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Background/objectives: Hypertension is linked to slower walking pace and cognitive decline, but the ability of slow gait to predict dementia in older adults with hypertension is unclear. This study examined whether slow baseline gait predicts future cognitive impairment in older adults with hypertension enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (MIND) study., Methods: SPRINTMIND randomized adults ≥50 years of age with hypertension to intensive (target systolic blood pressure <120 mmHg) or standard (<140 mmHg) blood pressure control. Baseline gait speed was measured in participants ≥75 years of age. We defined slow gait as speed ≤0.8 m/s. Outcomes were probable dementia (pD), mild cognitive impairment (MCI), and composite pD or MCI., Results: Among 2,351 participants, 33.3% had slow baseline gait. Over median 4-year follow-up, the slow gait group had higher rates of incident pD (13.5% vs 6.4%), MCI (19.4% vs 11.9%), and pD or MCI (29.2% vs 16.3%) compared with normal gait. Adjusted Cox regression models revealed that slow gait was associated with a 1.85-fold higher risk of pD (95% confidence interval [1.37, 2.50], p < .001), 1.52-fold higher risk of MCI (95% confidence interval [1.20, 1.93], p = .001), and 1.61-fold higher risk of pD or MCI (95% confidence interval [1.32, 1.97], p < .001). Intensive blood pressure control did not significantly affect cognitive outcomes in either gait group., Conclusion: Slow gait speed predicts increased cognitive decline risk among older adults with hypertension. Significance/Implications: Gait speed assessment can identify older adults with hypertension at higher risk of cognitive decline, allowing earlier intervention to potentially delay progression.

Neuro-electrophysiological recordings contain prominent aperiodic activity - meaning irregular activity, with no characteristic frequency - which has variously been referred to as 1/f (or 1/f-like activity), fractal, or 'scale-free' activity. Previous work has established that aperiodic features of neural activity is dynamic and variable, relating (between subjects) to healthy aging and to clinical diagnoses, and also (within subjects) tracking conscious states and behavioral performance. There are, however, a wide variety of conceptual frameworks and associated methods for the analyses and interpretation of aperiodic activity - for example, time domain measures such as the autocorrelation, fractal measures, and/or various complexity and entropy measures, as well as measures of the aperiodic exponent in the frequency domain. There is a lack of clear understanding of how these different measures relate to each other and to what extent they reflect the same or different properties of the data, which makes it difficult to synthesize results across approaches and complicates our overall understanding of the properties, biological significance, and demographic, clinical, and behavioral correlates of aperiodic neural activity. To address this problem, in this project we systematically survey the different approaches for measuring aperiodic neural activity, starting with an automated literature analysis to curate a collection of the most common methods. We then evaluate and compare these methods, using statistically representative time series simulations. In doing so, we establish consistent relationships between the measures, showing that much of what they capture reflects shared variance - though with some notable idiosyncrasies. Broadly, frequency domain methods are more specific to aperiodic features of the data, whereas time domain measures are more impacted by oscillatory activity. We extend this analysis by applying the measures to a series of empirical EEG and iEEG datasets, replicating the simulation results. We conclude by summarizing the relationships between the multiple methods, emphasizing opportunities for reexamining previous findings and for future work., Competing Interests: Conflicts of Interest The authors declare no competing interests.

To support complex cognition, neuronal circuits must integrate information across multiple temporal scales, ranging from milliseconds to decades. Neuronal timescales describe the duration over which activity within a network persists, posing a putative explanatory mechanism for how information might be integrated over multiple temporal scales. Little is known about how timescales develop in human neural circuits or other model systems, limiting insight into how the functional dynamics necessary for cognition emerge. In our work, we show that neuronal timescales develop in a nonlinear fashion in human cortical organoids, which is partially replicated in dissociated rat hippocampus cultures. We use spectral parameterization of spiking activity to extract an estimate of neuronal timescale that is unbiased by coevolving oscillations. Cortical organoid timescales begin to increase around month 6 postdifferentiation. In rodent hippocampal dissociated cultures, we see that timescales decrease from in vitro days 13 - 23 before stabilizing. We speculate that cortical organoid development over the duration studied here reflects an earlier stage of a generalized developmental timeline in contrast to the rodent hippocampal cultures, potentially accounting for differences in timescale developmental trajectories. The fluctuation of timescales might be an important developmental feature that reflects the changing complexity and information capacity in developing neuronal circuits. NEW & NOTEWORTHY Neuronal timescales describe the persistence of activity within a network of neurons. Timescales were found to fluctuate with development in two model systems. In cortical organoids timescales increased, peaked, and then decreased throughout development; in rat hippocampal dissociated cultures timescales decreased over development. These distinct developmental models overlap to highlight a critical window in which timescales lengthen and contract, potentially indexing changes in the information capacity of neuronal systems.

Background Metabolic syndrome (MetS) has been recognized as a global health problem. Concurrent MetS diagnosis in patients with ST-elevation myocardial infarction (STEMI) is becoming increasingly common. Given the paucity of studies on the impact of MetS on treatment outcomes in STEMI patients, the purpose of this study was to evaluate in-hospital mortality in STEMI patients with a concurrent MetS diagnosis undergoing a stenting procedure to treat their underlying coronary artery disease. Method Patients with or without MetS who underwent coronary stenting following STEMI between 2005 and 2014 were identified from the National Inpatient Sample database. Patients' demographics, comorbidities, and outcomes were compared using a t-test and Pearson's Chi-square test. In addition, 1:1 propensity score matching was performed for age, gender, and race. Results Out of 1,938,097 STEMI patients, 5,817 patients with MetS underwent coronary stenting following STEMI and were matched with 5,817 patients with no Mets. MetS group had significantly higher rates of diabetes, hypertension, hyperlipidemia, chronic kidney disease, and obstructive sleep apnea than the no MetS group but lower rates of heart failure and chronic obstructive pulmonary disease. In-hospital mortality following STEMI was significantly lower in patients with MetS (2.5% vs. 7.1%, p<0.001) and remained significant after adjusting for potential confounders (odds ratio (OR) 0.34, 95% confidence interval (95% CI) 0.28-0.42, p<0.0001). Conclusion Concurrent diagnosis of MetS among patients undergoing coronary stenting is associated with a decreased in-hospital mortality risk. The impact of specific MetS components on the observed reduction in mortality remains unclear and warrants evaluation in future studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Igbinosa et al.)

