More children die from the indirect impact of armed conflict in Africa than those killed in the crossfire and on the battlefields, according to a new study by Stanford researchers. 

The study is the first comprehensive analysis of the large and lingering effects of armed conflicts — civil wars, rebellions and interstate conflicts — on the health of noncombatants.

The numbers are sobering: 3.1 to 3.5 million infants born within 30 miles of armed conflict died from indirect consequences of battle zones between 1995 and 2005. That number jumps to 5 million deaths of children under 5 in those same conflict zones.

“The indirect effects on children are so much greater than the direct deaths from conflict,” said Stanford Health Policy's Eran Bendavid, senior author of the study published today in The Lancet.

The authors also found evidence of increased mortality risk from armed conflict as far as 60 miles away and for eight years after conflicts. Being born in the same year as a nearby armed conflict is riskiest for young infants, the authors found, with the lingering effects raising the risk of death for infants by over 30 percent.

On the entire continent, the authors wrote, the number of infant deaths related to conflict from 1995 to 2015 were more than three times the number of direct deaths from armed conflict. Further, they demonstrated a strong and stable increase of 7.7 percent in the risk of dying before age 1 among babies born within 30 miles of an armed conflict.

The authors recognize it is not surprising that African children are vulnerable to nearby armed conflict. But they show that this burden is substantially higher than previously indicated. 

“We wanted to understands the effects of war and conflict, and discovered that this was surprisingly poorly understood,” said Bendavid, an associate professor of medicine at Stanford Medicine.  “The most authoritative source, the Global Burden of Disease, only counts the direct deaths from conflict, and those estimates suggest that conflicts are a minuscule cause of death.”

Paul Wise, a professor of pediatrics at Stanford Medicine and a senior fellow at the Freeman Spogli Institute for International Studies, has long argued that lack of health care, vaccines, food, water and shelter kills more civilians than combatants from bombs and bullets. 

This study has now put data behind the theory when it comes to children.

“We hope to redefine what conflict means for civilian populations by showing how enduring and how far-reaching the destructive effects of conflict have on child health,” said Bendavid, an infectious disease physician whose co-authors include Marshall Burke, PhD, an assistant professor of earth systems science and fellow at the Center on Food Security and the Environment.

“Lack of access to key health services or to adequate nutrition are the standard explanations for stubbornly high infant mortality rates in parts of Africa,” said Burke. “But our data suggest that conflict can itself be a key driver of these outcomes, affecting health services and nutritional outcomes hundreds of kilometers away and for nearly a decade after the conflict event”. 

The results suggest efforts to reduce conflict could lead to large health benefits for children.

The Data

The authors matched data on 15,441 armed-conflict events with data on 1.99 million births and subsequent child survival across 35 African countries. Their primary conflict data came from the Uppsala Conflict Data Program Georeferenced Events Dataset, which includes detailed information about the time, location, type and intensity of conflict events from 1946 to 2016. 

The researchers also used all available data from the Demographic and Health Surveys conducted in 35 African countries from 1995 to 2015 as the primary data sources on child mortality in their analysis.

The data, they said, shows that the indirect toll of armed conflict among children is three-to-five times greater than the estimated number of direct casualties in conflict. The indirect toll is likely even higher when considering the effects on women and other vulnerable populations.

Zachary Wagner, a health economist at RAND Corporation and first author of the study, said he knows few are surprised that conflict is bad for child health.

“However, this work shows that the relationship between conflict and child mortality is stronger than previously thought and children in conflict zones remain at risk for many years after the conflict ends.” 

He notes that nearly 7 percent of child deaths in Africa are related to conflict and reiterated the grim fact that child deaths greatly outnumber direct combatant deaths.

“We hope our findings lead to enhanced efforts to reach children in conflict zones with humanitarian interventions,” Wagner said. “But we need more research that studies the reasons for why children in conflict zones have worse outcomes in order to effectively intervene.” 

Another author, Sam Heft-Neal, PhD, is a research fellow at the Center for Food Security and the Environment and in the Department of Earth Systems Science. He, Burke and Bendavid have been working together to identify the impacts of extreme climate events on infant mortality in Africa.

