BMC Infectious Diseases [Accessed 28 June 2014]

BMC Infectious Diseases
Accessed 28 June 2014
http://www.biomedcentral.com/bmcinfectdis/content

Research article
Is expanding HPV vaccination programs to include school-aged boys likely to be value-for-money: a cost-utility analysis in a country with an existing school-girl program
Amber L Pearson, Giorgi Kvizhinadze, Nick Wilson, Megan Smith, Karen Canfell and Tony Blakely
Author Affiliations
BMC Infectious Diseases 2014, 14:351 doi:10.1186/1471-2334-14-351
Published: 26 June 2014
Abstract (provisional)
Background
Similar to many developed countries, vaccination against human papillomavirus (HPV) is provided only to girls in New Zealand and coverage is relatively low (47% in school-aged girls for dose 3). Some jurisdictions have already extended HPV vaccination to school-aged boys. Thus, exploration of the cost-utility of adding boys’ vaccination is relevant. We modeled the incremental health gain and costs for extending the current girls-only program to boys, intensifying the current girls-only program to achieve 73% coverage, and extension of the intensive program to boys.
Methods
A Markov macro-simulation model, which accounted for herd immunity, was developed for an annual cohort of 12-year-olds in 2011 and included the future health states of: cervical cancer, pre-cancer (CIN I to III), genital warts, and three other HPV-related cancers. In each state, health sector costs, including additional health costs from extra life, and quality-adjusted life-years (QALYs) were accumulated. The model included New Zealand data on cancer incidence and survival, and other cause mortality (all by sex, age, ethnicity and deprivation).
Results
At an assumed local willingness-to-pay threshold of US$29,600, vaccination of 12-year-old boys to achieve the current coverage for girls would not be cost-effective, at US$61,400/QALY gained (95% UI $29,700 to $112,000; OECD purchasing power parities) compared to the current girls-only program, with an assumed vaccine cost of US$59 (NZ$113). This was dominated though by the intensified girls-only program; US$17,400/QALY gained (95% UI: dominant to $46,100). Adding boys to this intensified program was also not cost-effective; US$128,000/QALY gained, 95% UI: $61,900 to $247,000).
Vaccination of boys was not found to be cost-effective, even for additional scenarios with very low vaccine or program administration costs – only when combined vaccine and administration costs were NZ$125 or lower per dose was vaccination of boys cost-effective.
Conclusions
These results suggest that adding boys to the girls-only HPV vaccination program in New Zealand is highly unlikely to be cost-effective. In order for vaccination of males to become cost-effective in New Zealand, vaccine would need to be supplied at very low prices and administration costs would need to be minimised.

Research article
Migration intensity has no effect on peak HIV prevalence: an ecological study
Chris Kenyon, Robert Colebunders, Helene Voeten and Mark Lurie
Author Affiliations
BMC Infectious Diseases 2014, 14:350 doi:10.1186/1471-2334-14-350
Published: 24 June 2014
Abstract (provisional)
Background
Correctly identifying the determinants of generalized HIV epidemics is crucial to bringing down ongoing high HIV incidence in these countries. High rates of migration are believed to be an important determinant of HIV prevalence. This study has two aims. Firstly, it evaluates the ecological association between levels of internal and international migration and national peak HIV prevalence using thirteen variables from a variety of sources to capture various aspects of internal and international migration intensity. Secondly, it examines the relationship between circular migration and HIV at an individual and population-level in South Africa.
Methods
Linear regression was used to analyze the association between the various measures of migration intensity and peak national HIV prevalence for 141 countries and HIV prevalence by province and ethnic group in South Africa.
Results
No evidence of a positive ecological association between national migration intensity and HIV prevalence was found. This remained the case when the analyses were limited to the countries of sub-Saharan Africa. On the whole, countries with generalized HIV epidemics had lower rates of internal and external migration. Likewise, no association was found between migration and HIV positivity at an individual or group-level in South Africa.
Conclusion
These results do not support the thesis that migration measured at the country level plays a significant role in determining peak HIV prevalence.

