Monday, November 17, 2014

Tackling vaccine backlash requires more than science


The advent of vaccines has dramatically changed the public health landscape by eliminating the threat of communicable diseases. However, vaccines have come under recent scrutiny with false claims linking vaccines to autism, sterility, etc. Despite the abundance of scientific evidence and benefit-risk ratios to disprove these claims, it has not been enough to quell the distrust of vaccines. Enforcing vaccinations should not involve a “one-click” paternalistic approach; acceptance and trust is a complex act. Confronting any threat of disease presents us with choices of liberty, dignity, and protection. These questions cannot be resolved with more science or data; it requires an encounter with the ethics. Our ethical beliefs underlie personal, political and cultural values in which we base our decisions and perceptions of trust.
Vaccine backlash in the US can been partly attributed to the absence of a serious outbreak in recent history (Larson et al, 2011). When vaccines were first introduced, there was widespread disease and suffering. Today’s lack of familiarity with vaccine-preventable diseases has led to some questioning its purpose. Furthermore, the public is surrounded with a culture of celebrities who are refusing to vaccinate their children, which has spurred a trend among other parents to withhold vaccines as well. Similar to the tobacco ads in the 1950s, foregoing vaccines is seen as glamorous and a symbol of choice among wealthy parents. The concept of a social movement may help change this “culture” around vaccination. Choosing key figures, that are seen as trustworthy and admirable in the community, to advocate for the benefits of vaccination may help counter these harmful portrayals. This “advertising” also drowns out the harmful evidence of refusing vaccination, and raises the question of whether individuals are making decisions with a lack of informed consent, violating the core of ethical guidelines outlined in the Belmont Report. If so, what role does the government play to increase trust?

Implementation of vaccine programs has been characterized by a series of paternalistic nudges, such as mandatory vaccination for school enrollment or providing cost-benefit analyses. However, these government interventions are not fully effective, particularly in a country characterized by personal liberties and freedom of choice. Non-compliance is most importantly exacerbated by the lack of transparency in the government and their contradictory actions (Eliot and Resnick, 2014). In 1999, the AAP and CDC asked vaccine makers to remove thiomersal from childhood vaccines as precaution, but the action only fueled the proposed link between vaccines and autism (Larson et al, 2011). While many studies since then have failed to demonstrate a causal link between the two, the public still remained distrustful. These actions have eroded the trust in government decisions. Promoting transparency could include incorporating scientists from a range of different stakeholder groups on government advisory boards or disclosing financial/non-financial interests (Eliot and Resnick, 2014). Before taking such precautionary measures in moments of scientific uncertainty, these perverse consequences should be taken into account. Research ethics should be fully consulted before allowing such claims to be initially presented.

Wednesday, July 23, 2014

The Price is Right: Is cost-effectiveness analysis the best way to evaluate surgical intervention?





A couple months ago, I had the opportunity to listen to a presentation from an NGO director. Towards the end of her presentation, she expressed her dismay for receiving a lower grading from the previous year on a non-profit score report. This was partly due to the increased attention on surgical care within the organization. According to evaluators, surgical care was not deemed as cost-effective as other interventions such as mental care, where you could treat many more patients with less resources and time. Naturally, I thought of the many problems associated with this assumption – the misconceptions about surgical intervention, and the ethics, limitations, and over-reliance on a cost-effective analysis.

Misconception #1: Surgical intervention only addresses rare problems, which are a small part of the Global Burden of Disease.
WHO has reported that more than 90% of deaths from injuries occur in low and middle income countries (1). Injuries kill more than 5 million people worldwide each year, with one third of injury-related mortalities among 15-44 year olds, the most economically productive population (1). Despite these figures, developing countries only receive 3.5% of surgical procedures conducted worldwide (1). Surgical conditions extend beyond injuries which include: malignancies, obstetrics complications, congential anomalies, cataracts and glaucoma, perinatal conditions, and trauma emergencies. The Global Burden of Disease 2010 study also notes an increase in non-communicable diseases, several which can be surgically treated. By implementing surgical interventions, we can further accelerate advancements in several of the MDGs and the post-2015 agenda.