The United States is in the grip of an opioid epidemic, which is affecting millions of Americans and claiming thousands of lives. Many trace their opioid dependence back to their doctor’s office, the drugs prescribed for pain after an injury, surgery, or dental procedure. Were these painkillers over prescribed? Did drug manufacturers exaggerate opioids’ effectiveness while deliberately underplaying their danger? Did drug distributors and retailers take necessary steps to ensure that pills weren’t falling in to the wrong hands?  

In this Q&A, Stanford Law Professors Michelle Mello, an expert in health law and core faculty member at Stanford Health Policy, and Nora Freeman Engstrom, an expert in tort law and complex litigation, explain the scope of the opioid problem and discuss the latest cases and legal challenges.

Just how big of a problem is the opioid crisis in the United States? Can you describe the problem’s scope and seriousness? 

Engstrom: The opioid problem is monstrous. Some 2.4 million Americans have an opioid use disorder, and the epidemic has already claimed 300,000 American lives, including 42,000 in 2016 alone. Worse, if the problem isn’t addressed, death tolls will rise: opioids are on track to claim the lives of another half-million Americans within the next decade. That’s like wiping out the entire city of Atlanta. The economic cost is also astronomical. The Council of Economic Advisors has estimated that, in 2015, “the economic cost of the opioid crisis was $504.0 billion, or 2.8 percent of GDP.”

Mello: If there’s one picture that brings home the shocking toll, it’s this one, showing trends in U.S. deaths based on data from the Centers for Disease Control and Prevention.  Nearly all of the “Poisoning” deaths shown here are opioid related. In terms of what’s killing Americans, opioids dwarf car crashes and guns.

Opioid lawsuits are now making news . Some of the actions are criminal, pursued by the states and federal government. Others of those suits are being initiated by cities, counties, and even states. What do those latter suits allege and what damages are the public plaintiffs trying to recover?

Engstrom: In the past four years, roughly 400 cities, counties, and states have initiated lawsuits seeking recovery for their additional public spending traceable to the opioid epidemic. The governmental entities claim they have been injured because defendants—typically, opioid manufacturers, distributors, and big retail pharmacies—have pumped opioids into the hands of their citizens and, in so doing, increased their spending for governmental services. Everything from policing, education, foster care, the provision of health care, even the operation of coroner’s officers, have all been made more expensive because, as compared to a healthy citizenry, an opioid-addicted populace is far less productive and needs much more by way of government help. Facing these spiraling costs, the governmental plaintiffs contend that the opioid defendants—who, they contend, caused and profited from this crisis—should foot the bill.

So, the typical defendants in these cases are opioid manufacturers, distributors, and big retail pharmacies. What is it that the plaintiffs are alleging these defendants did wrong?

Mello: There are some variations state to state, but for manufacturers, plaintiffs are typically claiming that they made false statements to prescribers and others that the drugs were safer and less addictive than alternatives, even when mounting evidence showed otherwise; that they failed to warn physicians and patients about the risks; and that the products were defectively designed—for example, because manufacturers didn’t make the pills tamper-resistant. For distributors and retailers, the claims are that these defendants failed to monitor, detect, investigate, and report suspicious orders of prescription drugs, even though reasonably prudent suppliers would have done so and the federal Controlled Substances Act requires suppliers to maintain effective controls against diversion of controlled substances to illicit markets.

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There are a billion guns in the world today. Those firearms took the lives of about 251,000 people in 195 countries in 2016, according to new research. 

That’s a lot of guns and fatalities, mostly by homicide, suicide and accidents with firearms.

About 35 percent of those gun deaths were by Americans committing suicide.

In the most comprehensive investigation of its kind, the findings, published this week in the Journal of the American Medical Association (JAMA), show 64 percent of firearm-related deaths were homicides, 27 percent were suicides and 9 percent were unintentional deaths.

And in all but one year of the 27-year study period — 1994 due to the Rwandan genocide — firearm deaths were more common along sidewalks than on the battlefields.

