The total cost of asthma due to pollution is much higher than past traditional risk assessments have indicated and there is growing evidence that exposure to traffic-related air pollution is a cause of asthma and a trigger for attacks, so it should be included, say the authors. They conducted the study in Long Beach and Riverside, Calif., communities with high regional air pollution levels and large roads near residential neighborhoods.

Total additional asthma-specific costs there due to traffic-related pollution is about $18 million per year, almost half of which is due to new asthma cases caused by pollution, they report. Brandt worked with researchers at the University of Basel, Switzerland, Sonoma Technology, Inc. and the University of Southern California.

Using updated techniques that count asthma cases attributable to air pollution for the first time and including a broader range of health care costs such as parents’ missed work days, extra doctor visits and travel time along with prescriptions, the researchers found that a single episode of bronchitic symptoms cost an average $972 in Riverside and $915 in Long Beach. Bronchitic symptoms (daily cough, congestion or phlegm, or bronchitis for three months in a row) are a critical outcome for children with asthma.

Further, people who live in cities with high traffic-related air pollution bear a higher burden of these costs than those in less polluted areas, they say.

Brandt and colleagues say the total annual cost for a typical asthma case was $3,819 in Long Beach and $4,063 in Riverside, and “the largest share of the cost of an asthma case was the indirect cost of asthma-related school absences.” School absences are an important economic consequence, they add, because “they often lead to parents or caregivers missing work.”

Overall, Brandt points out that the results are relevant and applicable to many settings and “families with children who have asthma are bearing a high cost. The total annual estimate between $3,800 and $4,000 represents 7 percent of median household income in our study in these two communities. This is troublesome because that is higher than the 5 percent considered to be a bearable or sustainable level of health care costs for a family.”

Riverside and Long Beach account for about 7 percent of the total population of California, the authors say, which suggests that state-wide costs of asthma related to air pollution are “truly substantial.”

For this work, Brandt and colleagues analyzed several surveys on health care visits by children with asthma and their previous estimates of the number of asthma cases attributable to pollution to estimate the annual costs of childhood asthma. They also estimated the cost of asthma exacerbation due to regional air pollutants. They feel the new method does a better job of accounting for the full impact of traffic-related pollution and will be widely applicable in urban areas.

She points out, “Traditional risk assessment methods for air pollution have underestimated both the overall burden of asthma and the cost of the disease associated with air pollution. Our findings suggest the cost has been substantially underestimated and steps must be taken to reduce the burden of traffic-related pollution.”

The paper was published online in the journal Nature Materials on Jan. 22.

Currently all other adjuvants (substances added to vaccines to help to boost the immune response) are thought to enhance immunity at the skin site where the vaccine is injected rather than going to the lymph nodes, where the most effective immune reactions occur. The current study used mice to show it is possible to shift the delivery path directly to the lymph nodes.

The researchers based their strategy on their observation that mast cells, which are cells that are found in the skin that fight infections, also communicate directly to the lymph nodes by releasing nanoparticles called granules.

“Our strategy is unique because we have based our bioengineered particles on those naturally produced by mast cells, which effectively solve the same problem we are trying to solve of combating infection,” said St. John, who is in the Duke-NUS Program in Emerging Infectious Diseases.

The synthetic granules consist of a carbohydrate backbone that holds tiny, encapsulated inflammatory mediators such as tumor necrosis factor (TNF). These particles, when injected, mimic the attributes of the granules found in natural cells, and the synthetic particles also target the draining lymph nodes and provide for the timed release of the encapsulated material.

Traditional vaccine adjuvants may help antigens (the small part of a pathogen that is injected during vaccination that the body reacts to) to persist so the body can have an immune reaction and build antibodies so that when a real pathogen, such as the flu virus arrives, it will be conquered. Alternatively, adjuvants may activate cells called dendritic cells, which pick up pathogen parts and must travel from the skin to lymph nodes where immune reactions are initiated.

The Duke team, however, has created a vaccine adjuvant of nanoparticles that are capable of traveling from the point of injection to the lymph nodes where they act on many cell types of the immune system to spur the right reaction for a greatly increased immune response.

The researchers found that they could use this adjuvant in vaccinations of mice with the influenza A virus.

