'History obligates us to do it': political capabilities of Indigenous grassroots leaders of health accountability initiatives in rural Guatemala.

Growing interest in how marginalised citizens can leverage countervailing power to make health systems more inclusive and equitable points to the need for politicised frameworks for examining bottom-up accountability initiatives. This study explores how political capabilities are manifested in the actions and strategies of Indigenous grassroots leaders of health accountability initiatives in rural Guatemala. Qualitative data were gathered through group discussions and interviews with initiative leaders (called defenders of the right to health) and initiative collaborators in three municipalities. Analysis was oriented by three dimensions of political capabilities proposed for evaluating the longer-term value of participatory development initiatives: political learning, reshaping networks and patterns of representation. Our findings indicated that the defenders' political learning began with actionable knowledge about defending the right to health and citizen participation. The defenders used their understanding of local norms to build trust with remote Indigenous communities and influence them to participate in monitoring to attempt to hold the state accountable for the discriminatory and deficient healthcare they received. Network reshaping was focused on broadening their base of support. Their leadership strategies enabled them to work with other grassroots leaders and access resources that would expand their reach in collective action and lend them more influence representing their problems beyond the local level. Patterns of representing their interests with a range of local and regional authorities indicated they had gained confidence and credibility through their evolving capability to navigate the political landscape and seek the right authority based on the situation. Our results affirm the critical importance of sustained, long-term processes of engagement with marginalised communities and representatives of the state to enable grassroots leaders of accountability initiatives to develop the capabilities needed to mobilise collective action, shift the terms of interaction with the state and build more equitable health systems.

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy.

Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.

Challenges with pediatric surgical financing and universal health coverage in Guatemala: A qualitative analysis.

The financing of surgical care for children in low- and middle-income countries (LMICs) remains challenging and may restrict adherence to universal health coverage (UHC) frameworks. Our aims were to describe Guatemala's national pediatric surgical financing structure, to identify financing challenges, and to develop recommendations to improve the financing of surgical care for children. We conducted a qualitative study of the financing of surgical care for children in Guatemala's public health system with key informant interviews (n = 20) with experts in the medical, financial, and political health sectors. We used this data to generate recommendations to improve surgical care financing for children. We identified several systemic challenges to the financing of surgical care for children, including passive purchasing structures, complex political contexts, health system fragmentation, widespread use of informal fees for surgical services, and lack of earmarked funding for surgical care. Patient and provider challenges include lack of provider input in non-personnel funding decisions, and patients functioning as both financing agents and beneficiaries in the same financing stream. Key recommendations include reducing health finance system fragmentation through resource pooling, increasing earmarked funding for surgical care with quantifiable outcome measures, engagement with clinical providers in non-personnel budgetary decision-making, and use of innovative financing instruments such as resource pooling. Surgical financing for children in Guatemala requires substantial remodeling to increase access to timely, affordable, and safe surgical care and improve alignment with Guatemala's UHC scheme.

Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model.

Background: In transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA. Methods: Six (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression. Results: Circulating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (p<0.05), while using a DSA assay. T-cell flow cross match (TFXM) was reduced to 40.6±12.5% of baseline, and B-cell FXCM to 52.2±19.3%. Circulating total IgM and DSA IgM were unaffected by treatment. Pathogen-specific antibodies (anti-gB and anti-tetanus toxin IgG) were significantly reduced for 14d post infusion. Post-transplant, circulating IgG responded to anti-FcRn mAb treatment, but DSA increased rapidly. Conclusion: Targeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.

A comparative study of human-and rhesus-specific antithymocyte globulins in Rhesus macaques.