Dampened behavioral inhibition and overactive behavioral approach motivation systems (i.e. BIS/BAS) are associated with cannabis use disorder (CUD), although the underlying neural mechanisms of these alterations have not yet been examined. The brain's executive control network (ECN) plays a role in decision-making and is associated with BIS/BAS. In this study, we tested the hypothesis that altered ECN resting-state functional connectivity (rsFC) underlies dysfunctional behavioral inhibition and approach motivation in cannabis users. To that end, we collected resting-state functional magnetic resonance imaging scans in 86 cannabis using adults and 59 non-using adults to examine group differences in the relationship between ECN rsFC and BIS/BAS. Our results showed that BIS was positively correlated with left ECN rsFC in cannabis users, while it was positively correlated with right ECN rsFC in non-users. There was a trend-level moderation effect of group on the association between BIS/BAS and ECN rsFC, showing a weaker association in BIS/BAS and ECN rsFC in cannabis users compared to non-users. An exploratory mediation analysis found that the severity of CUD mediated the relationship between users' BIS scores and left ECN rsFC. These findings suggest that cannabis use may lead to dysregulation in typical ECN functional organization related to BIS/BAS., (© The Author(s) 2021. Published by Oxford University Press.)

The ongoing trend toward legalization of cannabis for medicinal/recreational purposes is expected to increase the prevalence of cannabis use disorder (CUD). Thus, it is imperative to be able to predict the quantitative risk of developing CUD for a cannabis user based on their personal risk factors. Yet no such model currently exists. In this study, we perform preliminary analysis toward building such a model. The data come from n = 94 regular cannabis users recruited from Albuquerque, New Mexico during 2007-2010. As the data are cross-sectional, we only consider risk factors that remain relatively stable over time. We apply statistical and machine learning classification techniques that allow n to be small relative to the number of predictors. We use predictive accuracy estimated using leave-one-out-cross-validation to evaluate model performance. The final model is a LASSO logistic regression model consisting of the following seven risk factors: age; level of enjoyment from initial cigarette smoking; total score on Impulsive Sensation-Seeking Scale questionnaire; score on cognitive instability factor of Barratt Impulsivity Scale questionnaire; and scores on neuroticism, openness, and conscientiousness personality traits of Neuroticism, Extraversion, and Openness inventory. This model has an overall accuracy of 0.66 and the area under its receiver operating characteristic curve is 0.65. In summary, a preliminary relative risk model for predicting the quantitative risk of CUD is developed. It can be employed to identify users at high risk of CUD who may be provided with early intervention., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

The September 2019 United Nations High Level Meeting on Universal Health Coverage (UHC) aims to mobilize top-level political support for action on UHC to advance the health Sustainable Development Goal (SDG). A driving force behind this meeting is the "UHC Movement," led by UHC2030, which focuses on coordinating and amplifying efforts by WHO, the World Bank, civil society, and the private sector to strengthen health systems and achieve UHC. In line with Horton and Das, this paper contends that while the argument about UHC is won, it is crucially important to focus on "how" UHC will be delivered, and specifically, whether ongoing efforts to advance UHC align with efforts to realize the right to health. This paper offers a preliminary assessment of how UHC2030's contributions to global health governance advance, or not, the right to health care. It builds on a 2014 Go4Health study which identified key normative overlap and gaps in UHC and right to health care principles. Given the importance of civil society participation in advancing health rights, this analysis is complemented by an examination of how UHC2030 might amplify ongoing efforts to advance the right to health care in two UHC2030 partner countries, Kenya and Uganda., Competing Interests: Competing interests: None declared., (Copyright © 2019 Hammonds, Ooms, Mulumba, and Maleche.)

If health is a human right and if human rights are 'rights held by individuals simply because they are part of the human species', then all people, wherever they live, should be entitled to the same collective efforts that can protect or improve their health. In reality, not all people on the planet have access to the same set of health-related entitlements. There are huge disparities between the entitlements one can claim when living in a high-income country and the entitlements one can claim when living in a low-income country. Even within each country, there are disparities. The health-related entitlements people really have seem to be dependent on their belonging to a nation, family, or household. In this article, we explore and critically analyze two trends from a right-to-health perspective: the stagnation or even decrease of international assistance for health services in low- and middle-income countries and the increasing exclusion of undocumented migrants from health care in high-income countries. We argue that both trends constitute violations of the right to health; we posit an explanation for why they are occurring in countries that express support for human rights by expanding on the supposition that human rights are evolving from what were citizen's rights; and we discuss the role of individual human right supporters in an age of nationalism., (Copyright © 2019 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary drainage and previous small studies suggested survival benefit., Aims: To assess the difference in outcome between patients with BTC undergoing palliative stenting plus PDT versus stenting alone., Methods: 92 patients with confirmed locally advanced or metastatic BTC, ECOG performance status 0-3 and adequate biliary drainage were randomised (46 per group) to receive porfimer sodium PDT plus stenting or stenting alone. The primary end point was overall survival (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced for baseline factors and prior therapy., Results: No significant differences in grade 3-4 toxicities and no grade 3-4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively)., Conclusion: In patients with locally advanced or metastatic BTC, PDT was associated with worse outcome than stenting alone, explained only in part by the differences in chemotherapy treatments. We conclude that optimal stenting remains the treatment of choice for malignant biliary obstruction and the use of PDT for this indication cannot be recommended outside of clinical trials., Trial Registration Number: ISRCTN 87712758; EudraCT 2005-001173-96; UKCRN ID: 1461., Competing Interests: Competing interests: None declared.

