EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) MONDAY, MAY 21, 2012

International Panel Updates Definition of Acute Respiratory Distress Syndrome

Gordon D. Rubenfeld, M.D., of the Sunnybrook Health Sciences Center, Toronto, Canada, and colleagues with the ARDS (acute respiratory distress syndrome) Definition Task Force, developed a new definition of ARDS (the Berlin Definition) that focused on feasibility, reliability, validity and objective evaluation of its performance.

ARDS is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the blood. Among the changes the panel proposed was a draft definition with 3 mutually exclusive categories of mild, moderate, and severe ARDS based on degree of hypoxemia (insufficient oxygenation of the blood) and four ancillary variables for severe ARDS. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27 percent; 32 percent; and 45 percent, respectively), and increased median duration of mechanical ventilation in survivors. The authors write that compared with the previous definition for ARDS, the final Berlin Definition had better predictive validity for mortality. “This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the [previous] definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions, and to better inform clinical care, research, and health services planning.”

(doi:10.1001/JAMA. 2012.5669. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact Gordon D. Rubenfeld, M.D., call Laura Bristow at 416-480-4040 or email laura.bristow@sunnybrook.ca.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) MONDAY, MAY 21, 2012

Combination Antibiotic Treatment Does Not Result in Less Organ Failure Among Adults With Severe Sepsis

Frank M. Brunkhorst, M.D., of Friedrich-Schiller University, Jena, Germany, and colleagues conducted a study to compare the effect of the antibiotics moxifloxacin and meropenem with the effect of meropenem monotherapy on sepsis-related organ dysfunction. Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The authors hypothesized that maximizing the potential benefit and appropriateness of initial antibiotics by using 2 antibiotics would improve clinical outcomes compared with monotherapy.

The trial included 298 patients who fulfilled usual criteria for severe sepsis or septic shock who were randomized to receive monotherapy, and 302 to receive combination therapy. The trial was performed in 44 intensive care units in Germany from October 2007 to March 2010, and the number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. The intervention was recommended for 7 days and up to maximum of 14 days after randomization or until discharge from the intensive care units or death, whichever occurred first.

Among 551 evaluable patients, there was no statistically significant difference in average Sequential Organ Failure Assessment (SOFA; degree of organ failure) score between the meropenem and moxifloxacin group and the meropenem alone group. “The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9 percent) in the combination therapy group compared with 59 deaths (21.9 percent) in the monotherapy group. By day 90, there were 96 deaths (35.3 percent) in the combination therapy group compared with 84 deaths (32.1  percent) in the monotherapy group,” the authors write.

“In conclusion, in this randomized multicenter trial of adult patients with severe sepsis or septic shock, empirical treatment with the combination of meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure.”

(doi:10.1001/JAMA. 2012.5833. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact corresponding author Tobias Welte, M.D., email welte.tobias@mh-hannover.de.

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Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Study Evaluates Use of Inhaled Saline for Young Children With Cystic Fibrosis

Margaret Rosenfeld, M.D., M.P.H., of Seattle Children’s Hospital, and colleagues conducted a study to examine if hypertonic saline would reduce the rate of pulmonary exacerbations in children younger than 6 years of age with cystic fibrosis (CF). Inhaled hypertonic saline is recommended as therapy for patients 6 years or older with CF, but its efficacy has not been evaluated in patients younger than 6 years.

In the randomized trial, the active treatment group (n = 158) received 7 percent hypertonic saline and the control group (n = 163) received 0.9 percent isotonic saline, nebulized (dispensed in a fine mist) twice daily for 48 weeks. The researchers found that the average pulmonary exacerbation rate was similar between both groups. “Hypertonic saline did not reduce the rate of pulmonary exacerbations in these young children. In addition, hypertonic saline did not demonstrate any significant effects on secondary end points including weight, height, respiratory rate, oxygen saturation, antibiotic use, or parent report of respiratory signs and symptoms.”

(doi:10.1001/JAMA. 2012.5214. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact Margaret Rosenfeld, M.D., M.P.H., call Mary Guiden at 206-987-7334 or email mary.guiden@seattlechildrens.org.

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 EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Low-Dose CT Screening May Benefit Individuals at Increased Risk for Lung Cancer, But Uncertainty Exists About Potential Harms of Screening

Peter B. Bach, M.D., of the Memorial Sloan-Kettering Cancer Center, New York, and colleagues conducted a systematic review to examine the evidence regarding the benefits and harms of low-dose computerized tomography (LDCT) screening for lung cancer, which is the leading cause of cancer death. “Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival rate,” the authors write. “Renewed enthusiasm for lung screening arose with the advent of LDCT imaging, which is able to identify smaller nodules than can chest radiographs.”

For the review, the researchers identified 8 randomized controlled trials and 13 cohort studies of LDCT screening that met criteria for inclusion. Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (20 percent lower relative risk). The other 2 smaller studies showed no such benefit. “In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20 percent of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1 percent had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions.” The authors write that “Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.”

