A practical guide

Publisher Copyright: © 2022 Kiekens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Systems mapping methods are increasingly used to study complex public health issues. Visualizing the causal relationships within a complex adaptive system allows for more than developing a holistic and multi-perspective overview of the situation. It is also a way of understanding the emergent, self-organizing dynamics of a system and how they can be influenced. This article describes a concrete approach for developing and analysing a systems map of a complex public health issue drawing on well-accepted methods from the field of social science while incorporating the principles of systems thinking and transdisciplinarity. Using our case study on HIV drug resistance in sub-Saharan Africa as an example, this article provides a practical guideline on how to map a public health problem as a complex adaptive system in order to uncover the drivers, feedback-loops and other dynamics behind the problem. Qualitative systems mapping can help researchers and policy makers to gain deeper insights in the root causes of the problem and identify complexity-informed intervention points.publishersversionpublishe

the interplay of two wicked problems

Funding Information: This work was funded by VLIR-UOS, grant numbers TZ2019SIN263 and TZ2020JOI032A101. Publisher Copyright: ©Concern is justified observing the link between the AIDS and COVID-19 pandemics. COVID-19 outcomes are significantly worse in many people living with HIV (PLHIV), even when vaccinated, because of their impaired immune system. Moreover, CD4 T-cells are affected by both HIV and SARS-CoV-2.1-3 SARS-CoV-2 variants can evolve in immunosuppressed patients due to prolonged viral replication in the context of an inadequate immune response.4 Accelerated intrahost evolution of SARS-CoV-2 was reported in a South African HIV patient with antiretroviral therapy (ART) failure.5 6 With 25 million HIV patients in sub-Saharan Africa (SSA) of whom an estimated 8 million are not virologically suppressed, this potentially creates a reservoir for future variants. Such variants, arising in PLHIV anywhere in the world, can spread to other continents, as has been reported for variants of concern (VoCs) (Beta, Omicron) and variants of interest (B.1.6.20, B.1.640.2) that arose in Africa.7-9 Conversely, the COVID-19 pandemic impacts HIV treatment programmes, due to supply chain issues, overburdening of healthcare systems, limiting access to testing, treatment and prevention programmes and further increasing inequalities.10 Modelled COVID-19 disruptions of HIV programmes in SSA included decreased functionality of HIV prevention programmes, HIV testing and treatment, healthcare services such as viral load testing, adherence counselling, drug regimen switches and ART interruptions, which may lead to selection of drug-resistant HIV.11 A 6-month interruption affecting 50% of the population would lead to a median number of excess deaths of 296 000, during 1 year. Scientists advocate for the AIDS and COVID-19 pandemics in Africa to be addressed simultaneously, by increasing African access to COVID-19 vaccines, prioritising research on the interaction between HIV care and COVID-19, maintaining high-quality HIV services and integrating health services for both viruses.7 Both the COVID-19 and the AIDS pandemic, more specifically the issue of HIV drug resistance (HIVDR), have previously been described as wicked problems which are best studied as complex adaptive systems (CASs).12-15Wicked problems consist of diverse interconnected factors and require complexity-informed and locally adapted solutions rather than one solution that fits all. We recently designed a qualitative model of all known factors influencing HIVDR in SSA and analysed its complexity.13 Our detailed systems map featured three main feedback loops driving HIVDR, representing (1) the alternation between adherence and non-adherence, (2) the impact of an overburdened healthcare system and (3) the importance of sustaining global efforts of tackling HIVDR even when new antiretroviral drugs with high genetic barriers become available. These HIV-related feedback loops are interconnected with COVID-19 pandemic impact (in yellow, figure 1). The loop starts from PLHIV with an unsuppressed viral load, which weakens the immune system and may in turn slow down immune clearance of SARS-CoV-2, allowing prolonged replication and mutation of the virus in the context of an inadequate immune response. Prolonged viral clearance facilitates the selection of immune escape SARS-CoV-2 variants. Variants may emerge that have a selective advantage and therefore may spread through populations due to increased transmissibility (with possibly increased virulence), thereby creating an additional burden on the healthcare system, putting the overall healthcare system and the HIV care at risk. These stressors on the healthcare system lead to a higher risk of unsuppressed viral load in PLHIV, increasing the risk of HIVDR. Figure 1 shows the need to address both wicked problems simultaneously and to do so in a complexity-informed manner as they are inevitably linked and influence each other. Evidently, the exact interconnections between both pandemics need to be locally assessed. For instance, a study in South Africa showed that while lockdown severely impacted HIV testing and ART initiation, ART provision was largely maintained, indicating that the strength of the connection between the virological suppression-related loop and the pandemic, indicated in figure 1, are context-dependent.16publishersversionpublishe

conceptual mapping of a complex adaptive system based on multi-disciplinary expert insights

