On Tuesday, November 28, the International Initiative Human Well-being Working Group hosted a documentary film viewing and a scholarly panel discussion on "Endangered Childhood: Disease, Conflict, and Displacement." The film, Their Brothers' Keepers: Orphaned by AIDS, opened the session to provide insight into the plight of children orphaned by AIDS. Moderator Paul Wise and the other panelists spoke on the impact of conflict and displacement, the psychological effects on child health and development, and work done to assist children affected by AIDS. The session concluded with a Q&A session.

A proposal to assess the societal and security implications of the female deficit in China, a study of the impact of higher education's rapid expansion in large developing economies, and incentives for provision of health care services for one billion people in rural China were among the new projects funded by Stanford's Presidential Fund for Innovation in International Studies (PFIIS) in mid-February. Planning grants for an international health and society initiative in the Indian subcontinent and psychosocial treatment for children orphaned by the tsunami in Indonesia were also awarded.

"These projects show great potential to advance human knowledge, help devise sustainable solutions, and build a better, more secure future for millions around the world," said Stanford President John Hennessy. "In launching The Stanford Challenge, we committed to marshal university resources to address some of the 21st century's great challenges in human health, international peace and security, and the environment."

The $3 million, intellectual venture capital fund was established by the Office of the President and the Stanford International Initiative in 2005 to encourage new cross-campus, interdisciplinary research and teaching among all seven schools at Stanford on three overarching global challenges: pursuing peace and security, improving governance, and advancing human well-being. The first $1 million was awarded in February 2006 to eight interdisciplinary faculty teams examining such issues as the HIV/AIDS treatment revolution in sub-Saharan Africa, why Latin America has been left behind in recent gains by developing countries, and food security and the environment.

"It's impressive to see the committed, collaborative, and innovative ways Stanford faculty are joining together in new interdisciplinary research and teaching to generate new understanding of the linkages among complex problems and train a new generation of leaders to address them effectively," said Freeman Spogli Institute Director Coit D. Blacker, chair of the International Initiative Executive Committee.

New projects qualifying for funding and their principal investigators are:

• Female Deficit and Social Stability in China: Implications for International Security. Melissa Brown, anthropological sciences; Marcus Feldman, biological sciences, and Matthew Sommer, history. As the number of surplus, marriage-age men in China approaches 47 million in 2050, this project will study factors that predict men's inability to marry before 30, the availability of social welfare to men and their families, their contribution to the floating population of rural-to- urban migrants, the labor-related migration of unmarried women, and the impact of this migration for domestic stability and international security.
• Potential Economic and Social Impacts of Rapid Higher Education Expansion in the World's Largest Developing Economies. Martin Carnoy, education; Amos Nur, geophysics; and Krishna Saraswat, electrical engineering. The development of higher education systems in Brazil, Russia, India, and China (BRIC) will have a major impact on their ability to transition to large, developed, knowledge-based economies. Is the way nation states expand and reform higher education in response to global pressures an important indicator of societal capacity to achieve sustained economic growth? This project will examine differing approaches of BRIC governments to higher-education growth and reform, and ask whether these reflect differing levels of state capacity to expand the knowledge base for economic and social development and whether differing approaches result in significant changes in formation of analytical skills in university graduates, particularly scientists and engineers.
• Health Care for One Billion: Experimenting with Incentives for the Supply of Health Care in Rural China. Scott Atlas, radiology; Scott Rozelle, the Walter H. Shorenstein Asia-Pacific Research Center, FSI. This project examines the effects of existing health policies and institutions in rural areas of China - including rural health insurance, privatization of rural clinics, and investment in township hospitals - and introduces a new experiment to study and realign incentives to address a serious flaw in China's health care system, the practice in which doctors both prescribe and derive significant profits from drugs.