Linking international clinical research with stateless populations to justice in global health

BMC Medical Ethics
(Accessed 28 June 2014)
http://www.biomedcentral.com/bmcmedethics/content

Research article
Linking international clinical research with stateless populations to justice in global health
Bridget Pratt, Deborah Zion, Khin Maung Lwin, Phaik Yeong Cheah, Francois Nosten and Bebe Loff
Author Affiliations
BMC Medical Ethics 2014, 15:49 doi:10.1186/1472-6939-15-49
Published: 26 June 2014
Abstract (provisional)
Background
In response to calls to expand the scope of research ethics to address justice in global health, recent scholarship has sought to clarify how external research actors from high-income countries might discharge their obligation to reduce health disparities between and within countries. An ethical framework–‘research for health justice’–was derived from a theory of justice (the health capability paradigm) and specifies how international clinical research might contribute to improved health and research capacity in host communities. This paper examines whether and how external funders, sponsors, and researchers can fulfill their obligations under the framework.
Methods
Case study research was undertaken on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial, which was performed on the Thai-Myanmar border with Karen and Myanmar refugees and migrants. We conducted nineteen in-depth interviews with trial stakeholders, including investigators, trial participants, community advisory board members, and funder representatives; directly observed at trial sites over a five-week period; and collected trial-related documents for analysis.
Results
The vivax malaria treatment trial drew attention to contextual features that, when present, rendered the ‘research for health justice’ framework’s guidance partially incomplete. These insights allowed us to extend the framework to consider external research actors’ obligations to stateless populations. Data analysis then showed that framework requirements are largely fulfilled in relation to the vivax malaria treatment trial by Wellcome Trust (funder), Oxford University (sponsor), and investigators. At the same time, they demonstrate that it may be difficult for long-term collaborations to shift the focus of their research agendas in accordance with the changing burden of illness in their host communities and to build the independent research capacity of host populations when working with refugees and migrants. Obstructive factors included the research funding environment and staff turnover due to resettlement or migration.
Conclusions
Our findings demonstrate that obligations for selecting research targets, research capacity strengthening, and post-trial benefits that link clinical trials to justice in global health can be upheld by external research actors from high-income countries when working with stateless populations in LMICs. However, meeting certain framework requirements for long-term collaborations may not be entirely feasible.

Globalization and Health [Accessed 28 June 2014]

Globalization and Health
[Accessed 28 June 2014]
http://www.globalizationandhealth.com/

Research
Commentary
Accelerating learning for pro-poor health markets
Sara Bennett, Gina Lagomarsino, Jeff Knezovich and Henry Lucas
Author Affiliations
Globalization and Health 2014, 10:54 doi:10.1186/1744-8603-10-54
Published: 24 June 2014
Abstract (provisional)
Background
Given the rapid evolution of health markets, learning is key to promoting the identification and uptake of health market policies and practices that better serve the needs of the poor. However there are significant challenges to learning about health markets. We discuss the different forms that learning takes, from the development of codified scientific knowledge, through to experience-based learning, all in relationship to health markets.
Discussion
Notable challenges to learning in health markets include the difficulty of acquiring data from private health care providers, designing evaluations that capture the complex dynamics present within health markets and developing communities of practice that encompass the diverse actors present within health markets, and building trust and mutual understanding across these groups.
The paper proposes experimentation with country-specific market data platforms that can integrate relevant evidence from different data sources, and simultaneously exploring strategies to secure better information on private providers and health markets. Possible approaches to adapting evaluation designs so that they are better able to take account of different and changing contexts as well as producing real time findings are discussed. Finally capturing informal knowledge about health markets is key. Communities of practice that bridge different health market actors can help to share such experience-based knowledge and in so doing, may help to formalize it. More geographically-focused communities of practice are needed, and such communities may be supported by innovation brokers and/or be built around member-based organizations.
Summary
Strategic investments in and support to learning about health markets can address some of the challenges experienced to-date, and accelerate learning that supports health markets that serve the poor.