This qualitative study examines the role of communication among African American mothers living with HIV and their daughters in HIV prevention. Multiple themes emerged from our analysis of semistructured interviews with mothers (n = 15), and their adult daughters, (n = 15) such as perceptions of HIV risk communication, HIV/AIDS knowledge, attitudes, and beliefs. The findings of the study revealed differences in communication between mothers and daughters. Daughters felt they did not receive adequate and frequent HIV prevention advice from their mothers. Implications include strengthening communication content between mother-daughter dyads in HIV prevention programs that can aid in reducing HIV risk.

Solomon Benatar's paper "Politics, Power, Poverty and Global Health: Systems and Frames" examines the inequitable state of global health challenging readers to extend the discourse on global health beyond conventional boundaries by addressing the interconnectedness of planetary life. Our response explores existing models of international cooperation, assessing how modifying them may achieve the twin goals of ensuring healthy people and planet. First, we address why the inequality reducing post World War II European welfare model, if implemented state-by-state, is unfit for reducing global inequality and respecting environmental boundaries. Second, we argue that to advance beyond the 'Westphalian,' human centric thinking integral to global inequality and climate change requires challenging the logic of global economic integration and exploring the politically infeasible. In conclusion, we propose social policy focused changes to the World Trade Organisation (WTO) and a Green and Social Climate Fund, financed by new global greenhouse gas charges, both of which could advance human and planetary health. Recent global political developments may offer a small window of opportunity for out of the box proposals that could be advanced by concerted and united advocacy by global health activists, environmental activists, human rights activists, and trade unions., (© 2017 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

This paper explores the extent to which global health governance - in the context of the early implementation of the Sustainable Development Goals is grounded in the right to health. The essential components of the right to health in relation to global health are unpacked. Four essential functions of the global health system are assessed from a normative, rights-based, analysis on how each of these governance functions should operate. These essential functions are: the production of global public goods, the management of externalities across countries, the mobilization of global solidarity, and stewardship. The paper maps the current reality of global health governance now that the post-2015 Sustainable Development Goals are beginning to be implemented. In theory, the existing human rights legislation would enable the principles and basis for the global governance of health beyond the premise of the state. In practice, there is a governance gap between the human rights framework and practices in global health and development policies. This gap can be explained by the political determinants of health that shape the governance of these global policies. Current representations of the right to health in the Sustainable Development Goals are insufficient and superficial, because they do not explicitly link commitments or right to health discourse to binding treaty obligations for duty-bearing nation states or entitlements by people. If global health policy is to meaningfully contribute to the realization of the right to health and to rights based global health governance then future iterations of global health policy must bridge this gap. This includes scholarship and policy debate on the structure, politics, and agency to overcome existing global health injustices.

Background: Global constitutionalism is a way of looking at the world, at global rules and how they are made, as if there was a global constitution, empowering global institutions to act as a global government, setting rules which bind all states and people., Analysis: This essay employs global constitutionalism to examine how and why global health governance, as currently structured, has struggled to advance the right to health, a fundamental human rights obligation enshrined in the International Covenant on Economic, Social and Cultural Rights. It first examines the core structure of the global health governance architecture, and its evolution since the Second World War. Second, it identifies the main constitutionalist principles that are relevant for a global constitutionalism assessment of the core structure of the global health governance architecture. Finally, it applies these constitutionalist principles to assess the core structure of the global health governance architecture., Discussion: Leading global health institutions are structurally skewed to preserve high incomes countries' disproportionate influence on transnational rule-making authority, and tend to prioritise infectious disease control over the comprehensive realisation of the right to health., Conclusion: A Framework Convention on Global Health could create a classic division of powers in global health governance, with WHO as the law-making power in global health governance, a global fund for health as the executive power, and the International Court of Justice as the judiciary power.

Can the right to health, and particularly the core obligations of states specified under this right, assist in formulating and implementing universal health coverage (UHC), now included in the post-2015 Sustainable Development Goals? In this paper, we examine how core obligations under the right to health could lead to a version of UHC that is likely to advance equity and rights. We first address the affinity between the right to health and UHC as evinced through changing definitions of UHC and the health domains that UHC explicitly covers. We then engage with relevant interpretations of the right to health, including core obligations. We turn to analyze what core obligations might bring to UHC, particularly in defining what and who is covered. Finally, we acknowledge some of the risks associated with both UHC and core obligations and consider potential avenues for mitigating these risks., Competing Interests: Competing interests: None declared.

Background: As the human cost of the global economic crisis becomes apparent the ongoing discussions surrounding the post-2015 global development framework continue at a frenzied pace. Given the scale and scope of increased globalization moving forward in a post-Millennium Development Goals era, to protect and realize health equity for all people, has never been more challenging or more important. The unprecedented nature of global interdependence underscores the importance of proposing policy solutions that advance realizing global responsibility for global health., Discussion: This article argues for advancing global responsibility for global health through the creation of a Global Fund for Health. It suggests harnessing the power of the exceptional response to the combined epidemics of AIDS, TB and Malaria, embodied in the Global Fund to Fight AIDS, Tuberculosis and Malaria, to realize an expanded, reconceptualized Global Fund for Health. However this proposal creates both an analytical quandary embedded in conceptual pluralism and a practical dilemma for the scope and raison d'etre of a new Global Fund for Health. To address these issues we offer a logical framework for moving from conceptual pluralism in the theories supporting global responsibility for health to practical agreement on policy to realize this end. We examine how the innovations flowing from this exceptional response can be coupled with recent ideas and concepts, for example a global social protection floor, a Global Health Constitution or a Framework Convention for Global Health, that share the global responsibility logic that underpins a Global Fund for Health., Conclusions: The 2014 Lancet Commission on Global Governance for Health Report asks whether a single global health protection fund would be better for global health than the current patchwork of global and national social transfers. We concur with this suggestion and argue that there is much room for practical agreement on a Global Fund for Health that moves from the conceptual level into policies and practice that advance global health. The issues of shared responsibility and mutual accountability feature widely in the post-2015 discussions and need to be addressed in a coherent manner. Our article argues why and how a Global Fund for Health effectuates this, thus advancing global responsibility for global health.