In levels of flu virus exposure that would be lethal in typical mice, the vaccinated mice were able to fight off the disease and had an increased survival rate, thanks to the effective immune response the particles stimulated.

The researchers also showed they could load the same type of particles with a different immune factor, IL-12, that directed a response toward a different set of lymphocytes. This is an important finding since certain types of infections require specialized responses to be overpowered by the body.

St. John said the flexibility of the synthetic particles and their ability to target certain lymph nodes represented a new avenue of personalized medical treatment – personalized vaccines.

Senior author Soman Abraham, Ph.D., professor of pathology, immunology and molecular genetics and microbiology at Duke in Durham, N.C., and emerging infectious diseases at Duke-NUS, is cautiously optimistic that the mast-cell-inspired synthetic particles could make their way into human use soon.

“It should not be long because all the individual cytokines (immune system factors) and additional materials loaded into these particles are already FDA approved for use in humans,” Abraham said. “There is a lot of interest in nanoparticle-based therapy, but we are basing our materials on our observation of mast cells in nature. This is an informed application to deliver the right material to the right place in the body to get the most effective immune reaction.”

“We know that low birth weight is associated with an increased risk of asthma symptoms in children, but the effects of specific fetal and infant growth patterns on this risk had not been examined yet,” said researcher Liesbeth Duijts, MD, PhD. “In our study, weight gain acceleration in early infancy was associated with an increased risk of asthma symptoms in children of preschool age, independent of fetal growth patterns, suggesting that early infancy might be a critical period for the development of asthma.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

This study was embedded in the Generation R Study, a population-based prospective cohort study, and included 5,125 children who were followed from fetal life through the age of four. Information on asthma symptoms was obtained by questionnaires at the ages of 1, 2, 3, and 4.

No consistent relationships between fetal length and weight growth during different trimesters and the development of asthma symptoms were observed. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms, including wheezing (overall odds ratio (OR) 1.44 (95% confidence interval (CI): 1.22, 1.70), shortness of breath: 1.32 (1.12, 1.56), dry cough: 1.16 (1.01, 1.34), and persistent phlegm: 1.30 (1.07, 1.58)). The associations between accelerated infant growth and risk of developing asthma symptoms were independent of other fetal growth patterns and tended to be stronger among children of atopic mothers.

“Our results suggest that the relationship between infant weight gain and asthma symptoms is not due to the accelerated growth of fetal growth-restricted infants only,” said Dr. Duijts. “While the mechanisms underlying this relationship are unclear, accelerated weight growth in early life might adversely affect lung growth and might be associated with adverse changes in the immune system.”

The study had a few limitations, including the possibility of measurement error in the estimation of fetal weight and the use of self-report for asthma symptoms.

“Further research is needed to replicate our findings and explore the mechanisms that contribute to the effects of growth acceleration in infancy on respiratory health,” concluded Dr. Duijts. “The effects of infant growth patterns on asthma phenotypes in later life should also be examined.”

A new report by the Cochrane Collaboration says Roche’s refusal to provide full access to all its data leaves critical questions about how well the drug works unresolved.

A BMJ investigation, published to coincide with today’s report, also raises serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.

Meanwhile, Tamiflu has become the mainstay of influenza treatment in the UK. It has also made it onto the World Health Organisation’s list of Essential Medicines and Roche’s claims continue to be supported by influential health agencies.

The Cochrane researchers set out to test Roche’s claim that Tamiflu prevented complications and reduced the number of people needing hospital treatment. But their investigation was hampered by Roche’s refusal to provide all of its trial data for analysis. The team obtained some clinical study reports from the European Medicines Agency (EMA), but found inconsistencies with published reports and possible under-reporting of side effects.

When previously questioned by the BMJ, Roche also admitted that some of the published papers had been ghost written.

The BMJ investigation reveals how different regulators took different approaches to the data submitted to them, leading to conflicting messages about it effectiveness.

For example, the EMA released a proportion of the clinical study reports relating to the Tamiflu trials to Cochrane, but it admits that it did not ask for the remainder from the manufacturer, although it was legally entitled to do so. The EMA has since told the BMJ that it plans to start publishing reports for all drugs submitted for approval in the next few years.