Misconception #2: Surgical intervention is often considered too expensive, especially when compared to other public health measures such as vaccines. On the contrary, recent studies have shown that surgery is very cost-effective. To compare benefits between two interventions, analyses usually compare DALYs (Disability-Adjusted Life Year). This can often be thought of as one lost year of “healthy” life. Cost-effectiveness ratios (CER) are also used to determine the increase in costs for the benefits of an intervention/treatment.

Cost effectiveness of interventions:
Measles vaccine
$1-5/DALY averted
ARVs for HIV
$300-500/DALY averted
Surgery
$7-200/DALY averted
Figure 1: Taken from the CUGH presentation via the Disease Control Priorities Project (2)
Despite the greater cost-effectiveness of surgery, injury and road accidents are still 100x under-funded compared to HIV/AIDS (2).

Figure 2: Taken from Chao TE, et al (The Lancet Global Health, 2014). 
Three surgical procedures are comparable to the Expanded Program of Immunization and bednets for malaria prevention (red stars). Several procedures have median CERs that are similar to that of BCG vaccine (blue arrows). Caesarean deliveries and orthopaedic surgery had the highest median CERs from the listed surgical categories, but they still are much more cost-effective than treatment for chronic ischaemic heart disease and HIV treatment (7).

Misconception #3: Surgery is too difficult to implement because it requires more infrastructure - clean operating rooms, anaesthesia, electrical power, and laboratory services – and skilled workers.
Yes, it is true that surgical intervention requires more infrastructure. However, it also has greater potential to be sustainable over vertical programs. An increase of long-term infrastructure-related investments also strengthens horizontal health-care delivery. We also don’t have to build all new facilities. District hospitals can be surprisingly efficient and produce good results at lost cost (7).  Part of scaling up surgery requires a new approaches, in particular, partnerships. In the past, surgical intervention relied of volunteerism and short-term missions (7). Today, surgery should focus on building up research and training for long-term. By creating collaborations with universities and hospitals in developing countries, we can help teach and train students and physicians, while innovating low tech diagnostic and treatment methods. Creating opportunities "in-country" can also reduce the “brain-drain” problems many of these countries have. Furthermore, instead of creating a population of specialist surgical physicians, we can scale-up community health workers to perform simple surgical procedures such as obstetric care, which can help increase the population of skilled workers.

The limitations and ethics of a cost-effective analysis

Although recent positive results from cost-effectiveness analysis on surgery continue to debunk misconceptions, economical value should not solely determine the appropriateness of interventions. Like many other statistical models, cost-effectiveness is an inexact process with several inherent limitations. First, there are uncertain inputs into the equation, which calls for imputing data from one data source to another that may be inappropriate for certain situations. This also includes assigning a value to “the priceless.”  While costs are easily determined (eg. cost of a treatment, a medicine, etc.),  the benefits, which include human life, are often more difficult to assign value to.

A negative result should also not be a deterrent for new programs. Many of today’s most popular treatments, such as ARTs, were not deemed cost-effective. It was only through the tireless work of many individuals that the costs of such treatments were lowered. Dr. Paul Farmer initiated an MDR treatment program in the 90s despite the staggering costs (3). Despite skepticism of the global community on providing MDR-TB treatment, Farmer proved many wrong by carrying out a treatment program in Peru successfully. As Dr. Farmer points out, “failure of imagination is a greater threat that condemns many men and women in the developing world to unnecessary disability and untimely death.” (5) Existing policies often convince physicians, as well as governments and the WHO, that it is too expensive and too logistically difficult to provide modern drugs to many sick in poor countries (5). Instead of a defeatist attitude, it is our duty to advocate for lower costs for these treatments in developing countries. Farmer notes that calculating “cost effectiveness” of care becomes a convenient excuse for failing to provide treatment for those in need (5).

