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Background: Galicia (Spain) was one of the first regions worldwide to incorporate nirsevimab for universal respiratory syncytial virus (RSV) prophylaxis in infants into its immunisation programme. The NIRSE-GAL longitudinal population-based study aimed to assess nirsevimab effectiveness in preventing hospitalisations (ie, admittance to hospital)., Methods: The 2023-24 immunisation campaign with nirsevimab in Galicia began on Sept 25, 2023, and concluded on March 31, 2024. The campaign targeted three groups: infants born during the campaign (seasonal group), infants younger than 6 months at the start of the campaign (catch-up group), and infants aged 6-24 months with high-risk factors at the start of the campaign (high-risk group). Infants in the seasonal group were offered immunisation on the first day of life before discharge from hospital. Infants in the catch-up and high-risk groups received electronic appointments to attend a public hospital or health-care centre for nirsevimab administration. For this interim analysis, we used data collected from Sept 25 to Dec 31, 2023, from children born up to Dec 15, 2023. Data were retrieved from public health registries. Nirsevimab effectiveness in preventing RSV-associated lower respiratory tract infection (LRTI) hospitalisations; severe RSV-related LRTI requiring intensive care unit admission, mechanical ventilation, or oxygen support; all-cause LRTI hospitalisations; and all-cause hospitalisations was estimated using adjusted Poisson regression models. Data from five past RSV seasons (2016-17, 2017-18, 2018-19, 2019-20, and 2022-23), excluding the COVID-19 pandemic period, were used to estimate the number of RSV-related LRTI hospitalisations averted along with its IQR. The number needed to immunise to avoid one case in the 2023-24 season was then estimated from the averted cases. Nirsevimab safety was routinely monitored. The NIRSE-GAL study protocol was registered on ClinicalTrials.gov (NCT06180993), and follow-up of participants is ongoing., Findings: 9408 (91·7%) of 10 259 eligible infants in the seasonal and catch-up groups received nirsevimab, including 6220 (89·9%) of 6919 in the catch-up group and 3188 (95·4%) of 3340 in the seasonal group. 360 in the high-risk group were offered nirsevimab, 348 (97%) of whom received it. Only infants in the seasonal and catch-up groups were included in analyses to estimate nirsevimab effectiveness and impact because there were too few events in the high-risk group. In the catch-up and seasonal groups combined, 30 (0·3%) of 9408 infants who received nirsevimab and 16 (1·9%) of 851 who did not receive nirsevimab were hospitalised for RSV-related LRTI, corresponding to an effectiveness of 82·0% (95% CI 65·6-90·2). Effectiveness was 86·9% (69·1-94·2) against severe RSV-related LRTI requiring oxygen support, 69·2% (55·9-78·0) against all-cause LRTI hospitalisations, and 66·2% (56·0-73·7) against all-cause hospitalisations. Nirsevimab effectiveness against other endpoints of severe RSV-related LRTI could not be estimated because of too few events. RSV-related LRTI hospitalisations were reduced by 89·8% (IQR 87·5-90·3), and the number needed to immunise to avoid one RSV-related LRTI hospitalisation was 25 (IQR 24-32). No severe adverse events related to nirsevimab were registered., Interpretation: Nirsevimab substantially reduced infant hospitalisations for RSV-associated LRTI, severe RSV-associated LRTI requiring oxygen, and all-cause LRTI when given in real-world conditions. These findings offer policy makers and health authorities robust, real-world, population-based evidence to guide the development of strategies for RSV prevention., Funding: Sanofi and AstraZeneca., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests FM-T reports having acted as principal investigator in randomised controlled trials for Ablynx, Abbott, Seqirus, Sanofi Pasteur, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis, and GSK, with honoraria paid to his institution and relationships with GSK Vaccines, Pfizer, Sanofi Pasteur, Janssen Pharmaceuticals, MSD, and Seqirus that include consulting or advisory roles. RK, JJ, and LP-A are Sanofi employees and hold shares or stock options in the company. