Refractory Complex Research Articles

Native oxidation resistance of Al20Nb30Ta10Ti30Zr10 refractory complex concentrated alloy (RCCA)

The native oxidation resistance of an Al20Nb30Ta10Ti30Zr10 (at.%) refractory complex concentrated alloy (RCCA) was evaluated at 1000 °C in air. Oxidation tests revealed that the alloy exhibits linear oxidation kinetics out to 4 h of oxidation, with an adherence to parabolic, diffusion-controlled oxidation from 4 to 100 h. This transition was ultimately attributed to the formation of an outer oxide consisting primarily of TiO2 and Ti7Al2O15 layers. The 100 h oxide product contained multiple internal layers, but the overall oxidation kinetics was proposed to be controlled by the outer composite oxide layer. While this layer was morphologically continuous, it consisted of a non-continuous mixture of NbAlO4, ZrO2, Ti7Al2O15, and Ta2Nb4O15. The observed oxide scales are discussed relative to the oxidation behaviors of less-complex alloys.

P515 Costs associated with the management of refractory complex perianal fistulas in patients with Crohn's disease

P515 Costs associated with the management of refractory complex perianal fistulas in patients with Crohn's disease

Vigabatrin: Lessons Learned From the United States Experience.

Vigabatrin was introduced as an antiseizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns arose regarding peripheral visual field loss. When the drug was approved in the United States in 2009, it carried a black box warning for the risk of permanent visual loss, and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of preexisting, baseline visual deficits and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number of visual deficits at baseline. An unexpected finding during the first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential of drug toxicity involving the visual pathways.

Long Term Outcomes of Venetoclax Therapy for Complex Karyotype Relapsed/Refractory Chronic Lymphocytic Leukemia

Long Term Outcomes of Venetoclax Therapy for Complex Karyotype Relapsed/Refractory Chronic Lymphocytic Leukemia

Development of Macrolide Resistance and Reinfection in Refractory Mycobacterium avium Complex Lung Disease.

Patients with refractory Mycobacterium avium complex lung disease (MAC-LD) undergo long-term macrolide therapy, but macrolide resistance develops infrequently. The aim of this study was to determine whether reinfection was a factor in the low incidence of macrolide resistance in patients with refractory MAC-LD. Among 481 patients with treatment-naive MAC-LD who started antibiotic treatment between January 2002 and December 2013, we identified 72 patients with refractory disease, characterized by persistently positive sputum cultures despite ≥12 months of treatment. Molecular analyses of the 23S ribosomal RNA gene responsible for macrolide resistance and serial mycobacterial genotyping were performed using stored MAC isolates. The median duration of treatment was 32 months (interquartile range, 24-41 mo) in 72 patients. After treatment for a median of 33 months (interquartile range, 21-44 mo), macrolide resistance developed in 16 (22%) patients. Molecular analysis of isolates from 15 patients revealed that 80% (12 of 15) had a point mutation at position 2,058 or 2,059 of the 23S ribosomal RNA gene. Of the 49 patients who had stored pre- and post-treatment isolates, mycobacterial genotyping revealed that reinfection by new MAC strains occurred in 36 (73%) patients. New MAC strains were found in 24 (49%) patients, and mixed infections with original and new strains occurred in 12 (24%) patients. Only 13 (27%) patients had persistent infections with their original MAC strains. Refractory MAC-LD is commonly caused by reinfection with new strains rather than persistence of the original strain, which may explain the infrequent development of macrolide resistance in refractory MAC-LD. Clinical trial registered with www.clinicaltrials.gov (NCT00970801).