Rabbit antithymocyte globulin (RATG) preparations are widely used in transplantation. They are developed in vivo against thymocytes and contain polyclonal antibodies specific for myriad cellular targets. The rhesus monkey is commonly used as a preclinical transplant model, but the fidelity of commercially available human-specific RATGs to anticipate the effects of RATGs in rhesus has not been established. We therefore developed two rhesus-specific ATGs (rhATG) and compared them to human-specific RATG (huATG, Thymoglobulin® ) in rhesus monkeys, assessing the magnitude and phenotype of depletion peripherally and in lymph nodes. Four primates were assigned to each group and received 20 mg/kg of drug. Depletion, repopulation, and changes in lymphocyte subsets were evaluated in peripheral blood and lymph nodes by flow cytometry over four months. We observed similar qualitative changes in lymphocyte subsets, but a generally more profound depletion with huATG compared to either rhATG. Peripheral homeostatic proliferation rather than thymic output was the major mechanism for repopulation with all RATGs. Repopulation was slower but qualitatively similar when examining RATGs in additional animals receiving concomitant chronic immunosuppression. Depletional induction is similar to human- and rhesus-specific RATGs in rhesus macaques. Both rhesus- and human-specific agents appear appropriate for preclinical modeling of clinical RATG use.

Non-neutralizing Antibodies May Contribute to Suppression of SIVmac239 Viremia in Indian Rhesus Macaques.

The antiviral properties of broadly neutralizing antibodies against HIV are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. While current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (SIV) and HIV, the ability of these responses to restrict lentivirus transmission and replication remains controversial. Here, we investigated the antiviral properties of non-neutralizing antibodies in a group of Indian rhesus macaques (RMs) that were vaccinated with vif, rev, tat, nef, and env, as part of a previous study conducted by our group. These animals manifested rapid and durable control of viral replication to below detection limits shortly after SIVmac239 infection. Although these animals had no serological neutralizing activity against SIVmac239 prior to infection, their pre-challenge titers of Env-binding antibodies correlated with control of viral replication. To assess the contribution of anti-Env humoral immune responses to virologic control in two of these animals, we transiently depleted their circulating antibodies via extracorporeal plasma immunoadsorption and inhibition of IgG recycling through antibody-mediated blockade of the neonatal Fc receptor. These procedures reduced Ig serum concentrations by up to 80% and temporarily induced SIVmac239 replication in these animals. Next, we transferred purified total Ig from the rapid controllers into six vaccinated RMs one day before intrarectal challenge with SIVmac239. Although recipients of the hyperimmune anti-SIV Ig fraction were not protected from infection, their peak and chronic phase viral loads were significantly lower than those in concurrent unvaccinated control animals. Together, our results suggest that non-neutralizing Abs may play a role in the suppression of SIVmac239 viremia.

Social exclusion and universal health coverage: health care rights and citizen-led accountability in Guatemala and Peru.

BACKGROUND: While equity is a central concern in promoting Universal Health Coverage (UHC), the impact of social exclusion on equity in UHC remains underexplored. This paper examines challenges faced by socially excluded populations, with an emphasis on Indigenous peoples, to receive UHC in Latin America. We argue that social exclusion can have negative effects on health systems and can undermine progress towards UHC. We examine two case studies, one in Guatemala and one in Peru, involving citizen-led accountability initiatives that aim to identify and address problems with health care services for socially excluded groups. The case studies reveal how social exclusion can affect equity in UHC. METHODS: In-depth analysis was conducted of all peer reviewed articles published between 2015 and 2019 on the two cases (11 in total), and two non-peer reviewed reports published over the same period. In addition, two of the three authors contributed their first-hand knowledge gathered through practitioner involvement with the citizen-led initiatives examined in the two cases. The analysis sought to identify and compare challenges faced by socially excluded Indigenous populations to receive UHC in the two cases. RESULTS: Citizen-led accountability initiatives in Guatemala and Peru reveal very similar patterns of serious deficiencies that undermine efforts towards the realization of Universal Health Coverage in both countries. In each case, the socially excluded populations are served by a dysfunctional publicly provided health system marked by gaps and often invisible barriers. The cases suggest that, while funding and social rights to coverage have expanded, marginalized populations in Guatemala and Peru still do not receive either the health care services or the protection against financial hardship promised by health systems in each country. In both cases, the dysfunctional character of the system remains in place, undermining progress towards UHC. CONCLUSIONS: We conclude that efforts to promote UHC cannot stop at increasing health systems financing. In addition, these efforts need to contend with the deeper challenges of democratizing state institutions, including health systems, involved in marginalizing and excluding certain population groups. This includes stronger accountability systems within public institutions. More inclusive accountability mechanisms are an important step in promoting equitable progress towards UHC.