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cationic manganese(III) ortho N-substituted pyridylporphyrins (MnP) act as efficient antioxidants catalyzing superoxide dismutation and accelerating peroxynitrite reduction. Importantly, MnP can reach mitochondria offering protection against reactive species in different animal models of disease. Although an LC-MS/MS-based method for MnP quantitation and subcellular distribution has been reported, a direct method capable of evaluating both the uptake and the redox state of MnP in living cells has not yet been developed. In the present work we applied resonance Raman (RR) spectroscopy to analyze the intracellular accumulation of two potent MnP-based lipophilic SOD mimics, MnTnBuOE-2-PyP 5+ and MnTnHex-2-PyP 5+ within endothelial cells. RR experiments with isolated mitochondria revealed that the reduction of Mn(III)P was affected by inhibitors of the electron transport chain, supporting the action of MnP as efficient redox active compounds in mitochondria. Indeed, RR spectra confirmed that MnP added in the Mn(III) state can be incorporated into the cells, readily reduced by intracellular components to the Mn(II) state and oxidized by peroxynitrite. To assess the combined impact of reactivity and bioavailability, we studied the kinetics of Mn(III)TnBuOE-2-PyP 5+ with peroxynitrite and evaluated the cytoprotective capacity of MnP by exposing the endothelial cells to nitro-oxidative stress induced by peroxynitrite. We observed a preservation of normal mitochondrial function, attenuation of cell damage and prevention of apoptotic cell death. These data introduce a novel application of RR spectroscopy for the direct detection of MnP and their redox states inside living cells, and helps to rationalize their antioxidant capacity in biological systems., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Because of the increased insight into the biological role of hydrogen peroxide (H2O2) under physiological and pathological conditions and the role it presumably plays in the action of natural and synthetic redox-active drugs, there is a need to accurately define the type and magnitude of reactions that may occur with this intriguing and key species of redoxome. Historically, and frequently incorrectly, the impact of catalase-like activity has been assigned to play a major role in the action of many redox-active drugs, mostly SOD mimics and peroxynitrite scavengers, and in particular MnTBAP(3-) and Mn salen derivatives. The advantage of one redox-active compound over another has often been assigned to the differences in catalase-like activity. Our studies provide substantial evidence that Mn(III) N-alkylpyridylporphyrins couple with H2O2 in actions other than catalase-related. Herein we have assessed the catalase-like activities of different classes of compounds: Mn porphyrins (MnPs), Fe porphyrins (FePs), Mn(III) salen (EUK-8), and Mn(II) cyclic polyamines (SOD-active M40403 and SOD-inactive M40404). Nitroxide (tempol), nitrone (NXY-059), ebselen, and MnCl2, which have not been reported as catalase mimics, were used as negative controls, while catalase enzyme was a positive control. The dismutation of H2O2 to O2 and H2O was followed via measuring oxygen evolved with a Clark oxygen electrode at 25°C. The catalase enzyme was found to have kcat(H2O2)=1.5×10(6)M(-1) s(-1). The yield of dismutation, i.e., the maximal amount of O2 evolved, was assessed also. The magnitude of the yield reflects an interplay between the kcat(H2O2) and the stability of compounds toward H2O2-driven oxidative degradation, and is thus an accurate measure of the efficacy of a catalyst. The kcat(H2O2) values for 12 cationic Mn(III) N-substituted (alkyl and alkoxyalkyl) pyridylporphyrin-based SOD mimics and Mn(III) N,N'-dialkylimidazolium porphyrin, MnTDE-2-ImP(5+), ranged from 23 to 88M(-1) s(-1). The analogous Fe(III) N-alkylpyridylporphyrins