Attenuation of ischemic liver injury by augmentation of endogenous adenosine

Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous adenosine by inhibition of nucleoside transport with R75231 attenuates ischemic liver injury. Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a dose of 0.1 mg/kg (Group 2, n=6), 0.05 mg/kg (Group 3, n=6), or 0.025 mg/kg (Group 4, n=6). Nontreated animals were used as the control (Group 1, n= 10). Animal survival, hepatic tissue blood flow, liver function, and histopathology were analyzed. Two- week animal survival was 30% in Group 1, 83% in Group 2, 100% in Group 3, and 100% in Group 4. Postreperfusion hepatic tissue blood flow was markedly improved by the treatment. Treatment significantly attenuated liver enzyme release, lipid peroxidation, and changes in adenine nucleotides and purine catabolites. Structural abnormality of the liver after reperfusion was markedly improved by R75231 treatment, showing better architecture and less neutrophil infiltration. Preischemic administration of a nucleoside transport inhibitor ameliorated ischemic liver injury due to the positive effects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled non-heartbeating donor

Past practices, current debates and disputes:future engagements and opportunities regarding digital transformation for sustainable development

This chapter provides a historical account of the development of Working Group 9.4 from its inception in 1988 to the present day. The intellectual and practical issues that have drawn our attention, as well as the debates and disputes that we have had for over thirty years, are elicited and discussed. More attention is paid to the current opportunities and challenges that enthuse us, and to the impacts that we hope to exert through our work. The chapter concludes with an eye to the future and how the working group may yet develop. The sixteen co-authors of the chapter reflect on how the field of development has morphed over time and on the directions that are opening up.</p

High-quality health systems in the Sustainable Development Goals era: time for a revolution.

