Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia

: We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n = 10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy

Religion and HIV in Tanzania: Influence of Religious Beliefs on HIV stigma, Disclosure, and Treatment Attitudes.

Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups

Decisions at the end of life: have we come of age?

Decision making is a complex process and it is particularly challenging to make decisions with, or for, patients who are near the end of their life. Some of those challenges will not be resolved - due to our human inability to foresee the future precisely and the human proclivity to change stated preferences when faced with reality. Other challenges of the decision-making process are manageable. This commentary offers a set of approaches which may lead to progress in this field

Do specialty registrars change their attitudes, intentions and behaviour towards reporting incidents following a patient safety course?

<p>Abstract</p> <p>Background</p> <p>Reporting incidents can contribute to safer health care, as an awareness of the weaknesses of a system could be considered as a starting point for improvements. It is believed that patient safety education for specialty registrars could improve their attitudes, intentions and behaviour towards incident reporting. The objective of this study was to examine the effect of a two-day patient safety course on the attitudes, intentions and behaviour concerning the voluntary reporting of incidents by specialty registrars.</p> <p>Methods</p> <p>A patient safety course was designed to increase specialty registrars' knowledge, attitudes and skills in order to recognize and cope with unintended events and unsafe situations at an early stage. Data were collected through an 11-item questionnaire before, immediately after and six months after the course was given.</p> <p>Results</p> <p>The response rate at all three points in time assessed was 100% (n = 33). There were significant changes in incident reporting attitudes and intentions immediately after the course, as well as during follow-up. However, no significant changes were found in incident reporting behaviour.</p> <p>Conclusions</p> <p>It is shown that patient safety education can have long-term positive effects on attitudes towards reporting incidents and the intentions of registrars. However, further efforts need to be undertaken to induce a real change in behaviour.</p

Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016–40

Background: Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. Methods: We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. Findings: In the reference scenario, global health spending was projected to increase from US$10 trillion (95$20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4–5·1) per year, followed by lower-middle-income countries (4·0%, 3·6–4·5) and low-income countries (2·2%, 1·7–2·8). Despite global growth, per capita health spending was projected to range from only $40 (24–65) to$413 (263–668) in 2040 in low-income countries, and from $140 (90–200) to$1699 (711–3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3–38·6) in Nigeria to 97·9% (96·4–98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. Interpretation: We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC. Funding: The Bill & Melinda Gates Foundation

Two-photon microscopy analysis of leukocyte trafficking and motility

During the last several years, live tissue imaging, in particular using two-photon laser microscopy, has advanced our understanding of leukocyte trafficking mechanisms. Studies using this technique are revealing distinct molecular requirements for leukocyte migration in different tissue environments. Also emerging from the studies are the ingenious infrastructures for leukocyte trafficking, which are produced by stromal cells. This review summarizes the recent imaging studies that provided novel mechanistic insights into in vivo leukocyte migration essential for immunosurveillance

Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016–40

This online publication has been corrected. The corrected version first appeared at thelancet.com on May 3, 2018© 2018 The Author(s). Background: Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. Methods: We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. Findings: In the reference scenario, global health spending was projected to increase from US$10 trillion (95$20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4–5·1) per year, followed by lower-middle-income countries (4·0%, 3·6–4·5) and low-income countries (2·2%, 1·7–2·8). Despite global growth, per capita health spending was projected to range from only $40 (24–65) to$413 (263–668) in 2040 in low-income countries, and from $140 (90–200) to$1699 (711–3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3–38·6) in Nigeria to 97·9% (96·4–98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. Interpretation: We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC.The Bill & Melinda Gates Foundation

Spending on health and HIV/AIDS: domestic health spending and development assistance in 188 countries, 1995–2015

Copyright © 2018 The Author(s). Background: Comparable estimates of health spending are crucial for the assessment of health systems and to optimally deploy health resources. The methods used to track health spending continue to evolve, but little is known about the distribution of spending across diseases. We developed improved estimates of health spending by source, including development assistance for health, and, for the first time, estimated HIV/AIDS spending on prevention and treatment and by source of funding, for 188 countries. Methods: We collected published data on domestic health spending, from 1995 to 2015, from a diverse set of international agencies. We tracked development assistance for health from 1990 to 2017. We also extracted 5385 datapoints about HIV/AIDS spending, between 2000 and 2015, from online databases, country reports, and proposals submitted to multilateral organisations. We used spatiotemporal Gaussian process regression to generate complete and comparable estimates for health and HIV/AIDS spending. We report most estimates in 2017 purchasing-power parity-adjusted dollars and adjust all estimates for the effect of inflation. Findings: Between 1995 and 2015, global health spending per capita grew at an annualised rate of 3·1% (95% uncertainty interval [UI] 3·1 to 3·2), with growth being largest in upper-middle-income countries (5·4% per capita [UI 5·3–5·5]) and lower-middle-income countries (4·2% per capita [4·2–4·3]). In 2015, $9·7 trillion (9·7 trillion to 9·8 trillion) was spent on health worldwide. High-income countries spent$6·5 trillion (6·4 trillion to 6·5 trillion) or 66·3% (66·0 to 66·5) of the total in 2015, whereas low-income countries spent $70·3 billion (69·3 billion to 71·3 billion) or 0·7$29·9 billion), with an estimated $37·4 billion of development assistance being disbursed for health in 2017, of which$9·1 billion (24·2%) targeted HIV/AIDS. Between 2000 and 2015, $562·6 billion (531·1 billion to 621·9 billion) was spent on HIV/AIDS worldwide. Governments financed 57·6$48·9 billion (45·2 billion to 54·2 billion) in 2015. That year, low-income and lower-middle-income countries represented 74·6% of all HIV/AIDS disability-adjusted life-years, but just 36·6% (34·4 to 38·7) of total HIV/AIDS spending. In 2015, $9·3 billion (8·5 billion to 10·4 billion) or 19·0$27·3 billion (24·5 billion to 31·1 billion) or 55·8% (53·3 to 57·9) was dedicated to care and treatment. Interpretation: From 1995 to 2015, total health spending increased worldwide, with the fastest per capita growth in middle-income countries. While these national disparities are relatively well known, low-income countries spent less per person on health and HIV/AIDS than did high-income and middle-income countries. Furthermore, declines in development assistance for health continue, including for HIV/AIDS. Additional cuts to development assistance could hasten this decline, and risk slowing progress towards global and national goals. Funding: The Bill & Melinda Gates Foundation.The Bill & Melinda Gates Foundation

Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016–40

This online publication has been corrected. The corrected version first appeared at thelancet.com on May 3, 2018© 2018 The Author(s). Background: Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. Methods: We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. Findings: In the reference scenario, global health spending was projected to increase from US$10 trillion (95$20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4–5·1) per year, followed by lower-middle-income countries (4·0%, 3·6–4·5) and low-income countries (2·2%, 1·7–2·8). Despite global growth, per capita health spending was projected to range from only $40 (24–65) to$413 (263–668) in 2040 in low-income countries, and from $140 (90–200) to$1699 (711–3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3–38·6) in Nigeria to 97·9% (96·4–98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. Interpretation: We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC.The Bill & Melinda Gates Foundation