“This constitutes a major public health problem for humanity,” said Stanford Health Policy’s David Studdert, a professor of medicine and professor of law.

In an accompanying editorial alongside the research by a consortium of public health experts, the Global Burden of Disease 2016 Injury Collaborators, Studdert and his co-authors write:

“Injuries and deaths from firearms are increasingly part of modern consciousness, particularly in some countries. In the United States, gun-related massacres at schools, places of worship, workplaces, night clubs, and recreational venues have seared images of innocent victims in the minds of the populace. In the United States and elsewhere, acts of terrorism committed with firearms and other lethal means have changed the way people live, work, travel, and play.”

But Studdert and his co-authors — firearms and public health experts Frederick P. Rivara at the University of Washington and Garden J. Wintemute at the University of California, Davis — argue that the deaths from these headline-generating mass shootings and terrorist attacks are only a fraction of the public health burden of firearm-related murders and suicides.

“Mass shootings and terrorism perpetrated with guns are the most visible forms of firearm violence,” Studdert told SHP. “But most firearm deaths are private tragedies. They are homicides and suicides that occur behind closed doors, leaving families and communities devastated.”

The global burden of firearm mortality is highly concentrated, according to the research. In 2016, six countries in the Americas — Brazil, the United States, Mexico, Columbia, Venezuela and Guatemala — accounted for slightlymore than 50 percent of all deaths.

An estimated 32 percent of the deaths occurred in just two countries, Brazil and the United States, with Brazil accounting for one-fourth of all firearm homicides and the United States 35 percent of all firearm suicides.

“For individuals living in the United States, where the national policy debate has focused largely on interpersonal violence, the study provides a reminder of the importance of firearm suicide. In 2016, there were 2 firearm suicides for every firearm homicide, a margin that has widened over the past decade as suicide rates have increased and homicide rates have been relatively flat. Older white non-Hispanic men are at greatest risk of firearm suicide. Research and prevention efforts in the United States should proceed from a more inclusive definition of firearm violence.”

The authors believe more robust methods for estimating the number and distribution of firearms — as well as a better understanding of access — are critically important in determining which policies and prevention strategies are most effective and how best to implement them.

Studdert and his fellow researchers said research on firearm violence and public health has been impeded by the Dickey Amendment, the 1996 bill that mandated “none of the funds made available for injury prevention and control  at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.”

“In the absence of this funding, several private foundations have stepped in to fill the void," they wrote. "However, real progress in addressing the vast public health problem that the Global Burden of Injury Collaborators document will depend on sustained action from governments in both research and policy.”

African-American doctors could help reduce cardiovascular mortality among black men by 19 percent — if there was more racial diversity among physicians, according to a new study led by Stanford Health Policy’s Marcella Alsan.

After conducting a randomized clinical trial among 1,300 black men in Oakland, the researchers found that the men sought more preventive services after they were randomly seen by black doctors for a free health-care screening compared to non-black doctors.

“We found that, once African-American men were at the clinic, even though all services were free, those assigned to a black doctor took up more services,” such as flu shots and diabetes and cholesterol screenings, said Alsan, an economist and infectious disease physician who focuses on  health and socioeconomic disparities here at home and around the world.

“It was surprising to see the results,” said Alsan, an associate professor of medicine at Stanford Medicine, a faculty fellow at the Stanford Institute for Economic Policy Research, and an investigator at the VA Palo Alto Health Care System. “Prior to doing the study, we really were not sure if there would be any effect, much less the magnitude. The signal in our data ended up being quite strong.”

Those signals include the men were 29 percent more likely to talk with black doctors about other health problems and seeking more invasive screenings that likely required more trust in the person providing the service. They found subjects assigned to black doctors increased their uptake of diabetes and cholesterol screenings by 47 percent and 72 percent, respectively.

The researchers calculated that black doctors could reduce cardiovascular mortality by 16 deaths per 100,000 per year, accounting for 19 percent of the black-white gap in cardiovascular-related deaths. They believe that the results would be even larger if extrapolated to other leading causes of death that are amenable to prevention, such as cancer and HIV/AIDS. 

