Reduced-Dose Schedule for Pneumococcal Vaccine in Infants Shows Effectiveness

Infants who received two or three primary doses of the 7-valent pneumococcal conjugate vaccine (PCV-7) both had a decreased rate of carrying pneumococcal microorganisms that can cause pneumonia and other infections, compared to infants who were not vaccinated, according to a study in the July 8 issue of JAMA.

Crowded infant vaccine schedules and less favorable cost-effectiveness calculations have prompted exploration of reduced-dose vaccine schedules other than the currently recommended 3 + 1-dose schedule of PCV-7, which consists of 3 primary doses before age 6 months followed up by a booster vaccination in the second year of life, according to background information in the article.

Difficulty in implementing the 3 + 1-dose schedule in developing countries is another reason for exploring reduced schedules. The effects of reduced-dose schedules of PCV-7 on pneumococcal carriage in children are largely unknown.

Elske J. M. van Gils, M.D., of the University Medical Center Utrecht, the Netherlands, and colleagues examined the effects of a 2-dose and 2 + 1-dose PCV-7 schedule on nasopharyngeal (upper part of the throat behind the nose) pneumococcal carriage in young children. The randomized trial included 1,003 healthy newborns and 1 of their parents in a general community in the Netherlands, with follow-up to age 24 months.

Infants were randomly assigned to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (control group).

No significant differences in vaccine serotype (a strain of microorganisms having a set of antigens in common), nonvaccine serotype, and overall pneumococcal carriage were observed at 6 months in both vaccine groups compared with the control group. At 12 months, vaccine serotype carriage rates were significantly lower in both vaccine groups compared with the control group, with 25 percent in the 2-dose schedule group, 20 percent in the 2 + 1-dose schedule group, and 38 percent in the control group. A further decrease of vaccine serotype carriage was found at 18 months after 2 + 1-dose schedule and at 24 months after 2 primary doses compared with the control group.

In analysis comparing the 2-dose and 2 + 1-dose schedules, the researchers observed a significant difference in vaccine serotype carriage at 18 months with 24 percent vaccine serotype carriage in the 2-dose schedule group compared with 16 percent in the 2 + 1-dose schedule group. At 24 months, the estimates for vaccine serotype carriage in both vaccine groups were at the same level with 15 percent in the 2-dose schedule group and 14 percent in the 2 + 1-dose schedule group, compared with 36 percent in the control group.

“In conclusion, both 2-dose and 2 + 1-dose schedules of PCV-7 significantly reduce vaccine serotype pneumococcal carriage in children. This study supports future implementation of reduced-dose PCV-7 schedules,” the authors write.

JAMA. 2009;302[2]:159-167.

Online Computer Games Could Encourage Children to Eat Healthy Foods

Children who play an online game promoting healthy foods and beverages appear more likely to choose nutritious snacks than those who play a game promoting unhealthy products, according to a report in the July issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.

Obesity rates among U.S. children and youth have tripled during the past 40 years, according to background information in the article. “One potential contributor to the rise in obesity is media exposure, primarily because television advertising markets high-calorie foods and beverages that have little nutritional value,” the authors write.

“We know far less about how newer media influence children’s food preferences, but Internet use is a very popular activity among youth aged 8 to 18 years. Marketers have taken notice of this online revenue-generating opportunity in which exposure to products costs less than traditional television advertisements and legal restrictions and regulations are virtually non-existent.”

Advergames—online computer games developed specifically to promote a brand, often featuring logos and characters—are present on many food and beverage Web sites. Tiffany A. Pempek, Ph.D., and Sandra L. Calvert, Ph.D., of Georgetown University, Washington, D.C., conducted a study involving 30 low-income, African American children age 9 to 10 years.

One group played a game, based on Pac-Man, that rewarded them for having their computer character choose bananas, orange juice and other healthy foods and beverages. A second group played a different version of the same game that instead rewarded consumption of soda, candy bars, cookies and bags of potato chips.
These two groups were instructed to select a snack from among options featured in the game after playing, whereas a third, control group selected a snack and beverage before playing the healthy version of the game.

The children reported liking both versions of the game and played for an average of 9 minutes and 32 seconds.