Global Health in the Age of COVID-19: Responsive Health Systems Through a Right to Health Fund.

We propose that a Right to Health Capacity Fund (R2HCF) be created as a central institution of a reimagined global health architecture developed in the aftermath of the COVID-19 pandemic. Such a fund would help ensure the strong health systems required to prevent disease outbreaks from becoming devastating global pandemics, while ensuring genuinely universal health coverage that would encompass even the most marginalized populations. The R2HCF's mission would be to promote inclusive participation, equality, and accountability for advancing the right to health. The fund would focus its resources on civil society organizations, supporting their advocacy and strengthening mechanisms for accountability and participation. We propose an initial annual target of US$500 million for the fund, adjusted based on needs assessments. Such a financing level would be both achievable and transformative, given the limited right to health funding presently and the demonstrated potential of right to health initiatives to strengthen health systems and meet the health needs of marginalized populations-and enable these populations to be treated with dignity. We call for a civil society-led multi-stakeholder process to further conceptualize, and then launch, an R2HCF, helping create a world where, whether during a health emergency or in ordinary times, no one is left behind.

Building collective power in citizen-led initiatives for health accountability in Guatemala: the role of networks.

BACKGROUND: Citizen-led accountability initiatives are a critical strategy for redressing the causes of health inequalities and promoting better health system governance. A growing body of evidence points to the need for putting power relations at the forefront of understanding and operationalizing citizen-led accountability, rather than technical tools and best practices. In this study, we apply a network lens to the question of how initiatives build collective power to redress health system failures affecting marginalized communities in three municipalities in Guatemala. METHODS: Network mapping and interpretive discussions were used to examine relational qualities of citizen-led initiatives' networks and explore the resources they offer for mobilizing action and influencing health accountability. Participants in the municipal-level initiatives responded to a social network analysis questionnaire focused on their ties of communication and collaboration with other initiative participants and their interactions with authorities regarding health system problems. Discussions with participants about the maps generated enriched our view of what the ties represented and their history of collective action and also provided space for planning action to strengthen their networks. RESULTS: Our findings indicate that network qualities like cohesiveness and centralization reflected the initiative participants' agency in adapting to their sociopolitical context, and participants' social positions were a key resource in providing connection to a broad base of support for mobilizing collective action to document health service deficiencies and advocate for solutions. Their legitimacy as "representatives of the people" enabled them to engage with authorities from a bolstered position of power, and their iterative interactions with authorities further contributed to develop their advocacy capabilities and resulted in accountability gains. CONCLUSIONS: Our study provided evidence to counter the tendency to underestimate the assets and capabilities that marginalized citizens have for building power, and affirmed the idea that best-fit, with-the-grain approaches are well-suited for highly unequal settings characterized by weak governance. Efforts to support and understand change processes in citizen-led initiatives should include focus on adaptive network building to enable contextually-embedded approaches that leverage the collective power of the users of health services and grassroots leaders on the frontlines of accountability.

Anti-CD40 antibody 2C10 binds to a conformational epitope at the CD40-CD154 interface that is conserved among primate species.