Private sector, for-profit health providers in low and middle income countries: can they reach the poor at scale?
Elizabeth Tung and Sara Bennett
Author Affiliations
Globalization and Health 2014, 10:52 doi:10.1186/1744-8603-10-52
Published: 24 June 2014
Abstract (provisional)
Background
The bottom of the pyramid concept suggests that profit can be made in providing goods and services to poor people, when high volume is combined with low margins. To-date there has been very limited empirical evidence from the health sector concerning the scope and potential for such bottom of the pyramid models. This paper analyzes private for-profit (PFP) providers currently offering services to the poor on a large scale, and assesses the future prospects of bottom of the pyramid models in health.
Methods
We searched published and grey literature and databases to identify PFP companies that provided more than 40,000 outpatient visits per year, or who covered 15% or more of a particular type of service in their country. For each included provider, we searched for additional information on location, target market, business model and performance, including quality of care.
Results
Only 10 large scale PFP providers were identified. The majority of these were in South Asia and most provided specialized services such as eye care. The characteristics of the business models of these firms were found to be similar to non-profit providers studied by other analysts (such as Bhattacharya 2010). They pursued social rather than traditional marketing, partnerships with government, low cost/high volume services and cross-subsidization between different market segments. There was a lack of reliable data concerning these providers.
Conclusions
There is very limited evidence to support the notion that large scale bottom of the pyramid models in health offer good prospects for extending services to the poor in the future. In order to be successful PFP providers often require partnerships with government or support from social health insurance schemes. Nonetheless, more reliable and independent data on such schemes is needed.

Healthy People 2020: A Report Card on the Health of the Nation

JAMA
June 25, 2014, Vol 311, No. 24
http://jama.jamanetwork.com/issue.aspx

Viewpoint | June 25, 2014
Healthy People 2020: A Report Card on the Health of the Nation
Howard K. Koh, MD, MPH1; Carter R. Blakey, BS1; Allison Y. Roper, LICSW1
Author Affiliations
JAMA. 2014;311(24):2475-2476. doi:10.1001/jama.2014.6446.
Excerpt
For 4 decades, Healthy People has represented the United States’ vision for a healthier future. Each decade, it serves as a public health road map and compass for the nation by establishing a broad set of overarching health goals while specifying actions to improve length and quality of life. For the current decade, this comprehensive national health promotion and disease prevention agenda encompasses more than a thousand specific objectives organized into 42 topic areas.
To focus particular attention on the leading causes of preventable death and illness, Healthy People 2020 features Leading Health Indicators. This subset of 26 indicators from 12 topic areas offers high-priority targets for which concerted action could lead to major improvements for public health. This article reviews newly available Leading Health Indicators’ data for the first third of the decade, thereby offering a timely snapshot of the nation’s progress toward better health
:: (eTable in the Supplement).
[From Healthy People 2020 Leading Health Indicators: Progress Update]
Leading Health Topic and Indicator
Clinical Preventive Services
:: IID-8 Children receiving the recommended doses of DTaP, polio, MMR, Hib, hepatitis B, varicella and PCV vaccines (percent, aged 19–35 months)
– Baseline: (2009) – 44.3%
– Most Recent: (2011) – 68.5%
– Target: – 80.0%

Journal of Medical Ethics – July 2014

Journal of Medical Ethics
July 2014, Volume 40, Issue 7
http://jme.bmj.com/content/current

The concise argument
Why is informed consent important?
Rebecca Roache, Associate Editor
Decision-making is a prominent theme in this edition of the Journal of Medical Ethics. Our feature article examines the relationship between trust and informed consent. Informed consent is, of course, central to the decision-making process in medicine. In addition, several articles consider decision-making in medicine from a variety of angles.

Clinical ethics
Paper
Overriding parents’ medical decisions for their children: a systematic review of normative literature
Rosalind J McDougall, Lauren Notini
Author Affiliations
Centre for Health and Society, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
Abstract
This paper reviews the ethical literature on conflicts between health professionals and parents about medical decision-making for children. We present the results of a systematic review which addressed the question ‘when health professionals and parents disagree about the appropriate course of medical treatment for a child, under what circumstances is the health professional ethically justified in overriding the parents’ wishes?’ We identified nine different ethical frameworks that were put forward by their authors as applicable across various ages and clinical scenarios. Each of these frameworks centred on a different key moral concept including harm, constrained parental autonomy, best interests, medically reasonable alternatives, responsible thinking and rationality.