This report, a multisociety collaborative initiative, forms the basis of the American College of Chest Physicians and the American Society of Clinical Oncology clinical practice guideline, which, in summary is:

Recommendation 1: For smokers and former smokers ages 55 to 74 years who have smoked for 30 pack-years (number of packs of cigarettes smoked per day by the number of years the person has smoked) or more and either continue to smoke or have quit within the past 15 years, it is suggested that annual screening with LDCT should be offered over both annual screening with chest radiograph or no screening, but only in settings that can deliver the comprehensive care provided to National Lung Screening Trial participants. (Grade of evidence 2B, indicating a “weak recommendation based on moderate quality research data”)

Recommendation 2: For individuals who have accumulated fewer than 30 pack-years of smoking or are either younger than 55 years or older than 74 years, or individuals who quit smoking more than 15 years ago, and for individuals with severe comorbidities that would preclude potentially curative treatment, limit life expectancy, or both, it is suggested that CT screening should not be performed. (Grade of evidence 2C, indicating a “weak recommendation based on low quality research data”)

(doi:10.1001/JAMA. 2012.5521. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact Peter B. Bach, M.D., call Jeanne D’Agostino at 212-639-3573 or email dagostij@mskcc.org.

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SUNDAY, MAY 20, 2012

Study Finds No Significant Difference Between Treatments For Relieving Breathing Difficulties Among Patients With Lung Effusions  

Helen E. Davies, M.D., of the University Hospital of Wales, Cardiff, and colleagues compared the effectiveness of treatments to relieve breathing difficulties among patients with malignant pleural effusion (presence of fluid in the pleural cavity [space between the outside of the lungs and the inside wall of the chest cavity], as a complication of malignant disease). The treatments compared were chest tube drainage and talc slurry for pleurodesis (a procedure in which the pleural space is obliterated) vs. indwelling pleural catheters (IPCs).

Malignant pleural effusion causes disabling dyspnea (breathing difficulties) in more than 1 million people worldwide annually; patients have an average life expectancy of 4 months. “There are no robust clinical data to address which of these treatments is more effective at palliating symptoms and improving quality of life,” the authors write. “Indwelling pleural catheters are increasingly used as an alternative treatment to talc pleurodesis.”

The randomized controlled trial compared IPC (n = 52) and talc slurry for pleurodesis (n = 54) for patients with malignant pleural effusion who were treated at 7 U.K. hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. The researchers found that there was no significant difference between groups in dyspnea in the first 42 days after intervention. Indwelling pleural catheters reduced time in the hospital but were associated with an excess of adverse events. “As such, IPCs cannot be advocated as a superior treatment to talc pleurodesis for palliation of symptoms,” the authors write.

(doi:10.1001/JAMA. 2012.5535. Available pre-embargo to the media at https://media.jamanetwork.com)

To contact corresponding author Najib M. Rahman, D.Phil., email najib.rahman@ndm.ox.ac.uk.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012

Surface of Drug-Eluting Stents May Become Damaged During Balloon Expansion

Drug-eluting stents (DES) have advanced percutaneous treatment (such as balloon angioplasty) of coronary artery disease by reducing restenosis (re-narrowing of a coronary artery after angioplasty). However, DES are associated with complications, including thrombosis (formation of blood clots), restenosis, and microvascular dysfunction. Scott J. Denardo, M.D., of the Duke University Medical Center, Durham, N.C., and colleagues hypothesized that the polymer surface of DES may be damaged during delivery balloon expansion and that microparticles may detach, which could contribute to these limitations.

As reported in a Research Letter, the authors used optical microscopy to systematically image the polymer surface of the 4 U.S. Food and Drug Administration-approved DES following expansion using the accompanying delivery balloon. Following balloon expansion, the abluminal and adluminal polymer surfaces of all DES were damaged, affecting 4.6 percent to 100 percent of the surface area imaged. Surface damage ranged from deformation (ridging, cracking, peeling, or webbing) to complete delamination with visually confirmed separation of polymer. “Polymer damage and detached microparticles could theoretically contribute to DES-associated complications, including thrombosis, restenosis, and microvascular and endothelial dysfunction. Confirmation of our results would be useful, and further studies should determine physiological and clinical consequences of polymer damage and microparticle detachment.”
(JAMA. 2012;307[20]:2148-2150. Available pre-embargo to the media at https://media.jamanetwork.com)

Viewpoints in This Week’s JAMA

Retail Clinics and Drugstore Medicine

Christine K. Cassel, M.D., of the American Board of Internal Medicine, Philadelphia, writes that easy access to medical clinics in retail settings is gaining momentum in the United States. “Although questions remain about their future, evidence suggests that retail clinics may have an important role in U.S. health care.”

Dr. Cassel discusses the issue of retail clinics, including what they are currently doing and what the future may hold for them.
(JAMA. 2012;307[20]:2151-2152. Available pre-embargo to the media at https://media.jamanetwork.com)

Assessing Value in Health Care Programs

Kevin G. Volpp, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, and colleagues write that many health care services provided in the United States are of low value, meaning that the cost of providing those services is high relative to the health care benefit they confer. “Given estimates that 30 percent of the $2.5 trillion the United States spends on health care services each year may provide little benefit, there is a widespread eagerness to enhance the ratio of benefits to costs.”

The authors examine the question of return on investment for health care costs and other issues related to this topic.
(JAMA. 2012;307[20]:2153-2154. Available pre-embargo to the media at https://media.jamanetwork.com)

Deciphering Harm Measurement

Gareth Parry, Ph.D., of the Institute for Healthcare Improvement, Cambridge, Mass., and colleagues write that there is an urgent need to reach consensus on robust, pragmatic measures for assessing and tracking the rate that patients are harmed in hospitals.