If human rights are "inalienable rights of all members of the human family", as is enshrined in the Universal Declaration of Human Rights, then no government should be allowed to deny people of them. When some governments fail to realize them for the people under their jurisdiction, the international community has a responsibility to step in. This extra-territorial effect of human rights was not included in the original conception of human rights. It is of recent date, and, in practice, limited to interventions to end severe violations of civil and political human rights. For economic, social and cultural human rights, extra-territorial obligations are still contested. In this paper, we elaborate three contentions: first, that the realization of social human rights requires the acceptance of and compliance with extra-territorial obligations; second, that compliance with extra-territorial obligations would help transform the international assistance paradigm from charity into legal obligation; and third, that for global constitutionalism to succeed in improving the fairness of the international legal order requires acceptance of the indivisibility of human rights.

Introduction: In the year 2000, a set of eight Millennium Development Goals (MDGs) were presented as a way to channel global efforts into the reduction of poverty and the promotion of social development. A global discussion regarding how to renew these goals is underway and it is in this context that the Goals and Governance for Global Health (Go4Health) research consortium conducted consultations with marginalized communities in Asia, Latin America, the Pacific and Africa as a way to include their voices in world's new development agenda. The goal of this paper is to present the findings of the consultations carried out in Uganda with two groups within low-resource settings: older people and people living with disabilities., Methods: This qualitative study used focus group discussions and key informant interviews with older people in Uganda's Kamwenge district, and with persons with disabilities from the Gulu region. Thematic analysis was performed and emerging categories and themes identified and presented in the findings., Findings: Our findings show that a sense of community marginalization is present within both older persons and persons living with disabilities. These groups report experiencing political sidelining, discrimination and inequitable access to health services. This is seen as the key reason for their poor health. Clinical services were found to be of low quality with little or no access to facilities, trained personnel, and drugs and there are no rehabilitative or mental health services available., Conclusion: Uganda must fulfil its international obligations and take progressive measures to meet the right to health for all its peoples, but especially allocate its limited resources to proactively support its most marginalized citizens. The growing impetus within post-2015 development negotiations to redress in-country health and other inequalities through a comprehensive systems approach is of importance in the Ugandan development context. This approach reflects the participant's perspectives, which also calls for a more equitable approach to health and development as opposed to a narrow, vertical focus on specific population groups, as was the case with the MDGs.

It has been argued that the international community is moving 'beyond aid'. International co-financing in the international collective interest is expected to replace altruistically motivated foreign aid. The World Health Organization promotes 'universal health coverage' as the overarching health goal for the next phase of the Millennium Development Goals. In order to provide a basic level of health care coverage, at least some countries will need foreign aid for decades to come. If international co-financing of global public goods is replacing foreign aid, is universal health coverage a hopeless endeavor? Or would universal health coverage somehow serve the international collective interest?Using the Sustainable Development Solutions Network proposal to finance universal health coverage as a test case, we examined the hypothesis that national social policies face the threat of a 'race to the bottom' due to global economic integration and that this threat could be mitigated through international social protection policies that include international cross-subsidies - a kind of 'equalization' at the international level.The evidence for the race to the bottom theory is inconclusive. We seem to be witnessing a 'convergence to the middle'. However, the 'middle' where 'convergence' of national social policies is likely to occur may not be high enough to keep income inequality in check.The implementation of the international equalization scheme proposed by the Sustainable Development Solutions Network would allow to ensure universal health coverage at a cost of US$55 in low income countries-the minimum cost estimated by the World Health Organization. The domestic efforts expected from low and middle countries are far more substantial than the international co-financing efforts expected from high income countries. This would contribute to 'convergence' of national social policies at a higher level. We therefore submit that the proposed international equalization scheme should not be considered as foreign aid, but rather as an international collective effort to protect and promote national social policy in times of global economic integration: thus serving the international collective interest.

Background: The global response to HIV suggests the potential of an emergent global right to health norm, embracing shared global responsibility for health, to assist policy communities in framing the obligations of the domestic state and the international community. Our research explores the extent to which this global right to health norm has influenced the global policy process around maternal health rights, with a focus on universal access to emergency obstetric care., Methods: In examining the extent to which arguments stemming from a global right to health norm have been successful in advancing international policy on universal access to emergency obstetric care, we looked at the period from 1985 to 2013 period. We adopted a qualitative case study approach applying a process-tracing methodology using multiple data sources, including an extensive literature review and limited key informant interviews to analyse the international policy agenda setting process surrounding maternal health rights, focusing on emergency obstetric care. We applied John Kingdon's public policy agenda setting streams model to analyse our data., Results: Kingdon's model suggests that to succeed as a mobilising norm, the right to health could work if it can help bring the problem, policy and political streams together, as it did with access to AIDS treatment. Our analysis suggests that despite a normative grounding in the right to health, prioritisation of the specific maternal health entitlements remains fragmented., Conclusions: Despite United Nations recognition of maternal mortality as a human rights issue, the relevant policy communities have not yet managed to shift the policy agenda to prioritise the global right to health norm of shared responsibility for realising access to emergency obstetric care. The experience of HIV advocates in pushing for global solutions based on right to health principles, including participation, solidarity and accountability; suggest potential avenues for utilising right to health based arguments to push for policy priority for universal access to emergency obstetric care in the post-2015 global agenda.