Theoretical ethics
Paper
Islam and the four principles of medical ethics
Yassar Mustafa
Author Affiliations
Queen Elizabeth Hospital, Birmingham, West Midlands, UK
Abstract
The principles underpinning Islam’s ethical framework applied to routine clinical scenarios remain insufficiently understood by many clinicians, thereby unfortunately permitting the delivery of culturally insensitive healthcare. This paper summarises the foundations of the Islamic ethical theory, elucidating the principles and methodology employed by the Muslim jurist in deriving rulings in the field of medical ethics. The four-principles approach, as espoused by Beauchamp and Childress, is also interpreted through the prism of Islamic ethical theory. Each of the four principles (beneficence, non-maleficence, justice and autonomy) is investigated in turn, looking in particular at the extent to which each is rooted in the Islamic paradigm. This will provide an important insight into Islamic medical ethics, enabling the clinician to have a better informed discussion with the Muslim patient. It will also allow for a higher degree of concordance in consultations and consequently optimise culturally sensitive healthcare delivery.

Journal of Pediatrics – July 2014

Journal of Pediatrics
Vol 165 | No. 1 | July 2014 | Pages 1-216
http://www.jpeds.com/current

Immunization exemptions leave kindergarten entrants at higher risk for vaccine-preventable diseases
Sarah S. Long, MD
Abstract
School immunization laws have contributed substantially to the decline in vaccine-preventable disease in the US. Immunization laws are made at the state level: 2 states permit medical exemptions only, 46 states and the District of Columbia permit religious exemptions, and 18 states permit philosophical or personal-belief exemptions. States that do not permit personal-belief exemptions have lower rates of religious exemptions, but religious exemptions have increased in these states, suggesting that some parents might be using religious rather than personal-belief exemptions. It is noteworthy that except for Christian Scientists, opposition to immunization is not part of any organized religious doctrine.

United States Private Schools Have Higher Rates of Exemptions to School Immunization Requirements than Public Schools
Jana Shaw, MD, MPH, Boldtsetseg Tserenpuntsag, DrPH, Louise-Anne McNutt, PhD, Neal Halsey, MD
Abstract
Objective
To compare medical, religious, and personal belief immunization exemption rates between private and public schools in US.
Study design
Exemption rates were calculated using the Centers for Disease Control and Prevention School Immunization Assessment Surveys for the 2009-2010 school year excluding states with incomplete survey data. Standardized exemption rates weighted on enrollments in public and private schools were calculated. Differences in exemption rates between public and private schools were tested using Wilcoxon signed rank test.
Results
The overall state exemption rate was higher in US private than public schools, 4.25% (SD 4.27) vs 1.91% (1.67), P = .0001 and private schools had higher exemption rates for all types of exemptions; medical 0.58% (0.71) vs 0.34% (0.34) respectively (P = .0004), religious 2.09% (3.14) vs 0.83% (1.05) respectively (P = .0001), and personal belief 6.10% (4.12) vs 2.79% (1.57), respectively (P = .006). Overall exemption rates were significantly higher in states that allowed personal belief exemptions.
Conclusions
Exemption rates were significantly higher in US private than in public schools. Children attending private schools may be at higher risk of vaccine-preventable diseases than public school children.

Improving access to vaccines through tiered pricing

The Lancet
Jun 28, 2014 Volume 383 Number 9936 p2185 – 2268
http://www.thelancet.com/journals/lancet/issue/current

Viewpoint
Improving access to vaccines through tiered pricing
Dr Seth Berkley MD a

Immunisation is now widely recognised as one of the most efficient, successful, and cost-effective health investments in history, but despite a substantial effort over the past 50 years, nearly one in five deaths of children younger than 5 years is still caused by a vaccine-preventable disease. With more than 22 million children in the world still unimmunised against common but life-threatening diseases (as measured by a vaccine containing a third dose of diphtheria-tetanus-pertussis [DTP]), almost all in developing countries, there is clearly still a long way to go.
In addition to the traditional and inexpensive vaccines included in the expanded programme on immunisation, nowadays new, more expensive, and complex vaccines are available. Mainly manufactured by a few research-based vaccine companies, these vaccines target the most common causes of the diseases that kill children, such as diarrhoea and pneumonia. In 2000, the GAVI Alliance was created to help to reduce the delay in the introduction of these types of new vaccines in low-income countries. Since GAVI’s inception, about 440 million of the world’s poorest children will have been immunised with its support by the end of 2013, with 6 million future deaths averted in the process.1 And the latest estimates predict that in the period up to 2020, the vaccines that GAVI are supporting will help to avert a further 8 million deaths.2