Mesenchymal Stromal Cells in the Treatment of Perianal Fistulas in Crohn'S Disease

Significant unmet needs remain in patients with Crohn's disease and perianal fistulas. Mesenchymal stromal cells have potent immunomodulatory actions. The Phase II studies reported efficacy of local injection of mesenchymal stromal cells to achieve closure of fistulas. A Phase III trial demonstrated that in patients with Crohn's disease and refractory complex perianal fistulas, a single injection of 120×106 cells was superior to local injection of placebo associated with the same surgical procedure, in obtaining closure of the fistula tracts together with absence of abscesses>2cm, 24 weeks after the injection, a stringent combined primary end point. The benefit over placebo was sustained 52 weeks after the single injection. The therapy is safe with adverse events limited to local pain.

A Comparison of Vagal Nerve Stimulation and Responsive Neurostimulation for the Treatment of Medically Refractory Complex Partial Epilepsy

Background: Neuromodulatory applications such as vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) are safe and effective strategies for medically intractable epilepsy secondary to complex partial seizures, but researchers have yet to compare their efficacies. Objective: The goal of this study is to compare VNS and RNS efficacy at reducing seizure frequency and complication rates in subjects with medically intractable epilepsy secondary to complex partial seizures. Methods: This is a retrospective chart review of 30 patients with medically intractable complex partial epilepsy, who underwent either VNS or RNS placement at a single institution between June 2012 and January 2016. There was a mean follow-up of 19 months. Seizure frequency reduction and complications were identified. Results: The median seizure frequency reduction was similar for VNS (66%) and RNS (58%). There was no major morbidity or mortality, and the frequency of minor complications was similar between VNS (15%) and RNS (18%). Conclusion: We found that VNS and RNS reduced the median seizure frequency similarly with no difference in morbidity or mortality. Further prospective studies are warranted as VNS and RNS therapy improves over time.

Development and exploration of refractory high entropy alloys—A review

Abstract

Design of high-strength refractory complex solid-solution alloys

Nickel-based superalloys and near-equiatomic high-entropy alloys containing molybdenum are known for higher temperature strength and corrosion resistance. Yet, complex solid-solution alloys offer a huge design space to tune for optimal properties at slightly reduced entropy. For refractory Mo-W-Ta-Ti-Zr, we showcase KKR electronic structure methods via the coherent-potential approximation to identify alloys over five-dimensional design space with improved mechanical properties and necessary global (formation enthalpy) and local (short-range order) stability. Deformation is modeled with classical molecular dynamic simulations, validated from our first-principle data. We predict complex solid-solution alloys of improved stability with greatly enhanced modulus of elasticity (3× at 300 K) over near-equiatomic cases, as validated experimentally, and with higher moduli above 500 K over commercial alloys (2.3× at 2000 K). We also show that optimal complex solid-solution alloys are not described well by classical potentials due to critical electronic effects.

Pharmacotherapy for Refractory and Super-Refractory Status Epilepticus in Adults.

Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA)A receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N-methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABAA receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.

Aqueous process intensification through enhanced oxygen mass transfer using oxygen vector: An application to cleaner leaching

Intensification of chemical processes has surfaced many challenging but promising areas. Enhancement of Oxygen Mass Transfer (OMT) is one such area in aqueous chemical processes. Several attempts made to alleviate OMT limitation, however, remains futile in lowering energy and material requirement. In this regard, the use of n-Dodecane, an Oxygen Vector, could be a radically promising route for enhancing OMT. The present work explores the use of n-Dodecane (Oxygen Vector) for the enhancement of OMT, corroborated with the Classical Molecular Dynamic (MD) simulations. The results showed that 2.5% (v/v) n-Dodecane addition in aqueous systems (‘Na2SO3 solution – n-Dodecane’ and ‘H2O – n-Dodecane’) would lead to enhancement up to 750%. MD simulation results confirm the transfer of oxygen from n-Dodecane-to-aqueous medium with diffusivity of 10−8 m2/s, thus becomes the dominating route for the enhancement in OMT. In addition, it has been found that n-Dodecane fraction, temperature and the rate of oxygen consumption reaction are the dictating parameters for enhancement. The concept of Oxygen Vector for enhancing OMT has been successfully exploited for cleaner leaching of metals (>95 % Cu, Ni and Co) from refractory complex sulfides at moderate temperature-pressure conditions (T∼ 95 °C and pO2∼3 Bar), which would have otherwise been possible at T > 200 °C and pO2 > 10 Bar. In addition, recyclability of n-Dodecane, Oxygen Vector, in leaching system is an added advantage. Thus, this study offers a promising route in enhancing kinetics of oxidative aqueous processes and provides suggestive insights for lowering the material and energy requirements.