“… hospitals will need to address multiple types of harm before substantial improvement in all-cause harm rates will be observed. Delay in measuring the effect of best practices on harm rates will postpone the day when the nation can celebrate significant improvement in patient safety.”
(JAMA. 2012;307[20]:2155-2156. Available pre-embargo to the media at https://media.jamanetwork.com)

The Journey Across the Health Care (Dis)Continuum for Vulnerable Patients – Policies, Pitfalls, and Possibilities

Grace Jenq, M.D., and Mary E. Tinetti, M.D., of the Yale University School of Medicine, New Haven, Conn., write that there are gaps that need to be filled to ensure better care and outcomes facing vulnerable patients (such as those with multiple chronic conditions, serious injuries or illnesses) as they move through the health care system.

“Current policies and initiatives may benefit or disadvantage millions of vulnerable patients. It remains to be seen whether the most promising ones, assuming they survive the Supreme Court, prove to be a confusing array of piecemeal fixes that create other fissures and unintended consequences or are integrated into a seamless care continuum in which vulnerable patients receive appropriate care in the appropriate setting.”
(JAMA. 2012;307[20]:2157-2158. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012
Media Advisory: To contact Sascha Kopke, Ph.D., email sascha.koepke@uksh.de.

CHICAGO – Nursing homes that used a multicomponent intervention that included staff training and supportive materials for staff, residents and relatives had a lower rate of use of physical restraints such as bilateral bed rails and belts, according to a study in the May 23/30 issue of JAMA.

Despite unambiguous legal regulation and evidence for lack of effectiveness and safety, physical restraints are still frequently administered in nursing homes, with a recent survey reporting physical restraint rates of more than 20 percent for U.S. nursing homes, according to background information in the article. “Nursing home care does not necessitate the administration of physical restraints, as demonstrated by our own epidemiological research. We found pronounced center variation, with best-practice centers applying very few physical restraints. Reasons for differences between centers are unclear, but the ‘culture of care,’ as reflected in the attitudes and beliefs of nursing staff, may determine observed variation. Accordingly, a ‘culture change’ has been demanded for nursing homes because avoidance of physical restraints is mandatory from a professional point of view,” the authors write.

Sascha Kopke, Ph.D., of the University of Hamburg, Germany, and colleagues tested the effectiveness of a guideline- and theory-based multicomponent intervention to reduce the prevalence of physical restraints used in nursing homes. The randomized controlled trial of 6 months’ duration was conducted in 2 German cities between February 2009 and April 2010. Nursing homes were eligible if they had 20 percent or more residents with physical restraints. Eighteen nursing home clusters were included in the intervention group (2,283 residents) and 18 in the control group (2,166 residents). All nursing homes completed the study and all residents were included in the analysis.

The intervention was based on a specifically developed evidence-based guideline and applied the theory of planned behavior. Components were group sessions for all nursing staff; additional training for nominated key nurses; and supportive material for nurses, residents, relatives, and legal guardians. Control group clusters received standard information. The primary measured outcome was the percentage of residents with physical restraints (bilateral bed rails, belts, fixed tables, and other measures limiting free body movement) at 6 months, as assessed through direct unannounced observation by investigators on 3 occasions during 1 day.

At the beginning of the study, the prevalence of physical restraint use was comparable between groups: 31.5 percent in the intervention group vs. 30.6 percent in the control group. After 6 months, physical restraint prevalence was significantly lower in the intervention group, 22.6 percent, vs. 29.1 percent in the control group. All physical restraints were used less frequently in the intervention group compared with the control group. At 3 months, results were similar: intervention group: 23.9 percent, vs. 30.5 percent in the control group.

The researchers also found that results for falls, fall-related fractures, and prescriptions of psychotropic medication showed no statistically significant differences between groups.

“… considering the consistent effects after 3 and 6 months, we are confident that a ‘culture change’ has been achieved, resulting in a continuing avoidance of physical restraints. As it seems infeasible to further optimize the intervention with justifiable effort, more pronounced reduction or even complete prevention of physical restraint use may require more stringent implementation of legal regulations with clear penalties. The results of this study are likely generalizable to countries with comparable legal and professional conditions.”

The authors note that the guideline in their study was merely the basis for the intervention, not its central component. “As opposed to other guideline-based interventions, the central recommendation is not to perform a certain action, i.e., not to apply physical restraints. Therefore, the main message of the guideline and the related intervention is that it is possible to refrain from using restraints.”
(JAMA. 2012;307[20]:2177-2184. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by a grant from the German Federal Ministry of Education and Research within the Nursing Research Network Northern Germany. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of interest and none were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 22, 2012
Media Advisory: To contact Ferran Barbé, M.D., email fbarbe@arnau.scs.es. To contact José M. Marin, M.D., email jmmarint@unizar.es. To contact editorial co-author Edward M. Weaver, M.D., M.P.H., call Clare LaFond at 206-685-1323 or email clareh@uw.edu.

CHICAGO – Two studies that included adults with obstructive sleep apnea examined the effectiveness of reducing the risk of cardiovascular outcomes, including high blood pressure, by treatment with continuous positive airway pressure (CPAP), according to the articles in the May 23/30 issue of JAMA.

Obstructive sleep apnea (OSA) affects 3 percent to 7 percent of the general population and is caused by the collapse of the upper airway during sleep, which leads to transient asphyxia, according to background information in the first study. Studies have shown an association between OSA and hypertension and cardiovascular diseases. First-line treatment for patients with symptomatic OSA is CPAP, which acts as a pneumatic splint to keep the upper airway open during sleep and corrects the obstruction.

