Enhancing the practice of medicine with embedded multi-disciplinary researchers in a model of change.

Successfully embedding researchers in a health care setting brings unique challenges and opportunities. Through a joint clinical and academic partnership, we have developed a novel approach to problem-solving in the health care context, by employing a model for leading through change to embed researchers in transformative initiatives. Using the model, we have been able to leverage our local environment and resources to engage multi-disciplinary researchers in solving complex issues. An example is our initiative, Enhancing the Practice of Medicine, to address burnout among health care providers. Through this work, we have identified 3 primary factors critical to the successful deployment of embedded researchers. First and foremost, a multi-disciplinary team with diverse expertise is necessary to truly understand the root causes and potential solutions for complex issues. Second, this diverse team of embedded researchers must be involved from the initial stages of project design and have a voice throughout all phases of planning and assessing the initiative. Finally, embedded researchers will be most successful when they are supported to build relationships, navigate the system, and conduct research as part of an integrated and comprehensive effort that aligns with health system priorities.

Cost of integrated chronic care for severe non-communicable diseases at district hospitals in rural Rwanda.

BACKGROUND: Integrated clinical strategies to address non-communicable disease (NCDs) in sub-Saharan Africa have largely been directed to prevention and treatment of common conditions at primary health centres. This study examines the cost of organising integrated nurse-driven, physician-supervised chronic care for more severe NCDs at an outpatient specialty clinic associated with a district hospital in rural Rwanda. Conditions addressed included type 1 and type 2 diabetes, chronic respiratory disease, heart failure and rheumatic heart disease. METHODS: A retrospective costing analysis was conducted from the facility perspective using data from administrative sources and the electronic medical record systems of Butaro District Hospital in rural Rwanda. We determined initial start-up and annual operating financial cost of the Butaro district advanced NCD clinic for the fiscal year 2013-2014. Per-patient annual cost by disease category was determined. RESULTS: A total of US$47 976 in fixed start-up costs was necessary to establish a new advanced NCD clinic serving a population of approximately 300 000 people (US$0.16 per capita). The additional annual operating cost for this clinic was US$68 975 (US$0.23 per capita) to manage a 632-patient cohort and provide training, supervision and mentorship to primary health centres. Labour comprised 54% of total cost, followed by medications at 17%. Diabetes mellitus had the highest annual cost per patient (US$151), followed by heart failure (US$104), driven primarily by medication therapy and laboratory testing. CONCLUSIONS: This is the first study to evaluate the costs of integrated, decentralised chronic care for some severe NCDs in rural sub-Saharan Africa. The findings show that these services may be affordable to governments even in the most constrained health systems.

Cost of Treating Pediatric Cancer at the Butaro Cancer Center of Excellence in Rwanda.

PURPOSE: Improvements in childhood survival rates have been achieved in low- and middle- income countries that have made a commitment to improve access to cancer care. Accurate data on the costs of delivering cancer treatment in these settings will allow ministries of health and donors to accurately assess and plan for expansions of access to care. This study assessed the financial cost of treating two common pediatric cancers, nephroblastoma and Hodgkin lymphoma, at the Butaro Cancer Center of Excellence in rural Rwanda. METHODS: A microcosting approach was used to calculate the per-patient cost for Hodgkin lymphoma and nephroblastoma diagnosis and treatment. Costs were analyzed retrospectively from the provider perspective for the 2014 fiscal year. The cost per patient was determined using an idealized patient receiving a full course of treatment, follow-up, and recommended social support in accordance with the national treatment protocol for each cancer. RESULTS: The cost for a full course of treatment, follow-up, and social support was determined to be between $1,490 and $2,093 for a patient with nephroblastoma and between $1,140 and $1,793 for a pediatric patient with Hodgkin lymphoma. CONCLUSION: Task shifting, reduced labor costs, and locally adapted protocols contributed to significantly lower costs than those seen in middle- or high-income countries.

