Unni Gopinathan

Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries

Access to quality-assured antimicrobials is regarded as part of the human right to health, yet universal access is often undermined in low-income and middle-income countries. Lack of access to the instruments necessary to make the correct diagnosis and prescribe antimicrobials appropriately, in addition to weak health systems, heightens the challenge faced by prescribers. Evidence-based interventions in community and health-care settings can increase access to appropriately prescribed antimicrobials. The key global enablers of sustainable financing, governance, and leadership will be necessary to achieve access while preventing excess antimicrobial use.

LPS from Neisseria meningitidis is crucial for inducing monocyte- and microparticle-associated tissue factor activity but not for tissue factor expression:

Neisseria meningitidis causes sepsis with coagulopathy. The present study evaluated the tissue factor (TF)-inducing capacity of bacterial LPS in different presentation forms, i.e. membrane-bound LPS versus purified LPS, and of non-LPS components of N. meningitidis. By using a wild-type N. meningitidis, a mutant N. meningitidis lacking LPS (LPS-deficient N. meningitidis), purified LPS from N. meningitidis and Escherichia coli, we measured TF-expression and TF-activity on human monocytes and microparticles (MPs). The effect of TF-modulators, such as phosphatidylserine (PS), tissue factor pathway inhibitor (TFPI) and recombinant IL-10 (rhIL-10) was investigated. In plasmas from meningococcal patients, fibrinopeptide A (FPA), LPS and IL-10 were quantified. Monocytes and MPs exposed to purified LPS or wild-type N. meningitidis had much higher TF-activity than monocytes and MPs exposed to LPS-deficient N. meningitidis (clot formation assay). Incubation with wild-type N. meningitidis, but also LPS-deficient N. meningitidis, resulted in TF-expression on monocytes (flow cytometry, qRT-PCR). Increased cellular TF-activity is associated with coincident surface-exposure of PS and the number of monocytes positive for both PS and TF was significantly higher for monocytes exposed to wild-type N. meningitidis (7.6%) compared with monocytes exposed to LPS-deficient N. meningitidis (1.8%). Treatment with rhIL-10 reduced monocyte- and MP-associated TF-activity, the number of monocytes positive for both TF and PS, and microvesiculation. Patients with meningococcal septicemia had significantly higher levels of LPS, FPA and IL-10 than patients with distinct meningitis. Our results indicate that LPS from N. meningitidis is crucial for inducing TF-activity, but not for monocyte- and MP-associated TF-expression. TF-activity seems to require coincident expression of TF and PS on monocytes, and LPS induces such double-positive monocytes.

Global Effect of Interleukin-10 on the Transcriptional Profile Induced by Neisseria meningitidis in Human Monocytes

ABSTRACT In meningococcal septic shock, the dominant inducer of inflammation is lipopolysaccharide (LPS) in the outer membrane of Neisseria meningitidis, while interleukin-10 (IL-10) is the principal anti-inflammatory cytokine. We have used microarrays and Ingenuity Pathway Analysis to study the global effects of IL-10 on gene expression induced by N. meningitidis, after exposure of human monocytes (n = 5) for 3 h to N. meningitidis (106 cells/ml), recombinant human IL-10 (rhIL-10) (25 ng/ml), and N. meningitidis combined with rhIL-10. N. meningitidis and IL-10 differentially expressed 3,579 and 648 genes, respectively. IL-10 downregulated 125 genes which were upregulated by N. meningitidis, including NLRP3, the key molecule of the NLRP3 inflammasome. IL-10 also upregulated 270 genes which were downregulated by N. meningitidis, including members of the leukocyte immunuglobulin-like receptor (LIR) family. Fifty-three genes revealed a synergistically increased expression when N. meningitidis and IL-10 were combined. AIM2 (the principal molecule of the AIM2 inflammasome) was among these genes (fold change [FC], 18.3 versus 7.4 and 9.4 after stimulation by N. meningitidis and IL-10, respectively). We detected reduced concentrations (92% to 40%) of six cytokines (IL-1b, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], macrophage inflammatory protein alpha [MIP-α], MIP-β) in the presence of IL-10, compared with concentrations with stimulation by N. meningitidis alone. Our data analysis of the effects of IL-10 on gene expression induced by N. meningitidis suggests that high plasma levels of IL-10 in meningococcal septic shock plasma may have a profound effect on a variety of functions and cellular processes in human monocytes, including cell-to-cell signaling, cellular movement, cellular development, antigen presentation, and cell death.

Delinking Investment in Antibiotic Research and Development from Sales Revenues: The Challenges of Transforming a Promising Idea into Reality

Kevin Outterson and colleagues outline a model to address access, conservation, and innovation of antibiotics.

IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes.

