Determination of Specific Electrocatalytic Sites in the Oxidation of Small Molecules on Crystalline Metal Surfaces

The identification of active sites in electrocatalytic reactions is part of the elucidation of mechanisms of catalyzed reactions on solid surfaces. However, this is not an easy task, even for apparently simple reactions, as we sometimes think the oxidation of adsorbed CO is. For surfaces consisting of non-equivalent sites, the recognition of specific active sites must consider the influence that facets, as is the steps/defect on the surface of the catalyst, cause in its neighbors; one has to consider the electrochemical environment under which the “active sites” lie on the surface, meaning that defects/steps on the surface do not partake in chemistry by themselves. In this paper, we outline the recent efforts in understanding the close relationships between site-specific and the overall rate and/or selectivity of electrocatalytic reactions. We analyze hydrogen adsorption/desorption, and electro-oxidation of CO, methanol, and ammonia. The classical topic of asymmetric electrocatalysis on kinked surfaces is also addressed for glucose electro-oxidation. The article takes into account selected existing data combined with our original works.M.J.S.F. is grateful to PNPD/CAPES (Brazil). J.M.F. thanks the MCINN (FEDER, Spain) project-CTQ-2016-76221-P

Association of Polymorphisms in Oxidative Stress Genes with Clinical Outcomes for Bladder Cancer Treated with Bacillus Calmette-Guérin

Genetic polymorphisms in oxidative stress pathway genes may contribute to carcinogenesis, disease recurrence, treatment response, and clinical outcomes. We applied a pathway-based approach to determine the effects of multiple single nucleotide polymorphisms (SNPs) within this pathway on clinical outcomes in non-muscle-invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette-Guérin (BCG). We genotyped 276 SNPs in 38 genes and evaluated their associations with clinical outcomes in 421 NMIBC patients. Twenty-eight SNPs were associated with recurrence in the BCG-treated group (P<0.05). Six SNPs, including five in NEIL2 gene from the overall and BCG group remained significantly associated with recurrence after multiple comparison adjustments (q<0.1). Cumulative unfavorable genotype analysis showed that the risk of recurrence increased with increasing number of unfavorable genotypes. In the analysis of risk factors associated with progression to disease, rs3890995 in UNG, remained significant after adjustment for multiple comparison (q<0.1). These results support the hypothesis that genetic variations in host oxidative stress genes in NMIBC patients may affect response to therapy with BCG

Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. METHODS: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18–74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0·3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period—study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. FINDINGS: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (–15·1% [IQR –31·1 to 3·2] in the zilucoplan group vs –16·3% [–43·8 to 5·9] in the placebo group; p=0·46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). INTERPRETATION: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. FUNDING: Ra Pharmaceuticals (now part of UCB Pharma)

The role of population movement in the epidemiology and control of schistosomiasis in Brazil: a preliminary typology of population movement

This paper examines recent developments in migration studies. It reviews literature related to the potential role of internal population movement in the occurrence of schistosomiasis in Brazil and modifies Prothero's typology of population movement for use in Brazil. This modified classification system may contribute to a better understanding of schistosome transmission as well as improved research and control programs. The results of this study indicate that population movement in Brazil primarily involves economically-motivated rural-urban and interregional movement. However, several movement patterns have become increasingly important in recent years as a result of changing socioeconomic and urbanisation dynamics. These patterns include urban-urban, intracity and urban-rural movement as well as the movement of environmental refugees and tourists. Little is known about the epidemiological significance of these patterns. This paper also highlights the role of social networks in the decision to migrate and to settle. Prothero's classic population movement typology categorises movement as either one-way migrations or circulations and examines them along spatial and temporal scales. However, the typology must be modified as epidemiological information about new patterns becomes available. This paper identifies areas that require further research and offers recommendations that can improve the measurement and spatial analysis of the relationship between population movement and schistosomiasis