“I was definitely surprised,” said Owen Garrick, president and COO of Bridge Clinical Research, an Oakland-based organization that helps clinical researchers find patients from targeted ethnic groups. “If you ask most people, they feel that there is some impact of black men seeing black doctors — but it has never been quantified using an experimental design.”

Alsan and Garrick, along with U.C. Berkeley graduate student Grant Graziani, published their findings in this working paper for the National Bureau of Economic Research.

Garrick, himself an African-American physician, said black doctors tend to present themselves in a manner that puts a black patient at ease, making him more willing to open up and agree to certain care. “The black doctor might explain the medical services in a way that the black patient more clearly understands.”

Garrick called the findings “astounding,” but he warned that increasing the number of black doctors and getting black men to routinely see them are no small tasks.

There is a yawning gap between white physicians and those of color. While African-Americans comprise about 13 percent of the population, only 4 percent of physicians and less than 6 percent of medical school graduates are black, according to the study.

This is compounded by African-American men having the lowest life-expectancy in the country, due to lack of health insurance, lower socioeconomic status and structural racism. 

And there remains a distrust of the U.S. healthcare system at least partially attributed to the infamous Tuskegee study that began in 1932, when the U.S. Public Health Service began following about 600 African-American men in Tuskegee, Alabama. Some two-thirds of the men had syphilis, and USPHS declined to inform those afflicted by the disease. Even after penicillin became the standard of care for syphilis treatment in the mid-1940s, the USPHS continued to withhold treatment. The study was finally halted when a whistleblower went to the press in 1972.

Alsan— with her colleague Marianne Wanamaker at the University of Tennessee — published a study in The Quarterly Journal of Economics in February that found the 1972 Tuskegee study revelation was correlated with a reduction in health-seeking behavior and increases in medical mistrust and mortality among African-American men.

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The men who participated in the recent study were recruited from barbershops and flea markets in Oakland, a city known for its diversity, yet plagued by a 20 percent rate of poverty.

Field officers —including minority and low-income pre-med students from around the Bay Area — approached men to enroll in the study. After obtaining written consent, the men were given a short survey about socio-demographics, health care and mistrust. For completing the survey, the men received a voucher with up to $25 for their haircut or, in the flea market, a cash incentive.

The men were also given a coupon to receive a free health-care screening for blood pressure, BMI, cholesterol and diabetes at the clinic where the Stanford team operated on Saturdays in the fall and winter of 2017-2018. The patients who did not have transport to the clinic were given free rides courtesy of Uber. Attendance at the clinic was encouraged with another $50 incentive.

Subjects and the 14 participating doctors were told that they were taking part in a Stanford study designed to improve preventive health-care for African-American men.

On top of the significant increases in patients who agreed to diabetes or cholesterol screenings if suggested by a black doctor, the researchers found that the men were 56 percent more likely to get a flu vaccine if randomized to one of the African-American doctors.

The results suggested the more invasive the test, the greater the advantage of being assigned a black doctor. And the findings were even stronger among subjects who had a high mistrust of the medical system as well as those who had limited prior experience with routine medical care.

“In curative care, the patient feels ill and then may seek out medical care to fix the problem,” Alsan said. “But in preventive care, the patient may feel just fine — but must trust the doctor when he is told that certain measures must be taken to safeguard health.” 

The policy implications would suggest that medical schools need to open the pipeline to students from diverse backgrounds who are training for health-care professionals. 

Garrick recommends exposing more young people of color to the field of medicine and helping them to become more competitive applicants through tutoring and interview prep.

“And you need advocates,” he said. “Since much of the medical school selection process is subjective, you need to get people on the selection committees who will relate and see the potential of black applicants as much as people relate to other applicants.”

Some links to other media outlets that have written about this research: 

The New York Times

Harvard Business Review

The Daily Mail

ColorLines

Malaria claims nearly half-a-million lives worldwide each year — and yet we still know so little about the immunology of the disease that has plagued humanity for centuries.