The antagonistic anti-CD40 antibody, 2C10, and its recombinant primate derivative, 2C10R4, are potent immunosuppressive antibodies whose utility in allo- and xenotransplantation have been demonstrated in nonhuman primate studies. In this study, we defined the 2C10 binding epitope and found only slight differences in affinity of 2C10 for CD40 derived from four primate species. Staining of truncation mutants mapped the 2C10 binding epitope to the N-terminal portion of CD40. Alanine scanning mutagenesis of the first 60 residues in the CD40 ectodomain highlighted key amino acids important for binding of 2C10 and for binding of the noncross-blocking anti-CD40 antibodies 3A8 and 5D12. All four 2C10-binding residues defined by mutagenesis clustered near the membrane-distal tip of CD40 and partially overlap the CD154 binding surface. In contrast, the overlapping 3A8 and 5D12 epitopes map to an opposing surface away from the CD154 binding domain. This biochemical characterization of 2C10 confirms the validity of nonhuman primate studies in the translation of this therapeutic antibody and provides insight its mechanism of action.

IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.

Does Information and Communication Technology Add Value to Citizen-Led Accountability Initiatives in Health? Experiences from India and Guatemala.

Information and Communication Technology (ICT) may facilitate the collection and dissemination of citizen-generated data to enhance governmental accountability for the fulfillment of the right to health. The aim of this multiple case study research was to distill considerations related to the implementation of ICT and health accountability projects, describe the added operational value of ICT tools (as compared to similar projects that do not use ICT), and make preliminary statements regarding government responsiveness to accountability demands through ICT projects. In all three projects, the need for relationship building, continuous community engagement and technical support, and training for volunteers or service users was identified. Government responsiveness to the data varied, suggesting that political will is lacking in certain contexts. Despite these challenges, ICT initiatives provided an easy, accessible, and low-risk platform for reporting violations and demanding accountability from service providers and decision-makers. ICT-enabled citizen generated data can add significant operational value and some political value to project activities and goals, and may affect systems change when it is part of a broad-based, multi-level civil societal and governmental effort to improve health care quality.

Using information communication technology to identify deficits in rural health care: a mixed-methods evaluation from Guatemala.

BACKGROUND: In August 2014, the Centre for the Studies of Equity and Governance in Health Systems (CEGSS) in Guatemala launched an online platform, which facilitates complaints about health services via text messages. The aim is to collect, systemise and forward such complaints to relevant institutions, and to create a data pool on perceived deficits of health care in rural Guatemala. OBJECTIVE: To evaluate if the online platform is an accepted, user-friendly and efficient medium to engage citizens in the reporting of health care deficiencies in Guatemala. METHODS: The general study design of this research was a mixed-method approach including a quantitative analysis of complaints received and a qualitative exploration of the attitude of community leaders towards the platform. RESULTS: User statistics showed that a total of N = 228 messages were sent to the platform in the period August 2014-March 2015. The majority of complaints (n = 162, 71%) fell under the 'lack of drugs, equipment or supplies' category. The community leaders welcomed the platform, describing it as modern and progressive. Despite feedback mechanisms and methods to respond to complaints not yet being fully developed, many users showed a high intrinsic motivation to use the new tool. Others, however, were restrained by fear of personal consequences and distrust of the state's judicial system. Access to mobile phones, reception, and phone credit or battery life did not pose major obstacles, but the producing and sending of correctly formatted messages was observed to be difficult. CONCLUSION: The online platform paired with SMS technology appears to be a viable approach to collect citizens' complaints in health care and connect citizens with relevant institutions. Further studies should be conducted to quantify follow-up activities and the impact on local health care provision.

10 best resources on power in health policy and systems in low- and middle-income countries.