Establishing a reform agenda for the World Health Organization (WHO) requires understanding its role within the wider global health system and the purposes of that wider global health system. In this paper, the focus is on one particular purpose: achieving universal health coverage (UHC). The intention is to describe why achieving UHC requires something like a Framework Convention on Global Health (FCGH) that have been proposed elsewhere,(1) why WHO is in a unique position to usher in an FCGH, and what specific reforms would help enable WHO to assume this role., (Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Progress towards Millennium Development Goal 5a, reducing maternal deaths by 75% between 1990 and 2015, has been substantial; however, it has been too slow to hope for its achievement by 2015, particularly in sub-Saharan Africa, including Uganda. This suggests that both the Government of Uganda and the international community are failing to comply with their right-to-health-related obligations towards the people of Uganda. This country case study explores some of the key issues raised when assessing national and international right-to-health-related obligations. We argue that to comply with their shared obligations, national and international actors will have to take steps to move forward together. The Government of Uganda should not expect additional international assistance if it does not live up to its own obligations; at the same time, the international community must provide assistance that is more reliable in the long run to create the 'fiscal space' that the Government of Uganda needs to increase recurrent expenditure for health - which is crucial to addressing maternal mortality. We propose that the 'Roadmap on Shared Responsibility and Global Solidarity for AIDS, TB and Malaria Response in Africa', adopted by the African Union in July 2012, should be seen as an invitation to the international community to conclude a global social contract for health., (Copyright © 2013 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.)

Background: Given that many low income countries are heavily reliant on external assistance to fund their health sectors the acceptance of obligations of international assistance and cooperation with regard to the right to health (global health obligations) is insufficiently understood and studied by international health and human rights scholars. Over the past decade Global Health Initiatives, like the Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund) have adopted novel approaches to engaging with stakeholders in high and low income countries. This article explores how this experience impacted on acceptance of the international obligation to (help) fulfil the right to health beyond borders., Methods: The authors conducted an extensive review of international human rights law literature, transnational legal process literature, global public health literature and grey literature pertaining to Global Health Initiatives. To complement this desk work and deepen their understanding of how and why different legal norms evolve the authors conducted 19 in-depth key informant interviews with actors engaged with three stakeholders; the European Union, the United States and Belgium. The authors then analysed the interviews through a transnational legal process lens., Results: Through according value to the process of examining how and why different legal norms evolve transnational legal process offers us a tool for engaging with the dynamism of developments in global health suggesting that operationalising global health obligations could advance the right to health for all., Conclusions: In many low-income countries the health sector is heavily dependent on external assistance to fulfil the right to health of people thus it is vital that policies and tools for delivering reliable, long-term assistance are developed so that the right to health for all becomes more than a dream. Our research suggests that the Global Fund experience offers lessons to build on.

The first decade of the new millennium saw an upsurge in global financing for health. When the world took stock of progress on the Millennium Development Goals in mid-2010 the one addressing maternal health showed the least progress. Did maternal health miss the boat? In mid-2010 the Secretary-General of the United Nations launched a "Global Strategy for Women's and Children's Health", also known as the "Every Woman Every Child" initiative. Has the tide now turned in favour of maternal health? The authors try to answer this question by first examining whether maternal health really missed out with respect to increased global funding and why this may have occurred. They then assess whether the new initiative will make a difference by comparing several elements of the approach taken by HIV/AIDS activist to that of maternal health activists. They suggest that real progress requires international financing, thus pledges must become robust and reliable commitments. They conclude that the absence of an organisational structure in the current initiative means the global maternal health financing revolution will probably not happen.

The Millennium Development Goals (MDGs) were defined in 2001, making poverty the central focus of the global political agenda. In response to MDG targets for health, new funding instruments called Global Health Initiatives were set up to target specific diseases, with an emphasis on "quick win" interventions, in order to show improvements by 2015. In 2005 the UN Millennium Project defined quick wins as simple, proven interventions with "very high potential short-term impact that can be immediately implemented", in contrast to "other interventions which are more complicated and will take a decade of effort or have delayed benefits". Although the terminology has evolved from "quick wins" to "quick impact initiatives" and then to "high impact interventions", the short-termism of the approach remains. This paper examines the merits and limitations of MDG indicators for assessing progress and their relationship to quick impact interventions. It then assesses specific health interventions through both the lens of time and their integration into health care services, and examines the role of health systems strengthening in support of the MDGs. We argue that fast-track interventions promoted by donors and Global Health Initiatives need to be complemented by mid- and long-term strategies, cutting across specific health problems. Implementing the MDGs is more than a process of "money changing hands". Combating poverty needs a radical overhaul of the partnership between rich and poor countries and between rich and poor people within countries., (Copyright © 2011 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.)

In "Just Health", Norman Daniels makes a strong argument for obligations of mutual assistance to fulfill the right to health at the national level and challenges readers to develop arguments supporting obligations of mutual assistance at the global level. In this paper, we argue that there is global responsibility for global health and that there are obligations of justice (beyond charity) to help fulfill (not merely respect or even protect) the right to health in other countries; these we call obligations of global health justice. We show how international human rights law affirms obligations of global health justice - beyond national obligations and beyond obligations of charity - and assert that the human rights approach provides guidance on delineating the relationship between national and global responsibility for fulfilling the core obligations that arise from socioeconomic human rights and addressing global health inequities. We further argue that new ways of providing international assistance, originating from the global HIV/AIDS response, demonstrate the feasibility of improving health outcomes through exogenous efforts and that obligations of global health justice thus carry much weight: the weight of lives not saved. The global response to the HIV/AIDS pandemic has led to the emergence of a new international health assistance paradigm, and the Global Fund to fight AIDS, Tuberculosis and Malaria is, we suggest, an embryonic form of this new paradigm. We conclude that agreements on several common parameters delineating global and national responsibility for global health can advance the movement towards a global institution for the distribution of health-related goods.