There were 216 million cases in 2016, according to the World Health Organization. Sub-Saharan Africa carries 80 percent of the global burden of the mosquito-borne infectious disease which devastates families, disrupts education, and promotes the vicious cycle of poverty.

It is particularly brutal to pregnant women, who are three times more likely to suffer from a severe form of the disease, leading to lower birthweight among their newborns and higher rates of miscarriage, premature and stillborn deliveries.

“Pregnant women and their unborn children are more susceptible to the adverse consequences of malaria, so we are working to investigate new strategies and even lay the foundation for a vaccine to prevent malaria in pregnancy,” said Prasanna Jagannathan, MD, an assistant professor of medicine who is this year’s recipient of the Rosenkranz Prize.

Jagannathan, an infectious disease physician who is also a member of Stanford’s Child Health Research Institute, said the $100,000 stipend that comes with the prize will allow his lab members to ramp up their research in Uganda. A member of the nonprofit Infectious Disease Research Collaboration in Kampala, his team is particularly interested in how strategies that prevent malaria might actually alter the development of natural immunity to malaria.

“With support from the Rosenkranz Prize, we hope to identify maternal immune characteristics and immunologic targets that are associated with protection of malaria in pregnancy and infancy,” Jagannathan said.

The Dr. George Rosenkranz Prize for Health Care Research in Developing Countries is awarded each year by the Freeman Spogli Institute for International Studies and Stanford Health Policy to a young Stanford researcher who is trying to improve health care in underserved countries. It was established in 2009 by the family or Dr. George Rosenkranz, a chemist who first synthesized cortisone in 1951, and later progesterone, the active ingredient in oral birth control pills.

“My father has held a lifelong commitment to scientific research as a way to improve the lives and well-being of communities around the world,” said Ricardo T. Rosenkranz, MD. “In particular, he has always sought to improve the health of at-risk populations. Dr. Jagannathan’s work offers the very sort of innovative ingenuity that characterized my father’s early research, as well as his vision towards the future.”

Jagannathan and his collaborators at UCSF and in Uganda are currently conducting a randomized control trial of 782 Ugandan women who are receiving intermittent preventive treatment with a fixed dose of dihydroartemisinin-piperaquine(or IPTp-DP), a medication that has dramatically reduced the risk of maternal parasitemia, anemia, and placental malaria. Their preliminary data suggests that among 684 infants born to these women, maternal receipt of IPTp-DP may lead to a reduced incidence of malaria in the first year of life.

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“Having the discretionary support of the Rosenkranz Prize will allow us to generate some preliminary ideas from this trial that could lead to larger studies, to push this agenda further along,” Jagannathan said.

That agenda is to create a vaccine that targets pregnant women to prevent malaria both during pregnancy — but also potentially preventing malaria in infants, giving them a better start in life.

“We’re not the first ones to think of this, but we have the opportunity to test these hypotheses in incredibly unique settings, with really well-studied cohorts that have real-world implications in terms of what we find,” Jagannathan said. “I’m hopeful that the data that’s generated over the new few years will allow us to keep moving forward.”

Jagannathan has been traveling to Uganda for a decade to study malaria. He’s seen firsthand the relentless, gnawing impact the disease has on daily life.

“Before I went to Uganda I really didn’t understand the burden that malaria causes in communities — and it’s just incredible,” he said. His first study was on children aged 5 and under who had on average six episodes of malaria a year.

“They just get it over and over again, and the toll on society is enormous,” he said. The clinics are overwhelmed and a parent or sibling must miss work or school to stay home with that child.

Yet, in highly endemic settings, children eventually develop an immunity that protects against the adverse outcomes from malaria. If he and his colleagues can understand how pregnant women and children develop this clinical immunity to malaria, it could lead to better treatments and preventative strategies.

“If we understand the mechanisms that underlie naturally acquired immunity, that would offer some clues as to how we can develop a vaccine that actually allows either that immunity to occur more quickly or prevents us from developing immunity that allows for the parasite to persist without symptoms,” he said.