Despite the results that cost-effectiveness reveals, any type of intervention will still be better than nothing. I liked this quote from a lecture given by Dr. Farmer (taken from a newspaper report): 

“[The Clinton Foundation] … found that community health workers [accounted for] 4 percent of the total cost, 9 percent of the labor cost. So if you want to use the term cost-effectiveness, which I do, it’s about as cost-effective as you can get. But remember, this is not about HIV or TB or malaria. It’s about all of it. So to rebuild these hospitals … labor is the biggest expenditure. And if you go into an area where unemployment is 60 percent, are you embarrassed to spend 45 percent of your budget on labor? I’m not. I think it’s good. And if you go into a place where there’s a lot of hunger—happily, medical science, through revolutionary breakthroughs, has given us a treatment for hunger called food. And spending 19 or 20 percent of your budget on food is not an embarrassment, either.” (4)

The argument over cost-effectiveness is not only present in global health interventions, but also health insurance and coverage of procedures. Many countries – including Canada, Britain, and the Netherlands, ration health care based on cost-effectiveness and a place a $50,000 threshold-value to any new treatments (6). In other words, if a new procedure goes beyond the threshold value, insurance will not cover it. While many interpret this threshold value as assigning a value to human life, others argue that we already practice it in many other situations such as payouts for soldiers killed in action (6). The study of value and life is a tricky one. It forces us to assign values to things we would otherwise deem priceless. No amount or value could probably ever be sufficient, and so cost-effective analyses will never be perfect. Finding a balance in making decisions tightly or loosely based on cost-effective analysis is part of the challenge. While I understand why many believe there is a benefit and practicality in using it, part of me would like to ignore it all together. As public health workers, we can often get caught up in the numbers, but we should not forget our purpose – to provide services to those most in need.

References
(5) http://www.newrepublic.com/article/books-and-arts/magazine/79737/despair-paul-farmer-medicine
(7) Chao TE, et al. Cost-effectiveness of surgery and its policy implications for global health: a systematic review and analysis. The Lancet Global Health (2014); 2: e334-45.


Thursday, July 3, 2014

Tackling the "us versus them" mentality and the stigma of disease



With more than 450 deaths so far, the Ebola outbreak in West Africa has recently been described as “out of control”. In addition to controlling the spread of disease, governments have an uphill battle against the “second disease” of stigmatisation many survivors face.

Disease stigma is nothing new. Even stories in the bible recount the widespread stigma against leprosy. Stigmatization may have once had an evolutionary purpose for early humans, but today it creates more harm than good by hindering positive health behavior and perpetuating illness and reinforcing racist or unjust ideologies. Throughout history, almost every major disease outbreak has been linked to a “low” or “immoral” class of people who are threat to society. Black women were often targeted as carriers of disease, especially by publicizing figures such as “Typhoid Mary.” The spread of polio was also blamed on the poor urban immigrants in America. Although we know that disease does not discriminate, it is easy to blame marginalized groups or immigrants based on underlying racist and unjust stereotypes. This is demonstrated through the HIV/AIDS epidemic and the 2003 SARS epidemic.

While fear and stigma breeds from unfamiliarity, it also partly stems from our management techniques which tend to produce negative connotations. Ebola calls for health workers to be covered head-to-toe in biohazard suits, and infected people are kept quarantined for weeks without any contact allowed to family or friends. Quarantine, in particular, tends to produce an “us” versus “them” mentality. Often times, many of those quarantined do not have complete understanding of the rationale for these measures. The fact that there is no specific treatment or vaccine makes the disease even more unnerving. The importance of a strong, central public health system is crucial in these moments to provide clear, transparent information in a timely manner to manage perception of public health risks. With many conflicting reports and information, distrust breeds within healthcare providers and patients. 

With this panic and fear, reintegration is difficult and many develop psychological and social issues. After the SARS outbreak in 2003, 28.9% and 31.2% of 129 quarantined individuals surveyed from Toronto suffered from posttraumatic stress disorder and depression, respectively. This onset of mental illness and social isolation after quarantine can trigger a cycle of poverty when patients lack support systems and lose their jobs.