The severity of systemic meningococcal disease (SMD) correlates to plasma concentrations of LPS and IL-10, with the highest levels detected in non-survivors. Here, plasma from patients with SMD containing high and low concentrations of LPS were incubated with human monocytes before and after immunodepletion of IL-10 to study the effect of IL-10 on gene expression and cytokine release. Patient plasma containing IL-10 induced the expression of 1657 genes in human monocytes when compared with gene expression induced by low LPS plasma. After immunodepletion of IL-10, this number increased to 2260. By directly comparing the gene expression profiles induced before and after immunodepletion of IL-10, the presence of IL-10 differentially regulated 373 genes. Functional classes associated with these genes were cellular function and maintenance, cellular development, cellular growth and proliferation, cell–cell signaling and interaction and cellular movement. Immunodepletion of IL-10 resulted in down-regulation of genes of the leukocyte immunoglobulin-like receptor family, and up-regulation of genes of type I IFN signaling, TLR signaling, the inflammasomes, coagulation and fibrinolysis. Finally, immunodepletion of IL-10 increased the protein levels of IL-1β, IL-8, TNF-α, MIP-1α and MIP-1β. Data suggest that IL-10 in meningococcal sepsis plasma regulates a variety of genes and signaling pathways, likely leading to an overall inhibitory effect on the inflammatory response induced in meningococcal sepsis.

Conceptual and institutional gaps: understanding how the WHO can become a more effective cross-sectoral collaborator

BackgroundTwo themes consistently emerge from the broad range of academics, policymakers and opinion leaders who have proposed changes to the World Health Organization (WHO): that reform efforts are too slow, and that they do too little to strengthen WHO’s capacity to facilitate cross-sectoral collaboration. This study seeks to identify possible explanations for the challenges WHO faces in addressing the broader determinants of health, and the potential opportunities for working across sectors.MethodsThis qualitative study used a mixed methods approach of semi-structured interviews and document review. Five interviewees were selected by stratified purposive sampling within a sampling frame of approximately 45 potential interviewees, and a targeted document review was conducted. All interviewees were senior WHO staff at the department director level or above. Thematic analysis was used to analyze data from interview transcripts, field notes, and the document review, and data coded during the analysis was analyzed against three central research questions. First, how does WHO conceptualize its mandate in global health? Second, what are the barriers and enablers to enhancing cross-sectoral collaboration between WHO and other intergovernmental organizations? Third, how do the dominant conceptual frames and the identified barriers and enablers to cross-sectoral collaboration interact?ResultsAnalysis of the interviews and documents revealed three main themes: 1) WHO’s role must evolve to meet the global challenges and societal changes of the 21st century; 2) WHO’s cross-sectoral engagement is hampered internally by a dominant biomedical view of health, and the prevailing institutions and incentives that entrench this view; and 3) WHO’s cross-sectoral engagement is hampered externally by siloed areas of focus for each intergovernmental organization, and the lack of adequate conceptual frameworks and institutional mechanisms to facilitate engagement across siloes.ConclusionThere are a number of external and internal pressures on WHO which have created an organizational culture and operational structure that focuses on a narrow, technical approach to global health, prioritizing disease-based, siloed interventions over more complex approaches that span sectors. The broader approach to promoting human health and wellbeing, which is conceptualized in WHO’s constitution, requires cultural and institutional changes for it to be fully implemented.

EVIDENCE-INFORMED DELIBERATIVE PROCESSES FOR UNIVERSAL HEALTH COVERAGE: BROADENING THE SCOPE COMMENT ON “PRIORITY SETTING FOR UNIVERSAL HEALTH COVERAGE: WE NEED EVIDENCE-INFORMED DELIBERATIVE PROCESSES, NOT JUST MORE EVIDENCE ON COST-EFFECTIVENESS

Universal health coverage (UHC) is high on the global health agenda, and priority setting is fundamental to the fair and efficient pursuit of this goal. In a recent editorial, Rob Baltussen and colleagues point to the need to go beyond evidence on cost-effectiveness and call for evidence-informed deliberative processes when setting priorities for UHC. Such processes are crucial at every step on the path to UHC, and hopefully we will see intensified efforts to develop and implement processes of this kind in the coming years. However, if this does happen, it will be essential to ensure a sufficiently broad scope in at least two respects. First, the design of evidence-informed priority-setting processes needs to go beyond a simple view on the relationship between evidence and policy and adapt to a diverse set of factors shaping this relationship. Second, these processes should go beyond a focus on clinical services to accommodate also public health interventions. Together, this can help strengthen priority-setting processes and bolster progress towards UHC and the Sustainable Development Goals.