Ferran Barbé, M.D., of the Institut de Recerca Biomedica, Lleida, Spain, and colleagues conducted a study to evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in 723 patients with OSA without daytime sleepiness. The randomized controlled trial was conducted in 14 teaching hospitals in Spain between May 2004 and May 2006, with follow-up through May 2009. Patients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice. The primary outcomes measured for the study were the incidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event.

The patients in the study underwent followup for a median (midpoint) of 4 years; 357 in the CPAP group and 366 in the control group were included in the analysis. A total of 147 patients with new hypertension and 59 cardiovascular events were identified. In the CPAP group, there were 68 patients with new hypertension and 28 cardiovascular events (17 hospitalizations for unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal heart attack, 2 transient ischemic attack, 1 cardiovascular death). In the control group, there were 79 patients with new hypertension and 31 cardiovascular events (11 hospitalizations for unstable angina or arrhythmia, 8 nonfatal heart attack, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). Analysis of the data indicated that treatment with CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events.

However, the authors note that their study may have limited power to detect a significant difference, and that a larger study or longer follow-up might have been able to identify a significant association between treatment and outcome. “A post hoc analysis suggested that CPAP treatment may reduce the incidence of hypertension or cardiovascular events in patients with CPAP adherence of 4 hours/night or longer.”
(JAMA. 2012;307[20]:2161-2168. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, May 22 at this link.

Treatment of Obstructed Sleep Apnea With CPAP Therapy Associated With A Lower Risk Of Hypertension

In the second study, José M. Marin, M.D., of the Hospital Universitario Miguel Servet, Zaragoza, Spain, and colleagues examined whether CPAP therapy is associated with a lower rate of new-onset hypertension in patients with OSA. “Although treatment of OSA with CPAP therapy is associated with decreased overall cardiovascular risk, its efficacy in preventing new-onset hypertension is unknown,” the authors write. “Short-term studies indicate that CPAP therapy reduces blood pressure in patients with hypertension and OSA.”

The study included 1,889 participants without hypertension who were referred to a sleep center for nocturnal polysomnography between January 1994 and December 2000. Incident hypertension was documented at annual follow-up visits up to January 2011. Multivariable models adjusted for confounding (factors that can influence outcomes) factors, including changes in body mass index during the study, were used to calculate hazard ratios of new hypertension in participants without OSA (controls), with untreated OSA, and in those treated with CPAP therapy according to national guidelines.

The average follow-up of the study was 11.3 years (median 12.2 years). During follow-up, 705 patients (37.3 percent) developed incident hypertension. After including change in body mass index as a covariate in the fully adjusted model, the hazard ratios (risk) for incident hypertension remained 33 percent greater among patients with OSA who were ineligible for CPAP therapy; the risk was nearly twice as great among patients with OSA who declined CPAP therapy; and about 80 percent greater among patients with OSA who were nonadherent to CPAP therapy, compared with controls without OSA. In patients with OSA who were treated with CPAP therapy, the risk of new-onset hypertension was 29 percent lower than in controls.

“Although CPAP therapy was not allocated randomly to our patients, the associated lower excess risk of hypertension strongly suggests that OSA may be an independent modifiable risk factor for development of new-onset hypertension. The observed correlation between severity of OSA and the magnitude of risk for hypertension further supports OSA as a major contributor to cardiovascular risk. In conclusion, compared with participants without OSA, untreated OSA was associated with an increased risk of new-onset hypertension, whereas treatment with CPAP therapy was associated with a lower risk of new-onset hypertension,” the authors write.

“Our observational findings suggest that OSA appears to be a modifiable risk factor for new-onset hypertension. Such findings are clinically relevant considering that OSA, despite a high prevalence in Western populations, remains overwhelmingly unrecognized and untreated.”
(JAMA. 2012;307[20]:2161-2168. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the Instituto Carlos III, Ministry of Health, Madrid, from the Spanish Society of Respiratory Medicine. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Filling in the Pieces of the Sleep Apnea-Hypertension Puzzle

In an accompanying editorial, Vishesh K. Kapur, M.D., M.P.H., and Edward M. Weaver, M.D., M.P.H., of the University of Washington, Seattle, write that “although these studies significantly advance the understanding of the positive relationship between OSA and incident hypertension and the benefit of CPAP therapy, many questions remain regarding OSA, hypertension, and treatment.

“What are the susceptible and responsive subgroups (e.g. OSA severity subgroups, sleepy vs. nonsleepy, and demographic subgroups)? How much CPAP use is necessary for an important treatment effect? What are the effects of other OSA treatments? These questions will require randomized controlled trials when feasible, subgroup analyses within these trials, and well-controlled observational studies. Novel approaches are needed, such as treatment withdrawal protocols.”
(JAMA. 2012;307[20]:2197-2198. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, and by a grant from the National Institutes of Health. Dr. Kapur reported having owned stock within the last 3 years in Merck, Johnson & Johnson, and Bristol-Myers Squibb. Dr. Weaver reported no disclosures.
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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012
Media Advisory: To contact corresponding author Junfeng (Jim) Zhang, Ph.D., call Alison Trinidad at 323-442-3941 or email alison.trinidad@usc.edu; to contact corresponding author Tong Zhu, Ph.D., email tzhu@pku.edu.cn. To contact editorial co-author Francesca Dominici, Ph.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

CHICAGO – During the 2008 Beijing Olympics, changes in air pollution were associated with changes in biomarkers of systemic inflammation and thrombosis (formation of blood clot) as well as measures of cardiovascular physiology in healthy young persons, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“Air pollution is a risk factor for cardiovascular diseases (CVD), but the mechanisms by which air pollution leads to CVD is not well understood. Hypothesized mechanisms with associated biomarkers include systemic inflammation and thrombosis or endothelial [thin layer of cells that line the heart and certain vessels and cavities within the body] dysfunction,” according to background information in the article. “As a condition for hosting the 2008 Olympic Games, the Chinese government agreed to temporarily and substantially improve air quality in Beijing for the Olympics and subsequent Paralympics. This provided a unique opportunity to use a quasi-experimental design in which exposures and biomarkers were measured at baseline (pre-Olympics), following a change in pollution (during-Olympics), and then repeated after an expected return to baseline (post-Olympics).”