There is currently a malaria vaccine undergoing testing in Africa. The vaccine, known as RTS,S, was developed by GlaxoSmithKline and the PATH Malaria Vaccine Initiative, with support from the Bill and Melinda Gates Foundation. Decades in the making, four doses of the vaccine are required to reduce malaria infection in humans.

“It’s a remarkable vaccine in that it’s effective in the beginning, but the problem is that the efficacy wanes very rapidly,” Jagannathan said, noting that some studies show that beyond three years, the effectiveness drops to 15-20 percent.

“That’s the big issue and why people are really interested in trying to find new strategies and new approaches for a next-generation malarial vaccine,” he said. “That’s the overarching aspect of what motivates my work.”

Most participants in clinical trials believe the benefits of broadly sharing person-level data outweigh the risks, according to new research by Stanford Medicine's Michelle Mello and Steven N. Goodman. 

And despite low levels of trust in pharmaceutical companies, most of those who take part in clinical trials are willing to share their data with the drug firms.

The Stanford researchers surveyed 771 current and recent participants from a diverse sample of clinical trials at three academic medical centers in the United States. They asked about the practice of making personal data collected in medical research studies widely available, after information that could identify individual participants is removed. Nearly 80 percent of those surveyed responded to the questions — and fewer than 8 percent of the respondents felt that the potential negative consequences of data sharing outweighed the benefits.

Some 93 percent of those surveyed said they were very or somewhat likely to allow their data be shared with university scientists, and 82 percent were either very or somewhat likely to share with scientists in for-profit companies. They found that the willingness to share was high regardless of the purpose for which their data would be used, with the exception of litigation.

Although some researchers and trial funders have worried that participants might object to data sharing as an invasion of privacy, the respondents’ greatest concern was that “data sharing might make others less likely to enroll in clinical trials,” Stanford Health Policy's Michelle Mello and her co-authors write in The New England Journal of Medicine. “Less concern was expressed about discrimination (22 percent) and exploitation of data for profit (20 percent.)”

Mello is a professor of law at Stanford Law School and a professor of health research and policy at Stanford Medicine. Her co-authors are Van Lieou and Steven N. Goodman, a professor of medicine and of health research and policy at Stanford Medicine.

The authors acknowledge there is no turning back from clinical data sharing.

“We are rapidly moving toward a world in which broad sharing of participant-level clinical trial data is the norm,” they wrote.

The European Medicines Agency has implemented a policy to expand public access to data concerning products it approves, and the Food and Drug Administration is considering expanding access to data pooled within a product class. Major research sponsors and journal editors have begun promoting data sharing, and the National Institutes of Health now requires all of its grantees to share data.

Pharmaceutical industry associations have committed to making data more accessible, and several data platforms are now available, such as the Yale Open Data Access Project.

Mello said she was somewhat surprised by the survey results, “given the amount of consternation one hears at conferences about data sharing. Interestingly, nearly half our sample had experienced a breach of their personal data privacy in another context, yet they were still willing to share their clinical trial data.”

Then again, she said, people who take part in clinical trials may be special.

“I suspect that clinical trial participants may be different from the public at large. They are already incurring risks to benefit science by dint of their trial participation.”

Most of those participants, along with clinical researchers, believe the benefits of sharing data include accelerating scientific discovery and improving accurate reporting of trial results.

Yet some investigators and industry sponsors of clinical trials are leery of the swift move toward broad data sharing, the authors note, because of “potential harm to research participants,” the authors wrote. “Investigators express worries that participants’ privacy cannot be adequately protected, particularly in light of the fact that experts have demonstrated that it is possible to reidentify participant-level data.”

Furthermore, they said, some pharmaceutical companies have warned that data sharing could chill willingness to participate in trials, thereby delaying the availability of new therapies. In fact, 31 percent of those surveyed were somewhat or very concerned about having their personal information stolen.  Nevertheless, most felt the benefits of data sharing were more important. 

“Reaching a world in which the sharing of clinical trial data is routine requires surmounting several challenges — financial, technical, and operational,” the authors concluded. “But in this survey, participants’ objections to data sharing did not appear to be a sizeable barrier.”