The how: a message for the UN high-level meeting on NCDs

This September’s UN General Assembly high-level meeting (HLM) on noncommunicable diseases (NCDs) provides a strategic opportunity to propel the response—from “where do we want to be” to “how do we get there”. The WHO Independent High-Level Commission on NCDs made a number of solid proposals to inform HLM negotiations. These include a call for governments to enhance regulatory frameworks to protect health, for example, through a code on the marketing of some health–harming products and a full–cost accounting of these products. The draft of the HLM’s political declaration prioritises universal health coverage, including affordable treatment, and promotion of mental health but falls short on the primary prevention of NCDs and promot ing healthy societies as per Agenda 2030. The transition from health-harming to health-enhancing products and processes requires action across multiple sectors and strengthened public institutions. We propose an agenda for member state HLM negotiators (panel). First, accountability must be assigned at the highest political levels. The WHO NCD Commission called on heads of government to lead the NCD response, as was the case with effective AIDS responses. This will ultimately empower ministers of health by ensuring all government departments are accountable to national leadership and are enabled to manage political opportunities, barriers, and trade-offs for NCD prevention. Rather than create new vertical structures, the NCD agenda should be integrated into national Sustainable Development Goal (SDG) plans. The declaration must commit to distributed ownership, impact assessments, policy coherence, and accountability across ministries. Second, improving fiscal policies should be prioritised. Countries should implement a synergistic approach to taxing sugar (not just sugarsweetened beverages but also sugary snacks), tobacco and alcohol, as well as unhealthy nutrients. The international community should provide technical advice on taxation and removing subsidies for processed foods, alcohol, and fossil fuels, and for divesting from tobacco, alcohol, and fossil fuels; governments should also support healthy local food systems. Third, additional financial resources must be mobilised. The declaration should call for dramatic financial increases for NCDs over the US

Scientific Advisory Committees at the World Health Organization: A Qualitative Study of How Their Design Affects Quality, Relevance, and Legitimacy

1 billion currently spent annually. Domestic resource mobilisation, in line with the Addis Ababa Action Agenda, along with development assistance and catalytic external funding, is necessary to address issues of equity, provide public goods, and ensure value for money through evidence–informed resource allocation. Fourth, the commercial determinants of health should be more rigorously regulated. Evidence suggests that self–regulation cannot be relied on to deliver healthy outcomes. Building on experience from tobacco control, governments must regulate the alcohol, processed, and ultra–processed foods industries. Access to healthy foods demands effective regulation to improve production and formulation, restrict harmful marketing (particularly to children), mandate better labelling, and set price incentives for healthier consumption. This requires building country capacity, creating strong health provisions in international trade agreements, as well as strengthening international institutions to counteract interference in establishing and implementing evidence-informed standards. Fifth, the growing impact of pollution and urbanisation on NCDs, injuries, and mental health must be addressed. The declaration should call on governments and partners to (re)design and build healthy communities that enable people to exercise freely and safely, access healthy foods easily, and reduce their exposure to household, traffic, and industrial pollution. Sixth, support shoud be provided for meaningful civil society engagement. Agenda 2030 is premised on effective partnerships, including with civil society. The declaration must ensure meaningful engagement with and by affected communities, citizens, and public interest groups, explicitly highlighting their role in national multi sector planning and coordination platforms and independent accountability mechanisms. Countries should increase investment in the advocacy and service delivery functions of civil society and its networks. Seventh, principles of equity, human rights, and gender equality must be upheld. Recognising that burden of NCDs and mental health is inequitably distributed across populations, responses must address differential circumstances—for example, socioeconomic position, gender, ethnicity, and geography. Explicit commitment to a rights-based approach to prevention and treatment can help empower and protect populations living in vulnerable circumstances. As with previous UN General Assembly political declarations on AIDS, this would entail nondiscrimination in access to information, services, affordable care, medicines, and technology; meaningful participation of people affected by NCDs or mental

Large-scale reduction of tyrosine kinase activities in human monocytes stimulated in vitro with N. meningitidis

Abstract Governments and international organizations frequently convene scientific advisory committees (SACs) to support decision‐making with scientific advice. In this study, thematic analysis of interviews with 35 senior WHO staff identified five main themes characterizing WHOs experience with designing SACs to ensure quality, relevance, and legitimacy of scientific advice. First, in addition to technical matters, SACs are established to serve broader strategic objectives, including consensus building to promote high‐level political messages. Second, for SACs to be fully independent, they must have autonomy from the institutions convening or funding them, from the institutions from where SAC members are recruited, and from the institutions to whom the advice is directed. Third, since choices affecting quality, relevance, and legitimacy are closely linked, designing SACs often require trade‐offs among these three attributes. Fourth, staff supporting SACs need to balance between safeguarding SACs from external influence and being receptive to the external political environment. Fifth, the design of SACs need to balance the involvement of stakeholders with the power to act on recommendations against the need to protect the independence and integrity of the scientific process. Overall, this study highlights key choices conveners of SACs must make when seeking to promote quality, relevance, and legitimacy of scientific advice.