Funding Information: This study was partially funded by VLIR-UOS. The study sponsors had no role in the study design, the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Publisher Copyright: © 2022, The Author(s).Background: HIV drug resistance (HIVDR) continues to threaten the effectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR are driven by several interconnected factors. Though much has been done to uncover factors influencing HIVDR, overall interconnectedness between these factors remains unclear and African policy makers encounter difficulties setting priorities combating HIVDR. By viewing HIVDR as a complex adaptive system, through the eyes of multi-disciplinary HIVDR experts, we aimed to make a first attempt to linking different influencing factors and gaining a deeper understanding of the complexity of the system. Methods: We designed a detailed systems map of factors influencing HIVDR based on semi-structured interviews with 15 international HIVDR experts from or with experience in sub-Saharan Africa, from different disciplinary backgrounds and affiliated with different types of institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence. Results: Factors influencing HIVDR in sub-Saharan Africa and their interactions were sorted in five categories: biology, individual, social context, healthcare system and ‘overarching’. We identified three causal loops cross-cutting these layers, which relate to three interconnected subsystems of mechanisms influencing HIVDR. The ‘adherence motivation’ subsystem concerns the interplay of factors influencing people living with HIV to alternate between adherence and non-adherence. The ‘healthcare burden’ subsystem is a reinforcing loop leading to an increase in HIVDR at local population level. The ‘ART overreliance’ subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at different levels. Conclusions: Interconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in sub-Saharan Africa in order to target interventions and to prevent unwanted effects on other parts of the system. The three theories that emerged while studying HIVDR as a complex adaptive system form a starting point for further qualitative and quantitative investigation.publishersversionpublishe

PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

Factors Associated with HIV Drug Resistance in Dar es Salaam, Tanzania: Analysis of a Complex Adaptive System

HIV drug resistance (HIVDR) is a complex problem with multiple interconnected and context dependent causes. Although the factors influencing HIVDR are known and well-studied, HIVDR remains a threat to the effectiveness of antiretroviral therapy. To understand the complexity of HIVDR, a comprehensive, systems approach is needed. Therefore, a local systems map was developed integrating all reported factors influencing HIVDR in the Dar es Salaam Urban Cohort Study area in Tanzania. The map was designed based on semi-structured interviews and workshops with people living with HIV and local actors who encounter people living with HIV during their daily activities. We visualized the feedback loops driving HIVDR, compared the local map with a systems map for Sub-Saharan Africa, previously constructed from interviews with international HIVDR experts, and suggest potential interventions to prevent HIVDR. We found several interconnected balancing and reinforcing feedback loops related to poverty, stigmatization, status disclosure, self-esteem, knowledge about HIVDR and healthcare system workload, among others, and identified three potential leverage points. Insights from this local systems map were complementary to the insights from the Sub-Saharan systems map showing that both viewpoints are needed to fully understand the system. This study provides a strong baseline for quantitative modelling, and for the identification of context-dependent, complexity-informed leverage points

Factors Associated with HIV Drug Resistance in Dar es Salaam, Tanzania: Analysis of a Complex Adaptive System

HIV drug resistance (HIVDR) is a complex problem with multiple interconnected and context dependent causes. Although the factors influencing HIVDR are known and well-studied, HIVDR remains a threat to the effectiveness of antiretroviral therapy. To understand the complexity of HIVDR, a comprehensive, systems approach is needed. Therefore, a local systems map was developed integrating all reported factors influencing HIVDR in the Dar es Salaam Urban Cohort Study area in Tanzania. The map was designed based on semi-structured interviews and workshops with people living with HIV and local actors who encounter people living with HIV during their daily activities. We visualized the feedback loops driving HIVDR, compared the local map with a systems map for Sub-Saharan Africa, previously constructed from interviews with international HIVDR experts, and suggest potential interventions to prevent HIVDR. We found several interconnected balancing and reinforcing feedback loops related to poverty, stigmatization, status disclosure, self-esteem, knowledge about HIVDR and healthcare system workload, among others, and identified three potential leverage points. Insights from this local systems map were complementary to the insights from the Sub-Saharan systems map showing that both viewpoints are needed to fully understand the system. This study provides a strong baseline for quantitative modelling, and for the identification of context-dependent, complexity-informed leverage points

How to move towards a common understanding of progress? A transdisciplinary exercise involving 10 young researchers

status: publishe

HIV-positive men as a key population for fighting HIVDR in Africa

status: Published onlin

Transdisciplinary experience in a pilot year of a new Honors Program at the KU Leuven – University of Leuven: building a team, developing and improving a transdisciplinary project through addressing a challenge on HIV drug resistance in Africa

Challenge: A way to understand and instruct on best practices for delivering and accepting HIV drug treatments in Africa. During this pilot year of the "Transdisciplinary Insights" Honors Program at the KU Leuven – University of Leuven, together with the academic staff, students have developed a methodology for working on a transdisciplinary challenge. The pilot project was structured initially in three (partially overlapping) steps: building a transdisciplinary team, building a transdisciplinary project, and gathering knowledge. The Actor Constellation, Three Types of Knowledge and Ten Reflective Steps exercises (www.transdisciplinarity.ch/toolbox; Pohl et al, 2017) and 'complexity and collaborative knowledge co-creation' (Marc Craps) workshops were very helpful for building a team and identifying gaps and steps to be undertaken to solve the challenge. It also boosted students' creativity and team-working skills. In the coming years, more challenges will be addressed simultaneously, each by a dedicated student group, coach and stakeholders.status: Published onlin

Belgium - concerns about coronavirus contact-tracing apps

status: publishe