Two planning grants were also awarded, as follows:

• Stanford International Health and Society Initiative: Proposal to Plan for an Initial Program in the Indian Subcontinent. Vinod K. Bhutani, pediatrics; Nihar Nayak, obstetrics and gynecology. This project seeks to improve unacceptably high maternal and childhood morbidity and mortality rates in the Indian subcontinent by devising innovative strategies to bridge existing social and access barriers in the micro- and macro- health environment. Includes leadership training and cooperative work on practice and policy strategies with experts from Stanford and the subcontinent.
• Psychosocial Treatment of Children Orphaned by the Asian Tsunami in Indonesia. Hugh Solvason, psychiatry; Donald Barr, sociology. This project's goal is to develop and implement changes to reduce the sense of dislocation, anxiety, and behavioral problems among tsunami orphans at the As-Syafi`iyah Orphanage in Jakarta. By arranging the children into more cohesive groups that can operate like "families" rather than their current state of random associations typically found in orphanages, the project will create a new and ordered social system. In addition, Solvason and Barr plan to develop a system of counseling interventions for the most severely symptomatic children (supervised by Stanford Psychiatry faculty). Translated measures of depression, anxiety, and PTSD will be used to assess the success of the intervention.

The projects will produce new field research, conferences, research papers, books, symposia, and courses for Stanford students.

A third round of project awards will be made in February 2008. A formal request for proposals will be issued in the fall of 2007, with proposals due by December 14, 2007. Priority is given to teams of faculty who do not typically work together, represent multiple disciplines, and address issues that fall broadly within the three primary research areas of the International Initiative. Projects are to be based on collaborative research and teaching involving faculty from two or more disciplines, and where possible, from two or more of Stanford's seven schools.

For additional information, contact Catharine Kristian, ckristian@stanford.edu.

In late September, the federal Centers for Disease Control and Prevention announced new guidelines recommending that all Americans ages 13 to 64 be voluntarily screened for HIV infection. That's a significant change from the previous guidelines, which recommended testing only for high-risk individuals, such as injection drug users or those with multiple sex partners.

The new guidelines were influenced by a study published last year in the New England Journal of Medicine, led by Douglas K. Owens, a CHP/PCOR core faculty member and an investigator at the VA Palo Alto. Owens and his colleagues -- including CHP/PCOR researchers Gillian D. Sanders, Vandana Sundaram, Kristof Neukermans and Laura Lazzeroni -- found that expanding HIV screening would be a cost-effective way to increase life expectancy and decrease the transmission of HIV. Below, Owens discusses the research and the CDC's new screening guidelines.

Q. Why does this new policy matter, and whom will it help?

Owens: The policy is a profound change because it advises that all individuals ages 13 to 64 be screened for HIV. It matters because it will identify people who have HIV but don't know it. These people will benefit because they'll have access to life-prolonging drugs that they otherwise might not have received until very late in the course of HIV disease. The rest of the community will also benefit, through reduced transmission of HIV.

Q. How did your findings contribute to the CDC adopting the new guidelines?

Owens: First, we found that widespread screening provides a substantial health benefit to HIV-positive people who are identified through screening and receive anti-retroviral treatment earlier than they would have otherwise. Early treatment added about a year and a half of life expectancy for these people. Second, we found a substantial potential benefit to the community because of reduced transmission of HIV. Transmission is reduced because many people cut down on risky behaviors (such as having unprotected sex) when they're identified as having HIV, and because anti-retroviral treatment makes a person less infectious. Our key finding was that routine screening is cost-effective even if only 1 in 2,000 people who are screened have HIV. This means HIV screening is cost-effective in a much broader group than recognized previously.

Q. How and why did the CDC revise its previous guidelines? What role did you and your colleagues play in the decision-making?

Owens: CDC officials made this change because they saw mounting evidence that the prior approach to screening -- focusing on those with identifiable risk factors -- simply wasn't working. If you test people based on risk behavior, you miss many people who have HIV. Even among people who had easily identified risk behaviors, many of them weren't being tested. We also know that most people who have HIV are diagnosed very late in the disease, when they can't get the full benefit from anti-retroviral therapy.

Our involvement in the decision-making was to help assess the prevalence of HIV at which routine screening would be recommended. Through several conference calls with CDC officials, we presented our work and explained the issues related to cost-effectiveness and prevalence. Based on those results and the results of a similar study from Yale, the agency went in the direction of lowering the threshold for screening quite substantially -- to 1 in 1,000 from a prior threshold of 1 percent.