Because of the challenges survivors face upon reintegration into society, the stigma has probably fueled its spread as patients tried to conceal their symptoms to avoid being quarantined and labeled. Citizens often believe in superstitions blaming the illness on a curse. Instead, they go into hiding, discharge themselves early from health facilities and prevent some aid organizations from even entering their communities.

Many methods have been practiced to address these problems. WHO replaces some belongings that have been burned and buried (mattress, clothes, pots, pans, etc) and provides a small stipend to replace the rest. Psychologists provide counseling, and health workers travel back home with the patient to ease neighbors’ fears. Despite these measures, it is not enough. In Liberia, one survivor, Aissata Bangoura, has been cut off from her family since her husband had died months earlier. The quality of her life has been greatly diminished due to her prior connection to this disease. 

In an effort to convince the people of Ebola’s deadly effects, Liberia’s health ministry has began posting images of Ebola-ravaged corpses in newspapers and television. While this has been effective at educating citizens that this was not an illness that can be cured with their traditional cultural rituals, it has also bred fear. Public health messages about a disease influence a person’s perception. People may be more likely to spread rumors for a disease with visible symptoms rather than no visible symptoms. A visible symptom may suggest that infected people are different and instigate this gossip.


Along with outbreak management, we should ask ourselves the long-term consequences of how we are presenting the disease. How should we modify this "horror-story" connotation to quarantine? Is there a better way to present data or statements to the public that do not illicit fear? Is “out of control” really the most effective to describe the situation? Is our goal to create panic or an organized and calculated response? Can we provide better support for cured patients? Should we consider all aspects (economic, social, psychological, education) when creating a reintegration program?

References

Thursday, June 19, 2014

“One Laptop Per Woman”: Increasing the use of technology to bridge the gender gap in developing countries




Development lies in the hands of women.

In many developing countries, women are typically in charge of the household and raising the next generation – both essential factors to the growth of a nation – but they are also increasingly taking on additional new roles in business and education. Technology is allowing women to be more independent.

The key to development is to promote female empowerment and leadership, which can be achieved through the increased use and access of technology. Information communication technologies (ICTs) can address challenges of gender inequalities in developing countries, including access to employment, income, education and health services.

Technology has introduced the concept of microfinance in the developing world, allowing women to be more independent. Currently, in Sierra Leone, women can only get loans with collateral from male relatives and it’s common to be pressured into sex by bank staff if there is no man around. Introduction of microfinance, credit, and technology has allowed women to take control of their own lives and finances. Transferring the money to the hands of the women may invest more of that money for the household and more sustainable practices for economic growth.

According to Manuel Castells, technology can also lead to the transformation of many power structures. There is a move from a vertical (top-down) approach dominated by men to a more horizontal approach where citizens, including women can participate. In other words, decision-making and leadership no longer needs to be so exclusive and limited to a network of managers and policy makers – roles that are traditionally occupied by men in developing nations. As more countries are embracing the use of technology, more women are able to gain access to education, take charge, and innovate to solve community problems. For example, a group of twelve women from villages in Sierra Leone are bringing solar-powered electricity to rural communities. They were all first trained at a college in India, and now use their knowledge and training to benefit their community. By spreading access of technology, it may be possible to train women from home making it easier and more cost-effective to train and implement this energy infrastructure.

And finally, ICTs allow women communicate, exchange views, organize themselves can have huge implications of economic and political progress. Just simply allowing women to engage in public sphere, exchange ideas with one another and allow conversation can lead to surprising results in development through all sectors. Recent studies in India and Bangladesh found that the creation of women’s groups led to a decrease in child and maternal mortality. The study surprisingly found that when women came together and were allowed to discuss frustrations and have a support group. Increased health can lead to a stronger community and increased economic growth. Using the findings from these studies and integrating it with technology can enhance these effects.