Cost of Providing Quality Cancer Care at the Butaro Cancer Center of Excellence in Rwanda.

PURPOSE: The cost of providing cancer care in low-income countries remains largely unknown, which creates a significant barrier to effective planning and resource allocation. This study examines the cost of providing comprehensive cancer care at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. METHODS: A retrospective costing analysis was conducted from the provider perspective by using secondary data from the administrative systems of the BCCOE. We identified the start-up funds necessary to begin initial implementation and determined the fiscal year 2013-2014 operating cost of the cancer program, including capital expenditures and fixed and variable costs. RESULTS: A total of $556,105 US dollars was assessed as necessary start-up funding to implement the program. The annual operating cost of the cancer program was found to be $957,203 US dollars. Radiotherapy, labor, and chemotherapy were the most significant cost drivers. Radiotherapy services, which require sending patients out of country because there are no radiation units in Rwanda, comprised 25% of program costs, labor accounted for 21%, and chemotherapy, supportive medications, and consumables accounted for 15%. Overhead, training, computed tomography scans, surgeries, blood products, pathology, and social services accounted for less than 10% of the total. CONCLUSION: This study is one of the first to examine operating costs for implementing a cancer center in a low-income country. Having a strong commitment to cancer care, adapting clinical protocols to the local setting, shifting tasks, and creating collaborative partnerships make it possible for BCCOE to provide quality cancer care at a fraction of the cost seen in middle- and high-income countries, which has saved many lives and improved survival. Not all therapies, though, were available because of limited financial resources.

Expansion of cancer care and control in countries of low and middle income: a call to action.

Substantial inequalities exist in cancer survival rates across countries. In addition to prevention of new cancers by reduction of risk factors, strategies are needed to close the gap between developed and developing countries in cancer survival and the effects of the disease on human suffering. We challenge the public health community's assumption that cancers will remain untreated in poor countries, and note the analogy to similarly unfounded arguments from more than a decade ago against provision of HIV treatment. In resource-constrained countries without specialised services, experience has shown that much can be done to prevent and treat cancer by deployment of primary and secondary caregivers, use of off-patent drugs, and application of regional and global mechanisms for financing and procurement. Furthermore, several middle-income countries have included cancer treatment in national health insurance coverage with a focus on people living in poverty. These strategies can reduce costs, increase access to health services, and strengthen health systems to meet the challenge of cancer and other diseases. In 2009, we formed the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, which is composed of leaders from the global health and cancer care communities, and is dedicated to proposal, implementation, and evaluation of strategies to advance this agenda.

International collaborations in cancer control and the Third International Cancer Control Congress.

Over the past few decades, there has been growing support for the idea that cancer needs an interdisciplinary approach. Therefore, the international cancer community has developed several strategies as outlined in the WHO non-communicable diseases Action Plan (which includes cancer control) as the World Health Assembly and the UICC World Cancer Declaration, which both include primary prevention, early diagnosis, treatment, and palliative care. This paper highlights experiences/ideas in cancer control for international collaborations between low, middle, and high income countries, including collaborations between the European Union (EU) and African Union (AU) Member States, the Latin-American and Caribbean countries, and the Eastern Mediterranean countries. These proposals are presented within the context of the global vision on cancer control set forth by WHO in partnership with the International Union Against Cancer (UICC), in addition to issues that should be considered for collaborations at the global level: cancer survival (similar to the project CONCORD), cancer control for youth and adaptation of Clinical Practice Guidelines. Since cancer control is given lower priority on the health agenda of low and middle income countries and is less represented in global health efforts in those countries, EU and AU cancer stakeholders are working to put cancer control on the agenda of the EU-AU treaty for collaborations, and are proposing to consider palliative care, population-based cancer registration, and training and education focusing on primary prevention as core tools. A Community of Practice, such as the Third International Cancer Control Congress (ICCC-3), is an ideal place to share new proposals, learn from other experiences, and formulate new ideas. The aim of the ICCC-3 is to foster new international collaborations to promote cancer control actions in low and middle income countries. The development of supranational collaborations has been hindered by the fact that cancer control is not part of the objectives of the Millennium Development Goals (MGGs). As a consequence, less resources of development aids are allocated to control NCDs including cancer.

