Process Intensification of the Continuous Synthesis of Bio-Derived Monomers for Sustainable Coatings Using a Taylor Vortex Flow Reactor.

We describe the optimization and scale-up of two consecutive reaction steps in the synthesis of bio-derived alkoxybutenolide monomers that have been reported as potential replacements for acrylate-based coatings (Sci. Adv.2020, 6, eabe0026). These monomers are synthesized by (i) oxidation of furfural with photogenerated singlet oxygen followed by (ii) thermal condensation of the desired 5-hydroxyfuranone intermediate product with an alcohol, a step which until now has involved a lengthy batch reaction. The two steps have been successfully telescoped into a single kilogram-scale process without any need to isolate the 5-hydroxyfuranone between the steps. Our process development involved FTIR reaction monitoring, FTIR data analysis via 2D visualization, and two different photoreactors: (i) a semicontinuous photoreactor based on a modified rotary evaporator, where FTIR and 2D correlation spectroscopy (2D-COS) revealed the loss of the methyl formate coproduct, and (ii) our fully continuous Taylor Vortex photoreactor, which enhanced the mass transfer and permitted the use of near-stoichiometric equivalents of O2. The use of in-line FTIR monitoring and modeling greatly accelerated process optimization in the Vortex reactor. This led to scale-up of the photo-oxidation in 85% yield with a projected productivity of 1.3 kg day-1 and a space-time yield of 0.06 mol day-1 mL-1. Higher productivities could be achieved while sacrificing yield (e.g., 4 kg day-1 at 40% yield). The use of superheated methanol at 200 °C in a pressurized thermal flow reactor accelerated the second step, the thermal condensation of 5-hydroxyfuranone, from a 20 h batch reflux reaction (0.5 L, 85 g) to a space time of <1 min in a reactor only 3 mL in volume operating with projected productivities of >700 g day-1. Proof of concept for telescoping the two steps was established with an overall two-step yield of 67%, producing a process with a projected productivity of 1.1 kg day-1 for the methoxybutenolide monomer without any purification of the 5-hydroxyfuranone intermediate.

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy.

OBJECTIVE: Limited data are available regarding the evolution over time of the rate of sudden unexpected death in epilepsy patients (SUDEP) in drug-resistant epilepsy. The objective is to analyze a database of 40 443 patients with epilepsy implanted with vagus nerve stimulation (VNS) therapy in the United States (from 1988 to 2012) and assess whether SUDEP rates decrease during the postimplantation follow-up period. METHODS: Patient vital status was ascertained using the Centers for Disease Control and Prevention's National Death Index (NDI). An expert panel adjudicated classification of cause of deaths as SUDEP based on NDI data and available narrative descriptions of deaths. We tested the hypothesis that SUDEP rates decrease with time using the Mann-Kendall nonparametric trend test and by comparing SUDEP rates of the first 2 years of follow-up (years 1-2) to longer follow-up (years 3-10). RESULTS: Our cohort included 277 661 person-years of follow-up and 3689 deaths, including 632 SUDEP. Primary analysis demonstrated a significant decrease in age-adjusted SUDEP rate during follow-up (S = -27 P = .008), with rates of 2.47/1000 for years 1-2 and 1.68/1000 for years 3-10 (rate ratio 0.68; 95% confidence interval [CI] 0.53-0.87; P = .002). Sensitivity analyses confirm these findings. SIGNIFICANCE: Our data suggest that SUDEP risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study.

Efficacy of vagus nerve stimulation as a treatment for medically intractable epilepsy in brain tumor patients. A case-controlled study using the VNS therapy Patient Outcome Registry.

PURPOSE: Vagus nerve stimulation (VNS) therapy is a procedure to control seizure frequency in patients with medically intractable epilepsy. However, there is no data on efficacy in the subset of these patients with brain tumors. The purpose of this study is to evaluate the efficacy of VNS therapy in patients with brain tumor-associated medically intractable epilepsy. METHODS: Data from the VNS therapy Patient Outcome Registry, maintained by the manufacturer of the device, Cyberonics Inc. (Houston, TX, USA), was queried to characterize the response of patients in whom a brain tumor was listed as the etiology of epilepsy. A case-control analysis was implemented and patient outcome was measured by Engel classification, median seizure response and responder rate (≥50% seizure reduction) using t-tests and chi-squared tests. RESULTS: In 107 patients with an epilepsy etiology related to a brain tumor, seizure reduction was 45% at 3 months and 79% at 24 months with a responder rate of 48% at 3 months and 79% at 24 months. There was no statistical difference in seizure reduction compared with 326 case-control patients from the registry without brain tumors. There was no significant difference in anti-epileptic drug (AED) usage from baseline to 24 months post implant in either group. CONCLUSIONS: VNS therapy is equally effective in patients who suffer seizures secondary to brain tumors as in patients without history of a brain tumor. VNS therapy is a viable treatment option for patients with brain tumor associated medically intractable epilepsy, assuming cytoreductive and other adjuvant therapies have been fully explored.