Dr Fiona Godlee, BMJ Editor-in-Chief says: “We hope very much that the EMA will indeed take this important step in making the full study reports available. But we are still a long way away from having a full trial history for all drugs in clinical use. Public safety and the proper use of public money demands that we should stop at nothing less than this.”

Meanwhile, the US Food and Drug Administration (FDA), which has reviewed the Tamiflu trial programme in perhaps more detail than anyone outside of Roche, chose not to review the largest ever trial of Tamiflu when considering the drug for approval. It states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”

However, the US Centers for Disease Control and Prevention (CDC) continue to cite key published trials of Tamiflu, claiming a reduced risk of influenza complications, even after Roche admitted that some of these trials have been ghost written.

Dr Godlee says: “The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in. In a globalised world, regulators should cooperate and pool their limited resources. Otherwise we will continue to waste money and risk people’s health on drugs that don’t work.”

The investigation also raises questions about Tamiflu’s clinical effects. After careful evaluation of trial data, the Cochrane group say that Tamiflu appears to affect antibody production – a claim that Roche refutes. This is important, say Cochrane, because influenza vaccination relies on an antibody response to be effective. But when asked by the BMJ, Roche refused to explain how the drug works.

As such, the Cochrane group say that “until more is known about the mode of action of neuraminidase inhibitors, health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”

Cochrane also argue that Tamiflu’s ability to prevent the spread of influenza has not been demonstrated in trials. Yet this is one of the main reasons governments around the world have spent billions of dollars stockpiling Tamiflu in case of a pandemic.

Roche maintain they provided the Cochrane team with enough information to conduct their evaluation, but the Cochrane team say this is not the case. Dr Peter Doshi from Johns Hopkins University School of Medicine says: “In the BMJ in December 2009, Roche promised full study reports to any legitimate investigators. They have not provided a single full study report to Cochrane, despite our repeated requests.”

More than 170 million people worldwide suffer from hepatitis C, the disease caused by chronic HCV infection. The disease affects the liver and is one of the leading causes of liver cancer and liver transplant around the world. HCV is spread by blood-to-blood contact and there is no vaccine to prevent it. Current treatments for the disease are only moderately effective and can cause serious side effects.

“As HCV infects a person, it needs fat droplets in the liver to form new virus particles,” says François Jean, Associate Professor in the Department of Microbiology and Immunology and Scientific Director of the Facility for Infectious Disease and Epidemic Research (FINDER) at UBC. “In the process, it causes fat to accumulate in the liver and ultimately leads to chronic dysfunction of the organ.”

“HCV is constantly mutating, which makes it difficult to develop antiviral therapies that target the virus itself,” says Jean. “So we decided to take a new approach.”

Jean and his team developed an inhibitor that decreases the size of host fat droplets in liver cells and stops HCV from “taking residence,” multiplying and infecting other cells.

“Our approach would essentially block the lifecycle of the virus so that it cannot spread and cause further damage to the liver,” says Jean. The team’s method is detailed in the journal PLoS Pathogens.

According to Jean, HCV is one of a number of viruses that require fat to replicate in the human body. This new approach to curbing the replication of HCV could translate into similar therapies for other related re-emerging viruses that can cause serious and life threatening infections in humans, such as dengue virus. Dengue is endemic in more than 100 countries, with approximately 2.5 billion people at risk of infection globally. In some countries, Dengue has become the leading cause of child mortality.

The findings come from the INTERHEART study, a case-control study of over 29,000 people from 262 centres in 52 countries in Asia, Europe, the Middle East, Africa, Australia, North and South America. It is published online today (Wednesday) in the European Heart Journal [1].

“Until now, few studies have looked at the different aspects of physical activity both at work and during leisure time in relation to the risk of heart attacks,” said Professor Claes Held, the first author of the study. “Much is already known about the association between physical activity and cardiovascular risk, but what this study adds, among many other things, is a global perspective. The study shows that mild to moderate physical activity at work, and any level of physical activity during leisure time reduces the risk of heart attack, independent of other traditional risk factors in men and women of all ages, in most regions of the world and in countries with low, middle or high income levels. Interestingly, heavy physical labour at work did not protect against heart attacks.

