Reactive oxygen species (ROS) have been mainly viewed as unwanted byproducts of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general. A New Approach to Diabetes Mellitus and Reactive Oxygen Species Diabetes mellitus (DM) and its related end-organ damage, such as diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy, are major causes of death and long-term disability. Their underlying mechanisms are incompletely understood, which is why none of the current antidiabetic therapies target the underlying causes or are curative, but focus instead on normalizing surrogate parameters or risk factors such as blood glucose or hypertension [1]. Hence, our lack of mechanistic understanding of lifestyle change-resistant diabetic end-organ damage, together with the increasing prevalence of DM, represent a significant major unmet medical need. One mechanism that has been suggested for decades to cause pancreatic b cell dysfunction and diabetic end-organ damage is 'oxidative stress' (see Glossary), originally defined as an overproduction of reactive oxygen species (ROS). Antioxidants were considered the obvious therapeutic countermeasure but, clinically, have consistently disappointed [2]. Even worse, meta-analyses of clinical trials show that antioxidants may not only be ineffective, but harmful, and even increase mortality [2]. Recently, however, important conceptual breakthroughs in our understanding of ROS in general and DM in particular explain the failure of antioxidants and point towards entirely different mechanism-based and possibly curative therapeutic approaches. Our new understanding of ROS requires that many long-held misconceptions, such as the 'redox balance hypothesis' and the view that ROS are primarily stressors, disease triggers, and metabolic waste products, must be overcome. Instead, the many physiological roles of ROS and the existence of at least seven evolutionarily conserved ROS-producing enzymes (NOX1-5,

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This study aimed to investigate the association between exposure to different types of child maltreatment (CM) and the development of substance use disorders (SUDs) later in life. A systematic review was conducted: the PubMed, EMBASE and PsycINFO databases were searched for relevant papers and ten studies were identified for further analysis. Random effects meta‐analyses were performed for each type of maltreatment in order to estimate the odds ratio (OR) for SUD incidence, and meta‐regressions were performed to explore potential moderators. Individuals with a history of physical abuse during childhood had a 74 per cent increased risk for drug abuse later in life (OR = 1.74, 95% confidence interval (CI) = 1.362.18). The risk for drug abuse was also 73 per cent higher in individuals with a history of sexual abuse during childhood (OR = 1.73, 95% CI = 1.242.41). A meta‐regression found that gender has a moderating effect, with women at a greater risk of SUD incidence compared to men. Exposure to CM, such as physical and sexual abuse in childhood, increases the risk of further substance abuse. Understanding the interplay between the different factors associated with violence and abuse of psychoactive substances is of fundamental importance in designing prevention approaches and interventions for drug users. Key Practitioner Messages Child exposure to violence was associated with the development of substance use disorder. Exposure to violence affects men and women in a gender‐dependent manner, with females being at a higher risk. Understanding the interplay between the different factors associated with violence and drug abuse is of fundamental importance to design prevention approaches and interventions. Drug users have higher rates of child maltreatment and psychological suffering compared to the general population.

16Unphysiological reactive oxygen species (ROS) formation is considered an important 17 pathomechanism for several disease phenotypes with high unmet medical need. Therapeutically, 18 antioxidants have failed multiple times. Instead, focusing on only disease-relevant, enzymatic 19sources of ROS appears to be a more promising and highly validated approach. Here the family of 20 five NADPH oxidases (NOX) stands out as drug targets. Validation has been restricted, however, 21 mainly to genetically modified rodents and is lacking in other species including human. It is thus 22 unclear whether the different NOX isoforms are sufficiently distinct to allow selective 23 pharmacological modulation. Here we show for five of the most advanced NOX inhibitors that 24 indeed isoform selectivity can be achieved. NOX1 was most potently (IC 50 ) targeted by ML171 (0.1 25 µM); NOX2, by VAS2870 (0.7 µM); NOX4, by M13 (0.01 µM) and NOX5, by ML090 (0.01 µM). 26Conditions need to be carefully controlled though as previously unrecognized non-specific 27 antioxidant and assay artefacts may limit the interpretation of data and this included, surprisingly, 28 one of the most advanced NOX inhibitors, GKT136901. As proof-of-principle that now also 29 pharmacological and non-rodent target validation of different NOX isoforms is possible, we used a 30 human blood-brain barrier model and NOX inhibitor panel at IC 50 concentrations. The protective 31 efficacy pattern of this panel confirmed the predominant role of NOX4 in stroke from previous 32 genetic models. Our findings strongly encourage further lead optimization efforts for isoform-33 selective NOX inhibitors and clinical development and provide an experimental alternative when 34 genetic validation of a NOX isoform is not an option. 35 [2][3][4]. This paradox was initially explained by these compounds being underdosed, thereby not 41 reaching efficacy. It is now understood, however, that ROS are not only harmful metabolic by-42 products, but also serve important protective, metabolic and signaling functions, such as the 43 regulation of cell proliferation, differentiation, migration and survival, innate immune response, 44 vascular tone, neuronal signaling as well as inflammation [5][6][7][8]. Anti-oxidants are likely to 45 simultaneously interfere with both qualities of ROS, the physiological and pathophysiological ones 46 with overall neutral or even deleterious outcomes. Thus, ROS should not be modulated in a 47