GAVI has a simple business model. It supports countries with a gross national income (GNI) per head less than US$1550 (which is adjusted annually for inflation, and due to increase to $1570 in 2014) and negotiates reduced pricing from vaccine manufacturers to be able to supply them with vaccines.3 Because GAVI serves only the lowest-income countries, it has been able to negotiate the lowest prices from manufacturers. As part of the model, GAVI countries pay a small proportion of the vaccine costs—so that there is some form of cost sharing. As countries become wealthier, they pay an increasing copayment until their GNI exceeds the GAVI GNI threshold, and they graduate.4 After a transition period, countries must take on financing the full cost of the vaccines. Graduation is a way for GAVI and its financial supporters to focus their resources on the poorest countries, while enabling governments with growing economies to take increasing responsibility and ownership for vaccination programmes over time.

GAVI uses several means to reduce the price of the vaccines that it procures. GAVI’s ordering and purchasing on behalf of countries is backed by financial commitments from donors. These commitments give manufacturers predictability for their production planning. GAVI pools demand so that it can leverage economies of scale (at present GAVI serves 58% of the global birth cohort) while companies deal mainly with only one purchaser, procured by GAVI through UNICEF Supply Division. This process reduces transaction costs, allowing for even further savings. To give a sense of the scale of procurement, in 2012 UNICEF procured more than $790 million worth of vaccines from ten manufacturers on behalf of GAVI countries. GAVI and its Alliance partners also use push and pull mechanisms to incentivise manufacturers. For example, the Bill & Melinda Gates Foundation has provided developing-country manufacturers with investments to support product development and manufacturing scale-up in return for lower vaccine prices when they begin supplying.5 And the pneumococcal Advance Market Commitment (AMC) uses donor commitments and long-term contracts to incentivise manufacturers to accelerate and expand the supply of this vaccine.

The problem, however, is that countries with GNI greater than the GAVI threshold face much higher prices for these new, more technologically advanced vaccines. In many of these countries, governments cannot afford to pay, while private sector prices are unaffordable for most families. As a result, many children living in non-GAVI-eligible middle-income countries are not being vaccinated, and uptake of new vaccines risks lagging behind many GAVI-eligible countries. Although some of GAVI’s and the Alliance partners’ interventions can indirectly support non-GAVI-eligible middle-income countries—eg, incentivising new manufacturers increases competition and benefits all markets that they serve—GAVI’s focus has been on the poorest countries. However, as countries pass the threshold and graduate from GAVI support, there is concern that they could be at risk of suspending vaccination programmes because they face a so-called pricing cliff, with steep increases when they no longer have access to GAVI prices.

In view of the latest population trends, this situation is particularly worrying. In 1990, more than 90% of the world’s poorest people lived in countries classified as low-income countries;6 nowadays 70% of the world’s poorest people live in middle-income countries.7 Consequently the burden of vaccine-preventable disease is now about twice as great in middle-income countries as in low-income countries, with just four countries accounting for around half of the vaccine-preventable deaths in the world, or 75% of those occurring in all middle-income countries: India, Indonesia, Nigeria, and Pakistan. Although these countries still receive GAVI support, all but Pakistan are expected to graduate in the coming years.

So, what we need is a way to ensure that children who are not living in GAVI-eligible countries also have access to affordable life-saving vaccines that will ultimately increase their chances of living healthy and productive lives. And for GAVI-eligible countries, as their incomes grow we need to find a way to ensure that their immunisation coverage achievements do not stop when they graduate from GAVI support because of unsustainable prices.

A solution is transparent and consistent tiered pricing for vaccines. The idea is simple enough: to have countries pay prices according to their ability to pay, as determined by their varying level of national income. To some extent tiered pricing for vaccines already exists, with GAVI countries paying the lowest price and non-GAVI, lower middle-income and middle-income countries representing a middle tier.8 For example, the price of pneumococcal vaccines for GAVI countries, $3•30—3•50 per dose, is less than 5% of the $102 price that is paid for pneumococcal conjugate vaccines in the USA. However, prices in these slightly higher-income countries can vary substantially on the basis of the country’s size, region, and predictability of financing, and there is a lack of transparency about who is paying what because most of these countries negotiate individually with manufacturers. There is also the vaccine revolving fund of the Pan American Health Organization (PAHO) that bands together the PAHO countries in a buying group and requires companies to provide them with one offer for all countries at the lowest worldwide price. PAHO includes some low-income countries such as Haiti, which has a GNI as low as $760, but 70% of its members are middle-income or high-income countries with a GNI of more than $4085 and ranging up to $106 000. Yet, although it cuts across tiers PAHO has nevertheless achieved large discounts through this regional buying model. Indeed GAVI has benefited from lessons learned from this fund and from their granting of a waiver to the least price clause such that the poorest countries, including those within PAHO, can receive vaccines at the lowest prices. But given that this pooling cuts across a very broad range of GNIs and because of the single price principle, middle-income countries both within the PAHO region and outside might not obtain the best possible price.