David Q. Rich, Sc.D., of the University of Rochester, New York, and colleagues conducted a study to determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution. The researchers measured environmental air pollutants daily and also measured various biomarkers and other measures (heart rate, blood pressure) in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). The biomarkers measured included those associated with systemic inflammation (fibrinogen, C-reactive protein [CRP], white blood cell [WBC] count) and thrombosis or endothelial dysfunction (platelet activation markers P-selectin [sCD62P] and soluble CD40 ligand [sCD40L] as well as the adhesive endothelial glycoprotein von Willebrand factor).

Concentrations of particulate and gaseous pollutants decreased substantially (-13 percent to -60 percent) from the pre-Olympic period to the during-Olympic period. There were reductions in the average concentration of sulfur dioxide (-60 percent), carbon monoxide (-48 percent), nitrogen dioxide (-43 percent), elemental carbon (-36 percent), PM2.5 (-27 percent), organic carbon (-22 percent), and sulfate (-13 percent) from the pre-Olympic to the during-Olympic period. “In contrast, ozone concentrations increased (24 percent). Pollutant concentrations generally increased substantially from the during- to post-Olympic period for all the pollutants (21 percent to 197 percent) except ozone (-61 percent) and sulfate (-47 percent),” the authors write.

The researchers observed statistically significant improvements in SCD62P levels (by -34.0 percent), and von Willebrand factor (by -13.1 percent). Changes in the other outcomes were not statistically significant after adjustments for multiple comparisons. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. “The fraction of above-detection-limit values for CRP was reduced from 55 percent in the pre-Olympic period to 46 percent in the during-Olympic period and reduced further to 36 percent in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and SCD40L concentrations.”

“Although these findings are of uncertain clinical significance, this study provides quasi-experimental, mechanistic data to support the argument that air pollution may be a global risk factor for CVD.”
(JAMA. 2012;307[19]:2068-2078. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: China’s Air Quality Dilemma – Reconciling Economic Growth With Environmental Protection

Francesca Dominici, Ph.D., and Murray A. Mittleman, M.D., Dr.P.H., of the Harvard School of Public Health, Boston, write in an accompanying editorial that “China’s dilemma, like many countries with emerging industries, is how to reconcile rapid economic growth with environmental protection.”

“In recent decades, China has achieved industrialization and urbanization. However, China has been much less successful in maintaining the quality of urban air. Several factors challenge the implementation of air pollution controls in China: heavy reliance on coal as a main heating system, especially in subsidized housing; lack of political incentives for trading slower growth for less pollution; economic factors: most Chinese factories and power plants run on extremely thin margins and fines for polluting are generally lower than the cost of controlling emissions; and economic transformation of the landscape, from ubiquitous construction sites to the rapid expansion of the nation’s vehicle fleet. If air pollution in China and other Asian nations cannot be controlled, it could spread to other continents. A recent study by Lin et al provides compelling evidence that Asian emissions may account for as much as 20 percent of ground-level pollution in the United States. Clean air is a shared global resource. It is in the common interest to maintain air quality for the promotion of global health.”
(JAMA. 2012;307[19]:2100-2102. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012

Media Advisory: To contact Eran Bendavid, M.D., M.S., call Ruthann Richter at 650-725-8047 or email richter1@stanford.edu. To contact editorial author Ezekiel J. Emanuel, M.D., Ph.D., call Holly Auer at 215-349-5659 or email holly.auer@uphs.upenn.edu.

CHICAGO – Between 2004 and 2008, all-cause adult mortality declined more in African countries in which the AIDS relief program PEPFAR operated more intensively, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“The effect of global health initiatives on population health is uncertain. Between 2003 and 2008, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), the largest initiative ever devoted to a single disease, operated intensively in 12 African focus countries,” according to background information in the article. PEPFAR has targeted the rapidly expanding human immunodeficiency virus (HIV) epidemic with a coordinated effort to increase HIV treatment, prevention, and care. PEPFAR scaled up the delivery of expanded antiretroviral therapy (ART) and supported large-scale prevention efforts. The initiative’s effect on all-cause adult mortality has not been known.

Eran Bendavid, M.D., M.S., of Stanford University, Stanford, Calif., and colleagues examined the relationship between PEPFAR’s implementation and trends in adult mortality. Using person-level data from the Demographic and Health Surveys (DHS), the researchers conducted cross-country and within-country analyses of adult mortality (annual probability of death per 1,000 adults between 15 and 59 years old) and PEPFAR activities. Across countries, adult mortality was compared in 9 African focus countries (Ethiopia, Kenya, Mozambique, Namibia, Nigeria, Rwanda, Tanzania, Uganda, and Zambia) with adult mortality in 18 African nonfocus countries from 1998 to 2008.

