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The global ubiquity of overuse and underuse of health-care resources and the gravity of resulting harms necessitate an investigation of drivers to inform potential solutions. We describe the network of influences that contribute to poor care and suggest that it is driven by factors that fall into three domains: money and finance; knowledge, bias, and uncertainty; and power and human relationships. In each domain the drivers operate at the global, national, regional, and individual level, and are modulated by the specific contexts within which they act. We discuss in detail drivers of poor care in each domain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Underuse-the failure to use effective and affordable medical interventions-is common and responsible for substantial suffering, disability, and loss of life worldwide. Underuse occurs at every point along the treatment continuum, from populations lacking access to health care to inadequate supply of medical resources and labour, slow or partial uptake of innovations, and patients not accessing or declining them. The extent of underuse for different interventions varies by country, and is documented in countries of high, middle, and low-income, and across different types of health-care systems, payment models, and health services. Most research into underuse has focused on measuring solutions to the problem, with considerably less attention paid to its global prevalence or its consequences for patients and populations. Although focused effort and resources can overcome specific underuse problems, comparatively little is spent on work to better understand and overcome the barriers to improved uptake of effective interventions, and methods to make them affordable., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The preceding papers in this Series have outlined how underuse and overuse of health-care services occur within a complex system of health-care production, with a multiplicity of causes. Because poor care is ubiquitous and has considerable consequences for the health and wellbeing of billions of people around the world, remedying this problem is a morally and politically urgent task. Universal health coverage is a key step towards achieving the right care. Therefore, full consideration of potential levers of change must include an upstream perspective-ie, an understanding of the system-level factors that drive overuse and underuse, as well as the various incentives at work during a clinical encounter. One example of a system-level factor is the allocation of resources (eg, hospital beds and clinicians) to meet the needs of a local population to minimise underuse or overuse. Another example is priority setting using tools such as health technology assessment to guide the optimum diffusion of safe, effective, and cost-effective health-care services. In this Series paper we investigate a range of levers for eliminating medical underuse and overuse. Some levers could operate effectively (and be politically viable) across many different health and political systems (eg, increase patient activation with decision support) whereas other levers must be tailored to local contexts (eg, basing coverage decisions on a particular cost-effectiveness ratio). Ideally, policies must move beyond the purely incremental; that is, policies that merely tinker at the policy edges after underuse or overuse arises. In this regard, efforts to increase public awareness, mobilisation, and empowerment hold promise as universal methods to reset all other contexts and thereby enhance all other efforts to promote the right care., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Overuse, which is defined as the provision of medical services that are more likely to cause harm than good, is a pervasive problem. Direct measurement of overuse through documentation of delivery of inappropriate services is challenging given the difficulty of defining appropriate care for patients with individual preferences and needs; overuse can also be measured indirectly through examination of unwarranted geographical variations in prevalence of procedures and care intensity. Despite the challenges, the high prevalence of overuse is well documented in high-income countries across a wide range of services and is increasingly recognised in low-income countries. Overuse of unneeded services can harm patients physically and psychologically, and can harm health systems by wasting resources and deflecting investments in both public health and social spending, which is known to contribute to health. Although harms from overuse have not been well quantified and trends have not been well described, overuse is likely to be increasing worldwide., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Drug safety for the patients is of paramount importance for a medical professional. Pharmacovigilance attempts to ensure the safety of patients by keeping a close vigil on the pattern of adverse events secondary to drug use. Number of medicolegal cases is at rise since last few years. Forensic sciences and pharmacovigilance need to work hand in hand to unlock the mystery of many criminal and civil proceedings. Pharmacovigilance offers its wide scope in forensic sciences by putting forward its expertise on adverse profile of drugs which may be instrumental in solving the cases and bringing the justice forth. It may range from as simple affairs as defining the adverse drug reaction on one hand to putting expert advice in critical criminal cases on the other one. Pharmacovigilance experts have to abide by the ethics of the practice while executing their duties as expert else it may tarnish the justice and loosen its dependability. As a budding discipline of science, it is confronted with several hurdles and challenges which include reluctance of medical professionals for being involved in court proceedings, extrapolations of facts and data and variations in law across the globe etc. These challenges and hurdles call the medical fraternity come forward to work towards the momentous application of pharmacovigilance in the forensic sciences. Evidence based practice e.g. testing the biological samples for the presence of drugs may prove to be pivotal in the success of this collaboration of sciences., (Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mumol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.