However, the introduction of technology does not come without many challenges. Currently, in Sierra Leone, only around 0.3% of the population are described as internet users and women are 43% less likely to own a mobile phone. There are still huge gender gaps and donors must face the cultural stigma of increasing the roles of women in these countries. Furthermore, and most importantly, implementing technology is expensive. Women may have the ability and knowledge to set up solar-powered electricity for their community, but they may not have the funds to get the supplies or ensure sustainability.

Development is empowerment. Empowerment begins with information and knowledge. This presents the future challenge – focus implementing ICTs to promote female empowerment.

References 

1. Bhandari, M. (2011, Aug 17) “The women bringing solar power to Sierra Leone.” Retrieved from < http://www.guardian.co.uk/global-development/poverty-matters/2011/aug/17/sierra-leone-barefoot-solar-engineers?intcmp=239>
2. Bhandari, M. (2011, Aug 30) “Using technology to close the gender gap in Sierra Leone.” Retrieved from < http://www.guardian.co.uk/global-development/poverty-matters/2011/aug/29/closing-gender-technology-gap-sierra-leone?intcmp=239>
3. Castells, M. (2002) “The Contours of the Network Society.” Foresight, 2(2): 151-157.
Costello, A. (2010, March 5). “Women’s support groups improve newborn survival rates.” Retrieved from < http://www.ucl.ac.uk/news/news-articles/1003/10030801>
4. Shirky, C. (2011) “The Political Power of Social Media: Technology, the Public Sphere, and Political Change.” Foreign Policy, Jan/Feb 2011.

Wednesday, June 11, 2014

The New X-men Generation: how mutant mosquitoes will save the world


For my first blog post, I thought I'd bring back one of my favorite topics that I first read about last year. I heard about genetically modified mosquitoes on the news again recently, so I decided to expand and write a lengthy (blog post) but a short essay on this new technology. Enjoy! 


Brief points:
  • There are several advantages of GMMs over traditional interventions of insecticides, bed nets and SIT.
  • Among the various GMM methods, RIDL currently holds the most evidence of effectiveness so far. While RNAi and Wombachia are promising ideas, more studies in the laboratory and field are needed to evaluate its effects to different strains of dengue and possible resistance.
  • In addition to considering biological factors, there are also social and economic aspects including cost-effectiveness, community acceptance, and long-term sustainability with capacity building to consider.
  • For greater uptake within communities, more accurate information of its advantages and misconceptions should be addressed.


Background

According to WHO, around 50-100 million people are affected each year from dengue fever, one of the deadliest mosquito-borne diseases, primarily in tropical and sub-tropical regions1. While many interventions have been carried out to fight against vector-borne diseases, they have been ineffective to completely eradicate it. However, today’s technological advancements have allowed the development of promising innovative methods, including one that targets the mosquito population with genetic modifying mechanisms. Scientists have described this new approach as a “quantum leap” which has the potential to revolutionize, and possibly eradicate, malaria transmission. The idea of this “mutant mosquito” gained widespread attention and popularity through a TED talk from Oxitec. Since then, many institutions particularly in the UK have developed on this idea creating waves in the scientific community.  

Genetic modification (GM) serves as an incredibly useful tool that has been the subject of unfair and biased criticism2. Genetically modified mosquitoes (GMM) have several advantages to other techniques such as SIT (Sterile Insect Technique) and traditional methods of insecticides and bed nets. And while there are several ways in which to genetically modify a mosquito, such as the use of RNAi and Wolbachia, the RIDL (release of insects carrying a dominant lethal gene) technique seems to be the most effective and sustainable GM technique for the eradication of vector-borne disease. Oxitec, a biotechnology company, has used the RIDL technique to demonstrate short-term success in the Cayman Islands, Malaysia, and Brazil2.