Efficacy of vagus nerve stimulation in posttraumatic versus nontraumatic epilepsy.

OBJECT: In the US, approximately 500,000 individuals are hospitalized yearly for traumatic brain injury (TBI), and posttraumatic epilepsy (PTE) is a common sequela of TBI. Improved treatment strategies for PTE are critically needed, as patients with the disorder are often resistant to antiepileptic medications and are poor candidates for definitive resection. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy that results in a ≥ 50% reduction in seizure frequency in approximately 50% of patients after 1 year of therapy. The role of VNS in PTE has been poorly studied. The aim of this study was to determine whether patients with PTE attain more favorable seizure outcomes than individuals with nontraumatic epilepsy etiologies. METHODS: Using a case-control study design, the authors retrospectively compared seizure outcomes after VNS therapy in patients with PTE versus those with nontraumatic epilepsy (non-PTE) who were part of a large prospectively collected patient registry. RESULTS: After VNS therapy, patients with PTE demonstrated a greater reduction in seizure frequency (50% fewer seizures at the 3-month follow-up; 73% fewer seizures at 24 months) than patients with non-PTE (46% fewer seizures at 3 months; 57% fewer seizures at 24 months). Overall, patients with PTE had a 78% rate of clinical response to VNS therapy at 24 months (that is, ≥ 50% reduction in seizure frequency) as compared with a 61% response rate among patients with non-PTE (OR 1.32, 95% CI 1.07-1.61), leading to improved outcomes according to the Engel classification (p < 0.0001, Cochran-Mantel-Haenszel statistic). CONCLUSIONS: Vagus nerve stimulation should be considered in patients with medically refractory PTE who are not good candidates for resection. A controlled prospective trial is necessary to further examine seizure outcomes as well as neuropsychological outcomes after VNS therapy in patients with intractable PTE.

Decolorization of ionic liquids for spectroscopy.

It has been widely recognized that although ionic liquids should be colorless, they are frequently not. Colored samples appear to be pure by most analytical techniques (e.g., NMR spectroscopy, mass spectrometry, HPLC, and ion chromatography), and there have been many attempts to identify the source of color in our own laboratories and others-after 20 years the best that can be said is that the impurities are at a very low level (probably parts per billion) with very high molar extinction coefficients. In this paper, we do not identify these impurities but describe a practical method for removing them for spectrochemical applications. We clearly note that the method is not "green", but we anticipate that it will only be applied to the small volumes of ionic liquids required for fundamental spectroscopic studies in academia but not in industrial processes.

Estimates of internal energies of vaporisation of some room temperature ionic liquids.

Systematic variation in the bimolecular rate constant, k(q), for the reaction of singlet oxygen and 1,4-dimethylnaphthalene has led to estimates of the Hildebrand solubility parameter, cohesive pressures and internal energies of vaporisation of some room temperature ionic liquids.

Modelling catalytic turnover frequencies in ionic liquids: the determination of the bimolecular rate constant for solvent displacement from [(C6H6)Cr(CO)2Solv] in 1-n-butyl-3-methylimidazolium hexafluorophosphate.

The bimolecular rate constant for solvent displacement, k(2), from [(C(6)H(6))Cr(CO)(2)Solv] by an incoming ligand has been determined in the room temperature ionic liquid, [bmim][PF(6)], and is compared to that for the same process in cyclohexane and dichloroethane.

Bimolecular rate constants for diffusion in ionic liquids.

The temperature dependence of the bimolecular rate constants for a diffusion controlled reaction involving neutral reactants have been directly determined in five commonly used ionic liquids over the temperature range 5-70 degrees C.

High-pressure CO2-induced reduction of the melting temperature of ionic liquids.

An in situ ATR-IR spectroscopic study has shown that high-pressure CO2 reduces melting temperature of ionic liquids such as [C16mim][PF6].