Instead, I believe that country access and ultimately company interests would be better served by a more structured global framework of price tiers, each based on country income (with use, for example, of World Bank income groupings: low income, lower-middle income, upper-middle income, and high income).4 Because growth in GNI does not always represent country investment in social development and local risk situations can vary, criteria beyond GNI could additionally be used to tier countries (eg, burden of disease, immunisation coverage, etc). Furthermore, this approach could include banding within price tiers on the basis of factors such as volumes and certainty of demand. Public markets would of course be treated differently than private markets.8 To help graduating countries to transition from the GAVI environment to the wider tiered model, graduating countries could have a so-called grandfathering clause, which would allow them to keep the GAVI price for up to 5 years, following the end of GAVI support, before moving to the cost structure of their new income tier.

Tiered pricing is particularly relevant for vaccines. Technically challenging product development and high fixed costs contribute to high barriers to entry. For many vaccines, to sustain more than three or four manufacturers is difficult. This factor limits competition, which ordinarily would alone be an effective lever to drive down prices. Thus, tiered pricing could apply for all GAVI vaccines but would be most crucial for new vaccines when there are particularly few manufacturers.

Because giving industry visibility on demand is crucial to help to plan production, achieve appropriate scale-up, and ultimately secure lower prices, an instrument could also be put in place to support non-GAVI, lower middle-income countries through pooled procurement mechanisms to achieve the lowest available prices within a given tier. This approach would need to be supported by careful demand forecasting, and potentially some demand guarantees, to enable countries to procure at a GAVI price plus a fixed step premium for each tier.

So although it is for manufacturers to set the prices of vaccines, the tiers would act as a guide irrespective of whether they are multinational corporations or developing country vaccine manufacturers. Most countries, rich or poor, already tend to base the decision on whether to publicly fund the introduction of a new vaccine on some form of cost-effectiveness model, so to set the price in the tier according to that equation would make sense.9 The challenge is having reliable data to make such an assessment, so in the absence of such data GNI usually serves as a reasonable proxy.

For many middle-income countries, prices are often still too high to finance vaccines for their national programmes. Furthermore, the lack of demand predictability and transaction costs that come with dealing with countries on an individual basis, together with the fear of eroding profit margins in high-income countries because of price (and therefore implied cost) transparency, have historically resulted in keeping prices high.

But since GAVI’s inception much has changed. GAVI has shown how it is possible to provide demand predictability for low-income countries and a subset of lower-middle-income countries, and to use this information to secure lower prices. There have also been significant efforts by the vaccine industry to make new vaccines more affordable, as shown by the price reductions for rotavirus, pentavalent, and human papillomavirus vaccines,10 the latter going from open market prices in excess of $100 and lowest public sector price of $13 a dose, to a GAVI price of $4•50. With expanded and more predictably stable demand, new companies—particularly from developing countries—have begun to serve these markets, thus creating supply security and healthy competition.
A balance between fair access and fair profit levels can be struck.11 Moreover, the global health community should not be opposed to manufacturers making a profit, after all vaccines are not a commodity market. Indeed we should be mindful that to some extent overcapacity is needed for supply security, and that in view of the public health benefit we should be willing to pay for it. By giving countries prices for vaccines that reflect their ability to pay, this type of approach would give countries the ability to plan programmatically and financially, which should ultimately create better predictability. In return, vaccine companies will be able to access wider markets, increase their production volumes (which will reduce their manufacturing costs),5 and have the opportunity to do the right thing for people who need but cannot afford their vaccines today.

Declaration of interests
I declare that I have no competing interest.

References
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