The International Monetary Fund's recent claims concerning its impact on public health are evaluated against available data. First, the IMF claims that health spending either does not change or increases with IMF-supported programs, but there is substantial evidence to the contrary. Second, the IMF claims to have relaxed strict spending requirements in response to the 2008-9 financial crisis, but there is no evidence supporting this claim, and some limited evidence from the Center for Economic Policy Research contradicting it. Third, the IMF states that wage ceilings on public health are no longer part of its explicit conditionalities to poor countries, as governments can choose how to achieve public spending targets; but in practice, ministers are left with few viable alternatives than to reduce health budgets to achieve specific IMF-mandated targets, so the result effectively preserves former policy. Fourth, the IMF's claim that it has increased aid to poor countries also seems to be contradicted by its policies of diverting aid to reserves, as well as evidence that a very small fraction of the Fund's new lending in response to the financial crisis has reached poor countries. Finally, the IMF's claim that it follows public health standards in tobacco control contrasts with its existing policies, which fail to follow the guidelines recommended by the World Bank and World Health Organization. The authors recommend that the IMF (1) become more transparent in its policies, practices, and data to allow improved independent evaluations of its impact on public health (including Health Impact Assessment) and (2) review considerable public health evidence indicating a negative association between its current policies and public health outcomes.

People living in low-income countries require protection from the economic and social impacts of global economic competition, yet, historically, the International Monetary Fund's (IMF) fiscal austerity programs have weakened the potential for redistribution both within poor countries and between rich and poor countries. The current development paradigm's focus on "sustainability" is an obstacle to developing systems of global social protection and an impediment to future progress. Reforming IMF policy conditionality and democratizing the IMF's decision-making processes will be necessary for offsetting growing inequalities in health financing among poor nations.

Background and Study Aims: It is well recognized that myocardial ischemia can occur during endoscopic retrograde cholangiopancreatography (ERCP). Acute arrhythmias and ST segment changes have been reported by a number of authors, but the longer-term sequelae with regard to permanent myocardial damage are not known. The aim of this study was to determine the presence or absence of significant injury to the heart muscle., Patients and Methods: Sixty-two patients undergoing therapeutic ERCP were assessed clinically and with electrocardiography (ECG) for the presence of ischemic heart disease before the procedure. Extensive intraprocedural monitoring was carried out, postprocedural ECGs were recorded, and serum troponin T levels were measured. The ECGs were evaluated blindly by a single cardiologist., Results: In 61 of the 62 patients, no changes were observed between the ECGs before and after the procedure. One patient had postprocedural T wave inversion but a normal troponin T level, excluding myocardial damage. One patient with mild renal insufficiency and treated heart failure had borderline troponin T elevation (0.05 microg/l) but no ECG changes. No complications of ERCP occurred., Conclusions: Whilst ECG and rhythm changes indicating transient myocardial ischemia do occur during ERCP, there is no evidence that myocardial damage takes place as a consequence of this.

Rse, Ax1, and c-Mer comprise a family of cell adhesion molecule-related tyrosine kinase receptors. Human Gas6 was recently shown to act as a ligand for both human Rse (Godowski et al., 1995) and human Ax1 (Varnum et al., 1995). Gas6 contains an NH2-terminal Gla domain followed by four epidermal growth factor-like repeats and tandem globular (G) domains. The G domains are related to those found in sex hormone-binding globulin and to those utilized by laminin and agrin for binding to the dystroglycan complex. A series of Gas6 variants were tested for their ability to bind to Rse and Ax1. The Gla domain and epidermal growth factor-like repeats were not required for receptor binding, as deletion variants of Gas6 which lacked these domains bound to the extracellular domains of both Rse and Axl. A deletion variant of Gas6 containing just the G domain region was shown to activate Rse phosphorylation. These results provide evidence that G domains can act as signaling molecules by activating transmembrane receptor tyrosine kinases. Furthermore, they provide a structural link between the activation of cell adhesion related receptors and the control of cell growth and differentiation by the G domain-containing superfamily of proteins.

Reexamination of the hexapeptide GH-releasing peptide (GHRP-6) structure/function has lead to the development of four novel classes of compound that stimulate GH release. Each class is represented as follows: a pentapeptide, G-7039; a tetrapeptide, G-7134; a pseudotripeptide, G-7502; and a rigid cyclic heptapeptide, G-7203. The EC50 values for these compounds, determined by GH dose-response curves using primary cultures of rat pituitary cells, were 0.18, 0.34, 10.6, and 0.43 nM, respectively. To demonstrate that these compounds were acting at the putative GHRP receptor, challenges were made using combinations that included GHRP-6 and GH-releasing hormone (GHRH). All four new classes further increased GH release in combination with GHRH, but not with GHRP-6. Homologous desensitization occurred after 45 min of exposure to the new compounds while the cells remained sensitive to GHRH. Somatostatin inhibited all of these compounds. Additionally, G-7039 elevated free calcium, as occurs with GHRP-6. All four classes elicited a robust GH release, a small increase in PRL, and no change in LH, FSH, ACTH, or TSH. We conclude that these novel compounds are potent and direct stimulators of pituitary GH release, with in vitro attributes that suggest mediation via a specific GHRP-like mechanism.