The study included data on 1,538,612 African adults collected from 41 surveys conducted in 27 countries between 1998 and 2008. During this time period, 60,303 deaths were captured in the DHS used in this study. Analysis of the data indicated relatively greater mortality declines among adults living in focus countries between 2004 and 2008, with mortality in the focus countries declining from 8.30 per 1,000 adults in 2003 to 4.10 per 1,000 in 2008. The mortality trends in nonfocus countries did not show a similar decline during the study period (from 8.5 in 2003 to 6.9 in 2008). After adjustments for country-level and personal characteristics, the odds of all-cause death was lower in the focus countries.

The authors also examined district-level data for Tanzania and Rwanda.  High and low PEPFAR activity districts had similar populations, but program intensity was significantly different between the groups. Adults in Tanzania living in the regions with above-median (midpoint) PEPFAR intensity had a lower odds of mortality compared with adults living in regions with below-median intensity; in Rwanda, the similar comparison also revealed a lower odds of mortality for adults living in the regions with above-median PEPFAR intensity.

The researchers also found that, using the results for each focus country and generalizing to the size of each country’s adult population, an estimated total of 740,914 all-cause adult deaths were averted between 2004 and 2008 in association with PEPFAR. In comparison, PEPFAR was associated with an estimated 631,338 HIV-specific deaths averted during the same period.

“In conclusion, we provide new evidence suggesting that reductions in all- cause adult mortality were greater in PEPFAR’s focus countries relative to the nonfocus countries over the time period from 2004 through 2008. Our analysis suggests an association of PEPFAR with these improvements in population health,” the authors write.

(JAMA. 2012;307[19]:2060-2067. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Please Note: For this study, there will be multimedia content available, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, May 15 at this link.

Editorial: PEPFAR and Maximizing the Effects of Global Health Assistance

In an accompanying editorial, Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania, Philadelphia, writes that the “article by Bendavid et al is welcome news in helping to document the even greater benefits of PEPFAR not only on HIV/AIDS but on overall mortality in countries.”

“However, the further question that must be asked by ethically responsible people and policy makers becomes: Is PEPFAR worth it? Many other global health programs are improving the health of poor people worldwide but are not funded anywhere near the level of PEPFAR. The fundamental ethical, economic, and policy question is not whether PEPFAR is doing good, but rather whether other programs would do even more good in terms of saving life and improving health. Clearly, besides treatment for HIV/AIDS, there are other highly effective and lower-cost interventions for the world’s poor.”

(JAMA. 2012;307[19]:2097-2099. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Emanuel reported receiving payment for speaking engagements unrelated to this work.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012

Media Advisory: To contact Lars Ake Persson, M.D., Ph.D., email lars-ake.persson@kbh.uu.se. To contact editorial co-author Robert E. Black, M.D., M.P.H., call Tim Parsons at 410-955-7619 or email tmparson@jhsph.edu.

 CHICAGO – Pregnant women in poor communities in Bangladesh who received multiple micronutrients, including iron and folic acid combined with early food supplementation, had substantially improved survival of their newborns, compared to women in a standard program that included usual food supplementation, according to a study in the May 16 issue of JAMA, a theme issue on Global Health.

“Maternal and child undernutrition is estimated to be the underlying cause of 3.5 million annual deaths and 35 percent of the total disease burden in children younger than 5 years. The potential long-term consequences of nutritional imbalance or insult in fetal or early life also include cognitive impairment and chronic diseases in adulthood. Effective child nutrition interventions are available to reduce stunting, prevent consequences of micronutrient deficiencies, and improve survival. The knowledge base is weaker regarding prenatal nutrition interventions of benefit for mother and offspring,” according to background information in the article. “The proportion of malnourished mothers and children remains high in many areas of the world, especially in South Asia, where more than one-quarter of newborns have a low weight.”

Lars Ake Persson, M.D., Ph.D., of Uppsala University, Uppsala, Sweden, and colleagues conducted a study (the MINIMat trial) to examine whether a prenatal multiple micronutrient supplementation (MMS), as well as an early invitation to a daily food supplementation, would increase maternal hemoglobin level at 30 weeks’ gestation, birth weight, and infant survival, and that a combination of these interventions (early invitation with MMS) would further improve these outcomes. The randomized trial, conducted in Matlab, Bangladesh, included 4,436 pregnant women who were recruited between November 2001 and October 2003, with follow-up until June 2009. One-third of the women were illiterate and one-fifth experienced occasional or constant deficit in their perceived income-expenditure status.

Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 μg of folic acid, 60 mg of iron and 400 μg of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 μg of folic acid, was combined with food supplementation randomized to either early invitation (9 weeks’ gestation) or usual invitation (20 weeks’ gestation).

There were 3,625 live births out of 4,436 pregnancies. The average birth weight among 3,267 single-birth infants was 2,694 grams (5.9 lbs.). Overall, 31 percent of newborns weighed less than 2,500 g (5.5 lbs.). There was no significant difference in birth weight among treatment groups, and no main-effect differences between food groups or among micronutrient groups. The researchers found that infants in the early invitation with MMS group had a lower risk of death, with a mortality rate of 16.8 per 1,000 live births vs. 44.1 per 1,000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid. The early invitation with MMS group had an under 5-year mortality rate of 18 per 1,000 live births (54 per 1,000 live births for usual invitation with 60 mg of iron and 400 μg of folic acid). Usual care invitation with MMS had the highest infant mortality rate (47.1 per 1,000 live births).

