Anna J Dare

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

Catastrophic expenditure to pay for surgery worldwide: a modelling study

BACKGROUND Approximately 150 million individuals worldwide face catastrophic expenditure each year from medical costs alone, and the non-medical costs of accessing care increase that number. The proportion of this expenditure related to surgery is unknown. Because the World Bank has proposed elimination of medical impoverishment by 2030, the effect of surgical conditions on financial catastrophe should be quantified so that any financial risk protection mechanisms can appropriately incorporate surgery. METHODS To estimate the global incidence of catastrophic expenditure due to surgery, we built a stochastic model. The income distribution of each country, the probability of requiring surgery, and the medical and non-medical costs faced for surgery were incorporated. Sensitivity analyses were run to test the robustness of the model. FINDINGS 3·7 billion people (posterior credible interval 3·2-4·2 billion) risk catastrophic expenditure if they need surgery. Each year, 81·3 million people (80·8-81·7 million) worldwide are driven to financial catastrophe-32·8 million (32·4-33·1 million) from the costs of surgery alone and 48·5 million (47·7-49·3) from associated non-medical costs. The burden of catastrophic expenditure is highest in countries of low and middle income; within any country, it falls on the poor. Estimates were sensitive to the definition of catastrophic expenditure and the costs of care. The inequitable burden distribution was robust to model assumptions. INTERPRETATION Half the global population is at risk of financial catastrophe from surgery. Each year, surgical conditions cause 81 million individuals to face catastrophic expenditure, of which less than half is attributable to medical costs. These findings highlight the need for financial risk protection for surgery in health-system design. FUNDING MGS received partial funding from NIH/NCI R25CA92203.

Costs, affordability, and feasibility of an essential package of cancer control interventions in low-income and middle-income countries: key messages from Disease Control Priorities, 3rd edition

Investments in cancer control--prevention, detection, diagnosis, surgery, other treatment, and palliative care--are increasingly needed in low-income and particularly in middle-income countries, where most of the worlds cancer deaths occur without treatment or palliation. To help countries expand locally appropriate services, Cancer (the third volume of nine in Disease Control Priorities, 3rd edition) developed an essential package of potentially cost-effective measures for countries to consider and adapt. Interventions included in the package are: prevention of tobacco-related cancer and virus-related liver and cervical cancers; diagnosis and treatment of early breast cancer, cervical cancer, and selected childhood cancers; and widespread availability of palliative care, including opioids. These interventions would cost an additional US

Protection against renal ischemia-reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ

20 billion per year worldwide, constituting 3% of total public spending on health in low-income and middle-income countries. With implementation of an appropriately tailored package, most countries could substantially reduce suffering and premature death from cancer before 2030, with even greater improvements in later decades.

Global economic consequences of selected surgical diseases: a modelling study

Ischemia–reperfusion (IR) injury to the kidney occurs in a range of clinically important scenarios including hypotension, sepsis and in surgical procedures such as cardiac bypass surgery and kidney transplantation, leading to acute kidney injury (AKI). Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury and may initiate a damaging inflammatory response. Here we assessed whether the mitochondria targeted antioxidant MitoQ could decrease oxidative damage during IR injury and thereby protect kidney function. To do this we exposed kidneys in mice to in vivo ischemia by bilaterally occluding the renal vessels followed by reperfusion for up to 24 h. This caused renal dysfunction, measured by decreased creatinine clearance, and increased markers of oxidative damage. Administering MitoQ to the mice intravenously 15 min prior to ischemia protected the kidney from damage and dysfunction. These data indicate that mitochondrial oxidative damage contributes to kidney IR injury and that mitochondria targeted antioxidants such as MitoQ are potential therapies for renal dysfunction due to IR injury.

Preoperative assessment of the deceased-donor kidney: from macroscopic appearance to molecular biomarkers.

BACKGROUND The surgical burden of disease is substantial, but little is known about the associated economic consequences. We estimate the global macroeconomic impact of the surgical burden of disease due to injury, neoplasm, digestive diseases, and maternal and neonatal disorders from two distinct economic perspectives. METHODS We obtained mortality rate estimates for each disease for the years 2000 and 2010 from the Institute of Health Metrics and Evaluation Global Burden of Disease 2010 study, and estimates of the proportion of the burden of the selected diseases that is surgical from a paper by Shrime and colleagues. We first used the value of lost output (VLO) approach, based on the WHOs Projecting the Economic Cost of Ill-Health (EPIC) model, to project annual market economy losses due to these surgical diseases during 2015-30. EPIC attempts to model how disease affects a countrys projected labour force and capital stock, which in turn are related to losses in economic output, or gross domestic product (GDP). We then used the value of lost welfare (VLW) approach, which is conceptually based on the value of a statistical life and is inclusive of non-market losses, to estimate the present value of long-run welfare losses resulting from mortality and short-run welfare losses resulting from morbidity incurred during 2010. Sensitivity analyses were performed for both approaches. FINDINGS During 2015-30, the VLO approach projected that surgical conditions would result in losses of 1·25% of potential GDP, or

A global country‐level comparison of the financial burden of surgery

20·7 trillion (2010 US

Changing global policy to deliver safe, equitable, and affordable care for women’s cancers

, purchasing power parity) in the 128 countries with data available. When expressed as a proportion of potential GDP, annual GDP losses were greatest in low-income and middle-income countries, with up to a 2·5% loss in output by 2030. When total welfare losses are assessed (VLW), the present value of economic losses is estimated to be equivalent to 17% of 2010 GDP, or

Deaths from acute abdominal conditions and geographical access to surgical care in India: a nationally representative spatial analysis

14·5 trillion in the 175 countries assessed with this approach. Neoplasm and injury account for greater than 95% of total economic losses with each approach, but maternal, digestive, and neonatal disorders, which represent only 4% of losses in high-income countries with the VLW approach, contribute to 26% of losses in low-income countries. INTERPRETATION The macroeconomic impact of surgical disease is substantial and inequitably distributed. When paired with the growing number of favourable cost-effectiveness analyses of surgical interventions in low-income and middle-income countries, our results suggest that building surgical capacity should be a global health priority. FUNDING US National Institutes of Health/National Cancer Institute.

Renal failure deaths and their risk factors in India 2001–13: nationally representative estimates from the Million Death Study

Variation in deceased-donor kidney quality can significantly affect outcomes after kidney transplantation. Suboptimal organ selection for a given recipient can result in primary nonfunction, premature graft failure, or inappropriate discard of a suitable organ. Appraisal and appropriate selection of deceased-donor kidneys for use in transplantation is therefore critical. A number of predictive tools have been developed to assist the transplant team in evaluating the suitability of a deceased-donor kidney for transplantation to a given recipient. These include stratification of donors into “standard-” or “expanded-criteria” categories based on clinical parameters, pre-implantation biopsy scores, donor risk scores, machine perfusion characteristics, functional kidney weight, donor biomarkers and molecular diagnostic tools, ex vivo viability assessment using postmortem normothermic perfusion, and overall macroscopic appraisal by the surgical team. Consensus as to the role and predictive value of each of these tools is lacking and clinical practice regarding evaluation and selection of kidneys varies considerably. In this review, we seek to critically appraise the literature and evaluate the levels of evidence for tools used to assess deceased-donor kidneys. Although a plethora of appraisal tools exist, very few demonstrate desirable predictive power to be useful in clinical decision-making. Further research using large, well-designed prospective studies is urgently needed to advance this important field of transplantation science.