The traditional methods

Traditional methods of pesticides and larvicides have not been fully effective at reducing disease transmission and face many challenges due to resistance and unsustainable high costs3. The challenge is that mosquitoes have many breeding site options within a community, and targeting every source of water with chemicals is impractical and restricted due to potential human toxicity3. Furthermore, the Ae. Aegypti species, which primarily transmits dengue, is a day-biter making the use of bed nets generally ineffective4. In response to these challenges, scientists in the past have used a technique known as SIT. The SIT technique is an insect population control method where mosquitoes are sterilized by irradiation then released to mate with wild mosquitoes, which would hopefully produce fewer progeny5. One of the largest issues with SIT is the emergence of behavioural resistance due to decreased fitness of the irradiated males5. In some cases, females are able to identify the sterile males and avoid mating with them. So far, there have been no signs of resistance to the RIDL modified mosquitoes5. Because of this adaptation of the resistance among female mosquitoes, SIT is an unsustainable method.


The new approach

To improve upon these challenges, scientists at Oxitec are utilizing GMM strategies, which may be safer and more effective than SIT4. One of the most effective GMM techniques is known as RIDL. RIDL, also known as conditional lethality, modifies male mosquitoes not by irradiation, but by genetically modifying a mosquito to carry a dominant lethal6. When this transgene is activated – there are several activation methods - it can cause lethality in progeny. The most important advantage of RIDL over SIT is the ability to control the activation of the lethal gene allowing it to be sex-specific and to time lethality6.

Oxitec has developed two main activation methods:  

(1) The first approach is sex-specific which aims to create flightless female. A construct is developed to reduce the expression of a female-specific gene that is critical for flight in pupae. This construct is inserted into the strain of male mosquitoes7. Once these modified males are released and mate with wild females, the immediate progeny inherits this dominant female-specific lethal gene, and the mutation is expressed in a female mosquito progeny7. This results in F1 females unable to fly to find mates or bite human hosts7. The F1 males, however, remain viable and fertile4. This will decrease the overall reproductive potential of the wild population5. Instead of random mutations caused by SIT, males can carry and deliver female-acting transgenes into the population4.

(2) A second approach of RIDL focuses on stage-specific killing. This allows scientists to control age of mortality, either in pupae, or in adults, and targets both males and females4. One way this is achieved is by inserting mutations so that lethal genes are only expressed in the absence of tetracycline8. A RIDL transgene is created, which carries the instructions for the production of a protein called tetracycline transactivator (tTA), and is inserted into the a strain in Ae. Aegypti mosquitoes9. This transgene is composed of two proteins, which allow it to continuously produce even more tTA protein resulting in a positive feedback loop9. tTA will interefere with the cellular process causing mosquito larvae to die. However in the presence of tetracycline, tTA expression can be turned off by binding to tetracycline9. In other words, scientists can control whether survival of larvae by increasing or removing tetracycline from the environment. Because these constructs use either female or stage-specific promoters, they do not affect male fitness or interfere with other stages of a mosquito’s life4. This helps ensure stability of the mosquito’s competitiveness in the wild and reduces the possibility of resistance, which has been a challenge for the SIT method.

Figure 1. Because I always love drawn out explanations, I outlined the stage-specific killing method (conditional lethality)d below in a detailed and graphic visualization:


Some other new GM methods gaining traction

RNAi: Using RNAi, scientists hope to improve the mosquito’s own natural immune defense system. This method calls for a genetic construct to be developed that expresses copies of an inverted repeat from a dengue virus 2 (DENV-2) genomic RNA4. Once the virus invades the mosquito, the resulting double stranded RNA forms and triggers an RNAi response degrading the virus and protecting the mosquito4. However, this method was only found effective in laboratory so far.

Wolbachia: The other GM technology utilizes the natural symbiotic bacteria Wolbachia, which naturally infects other insects such as Drosophila and protects them against infection by certain RNA viruses10. The idea aims to boost a mosquito’s defense system by infecting A.aegypti mosquitos with Wolbachia to prevent dengue infection10. While this is a promising idea and has been successful in small laboratory studies, it has several limitations. Research has only tested infection to protect against DENV-2; its effectiveness against the three other dengue serotypes has yet to investigated4. On the other hand, the RIDL method that Oxitec has employed eradicates the entire mosquito species with no challenges of targeting virus serotypes. Most importantly, the mechanism of how Wolbachia blocks pathogens is still unknown4. Without knowing this mechanism, it is difficult to foresee long-term effects of implementing Wolbachia in specific mosquito populations and predicting whether they may have adverse effects, such as if resistance will arise and how we may prevent it.