Adjusted maternal hemoglobin level at 30 weeks’ gestation was 115.0 g/L, with no significant differences among micronutrient groups. Women in the early invitation group had a small (0.9 g/L) but statistically significant lower hemoglobin level concentration than those in the usual invitation group.

“Scientists and policymakers have recommended replacing the current iron-folic acid supplements with MMS in the package of health and nutrition interventions delivered to pregnant women to improve size at birth and child growth and development. Other studies have questioned this view based on the limited size of the effect on birth weight and the absence of positive effect on fetal and neonatal survival. The MINIMat trial provides evidence that mortality of the offspring was reduced if multiple micronutrients were combined with a balanced protein-energy supplementation that began early in pregnancy,” the researchers conclude.

(JAMA. 2012;307[19]:2050-2059. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Food, Micronutrients, and Birth Outcomes

In an accompanying editorial, Parul Christian, Dr.P.H., M.Sc., and Robert E. Black, M.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, write that results from one country, such as in this study, “may not be applicable in other settings for a number of reasons, including variable maternal prepregnancy status, levels of macronutrient and micronutrient deficiencies, and antenatal [before birth] and delivery care availability.”

“Several nutrition programs in Asia and Africa have long targeted pregnant and lactating women in large-scale food supplementation programs, such as the one ongoing in Bangladesh when this trial was conducted. Coverage rates in these programs are known to be generally low and women are normally identified late in pregnancy. Further research on the timing of nutritional interventions including prior to and early and late in pregnancy is needed to examine their efficacy and safety both for survival and other long-term developmental consequences.”

(JAMA. 2012;307[19]:2094-2096. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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Prevalence of Girl Child Marriage Decreases in South Asia

Girl child marriage (i.e., < 18 years of age) affects more than 10 million girls globally each year and is linked to maternal and infant morbidities (e.g., delivery complications, low birth weight) and an increased risk of death. Half (46 percent) of child marriages occur in South Asia. Anita Raj, Ph.D., M.S., of the

University of California, San Diego, and colleagues conducted a study to assess whether the prevalence of girl child marriage has changed over the past 2 decades in 4 South Asian nations (Bangladesh, India, Nepal, and Pakistan) with a girl child marriage prevalence of 20 percent or greater.

As reported in a Research Letter, the authors found that the prevalence of girl child marriage decreased in all countries from 1991-1994 to 2005-2007. Significant relative reductions occurred in marriage of girls prior to age 14 years across all 4 nations.  Little or no change over time was seen in marriage of 16- to 17-year-old adolescent girls for any nation except Bangladesh, where such marriages increased by 35.7 percent. “Reductions in girl child marriage in South Asia have occurred but are largely attributable to success delaying marriage among younger but not older adolescent girls. Improvements in education of girls and increasing rural to urban migration may have supported these reductions, but many schools graduate students at the 10th standard (about 15-16 years), maintaining vulnerability to early marriage for 16- to 17-year-old girls.”

(JAMA. 2012;307[19]:2027-2029. Available pre-embargo to the media at www.jamamedia.org)

A Framework Convention on Global Health – Health for All, Justice for All

In a Special Communication, Lawrence O. Gostin, J.D., of the Georgetown University Law Center, Washington, D.C., writes that “health inequalities represent perhaps the most consequential global health challenge and yet they persist despite increased funding and innovative programs.”

A global coalition of civil society and academics—the Joint Action and Learning Initiative on National and Global Responsibilities for Health (JALI)— has formed an international campaign to advocate for a Framework Convention on Global Health (FCGH). Recently endorsed by the UN Secretary-General, the FCGH would re-imagine global governance for health. Mr. Gostin examines the key modalities of an FCGH to illustrate how it would improve health and reduce inequalities. “The modalities would include defining national responsibilities for the population’s health; defining international responsibilities for reliable, sustainable funding; setting global health priorities; coordinating fragmented activities; reshaping global governance for health; and providing strong global health leadership through the World Health Organization.”

(JAMA. 2012;307[19]:2087-2092. Available pre-embargo to the media at www.jamamedia.org)

Viewpoints in This Week’s JAMA

Primary Health Care in Low-Income Countries – Building on Recent Achievements

Jeffrey D. Sachs, Ph.D., of Columbia University, New York, discusses the advances and challenges of providing health care in low-income countries.

“The dozen years since the adoption of the Millennium Development Goals have been a period of great achievement and advances in public health in the poorest countries. The cynics and naysayers were proven wrong. Ancient scourges such as malaria and newer ones such as AIDS can be controlled, even in the poorest places. Now is the time to redouble efforts to ensure that the gains of the past decade are pushed forward to become lasting triumphs.”

(JAMA. 2012;307[19]:2031-2032. Available pre-embargo to the media at www.jamamedia.org)

Policy Making With Health Equity at Its Heart

Michael G. Marmot, F.R.C.P., of University College London, examines the importance of putting health equity – defined as the systematic inequalities in health between social groups that are deemed to be avoidable by reasonable means – at the heart of all policy making, nationally and globally.

“When governments cut social expenditures, the effect is greatest on those at the lower end of the social hierarchy, those who are most dependent on cash and in-kind government expenditures. It should be of the highest priority to ensure that government policies do not unfairly increase avoidable health inequalities. What applies to policies of governments should also apply to global decision making whether on trade, overseas development assistance, or financial flows—put health equity at the heart of all policy making.”