Q. Will most physicians follow the new guidelines? What can be done to make sure they do?

Owens: That's the big question. The CDC's previous screening guidelines were not widely adopted. The new recommendations are much easier to adopt, because they don't depend on clinicians determining the prevalence of HIV in their patient population. Still, it will take a lot of follow-up to make sure physicians implement the guidelines. One key obstacle will be getting payers to reimburse for HIV testing. That's a critical issue, which the CDC is well aware of.

Q. Some HIV/AIDS advocates object to the new guidelines because they recommend removing two requirements that some states now have: mandatory signed consent forms and counseling before testing. Does removing these requirements pose a big problem?

Owens: It's important to emphasize that the new guidelines say people should always be informed before testing and should be able to decline. Informed consent and pretest counseling had become significant barriers that were preventing people from being tested who should have been tested. Everyone agrees that no one should be tested without their knowledge, but that doesn't mean you need a separate consent form. Of course, the confidentiality of the test results should continue to be carefully protected. I would point out that some states have laws requiring informed consent, but whether they will now change those laws isn't clear.

In 1979, anthrax was accidentally released in the city of Sverdlovsk (pop. 1,200,000) in the former Soviet Union, infecting about 80 to 100 people and killing at least 70. Russian officials claimed at the time that tainted meat sold on the black market was responsible; American officials argued that a nearby biological weapons facility released the killer spores. In the early 1990s, Harvard researchers visited the city to piece together the epidemiology of the outbreak. Their investigation, published in Science magazine in 1994, concluded that the Soviet cover story was false.

Now, physicist Dean A. Wilkening, director of the science program at Stanford's Center for International Security and Cooperation (CISAC), has revisited this Cold War tragedy and used its real-world data to improve our ability to model the medical effects of inhalational anthrax. This, in turn, allows him to model more accurately hypothetical scenarios such as the release of a kilogram of aerosolized anthrax in Washington, D.C., today.

The models researchers have used in such thought experiments "predict very different outcomes," says Wilkening, whose work to better understand the human effects of inhalational anthrax was supported by grants from the John D. and Catherine T. MacArthur Foundation and the Carnegie Corporation. Using real-world data from the Sverdlovsk outbreak and from limited nonhuman primate experiments, he was able to eliminate two of four theoretical models currently used in "what if?" scenarios that inform bioterrorism policies ranging from how much medicine we should have on hand in the Strategic National Stockpile to how rigorous post-attack decontamination efforts need to be. He reports his findings in the May 1 issue of Proceedings of the National Academy of Sciences.

"To date, researchers haven't paid enough attention to which model they use," Wilkening says. "Different models can give predictions that vary by a factor of 10 or more, so it matters which model one uses for predicting the human effects of inhalational anthrax." Wilkening aims to anchor models on the best available data and provide realistic models that the bioterrorism community can employ in policy studies.

The Sverdlovsk outbreak is "a sort of natural experiment," he says. "It's a tragic incident, but it also is a very valuable source of scientific data that one can use to distinguish between the four models currently in use." The upshot of his analysis is that two of the models currently in use are not accurate for predicting the human response to inhalational anthrax.

Insufficient data is available to resolve which of the remaining two models he examined is most accurate. That answer will have to await further data from costly nonhuman primate experiments, should they ever be performed (none are planned). "We have to use both [models] right now, or use them as bounding cases," he advises.

Wilkening explored four policy issues that illustrate the consequences of choosing different models: 1) calculating how many anthrax-exposed people would become infected and how many would die; 2) assessing if decontamination would be needed; 3) determining how soon exposed people would show symptoms and how soon doctors would recognize those symptoms as anthrax; and 4) calculating how soon exposed people need to receive antibiotics to avoid contracting the disease.

"To figure out what happens in a bioterrorist event, you need to know two basic properties about the pathogen you're dealing with," Wilkening says. One is the dose-response curve, which determines the likelihood of becoming infected at different exposure levels--the higher the dose of anthrax you get, the higher the probability that you will become infected. The dose at which 50 percent of an exposed population becomes infected, called the ID50, is around 10,000 spores. The other basic property is the incubation-period distribution, or the time the pathogen takes to grow in the body before symptoms first appear.