showed ~10-fold higher activity than the corresponding MnPs, but the values of kcat(H2O2) are still ~4 orders of magnitude lower than that of the enzyme. While the kcat(H2O2) values for Fe ethyl and n-octyl analogs were 803.5 and 368.4M(-1) s(-1), respectively, the FePs are more prone to H2O2-driven oxidative degradation, therefore allowing for similar yields in H2O2 dismutation as analogous MnPs. The kcat(H2O2) values are dependent on the electron deficiency of the metal site as it controls the peroxide binding in the first step of the dismutation process. SOD-like activities depend on electron deficiency of the metal site also, as it controls the first step of O2(●-) dismutation. In turn, the kcat(O2(●-)) parallels the kcat(H2O2). Therefore, the electron-rich anionic non-SOD mimic MnTBAP(3-) has essentially very low catalase-like activity, kcat(H2O2)=5.8M(-1) s(-1). The catalase-like activities of Mn(III) and Fe(III) porphyrins are at most, 0.0004 and 0.05% of the enzyme activity, respectively. The kcat(H2O2) values of 8.2 and 6.5M(-1) s(-1) were determined for electron-rich Mn(II) cyclic polyamine-based compounds, M40403 and M40404, respectively. The EUK-8, with modest SOD-like activity, has only slightly higher kcat(H2O2)=13.5M(-1) s(-1). The biological relevance of kcat(H2O2) of MnTE-2-PyP(5+), MnTDE-2-ImP(5+), MnTBAP(3-), FeTE-2-PyP(5+), M40403, M40404, and Mn salen was evaluated in wild-type and peroxidase/catalase-deficient E. coli., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hydrogen sulfide and peroxynitrite are endogenously generated molecules that participate in biologically relevant pathways. A revision of the kinetic features of the reaction between peroxynitrite and hydrogen sulfide revealed a complex process. The rate constant of peroxynitrite decay, (6.65 ± 0.08) × 10(3) M(-1) s(-1) in 0.05 M sodium phosphate buffer (pH 7.4, 37°C), was affected by the concentration of buffer. Theoretical modeling suggested that, as in the case of thiols, the reaction is initiated by the nucleophilic attack of HS(-) on the peroxide group of ONOOH by a typical bimolecular nucleophilic substitution, yielding HSOH and NO2(-). In contrast to thiols, the reaction then proceeds to the formation of distinct products that absorb near 408 nm. Experiments in the presence of scavengers and carbon dioxide showed that free radicals are unlikely to be involved in the formation of these products. The results are consistent with product formation involving the reactive intermediate HSSH and its fast reaction with a second peroxynitrite molecule. Mass spectrometry and UV-Vis absorption spectra predictions suggest that at least one of the products is HSNO2 or its isomer HSONO., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hydrogen sulfide (H(2)S) is an endogenously generated gas that can also be administered exogenously. It modulates physiological functions and has reported cytoprotective effects. To evaluate a possible antioxidant role, we investigated the reactivity of hydrogen sulfide with several one- and two-electron oxidants. The rate constant of the direct reaction with peroxynitrite was (4.8±1.4)×10(3)M(-1) s(-1) (pH 7.4, 37°C). At low hydrogen sulfide concentrations, oxidation by peroxynitrite led to oxygen consumption, consistent with a one-electron oxidation that initiated a radical chain reaction. Accordingly, pulse radiolysis studies indicated that hydrogen sulfide reacted with nitrogen dioxide at (3.0±0.3)×10(6)M(-1) s(-1) at pH 6 and (1.2±0.1)×10(7)M(-1) s(-1) at pH 7.5 (25°C). The reactions of hydrogen sulfide with hydrogen peroxide, hypochlorite, and taurine chloramine had rate constants of 0.73±0.03, (8±3)×10(7), and 303±27M(-1) s(-1), respectively (pH 7.4, 37°C). The reactivity of hydrogen sulfide was compared to that of low-molecular-weight thiols such as cysteine and glutathione. Considering the low tissue concentrations of endogenous hydrogen sulfide, direct reactions with oxidants probably cannot completely account for its protective effects., (Copyright © 2010 Elsevier Inc. All rights reserved.)