“These data extend the importance of physical activity and confirm a consistent protective effect of physical activity across all country income levels in addition to the known benefits of modifying traditional risk factors such as smoking. Furthermore, ownership of a car and TV, which promotes sedentary behaviour, was found to be independently associated with the risk of heart attacks.”

Prof Held (MD, PhD), who is associate professor at Uppsala Clinical Research Center and the Department of Cardiology, at Uppsala University Hospital, Sweden [2], and colleagues from Canada and the USA, compared the work and leisure exercise habits of 10,043 people who had suffered their first heart attack with 14,217 healthy people (the control group). They asked the participants whether their work was mainly sedentary, or predominantly walking at one level, or mainly walking including walking uphill or lifting heavy objects, or heavy physical labour. For physical activity during their leisure time, participants could select from four possible responses: mainly sedentary (sitting activities, such as sitting reading, watching TV), mild exercise (minimal effort activities, such as yoga, fishing, easy walking), moderate exercise (moderate effort, such as walking, cycling or light gardening at least four hours a week), and strenuous exercise (when the heart beats rapidly, such as running, football or vigorous swimming).

They also asked about the ownership of goods such as a car, motorcycle, radio/stereo, TV, computer, land and livestock.

After adjusting for various confounding factors such as age, sex, country, income, smoking, alcohol, education, health, diet etc, they found that people whose work involved either light or moderate physical activity had a fifth (22%) or a tenth (11%) lower risk of having a heart attack when compared to people whose occupation was mainly sedentary. However, heavy physical labour did not reduce the risk at all. During leisure time, the risk of a heart attack was lower for any level of exercise when compared with being mainly sedentary, reducing by 13% for mild activity and 24% for moderate or strenuous activity.

People who owned both a car and a TV, both indicators of a sedentary lifestyle, had a 27% increased risk of a heart attack, compared to those who owned neither a car nor a TV.

A greater proportion of people in low-income countries had sedentary jobs and undertook less physical activity in their leisure time, than in middle- and high-income countries. “These differences in PA [physical activity] were most pronounced regarding leisure-time activity,” write the authors. “This may partly be explained by differences in education and other socio-economic factors. In addition, this may also reflect differences in culture and in climate. The likelihood of a subject performing leisure-time PA in tropical or hot climate zones is lesser than in more temperate areas of the world.”

The authors conclude that daily moderate physical exercise should be encouraged in everyone to prevent heart disease. Prof Held added: “The data have some real-life implications. One suggestion may be for the lower income countries to be more involved in promoting physical activity as their societies starts to use more labour-saving devices, so as to counter-act the inactivity that this can lead to; however, it also important to promote physical activity in all parts of the world.”

In an accompanying editorial [3], Drs Emeline Van Craenenbroeck and Viviane Conraads from Antwerp University Hospital, Belgium, write: “Two main questions were tackled [by the INTERHEART study]: do the different constituents of daily physical activity (work or leisure) diverge in their ability to reduce the risk of AMI [acute myocardial infarction] and, secondly, are potential markers of a sedentary lifestyle, such as owning a car or a TV, associated with increased cardiovascular risk? The answer to both questions seems to be a heartfelt ‘yes’.”

One of the findings they highlight is that the risk of a heart attack was reduced even in those who exercised well below currently accepted guidelines for activity, and they point out this may be “particularly useful when it comes to motivational strategies”.

They conclude: “Although timely and highly relevant, the paper of Held et al. leaves clinicians with the Herculean task of translating this evidence into effective preventive care. If we want to support healthy longevity, we should put a stop to the pandemic of sedentarism.

“Staying physically fit throughout life may well be one of the easiest, cheapest, and most effective ways to avoid the coronary care unit.”

The consequences of delaying effective hypertension treatment for up to a year were small—a two-day reduction in quality-adjusted life expectancy—according to a study by University of Chicago researchers published online for the Journal of General Internal Medicine. But as the delay gets longer, the damages multiply. A ten-year delay decreased life expectancy by almost five months.

“For newly diagnosed patients, this means we have time,” said study author Neda Laiteerapong, MD, instructor of medicine at the University of Chicago. “Most patients would prefer to control their blood pressure through diet and exercise rather than with medications, and it can take months to learn how to change old habits and master new skills. Our results indicate that it’s OK to spend from six months to a year, perhaps even longer, to make the difficult lifestyle changes that are necessary and will pay off in the long run.”