High temperature oxidation behaviors of equimolar NbTiZrV and NbTiZrCr refractory complex concentrated alloys (RCCAs)

Refractory complex concentrated alloys (RCCAs) represent an emerging class of materials that have displayed significant potential for increased mechanical performance at extreme temperatures over conventional refractory alloys and Ni-base superalloys. While limited work has been conducted in this area, several RCCAs have shown remarkable levels of oxidation resistance in comparison to the majority of uncoated commercial refractory alloys. However, the oxidation mechanisms in these types of alloys have not been well understood. This study aims to develop the foundation for understanding RCCA oxidation mechanisms through the systematic evaluation of NbTiZrV and NbTiZrCr, which display vastly different oxidation behaviors. In both cases, the predominant mechanism appeared to be internal oxidation, where a mixture of simple and complex oxides was observed after prolonged oxidation times. This resulted in extended linear oxidation kinetics for the NbTiZrV alloy and linear to near-parabolic oxidation kinetics for the NbTiZrCr alloy. Under this mindset, novel design strategies for promoting increased oxidation resistance in both RCCAs and dilute refractory alloys based on sluggish complex oxides are proposed.

Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers

PurposeA thorough QT study was performed to assess the proarrhythmic potential of vigabatrin, an antiepileptic drug approved in the United States for the treatment of infantile spasms and refractory complex partial seizures. MethodsIn this Phase I, randomized, double-blind, placebo- and active-controlled (moxifloxacin), 4-sequence, crossover study conducted at a single center, healthy participants received 1 of 4 randomly assigned treatments: 3.0g vigabatrin solution (therapeutic dose) and 1 moxifloxacin placebo tablet; 6.0g vigabatrin solution (supratherapeutic dose) and 1 moxifloxacin placebo tablet; 400 mg moxifloxacin and vigabatrin placebo solution; moxifloxacin placebo tablet and vigabatrin placebo solution. FindingsMean changes from baseline in placebo-corrected QTcF, QTcB, and QTcI with vigabatrin 3.0 g and 6.0 g indicated no signal for any QTc effect relative to baseline. All 1-sided upper 95% confidence intervals for the differences between each vigabatrin dose and placebo were <10 ms at all time points. QTcF was unaffected by increasing plasma vigabatrin concentrations; no arrhythmias were observed in any treatment group. Low rates of first-degree atrioventricular block, sinus tachycardia, and sinus bradycardia occurred in all treatment groups. Most adverse events were mild. ImplicationsThe findings from this thorough QT study are consistent with existing clinical data and confirm a lack of proarrhythmic potential of vigabatrin.

Clinical benefits of electroconvulsive therapy for depressed patients with refractory complex regional pain syndrome (CRPS) type 1: A preliminary result

Clinical benefits of electroconvulsive therapy for depressed patients with refractory complex regional pain syndrome (CRPS) type 1: A preliminary result

Poster 377 The Mystery Case of the Edematous and Painful Foot: Refractory Lower Limb Complex Regional Pain Syndrome (CRPS) in the Setting of Lymphedema in a Patient with Endometrial Cancer and Lynch Syndrome: A Case Report.

Poster 377 The Mystery Case of the Edematous and Painful Foot: Refractory Lower Limb Complex Regional Pain Syndrome (CRPS) in the Setting of Lymphedema in a Patient with Endometrial Cancer and Lynch Syndrome: A Case Report.