Another class of growth hormone (GH) secretagogues has been discovered by altering the backbone structure of a flexible linear GH-releasing peptide (GHRP). In vitro and in vivo characterization confirms these GH secretagogues as the most potent and smallest (M(r) < 500) reported. Anabolic efficacy is demonstrated in rodents with intermittent delivery. A convergent model of the bioactive conformation of GHRPs is developed and is supported by the NMR structure of a highly potent cyclic analog of GHRP-2. The model and functional data provide a logical framework for the further design of low-molecular weight secretagogues and illustrate the utility of an interdisciplinary approach to elucidating potential bound-state conformations of flexible peptide ligands.

In many cell systems, cell-cell and cell-matrix interactions are mediated by integrins, a family of cell surface heterodimeric glycoprotein receptors. Osteoclast integrins may play a role in the process of bone resorption. Osteoclasts express the alpha v and beta 3 subunits of the vitronectin receptor and adhere to a wide range of proteins in vitro, all which contain the amino acid sequence Arg-Gly-Asp (RGD), an adhesion site recognition sequence common to many protein ligands that bind to integrins. The effect of kistrin, an RGD-containing snake venom protein, on osteoclast-mediated bone resorption was investigated in vivo and in vitro. When kistrin was infused into normocalcemic and hypercalcemic mice, serum calcium was significantly lowered at 3 and 6 h after the start of infusion, indicating an inhibitory effect on osteoclast activity in vivo. In vitro, kistrin potently inhibited bone resorption by isolated rat osteoclasts cultured on slices of bovine bone, and kistrin also inhibited the attachment of 293 cells expressing recombinant human alpha v beta 3 to fibrinogen (IC50 = 1 nM). These results indicate the potential therapeutic use of RGD-containing molecules for hypercalcemia of malignancy or for other disorders associated with bone loss.

Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein 4 (BMP 4) are both able, under certain circumstances, to induce endochondral bone formation in vivo. This study compared the effects of TGF-beta 1 and BMP 4 on the gene expression of a retinoic acid (RA) responsive rat clonal preosteoblast cell line, UMR 201, as well as the way in which these proteins interact with RA in these cells. Both similarities as well as differences between the effects and mechanism of action of TGF-beta 1 and BMP 4 were demonstrated. TGF-beta 1 (0.1 ng/ml) strongly induced matrix gla protein (MGP) mRNA and increased the steady state osteonectin (ON) mRNA level. Cotreatment with TGF-beta 1 and RA did not result in a further increase in MGP mRNA expression. In contrast, BMP 4 alone had no influence on MGP or ON mRNA expression but it significantly enhanced the RA induction of MGP mRNA. Pro-alpha 1(l) collagen mRNA was increased by TGF-beta 1 (1 ng/ml) and BMP 4 (50 ng/ml). The addition of either TGF-beta 1 or BMP 4 together with RA resulted in a further increase in pro-alpha 1 (l) collagen mRNA levels. Both RA and TGF-beta 1, but not BMP 4, increased the transcriptional rate of the pro-alpha 1 (l) collagen gene. TGF-beta 1 reduced the constitutive as well as RA-induced expression of osteopontin (OP) mRNA while BMP 4 reduced only the constitutive expression of OP mRNA. RA increased the transcriptional rate of the OP gene. Since the responses of UMR 201 cells to these structurally related factors were not identical, the results lend support to the concept that the coordinated expression of members of the TGF-beta 1 superfamily may be necessary to control the progression of specific cell types through their differentiation pathways.

Osteogenin and related bone morphogenetic proteins are members of the transforming growth factor-beta superfamily, and were isolated by their ability to induce cartilage and bone formation in vivo. The influence of osteogenin, purified from bovine bone, and of recombinant human bone morphogenetic protein-2B (BMP-2B) has been examined in bovine articular cartilage explants. Both differentiation factors stimulated in a dose-dependent manner the synthesis of proteoglycans and decreased their rate of degradation. At a dose of 30 ng/ml, proteoglycan synthesis was increased to levels observed with either 20 ng/ml insulin-like growth factor I, 10 ng/ml transforming growth factor-beta, or 20% fetal bovine serum. This increase of biosynthetic rates above basal medium levels was observed in young, adolescent, and adult tissues. Analysis of the size of the newly synthesized proteoglycans, the glycosaminoglycan chain size, and the glycosaminoglycan type of explants treated with osteogenin or BMP-2B were very comparable to each other, and to proteoglycans isolated from cartilage treated with either insulin-like growth factor I or fetal bovine serum. These results demonstrate that osteogenin and BMP-2B alone are capable of stimulating and maintaining the chondrocyte phenotype in vitro.

The biologic effects of recombinant human bone morphogenetic protein-2b (BMP-2b = BMP-4) were studied and compared with transforming growth factor-beta 1 (TGF-beta 1) in fetal rat osteoblast-like (ROB) cells. Similar to the effects of TGF-beta 1, BMP-2b stimulated DNA and collagen synthesis as well as protein accumulation. Unlike TGF-beta 1, which inhibited alkaline phosphatase activity, BMP-2b enhanced enzyme activity eight-to ninefold over the control level. The present study demonstrates direct actions of BMP-2b on bone-associated cells to stimulate osteogenic phenotypes in vitro and provides a cellular mechanism for the induction of bone formation by BMP-2b in vivo.

We have recently shown that a carboxyl-terminal sequence of parathyroid hormone-related protein, PTHrP[107-139], is a potent direct inhibitor of osteoclastic bone resorption. We now report that this bone resorption inhibitory activity, which we have called osteostatin, is entirely contained within the highly conserved pentapeptide PTHrP[107-111]. Our results indicate that processing at residue 106 and a free amino terminus is required for full activity of the peptide. The retroinverted peptide is considerably less potent than the parent peptide. The retention of full biological activity in such a short fragment was unexpected. This data provides the basis for the development of further analogs with potential therapeutic use in disorders associated with increased osteoclastic bone resorption.