 

Challenges ahead for GM technology

The main challenge for any mosquito suppression technique is sustainability - maintaining stability of the competitiveness of the mosquito and preventing possible resistance4. All of the GM techniques including RIDL, have not been tested long enough yet to ascertain long-term effects. However, RIDL has shown successful short-term effects thus far. In 2010, male mosquitoes with modified strains were released in field tests in the Cayman Islands; the results showed a reduction in A.aegypti population by 80%2. Currently, RIDL technologies have only used single gene insertions. To avoid the possibility of resistance, future studies can introduce several conditional lethal systems in a genome8. RIDL future intervention programs will most likely be used in combination with other traditional or GM methods to boost effectiveness3.


Misconceptions and advantage

  • The most common belief is that scientists are aiming to eradicate all mosquitoes, which would possibly disrupt ecological systems. However, the focus of GMM research is on specific species that transmit disease-causing pathogens to humans, most of which are invasive species in an area in the first place3.
  • RIDL has several advantages in safety and in acceptance within a community. If RIDL is successful, the population can anticipate a short-lived presence of the GMM in their community once the mosquito species has been eradicated11. Since only males are released, it may also reduce nuisance biting and the risk of crop damage from egg-laying females11. These mosquitoes can also be manufactured and released locally after training communities allowing for capacity building and empowerment through employment11.
  • The RIDL technique allows scientists to control lethality timing by controlling tetracycline release to a mosquito’s diet. This tetracycline requirement produces the conditional lethality aspect of RIDL, which also ensures protection against the accidental release of mosquitoes11


References 1. Sifferlin, A. How Mutant Mosquitoes are Fighting Dengue Fever. Time, 9 November 2012. < http://healthland.time.com/2012/11/09/how-mutant-mosquitoes-are-fighting-dengue-fever> 2. Parry, Hadyn. “Re-engineering mosquitos to fight disease.” TedSalon London Fall 2012. November 2012. <http://www.ted.com/talks/hadyn_parry_re_engineering_mosquitos_to_fight_disease.html? 3. Benedict, M.Q., James, A.A., and Collins, F.H. (2011) Safety of Genetically Modified Mosquitoes. JAMA, 305 (20). 4. McGraw, E.A. and O’Neill, S.L. (2013). Beyond insecticides: new thinking on an ancient problem. Nature Reviews Microbiology, 11. 5. Alphey, N., Bonsall, M.B. and Alphey L. (2011) Modeling resistance to genetic control of insects. Journal of Theoretical Biology, 270: 42-55. 6. Fu, et al. (2010) Female-specific flightless phenotype for mosquito control. PNAS, 107 (10). 7. Wise de Valdez, M.R. et al. (2011) Genetic elimination of dengue vector mosquitoes. PNAS, 108 (12). 8. Black, W.C. Alphey, L., and James A.A. (2011) Why RIDL is not SIT. Trends in Parasitology, 27 (8). 9. AmsianV. Dengue Fever, GMOsquitoes, and a “Wolbachian” Invasion. Amasian Science. 3 January 2013. Web. 25 March 2013. < http://amasianv.wordpress.com/2013/01/03/dengue-fever-gmosquitos-and-a-wolbacchian-invasion/> 10. Le, Viet.  Could Wolbachia be an alternative to dengue-fighting GMOsquitos? Plos Blogs. 3 January 2013. Web. 25 March 2013 < http://blogs.plos.org/publichealth/2013/01/03/could-wolbachia-be-an-alternative-to-dengue-fighting-gmosquitos/> 11. “Oxitec: Benefits of RIDL Science,” Oxitec.com. n.d. Web. 25 March 2013. <http://www.oxitec.com/ridl-science/benefits-of-ridl/>