High blood pressure is especially damaging for people with diabetes, raising their risk of stroke, coronary artery disease, kidney failure, vision loss and amputations. Both the American Diabetes Association (ADA) and the National Institutes of Health recommend a lower blood pressure target for patients with diabetes than for the general public, urging them to keep their pressures below 130/80 mmHg.

Two out of three adults with diabetes, however, never reach that goal. Many patients are hampered by limited access to health care. Others are delayed by what the authors call “clinical inertia,” a disinclination by patients to implement lifestyle changes or reluctance by their doctors to push additional medications. Among those who are prescribed blood pressure drugs, at least 20 percent of patients with diabetes do not stick to their treatments.

Until now, the implications of these delays on patients’ health had not been quantified. Laiteerapong and colleagues built computer models using published data to determine the magnitude of harm caused by different delays in controlling blood pressure in patients from 50-59 years of age with newly diagnosed type 2 diabetes. The damage caused by a one-year delay “may be small,” they concluded but delays of ten years or more were comparable to smoking in patients with cardiovascular disease.

Given time to learn how, many patients would prefer to control blood pressure through diet and exercise rather than with antihypertensive medications. Most guidelines, however, including those of the ADA, recommend at most a three-month trial of medication-free lifestyle therapy for patients with moderately elevated blood pressure. They call for immediate initiation of medication for those with blood pressure more than 10mmHg above the goal.

That is often not enough time for patients to learn the methods, develop good habits and demonstrate improvements.

“We ask patients with diabetes to do a billion things,” Laiteerapong said, “to test their blood sugars, to count carbohydrates, to spend 30 minutes a day doing exercise, including cardio and weight training. Most, if not all, of this is new to them. They need time to adapt. It’s important to do this right, but our results say it’s not that important to do it so fast.”

This study argues that caregivers should work with patients to help them gain the knowledge and develop the necessary skills gradually rather than rushing to drug treatment, especially if their blood pressure is only mildly elevated. It suggests that patients and providers “have more time,” the authors write, “at least up to one year, to focus on diabetes self-management and lifestyle modification.”

“Among middle-aged adults with diabetes, the harms of a one-year delay in managing blood pressure may be small,” the authors conclude. “Health care providers may wish to focus on diabetes management alone in the first year after diagnosis, to help patients establish effective self-management and lifestyle modification. However, after the first year, it is clear that achieving and maintaining tight blood pressure control among US middle-aged adults with diabetes has the potential to generate substantial population-level health benefits.”

The team, from the University of Cambridge and the Medical Research Council (MRC) Toxicology Unit at the University of Leicester, publish their findings today (Friday 6 January) in the journalCell Death and Differentiation.

The research shows that, in both rats and humans, individuals who experience a poor diet in the womb are less able to store fats correctly in later life. Storing fats in the right areas of the body is important because otherwise they can accumulate in places like the liver and muscle where they are more likely to lead to disease.

Professor Anne Willis of the MRC Toxicology Unit at the University of Leicester explains “One of the ways that our bodies cope with a rich modern western diet is by storing excess calories in fat cells. When these cells aren’t able to absorb the excess then fats get deposited in other places, like the liver, where they are much more dangerous and can lead to type 2 diabetes.”

The team found that this process is controlled by a molecule called miR-483-3p. They found that miR-483-3p was produced at higher levels in individuals who had experienced a poor diet in their mother’s wombs than those who were better nourished.

When pregnant rats were fed low protein diets their offspring had higher levels of miR-483-3p. This led to them developing smaller fat cells and left them less able to store fats in adulthood. These rats were less likely to get fat when fed a high calorie diet but were at a higher risk of developing diabetes. Rats are known to be a good model for studying human dietary diseases and the team also found that miR-483-3p was present in elevated levels in a group of people who were born with a low birth weight.

Dr Susan Ozanne, a British Heart Foundation Senior Fellow, who led the work at the University of Cambridge, adds “It has been known for a while that your mother’s diet during pregnancy plays an important role in your adult health, but the mechanisms in the body that underlie this aren’t well understood. We have shown in detail how one mechanism links poor maternal diet to diabetes and other diseases that develop as we age.”