Bone morphogenetic protein 2B (BMP-2B) also called BMP-4 is one of a family of cartilage and bone-inductive proteins derived from bone matrix and belongs to the transforming growth factor beta (TGF-beta) superfamily. These bone-inductive proteins isolated from adult bone may be involved in bone repair. However, they may also play a role in cartilage and bone formation during embryonic development. To test whether BMP-2B influences cartilage formation by embryonic cells, recombinant human BMP-2B was applied to cultured limb bud mesoderm plated at three different densities. BMP-2B stimulated cartilage formation as assessed by Alcian blue staining and incorporation of radioactive sulfate into sulfated proteoglycans. Cells cultured at all three densities in the presence of 10 ng/ml BMP-2B formed a nearly continuous sheet of cartilage with abundant extracellular matrix and type II collagen. In addition, when cells were cultured in 0.5% serum in the presence of 10 ng/ml of BMP-2B for 5 days there was an increase in alkaline phosphatase as detected by histochemical and biochemical methods. Transforming growth factor beta isoforms (TGF-beta 1 and TGF-beta 2) inhibited sulfate incorporation into proteoglycans in a dose-dependent manner. This inhibition by TGF beta was overcome by recombinant BMP-2B. This study demonstrates that recombinant BMP-2B stimulates cartilage formation by chick limb bud mesoderm in vitro and is further modulated by TGF-beta isoforms.

Clonal cell lines presumably "arrested" at a particular stage of differentiation are useful models to study the processes of differentiation in osteoblasts. UMR-201 is a presumptive preosteoblastic nontransformed rat clonal cell line with a limited life span in culture. Two immortalized cell lines, UMR-201-10A (10A) and UMR-201-10B (10B), were derived from UMR-201 by stable transfection with simian virus (SV) 40 large T antigen. This study compares the growth and profile of gene expression of the immortalized cell lines with those of UMR-201 and UMR-106-06, a rat clonal cell line with well-defined osteoblast-like phenotypic characteristics. All four cell lines constitutively expressed the mRNA for the gamma, alpha, and beta receptors for retinoic acid (RA), the growth hormone receptor, pro-alpha 1(I) collagen, osteonectin, bone proteoglycan I, and bone morphogenetic proteins (BMP) 1 and 2A. Alkaline phosphatase mRNA was absent in the preosteoblast cell lines but was induced by treatment with 10(-6) M RA, which also increased the steady-state levels of mRNA for osteopontin and BMP1. mRNA for matrix gla protein was constitutively present and further induced by RA in UMR-201 and 10B only. Messenger RNA for bone sialoprotein and bone morphogenetic protein 3 were constitutively expressed in UMR-106-06 and UMR-201 but absent in the immortalized cell lines. None of the cell lines expressed measurable mRNA for bone gla protein or bone proteoglycan II. 10B grew more rapidly than UMR-201, but unlike UMR-201, it was also able to proliferate in serum-free medium and exhibit anchorage-independent growth. In summary, this study identifies novel retinoic acid effects on gene expression in these cells. Differences noted in the expression of mRNAs between UMR-106-06 and the other cell lines may provide some insight into the sequence of expression of these phenotypic characteristics as osteoblasts differentiate.

Bone morphogenetic protein 2B (BMP 2B), is a heparin-binding bone differentiation factor that initiates endochondral bone formation in rats when implanted subcutaneously. The molecular mechanism of action of this differentiation factor is not known, and as a first step we have examined BMP 2B-responsive cells for the presence of specific cellular binding proteins. Using 125I-labeled BMP 2B, specific high-affinity binding sites for recombinant human BMP 2B on MC3T3 E1 osteoblast-like cells as well as on NIH 3T3 fibroblasts were identified. Platelet-derived growth factor, insulin-like growth factor 1, basic fibroblast growth factor, epidermal growth factor, and transforming growth factor beta did not compete for the binding of radiolabeled BMP 2B. The binding of BMP 2B is a time- and temperature-dependent process. Chemical crosslinking of radiolabeled BMP showed two components (apparent size, 200 and 70 kDa in MC3T3 E1 cells and 200 and 90 kDa in NIH 3T3 cells). A minor component at 60 kDa was also detected in both cell lines. Scatchard analysis of the binding data showed a high-affinity receptor with an apparent dissociation constant of 128 +/- 40 pM in MC3T3 E1 cells. These data demonstrate specific, high-affinity cell-surface binding proteins for BMP 2B.

The human osteoinductive proteins BMP-2a and BMP-2b have been cloned and expressed in mammalian cells. In order to improve expression levels we examined the role of the proregion in assembly and export. Use of the BMP-2a proregion combined with the mature region of BMP-2b leads to dramatically improved expression of mature BMP-2b. Mature BMP-2b has been purified to near homogeneity from the BMP-2a/2b hybrid, and its structural properties and biological activity determined. Recombinant mature BMP-2b homodimer elicits bone formation in vivo.

The fetal plasma magnesium concentration exceeds that of the mother but the difference is small compared to that of ionized calcium concentration. Although not fully independent of changes in maternal magnesaemia, fetal magnesaemia showed a high degree of autonomy during both hypermagnesaemic and hypomagnesaemic changes induced in the ewe. As with calcium, the placental gradient is reversed after fetal thyroparathyroidectomy (TXPTX) with thyroxine replacement. During perfusion in situ of the placenta from such TXPTX fetuses isolated from the fetus itself, a stable positive placental gradient of magnesium concentration could be re-established between the perfusing blood and the maternal circulation. As with calcium, this gradient could be increased by fetal calf parathyroid extract, parathyroid hormone-related protein (PTHrP 1-141), PTHrP (1-84) but not by PTHrP (1-34). It was concluded that a mid-molecule portion of PTHrP can stimulate a putative placental pump which is responsible for the gradients of both calcium ions and magnesium across the ovine placenta.