and DFT. Enantiomer discrimination of the weakly bound epoxides by the vanadyl complex was evident by cw-ENDOR. The origin of this discrimination was attributed to a number of factors including H-bonds, steric properties and electrostatic contributions, which collectively control the outcome of the chiral interaction. DFT revealed the role of a key H-bond, formed between the epoxide oxygen atom (O(epoxide)) and the methine proton (H(exo)) attached to the asymmetric carbon atom of the chiral vanadyl salen complex, thereby providing a direct pathway for stereochemical communication between complex and substrate. These findings reveal the potential importance of weak outer sphere interactions in stereoselectivities of enantioselective homogeneous catalysis.