Executive summary: Although health outcomes have improved in low-income and middle-income countries (LMICs) in the past several decades, a new reality is at hand. Changing health needs, growing public expectations, and ambitious new health goals are raising the bar for health systems to produce better health outcomes and greater social value. But staying on current trajectory will not suffice to meet these demands. What is needed are high-quality health systems that optimise health care in each given context by consistently delivering care that improves or maintains health, by being valued and trusted by all people, and by responding to changing population needs. Quality should not be the purview of the elite or an aspiration for some distant future; it should be the DNA of all health systems. Furthermore, the human right to health is meaningless without good quality care because health systems cannot improve health without it. We propose that health systems be judged primarily on their impacts, including better health and its equitable distribution; on the confidence of people in their health system; and on their economic benefit, and processes of care, consisting of competent care and positive user experience. The foundations of high-quality health systems include the population and their health needs and expectations, governance of the health sector and partnerships across sectors, platforms for care delivery, workforce numbers and skills, and tools and resources, from medicines to data. In addition to strong foundations, health systems need to develop the capacity to measure and use data to learn. High-quality health systems should be informed by four values: they are for people, and they are equitable, resilient, and efficient. For this Commission, we examined the literature, analysed surveys, and did qualitative and quantitative research to evaluate the quality of care available to people in LMICs across a range of health needs included in the Sustainable Development Goals (SDGs). We explored the ethical dimensions of high-quality care in resource-constrained settings and reviewed available measures and improvement approaches. We reached five conclusions: The care that people receive is often inadequate, and poor-quality care is common across conditions and countries, with the most vulnerable populations faring the worst Data from a range of countries and conditions show systematic deficits in quality of care. In LMICs, mothers and children receive less than half of recommended clinical actions in a typical preventive or curative visit, less than half of suspected cases of tuberculosis are correctly managed, and fewer than one in ten people diagnosed with major depressive disorder receive minimally adequate treatment. Diagnoses are frequently incorrect for serious conditions, such as pneumonia, myocardial infarction, and newborn asphyxia. Care can be too slow for conditions that require timely action, reducing chances of survival. At the system level, we found major gaps in safety, prevention, integration, and continuity, reflected by poor patient retention and insufficient coordination across platforms of care. One in three people across LMICs cited negative experiences with their health system in the areas of attention, respect, communication, and length of visit (visits of 5 min are common); on the extreme end of these experiences were disrespectful treatment and abuse. Quality of care is worst for vulnerable groups, including the poor, the less educated, adolescents, those with stigmatised conditions, and those at the edges of health systems, such as people in prisons. Universal health coverage (UHC) can be a starting point for improving the quality of health systems. Improving quality should be a core component of UHC initiatives, alongside expanding coverage and financial protection. Governments should start by establishing a national quality guarantee for health services, specifying the level of competence and user experience that people can expect. To ensure that all people will benefit from improved services, expansion should prioritise the poor and their health needs from the start. Progress on UHC should be measured through effective (quality-corrected) coverage. High-quality health systems could save over 8 million lives each year in LMICs More than 8 million people per year in LMICs die from conditions that should be treatable by the health system. In 2015 alone, these deaths resulted in US$6 trillion in economic losses. Poor-quality care is now a bigger barrier to reducing mortality than insufficient access. 60% of deaths from conditions amenable to health care are due to poor-quality care, whereas the remaining deaths result from non-utilisation of the health system. High-quality health systems could prevent 2·5 million deaths from cardiovascular disease, 1 million newborn deaths, 900 000 deaths from tuberculosis, and half of all maternal deaths each year. Quality of care will become an even larger driver of population health as utilisation of health systems increases and as the burden of disease shifts to more complex conditions. The high mortality rates in LMICs for treatable causes, such as injuries and surgical conditions, maternal and newborn complications, cardiovascular disease, and vaccine preventable diseases, illustrate the breadth and depth of the health-care quality challenge. Poor-quality care can lead to other adverse outcomes, including unnecessary health-related suffering, persistent symptoms, loss of function, and a lack of trust and confidence in health systems. Waste of resources and catastrophic expenditures are economic side effects of poor-quality health systems. As a result of this, only one-quarter of people in LMICs believe that their health systems work well. Health systems should measure and report what matters most to people, such as competent care, user experience, health outcomes, and confidence in the system Measurement is key to accountability and improvement, but available measures do not capture many of the processes and outcomes that matter most to people. At the same time, data systems generate many metrics that produce inadequate insight at a substantial cost in funds and health workers' time. For example, although inputs such as medicines and equipment are commonly counted in surveys, these are weakly related to the quality of care that people receive. Indicators such as proportion of births with skilled attendants do not reflect quality of childbirth care and might lead to false complacency about progress in maternal and newborn health. This Commission calls for fewer, but better, measures of health system quality to be generated and used at national and subnational levels. Countries should report health system performance to the public annually by use of a dashboard of key metrics (eg, health outcomes, people's confidence in the system, system competence, and user experience) along with measures of financial protection and equity. Robust vital registries and trustworthy routine health information systems are prerequisites for good performance assessment. Countries need agile new surveys and real-time measures of health facilities and