Retinal structure and function in vigabatrin‐treated adult patients with refractory complex partial seizures

Evaluate visual-field and retinal-structure changes following adjunctive vigabatrin treatment in vigabatrin-naive adults with refractory complex partial seizures (rCPS). Prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible patients (≥2 seizures/month who failed ≥3 therapies) who could reliably perform perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) prior to vigabatrin exposure. Following vigabatrin initiation, testing occurred within 1 month (reference) and 3, 6, 9, and 12 months. End points included mean change from reference in mean deviation (dB) and average retinal nerve fiber layer (RNFL) thickness, visual-acuity changes from baseline, and number of patients who met predefined vision-parameter changes at two (confirmed) or three (persistent) consecutive visits. Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 55 had valid reference and ≥1 post-reference assessments (full-analysis set [FAS]). Thirty-six APTS patients with valid pre-/post-reference values completed all planned visits (per-protocol set [PPS]). Thirty-eight (59%) APTS patients completed the study; 27 (42%) withdrew (none for visual-field changes); 32% and 15% had abnormally thin RNFL and abnormal visual acuity at baseline, respectively; 20% had abnormal central 30 degree visual fields in the reference period. No significant mean near visual-field changes were observed (PPS); mean change in average RNFL thickness increased significantly (1-year data: Left-eye: 6.37 μm, confidence interval (CI) 4.66-8.09; right-eye: 7.24 μm CI 5.47-9.01; PPS). No confirmed three-line decreases in visual acuity (FAS) were observed; five patients had predefined confirmed/persistent visual-field changes (FAS). All vision-related adverse events were nonserious; the most common was vision blurred (9%). Prior to vigabatrin initiation, rCPS patients may already exhibit vision deficits. Up to 1 year of adjunctive vigabatrin treatment did not significantly change population near visual fields. Five patients met predefined visual-field-change criteria. RNFL thickening of unknown clinical significance was observed. Limitations include single-arm, open-label design; patients' inability to perform ophthalmic/visual-field examinations; and limited vigabatrin-exposure duration.

Results of the Treatment of Chronic, Refractory CRPS with Ketamine Infusions: a Preliminary Report.

Chronic, refractory complex regional pain syndrome remains very difficult to treat. A sub-anaesthetic low-dose ketamine has shown promise in advanced CRPS. We investigated the efficacy of ketamine in anaesthetic dosage in chronic, refractory CRPS patients that had failed available standard therapies. 5 female patients, aged a mean of 34 years with long-standing, a mean of 8 years', CRPS received ketamine in anaesthetic dosage over 10 days. The patients received 1-5 ketamine courses. The effect of gradual pain reduction was observed beginning on the 4(th)-5(th) day of treatment, associated with a decrease in the intensity of the allodynia (pain at light touch). No improvement in function (finger range of motion, grip strength) of the affected hands was noted in any patient. This beneficial analgesic effect was confined to 1.5-2.5 months after treatment and then pain relapsed to the baseline level. The results of this study show a short-term analgesic effect for this therapy, with no effect on movement and function of the affected limbs. Nevertheless, this method brings hope to the most severely ill patients who cannot be offered any other reasonable treatment option.

Which children receive vigabatrin? Characteristics of pediatric patients enrolled in the mandatory FDA registry.