Wilkening's study brought dose-dependence to a debate over how long the incubation period is for inhalational anthrax. Published data from vaccine efficacy tests in which nonhuman primates were challenged with high doses of anthrax--up to a million spores--indicate an incubation period of one to five days. Data from Sverdlovsk, which exposed people to low doses probably on the order of 1 to 10 spores, indicate a longer incubation period, about 10 days. Whereas previous authors have debated whether nonhuman primate experiments or the Sverdlovsk data should be used to determine the incubation period for inhalational anthrax in humans, Wilkening demonstrates that both estimates are correct, with the difference between them being due to the dose dependence of the incubation period and the very different doses received in each case.

"If you are exposed to a higher dose, there is a much higher chance that an anthrax spore will germinate quickly, thus leading to a shorter incubation period," he says. "Sverdlovsk was a low-dose exposure event and, consequently, one would expect anthrax spore germination to take a longer time, thus leading to a longer incubation period."

Truth and consequences

Russian officials confiscated the medical records of the Sverdlovsk victims and have so far refused to release details of what happened on April 2, 1979. "It would be nice to know exactly what happened, because that would allow us to model the event more accurately," Wilkening says.

Nevertheless, based on weather and other data from the day of the event, scientists think that around 2 p.m. spores, or dormant cells that revive under the right conditions, were released from a military facility, and the Bacillus anthracis spores spread up to 5 kilometers downwind. People breathed in the spores, which geminated and incubated in the body for between four to 40 days before people began to feel ill or show signs of illness such as sore throat, coughing, pains, aches and runny nose--the same symptoms as flu--that indicated they had entered what doctors call the prodromal phase. Within four days, people passed the point of no return, called the fulminant phase, in which toxins from the bacteria had built up to such an extent that people went into shock and died.

It's impossible to save those who've entered the fulminant phase and difficult to save those who've entered the prodromal phase. But if people can start treatment after exposure but before symptoms appear, there's a good chance that they will survive--a conclusion Wilkening draws from work by colleagues at Stanford's Center for Health Policy. Treatment primarily consists of antibiotics such as ciprofloxacin, doxycycline or penicillin. While a vaccine to prevent anthrax exists, it is not yet available for the general public but would be made available to people exposed to anthrax, according to the Centers for Disease Control and Prevention website.

In his study, Wilkening ruled out two of the four models because they either did not fit the Sverdlovsk data or the nonhuman primate data, or both. "There are two models that people have used that should no longer be used to predict fatalities, models B and C." (The four models used in his analysis are labeled A-D for convenience.)

Using the two remaining models A and D, he predicted that a hypothetical attack releasing 1 kilogram of anthrax spores in Washington, D.C., would infect between 4,000 and 50,000 people, most of whom would die if not treated quickly with antibiotics. The difference of a factor of 10, Wilkening points out, is "an uncertainty with which we must live for the time being until better data can resolve which of the models A or D is more accurate."

Regarding decontamination efforts, the higher the probability of becoming infected at low exposure levels, the greater the need for effective decontamination, especially for indoor environments. Spores "by nature are hardy," Wilkening says. In the soil, out of the way of sunlight, they can last for a decade. "Residual contamination can be a very serious problem in the wake of an attack," Wilkening says. "Unfortunately, both models A and D predict that residual surface contamination from anthrax spores will be a problem. Consequently, we need to come up with effective indoor decontamination strategies."

Analysts such as Professor Lawrence Wein of the Graduate School of Business are considering the issue. Last year, he assessed decontamination and concluded cleaning buildings to make them safe to reoccupy was a billion-dollar proposition.

In addition, the four models make very different predictions about when symptoms would occur. The day after exposure, they predict between 10 and 1,000 people feeling sick, with more people getting sick in the viable versus discredited models.

"In terms of detecting the outbreak rapidly, this is a good thing because it says that doctors could recognize it [sooner]," Wilkening says.

In terms of treating people before they reach the prodromal phase, however, this is a bad thing because people become sick quicker. Wilkening's analysis may help policymakers reassess how fast antibiotics need to reach people. His best model says administering antibiotics by day three saves 90 percent of exposed people. "Today we cannot meet the three-day requirement," he warns.