(JAMA. 2012;307[19]:2033-2034. Available pre-embargo to the media at www.jamamedia.org)

Achieving Equity in Global Health – So Near and Yet So Far

Zulfiqar A. Bhutta, F.R.C.P.C.H., Ph.D., of Aga Khan University, Karachi, Pakistan, and K. Srinath Reddy, M.D., D.M., (Card), of the Public Health Foundation of India, New Delhi, write that “few issues have generated as much passion and imagination over the last few decades as the challenge of global health. From major studies on the global burden of disease to the recognition of the global epidemic of human immunodeficiency virus, AIDS, and tuberculosis, health has been center stage of the global development debate.”

The authors discuss the needs of several major global health issues and cite initiatives that have experienced positive outcomes in certain areas of public health.

(JAMA. 2012;307[19]:2035-2036. Available pre-embargo to the media at www.jamamedia.org)

Noncommunicable Diseases – A Global Health Crisis in a New World Order

Shannon L. Marrero, B.A., of Brown University, Providence, R.I., and colleagues write that in September 2011, the United Nations General Assembly (UNGA) held a High-Level Meeting on the Prevention and Control of Non-communicable Diseases. It is only the second time in history that the UNGA convened a high-level meeting in response to a global health crisis. The authors discuss the outcomes and aftermath of the high-level meeting and affirm that the previously unrecognized non-communicable diseases (NCDs) epidemic has at last acquired a voice.

“The NCDs—cardiovascular disease, chronic respiratory disease, diabetes, and cancers—are the dominant public health challenge of the 21st century. Left unattended, NCDs compromise the Millennium Development Goals, thwart the eradication of poverty, and undercut economic growth.”

(JAMA. 2012;307[19]:2037-2038. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: Please see the articles for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 15, 2012
Media Advisory: To contact R. Matthew Chico, M.P.H., email Katie Steels at katie.steels@lshtm.ac.uk or call +44 (0)20-7927-2802.

CHICAGO – A review of studies reporting estimates of the prevalence of sexually transmitted infections/reproductive tract infections (STIs/RTIs) and malaria over the past 20 years suggests that a considerable burden of malaria and STIs/RTIs exists among pregnant women attending antenatal (before birth) facilities in sub-Saharan Africa, according to a review and meta-analysis of previous studies published in the May 16 issue of JAMA, a theme issue on Global Health.

“There are 880,000 stillbirths and 1.2 million neonatal deaths each year in sub-Saharan Africa. Low birth weight (< 2.5 kg [5.5 lbs.]), attributable to intrauterine growth retardation, preterm delivery, or both, is the leading risk factor for neonatal mortality. Intrauterine infection is implicated in stillbirth and is associated with 25 percent to 40 percent of preterm births. Sexually transmitted infections and reproductive tract infections and malaria are associated with adverse birth outcomes, but both may be mitigated with preventive or presumptive treatment or by repeated screening and treatment throughout the antenatal period. The extent to which either approach may be beneficial depends on the underlying prevalence of STIs/RTIs and malaria in pregnancy,” according to background information in the article.

R. Matthew Chico, M.P.H., of the London School of Hygiene and Tropical Medicine, London, and colleagues conducted a systematic review and meta-analysis to provide estimates for the dual prevalence of STIs/RTIs and malaria in pregnancy among women in sub-Saharan Africa. The researchers conducted a search for studies reporting malaria, syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, or bacterial vaginosis among pregnant women attending antenatal care facilities in sub-Saharan Africa. A total of 171 studies, which were conducted from 1990-2011, were identified that met inclusion criteria.

The studies included 340,904 women. The researchers found that the pooled prevalence estimates among studies in East and Southern Africa were: syphilis, 4.5 percent (n = 8,346 positive diagnoses), N gonorrhoeae, 3.7 percent (n = 626), C trachomatis, 6.9 percent (n = 350), T vaginalis, 29.1 percent (n = 5,502), bacterial vaginosis, 50.8 percent (n = 4,280), peripheral malaria, 32.0 percent (n = 11,688), and placental malaria, 25.8 percent (n = 1,388).

“West and Central Africa prevalence estimates were as follows: syphilis, 3.5 percent (n = 851), N gonorrhoeae, 2.7 percent (n = 73), C trachomatis, 6.1 percent (n = 357), T vaginalis, 17.8 percent (n = 822), bacterial vaginosis, 37.6 percent (n = 1,208), peripheral malaria, 38.2 percent (n = 12,242), and placental malaria, 39.9 percent (n = 4,658),” the authors write.

“The dual prevalence of malaria and STIs/RTIs is evident among pregnant women who attend antenatal facilities in sub-Saharan Africa. As malaria control and elimination efforts are brought to scale, the relative contribution of STIs/RTIs to adverse birth outcomes most likely will increase proportionately. Coinfection prevalence estimates for malaria and STIs/RTIs need to be established and routinely reported. Rigorous studies using molecular diagnostic methods are needed to characterize more accurately the prevalence of these infections and their clinical consequences. Clinical trials are needed to compare birth outcomes, operational feasibility/acceptability, and cost-effectiveness of intermittent preventive treatment during pregnancy (IPTp) with azithromycin-based combination therapy against an approach of integrated screening and treatment for malaria and STIs/RTIs,” the researchers conclude.
(JAMA. 2012;307[19]:2079-2086. Available pre-embargo to the media at www.jamamedia.org)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr. Chico reports having previously received funding as part of 2 studies co-financed by Pfizer and the Medicines for Malaria Venture that are investigating the use of azithromycin plus chloroquine in IPTp. No other disclosures were reported.

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