populations that reflect the health systems of today and not those of the past. To generate and interpret data, countries need to invest in national institutions and professionals with strong quantitative and analytical skills. Global development partners can support the generation and testing of public goods for health system measurement (civil and vital registries, routine data systems, and routine health system surveys) and promote national and regional institutions and the training and mentoring of scientists. New research is crucial for the transformation of low-quality health systems to high-quality ones Data on care quality in LMICs do not reflect the current disease burden. In many of these countries, we know little about quality of care for respiratory diseases, cancer, mental health, injuries, and surgery, as well as the care of adolescents and elderly people. There are vast blind spots in areas such as user experience, system competence, confidence in the system, and the wellbeing of people, including patient-reported outcomes. Measuring the quality of the health system as a whole and across the care continuum is essential, but not done. Filling in these gaps will require not only better routine health information systems for monitoring, but also new research, as proposed in the research agenda of this Commission. For example, research will be needed to rigorously evaluate the effects and costs of recommended improvement approaches on health, patient experience, and financial protection. Implementation science studies can help discern the contextual factors that promote or hinder reform. New data collection and research should be explicitly designed to build national and regional research capacity. Improving quality of care will require system-wide action To address the scale and range of quality deficits we documented in this Commission, reforming the foundations of the health system is required. Because health systems are complex adaptive systems that function at multiple interconnected levels, fixes at the micro-level (ie, health-care provider or clinic) alone are unlikely to alter the underlying performance of the whole system. However, we found that interventions aimed at changing provider behaviour dominate the improvement field, even though many of these interventions have a modest effect on provider performance and are difficult to scale and sustain over time. Achieving high-quality health systems requires expanding the space for improvement to structural reforms that act on the foundations of the system. This Commission endorses four universal actions to raise quality across the health system. First, health system leaders need to govern for quality by adopting a shared vision of quality care, a clear quality strategy, strong regulation, and continuous learning. Ministries of health cannot accomplish this alone and need to partner with the private sector, civil society, and sectors outside of health care, such as education, infrastructure, communication, and transport. Second, countries should redesign service delivery to maximise health outcomes rather than geographical access to services alone. Primary care could tackle a greater range of low-acuity conditions, whereas hospitals or specialised health centres should provide care for conditions, such as births, that need advanced clinical expertise or have the risk of unexpected complications. Third, countries should transform the health workforce by adopting competency-based clinical education, introducing training in ethics and respectful care, and better supporting and respecting all workers to deliver the best care possible. Fourth, governments and civil society should ignite demand for quality in the population to empower people to hold systems accountable and actively seek high-quality care. Additional targeted actions in areas such as health financing, management, district-level learning, and others can complement these efforts. What works in one setting might not work elsewhere, and improvement efforts should be adapted for local context and monitored. Funders should align their support with system-wide strategies rather than contribute to the proliferation of micro-level efforts. In this Commission, we assert that providing health services without guaranteeing a minimum level of quality is ineffective, wasteful, and unethical. Moving to a high-quality health system—one that improves health and generates confidence and economic benefits—is primarily a political, not technical, decision. National governments need to invest in high-quality health systems for their own people and make such systems accountable to people through legislation, education about rights, regulation, transparency, and greater public participation. Countries will know that they are on the way towards a high-quality, accountable health system when health workers and policymakers choose to receive health care in their own public institutions.Fil: Kruk, Margaret E.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Gage, Anna D.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Arsenault, Catherine. Harvard University. Harvard School of Public Health; Estados UnidosFil: Jordan, Keely. New York College of Global Public Health; Estados UnidosFil: Leslie, Hannah H.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Roder DeWan, Sanam. Harvard University. Harvard School of Public Health; Estados UnidosFil: Adeyi, Olusoji. Banco Mundial; Estados UnidosFil: Barker, Pierre. Institute For Healthcare Improvement; Estados UnidosFil: Daelmans, Bernadette. Organizacion Mundial de la Salud; SuizaFil: Doubova, Svetlana V.. Instituto Mexicano del Seguro Social; MéxicoFil: English, Mike. KEMRI - Wellcome Trust; KeniaFil: Garcia Elorrio, Ezequiel. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guanais, Frederico. Banco Interamericano de Desarrollo; Estados UnidosFil: Gureje, Oye. University Of Ibadan; NigeriaFil: Hirschhorn, Lisa R.. Northwestern University; Estados UnidosFil: Jiang, Lixin. National Center For Cardiovascular Diseases; ChinaFil: Kelley, Edward. Organizacion Mundial de la Salud; SuizaFil: Lemango, Ephrem Tekle. Federal Ministry of Health; EtiopíaFil: Liljestrand, Jerker. Bill and Melinda Gates Foundation; Estados UnidosFil: Malata, Address. Malawi University Of Science And Technology; MalauiFil: Marchant, Tanya. London School of Hygiene & Tropical Medicine; Reino UnidoFil: Matsoso, Malebona Precious. National Department of Health of the Republic of South Africa; SudáfricaFil: Meara, John G.. Harvard Medical School; Estados UnidosFil: Mohanan, Manoj. University of Duke; Estados UnidosFil: Ndiaye, Youssoupha. Ministry of Health and Social Action of the Republic of Senegal; SenegalFil: Norheim, Ole F.. University of Bergen; NoruegaFil: Reddy, K. Srinath. Public Health Foundation of India; IndiaFil: Rowe, Alexander K.. Centers for Disease Control and Prevention; Estados UnidosFil: Salomon, Joshua A.. Stanford University School Of Medicine; Estados UnidosFil: Thapa, Gagan. Legislature Parliament Of Nepal; NepalFil: Twum Danso, Nana A. Y.. Maza; GhanaFil: Pate, Muhammad. Big Win Philanthropy; Reino Unid

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.