Vigabatrin (Sabril®) is an antiepileptic drug (AED) currently indicated in the US as a monotherapy for patients 1month to 2years of age with infantile spasms (IS) and as adjunctive therapy for patients ≥10years of age with refractory complex partial seizures (rCPS) whose seizures have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. The approval required an FDA mandated registry. This article describes 5years of demographic and treatment exposure data from US pediatric patients (<17years). Participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented for patient progression to maintenance therapy. This includes demographic diagnosis and reports of ophthalmologic assessments (where available). Patient data were grouped by age as proxies for indication (IS: <3years, rCPS: ≥3 to <17years). As of August 26, 2014, 5546/6823 enrolled patients were pediatric/total; 4472 (81%) were vigabatrin-naïve. Seventy-one percent of patients were <3years of age; 29% were ≥3 to <17years of age. Etiologies of IS were identified as cryptogenic (21%), symptomatic tuberous sclerosis (17%), and symptomatic other (42%). The majority of patients with IS (56%) attempted no prior treatments; 16% received adrenocorticotropic hormone prior to vigabatrin. A third of patients with IS were receiving 1 concomitant treatment with vigabatrin. For patients with rCPS, 39% attempted 1-3 prior treatments; 27% were receiving 2 concomitant treatments at enrollment. A total of 1852 (41%) patients did not undergo baseline ophthalmological assessment; 25% of patients with IS and 42% of patients with rCPS were exempted for neurologic disabilities. Kaplan-Meier estimates predict that 71% and 65% of vigabatrin-naïve patients with IS and rCPS, respectively, would remain in the registry at 6months. Most pediatric vigabatrin patients have IS as an underlying diagnosis, especially those <3years of age. A proportion of those with rCPS remain on long-term vigabatrin despite the risk of adverse events.

Ketamine infusions for refractory complex regional pain syndrome: a review

Complex regional pain syndrome (CRPS) is a debilitating pain disorder that is often resistant to conventional treatment options. Al­though the precise pathophysiology of CRPS has not yet been fully elucidated, it is thought that central sensitization through the proliferation of N-methyl-D-aspartate (NMDA) receptors leads to the amplification of pain transmission within the central nervous system. Accordingly, the NMDA antagonist ketamine has been employed for its potential ability to reverse central sensitization and provide analgesia. Promising studies have shown that ketamine, when administered through prolonged intravenous infusions, may be effective for relieving pain in cases of refractory CRPS. Currently, ketamine infusions for CRPS are offered at select pain clinics in North America. However, it should be emphasized that evidence from high-quality trials is lacking and unresolved concerns over potenial neurotoxicity, urological toxicity, and hepatotoxicity of prolonged ketamine use remain. These concerns render the long-term use of ketamine questionable. Therefore, ketamine infusions should be used with caution, and may be a reasonable therapeutic option only for refractory cases of CRPS. Proper monitoring for signs of toxicity must be ensured. In addition, a physical intervention program should be used in conjunction with ketamine to fully restore function and quality of life for refractory CRPS patients. Le syndrome douloureux régional complexe (SDRC) est un trouble de douleur débilitante qui est souvent résistant à des options de traitements conventionnels. Malgré le fait que la pathophysiologie précise du SDRC n’a pas encore été confirmée, certains chercheurs pensent qu’il y a une sensibilisation centrale par l’intermédiaire de la prolifération de récepteurs N-méthyl-D-aspartate (NMDA) qui conduisent à l’amplification de la transmission de la douleur dans le système nerveux central. En conséquence, l’antagoniste-NMDA, la kétamine, a été utilisé pour sa capacité de renverser la sensibilité centrale en créant un effet analgésique. Des études prometteuses ont démontré que la kétamine, lorsqu’administrée par des infusions intraveineuses prolongées, pourrait s’avérer efficace pour apaiser la douleur dans des cas de SDRC réfractaires. Des infusions de kétamine pour le SDRC sont offertes actuellement à des cliniques de douleur spécifiques en Amérique du Nord. Toutefois, il manque d’essais randomisés de qualité pour démontrer clairement l’efficacité de ce traitement. Des connaissances plus approfondies sur le potentiel neurotoxique, la toxicité urologique, et l’hépatotoxicité de l’utilisation prolongée de kétamine sont nécessaires. Ainsi, les infusions de kétamine doivent être utilisées avec précaution et ont un potentiel thérapeutique seulement pour les cas réfractaires de SDRC. Il est important d’assurer un suivi adéquat pour des signes de toxicité. De plus, un programme d’intervention physique devrait également être offert en plus des traitements de kétamine pour op­timiser la fonction et la qualité de vie des patients avec un SDRC réfractaire.

Sabril Vision Study: Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin (S14.004)

Sabril Vision Study: Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin (S14.004)