Dr Ozanne and Professor Willis and their team found that miR-483-3p works by suppressing a protein called GDF3. When they studied a group of adult humans who were born with a low birth weight, they found that GDF3 protein was present at around only thirty percent of the levels found in people born at a normal weight.

Professor Willis, Director of the MRC Toxicology Unit, adds “Improving people’s diets and encouraging exercise is clearly the best way to combat the epidemic of diabetes and diet-related disease which is sweeping through our society. However some people are at particular risk of these diseases, despite not looking visibly overweight. This research will hopefully allow us to help these people to take precautionary steps to reduce their likelihood of developing type 2 diabetes.”

Professor Douglas Kell, Chief Executive of BBSRC said “People are continuing to live ever longer and healthier lives thanks to improvements in nutrition and healthcare. However modern diets and lifestyles are posing new challenges to which our bodies sometimes seem poorly adapted – and this has caused unforeseen health problems.

“If we are to remain healthy throughout our lives and into old age it is vital that scientists work to understand our fundamental biology in the context of social and environmental changes. By identifying a mechanism that links maternal diet to diabetes this research has made an important contribution to the fight against a growing epidemic of metabolic diseases.”

Heart attack with ST-segment elevation accounts for 29 percent to 38 percent of all heart attacks. “In the present era of primary percutaneous coronary intervention [PCI; procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries], survival to hospital discharge has improved dramatically. Subsequently, patients who survive to hospital discharge are at risk for early postdischarge hospital readmission,” according to background information in the article. “Recently, 30-day readmission rates have been proposed as a metric for care of patients with STEMI. However, international rates and predictors of 30-day readmission after STEMI have not been studied.”

Robb D. Kociol, M.D., of Duke University Medical Center, Durham, N.C., and colleagues analyzed data from the Assessment of Pexelizumab in Acute Myocardial Infarction study, a large multinational clinical trial, to determine international variation in and predictors of 30-day readmission rates after STEMI and country-level care patterns. The trial enrolled 5,745 patients with STEMI at 296 sites in the United States, Canada, Australia, New Zealand, and 13 European countries from July 2004 to May 2006. Analysis was performed to identify predictors of all-cause and nonelective 30-day postdischarge hospital readmission.

Of the patients enrolled in the trial, there were 5,571 (97.0 percent) included in the analysis who survived to hospital discharge and represented 17 countries; 631 (11.3 percent) were readmitted within 30 days from hospital discharge. The researchers found that factors associated with 30-day readmission were multivessel coronary artery disease, U.S. enrollment (vs. rest of the world), and baseline heart rate. Patients with multivessel disease had almost twice the odds of readmission compared with those without; patients in the United States had a 68 percent increased odds of readmission vs. those outside the United States; and baseline heart rate per 10/min increase was associated with a 9 percent increased odds of readmission.

Thirty-day readmission rates were higher for the United States than other countries (14.5 percent vs. 9.9 percent). Median (midpoint) length of stay was shortest for U.S. patients (3 days) and longest for patients in Germany (8 days).

“Excluding elective readmission for revascularization, U.S. enrollment was still an independent predictor of readmission. After adjustment of the models for country-level median length of stay, U.S. location was no longer an independent predictor of 30-day all-cause or nonelective readmission. Location in the United States was not a predictor of in-hospital death or 30-day postadmission death,” the authors write.

Other predictors of readmission included recurrent ischemia, chronic obstructive pulmonary disease, chronic inflammatory conditions, and a history of hypertension.

The authors write that the finding that STEMI patients in the United States have a higher likelihood of 30-day all-cause hospital readmission may be related to differential rates of early readmission for elective revascularization and shorter median length of stay (LOS) in the United States. “In particular, country-level median LOS attenuates the relationship between the United States and early readmission. Further research is needed to better understand the relationship between LOS and readmission rates and define and optimize overall efficiency of care internationally.”

“Significant attention has been focused on reducing acute myocardial infarction readmission rates in the United States as a means of reducing health care costs, according to the assumption that readmission is (at least in part) preventable. Our analysis shows that readmission may be preventable because rates are nearly one-third lower in other countries, suggesting that the U.S. health care system has features that can be modified to decrease readmission rates. Understanding these international differences may provide important insight into reducing such rates, particularly in the United States.”