Advocacy and adolescent/young adult cancer survivors.

Strong advocacy efforts are vital to ensuring that the unique medical, psychosocial, support and educational needs of teenagers/adolescents and young adults living with cancer are met. Advocacy groups can help bring individuals interested in change together, and provide coordinated education and support services as well as policy analysis and response. Recent improvements in services and treatment indicate the success of organised and professional advocacy in addressing the needs of teenage/adolescent and young adult survivors. The advocacy community can continue to make great advances by joining together to support worldwide recognition of the unique needs of this population, the development of specialist facilities for teenagers/adolescents and young adults, increased awareness of cancer in this population to combat delayed diagnosis and improve access and quality of care, and alleviating the challenges of working with a multidisciplinary health care team.

Structural basis for the activation of cholera toxin by human ARF6-GTP.

The Vibrio cholerae bacterium causes devastating diarrhea when it infects the human intestine. The key event is adenosine diphosphate (ADP)-ribosylation of the human signaling protein GSalpha, catalyzed by the cholera toxin A1 subunit (CTA1). This reaction is allosterically activated by human ADP-ribosylation factors (ARFs), a family of essential and ubiquitous G proteins. Crystal structures of a CTA1:ARF6-GTP (guanosine triphosphate) complex reveal that binding of the human activator elicits dramatic changes in CTA1 loop regions that allow nicotinamide adenine dinucleotide (NAD+) to bind to the active site. The extensive toxin:ARF-GTP interface surface mimics ARF-GTP recognition of normal cellular protein partners, which suggests that the toxin has evolved to exploit promiscuous binding properties of ARFs.

Structural biology and structure-based inhibitor design of cholera toxin and heat-labile enterotoxin.

Structural biology studies on cholera toxin and the closely related heat-labile enterotoxin from enterotoxigenic Escherichia coli over the past decade have shed light on the mechanism of toxin action at molecular and atomic levels. Also, components of the extracellular protein secretion apparatus that translocate the toxins across the outer membrane are being investigated. At the same time, structure-based design has led to various classes of compounds targeting different toxin sites, including highly potent multivalent inhibitors that block the toxin receptor-binding process.

Crystal structures of an intrinsically active cholera toxin mutant yield insight into the toxin activation mechanism.

Cholera toxin (CT) is a heterohexameric bacterial protein toxin belonging to a larger family of A/B ADP-ribosylating toxins. Each of these toxins undergoes limited proteolysis and/or disulfide bond reduction to form the enzymatically active toxic fragment. Nicking and reduction render both CT and the closely related heat-labile enterotoxin from Escherichia coli (LT) unstable in solution, thus far preventing a full structural understanding of the conformational changes resulting from toxin activation. We present the first structural glimpse of an active CT in structures from three crystal forms of a single-site A-subunit CT variant, Y30S, which requires no activational modifications for full activity. We also redetermined the structure of the wild-type, proenzyme CT from two crystal forms, both of which exhibit (i) better geometry and (ii) a different A2 "tail" conformation than the previously determined structure [Zhang et al. (1995) J. Mol. Biol. 251, 563-573]. Differences between wild-type CT and active CTY30S are observed in A-subunit loop regions that had been previously implicated in activation by analysis of the structure of an LT A-subunit R7K variant [van den Akker et al. (1995) Biochemistry 34, 10996-11004]. The 25-36 activation loop is disordered in CTY30S, while the 47-56 active site loop displays varying degrees of order in the three CTY30S structures, suggesting that disorder in the activation loop predisposes the active site loop to a greater degree of flexibility than that found in unactivated wild-type CT. On the basis of these six new views of the CT holotoxin, we propose a model for how the activational modifications experienced by wild-type CT are communicated to the active site.