Power is a critical concept to understand and transform health policy and systems. Power manifests implicitly or explicitly at multiple levels-local, national and global-and is present at each actor interface, therefore shaping all actions, processes and outcomes. Analysing and engaging with power has important potential for improving our understanding of the underlying causes of inequity, and our ability to promote transparency, accountability and fairness. However, the study and analysis of the role of power in health policy and systems, particularly in the context of low- and middle-income countries, has been lacking. In order to facilitate greater engagement with the concept of power among researchers and practitioners in the health systems and policy realm, we share a broad overview of the concept of power, and list 10 excellent resources on power in health policy and systems in low- and middle-income countries, covering exemplary frameworks, commentaries and empirical work. We undertook a two-stage process to identify these resources. First, we conducted a collaborative exercise involving crowdsourcing and participatory validation, resulting in 24 proposed articles. Second, we conducted a structured literature review in four phases, resulting in 38 articles reviewed. We present the 10 selected resources in the following categories to bring out key facets of the literature on power and health policy and systems-(1) Resources that provide an overarching conceptual exploration into how power shapes health policy and systems, and how to investigate it; and (2) examples of strong empirical work on power and health policy and systems research representing various levels of analyses, geographic regions and conceptual understandings of power. We conclude with a brief discussion of key gaps in the literature, and suggestions for additional methodological approaches to study power.

Engaging with complexity to improve the health of indigenous people: a call for the use of systems thinking to tackle health inequity.

The 400 million indigenous people worldwide represent a wealth of linguistic and cultural diversity, as well as traditional knowledge and sustainable practices that are invaluable resources for human development. However, indigenous people remain on the margins of society in high, middle and low-income countries, and they bear a disproportionate burden of poverty, disease, and mortality compared to the general population. These inequalities have persisted, and in some countries have even worsened, despite the overall improvements in health indicators in relation to the 15-year push to meet the Millennium Development Goals. As we enter the Sustainable Development Goals (SDGs) era, there is growing consensus that efforts to achieve Universal Health Coverage (UHC) and promote sustainable development should be guided by the moral imperative to improve equity. To achieve this, we need to move beyond the reductionist tendency to frame indigenous health as a problem of poor health indicators to be solved through targeted service delivery tactics and move towards holistic, integrated approaches that address the causes of inequalities both inside and outside the health sector. To meet the challenge of engaging with the conditions underlying inequalities and promoting transformational change, equity-oriented research and practice in the field of indigenous health requires: engaging power, context-adapted strategies to improve service delivery, and mobilizing networks of collective action. The application of systems thinking approaches offers a pathway for the evolution of equity-oriented research and practice in collaborative, politically informed and mutually enhancing efforts to understand and transform the systems that generate and reproduce inequities in indigenous health. These approaches hold the potential to strengthen practice through the development of more nuanced, context-sensitive strategies for redressing power imbalances, reshaping the service delivery environment and fostering the dynamics of collective action for political reform.

Providers' perspectives on inbound medical tourism in Central America and the Caribbean: factors driving and inhibiting sector development and their health equity implications.

BACKGROUND: Many governments and health care providers worldwide are enthusiastic to develop medical tourism as a service export. Despite the popularity of this policy uptake, there is relatively little known about the specific local factors prospectively motivating and informing development of this sector. OBJECTIVE: To identify common social, economic, and health system factors shaping the development of medical tourism in three Central American and Caribbean countries and their health equity implications. DESIGN: In-depth, semi-structured interviews were conducted in Mexico, Guatemala, and Barbados with 150 health system stakeholders. Participants were recruited from private and public sectors working in various fields: trade and economic development, health services delivery, training and administration, and civil society. Transcribed interviews were coded using qualitative data management software, and thematic analysis was used to identify cross-cutting issues regarding the drivers and inhibitors of medical tourism development. RESULTS: Four common drivers of medical tourism development were identified: 1) unused capacity in existing private hospitals, 2) international portability of health insurance, vis-a-vis international hospital accreditation, 3) internationally trained physicians as both marketable assets and industry entrepreneurs, and 4) promotion of medical tourism by public export development corporations. Three common inhibitors for the development of the sector were also identified: 1) the high expense of market entry, 2) poor sector-wide planning, and 3) structural socio-economic issues such as insecurity or relatively high business costs and financial risks. CONCLUSION: There are shared factors shaping the development of medical tourism in Central America and the Caribbean that help explain why it is being pursued by many hospitals and governments in the region. Development of the sector is primarily being driven by public investment promotion agencies and the private health sector seeking economic benefits with limited consideration and planning for the health equity concerns medical tourism raises.