Children who played the healthy version before selecting a snack were significantly more likely than those playing the unhealthy version to choose a banana and orange juice instead of soda and potato chips. “With only 10 minutes of exposure, our results revealed that children selected and ate whatever snacks were being marketed by the advergame, healthy or not,” the authors write.

The findings suggest that public concerns about online games that market unhealthy foods are justified, the authors note, but also that the technology could be used to promote nutritious foods. “Eating patterns established during childhood affect health throughout the lifespan. Thus, it is important that we find ways to promote a healthy lifestyle for our children from an early age, particularly those who come from low-income neighborhoods where the risk of obesity is greatest,” the authors write.

Despite concerns that low-income children do not have Internet access, children in the study reported being online daily or at least several times per week. “Overall, our results suggest that reaching low-income African American children via the Internet is feasible and that the use of advergames is a potential way to alter their eating habits in favor of more nutritious foods,” the authors conclude.

Arch Pediatr Adolesc Med. 2009;163[7]:633-637.

Sugar Substitute Appears to Prevent Early-Childhood Cavities

Children given an oral syrup containing the naturally occurring sweetener xylitol may be less likely to develop decay in their baby teeth, according to a report in the July issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.1

Early childhood caries (cavities), also called baby bottle tooth decay or nursing caries, continue to increase in prevalence, according to background information in the article. “Poor children experience rates twice as high as those of their more affluent peers, and their disease is more likely to be untreated,” the authors write.

“Poor oral health affects diet and nutrition and significantly diminishes quality of life. However, tooth decay is a disease that is largely preventable.”

Xylitol, approved in the United States for use in food since 1963, has been shown to effectively prevent tooth decay by acting as an antibacterial agent against organisms that cause cavities. These previous investigations have primarily involved chewing gum or lozenges used in school-age children with permanent teeth. Peter Milgrom, D.D.S., of the University of Washington, Seattle, and colleagues evaluated the effectiveness of applying oral syrup containing xylitol among 94 children age 9 to 15 months in the Republic of the Marshall Islands, where early childhood tooth decay is a serious health care problem.

Two active treatment groups received 8 grams per day of xylitol syrup divided into two (33 children) or three (32 children) doses per day. A third, control group of 29 children received a small amount (a single 2.67-gram dose) of xylitol syrup per day because the internal review committee appointed by the secretary of health of the

Republic of the Marshall Islands did not permit the use of a placebo.
After an average of 10.5 months, eight of 33 children (24.2 percent) receiving two doses of xylitol per day and 13 of the 32 children (40.6 percent) receiving three doses of xylitol per day had tooth decay, compared with 15 of the 29 children (51.7 percent) in the control group. The average numbers of decayed teeth were 0.6 in the two-dose xylitol group, one in the three-dose xylitol group and 1.9 in the control group.

“Our results suggest that exposure to xylitol (8 grams per day) in a twice-daily topical oral syrup during primary tooth eruption could prevent up to 70 percent of decayed teeth,” the authors write. “Dividing the 8 grams into three doses did not increase the effectiveness of the treatment. These results provide evidence for the first time (to our knowledge) that xylitol is effective for the prevention of decay in primary teeth of toddlers.”

More research is needed to develop vehicles and strategies for optimal public health, but in populations with high rates of tooth decay, xylitol is likely to be a cost-effective preventive measure, they conclude.

“Early childhood caries is well understood by microbiologists and research dentists—if not by the general public and their health care providers—as ordinary tooth decay run amok,” writes Burton L. Edelstein, D.D.S., M.P.H., of the College of Dental Medicine, Columbia University, in an accompanying editorial.2

“It most commonly manifests as extensive tooth destruction and associated pain, with or without infection, by age 22 months and sometimes much earlier,” Dr. Edelstein continues. “The Centers for Disease Control and Prevention reports that more than one-quarter of all U.S. toddlers and preschoolers (28 percent) are affected.”

“Findings reported herein by Milgrom and colleagues that xylitol application holds strong promise to significantly dampen early childhood caries occurrence are encouraging and suggest the addition of this approach to pharmacologic management in public health and individual care settings. Xylitol application, like fluoride varnish application, will likely become a routine element of early childhood caries control.

The finding, however, that early childhood caries prevalence remained at 24 percent to 41 percent among treated children at the close of the trial in a high-caries-experience population reminds us that no single ‘silver bullet’ is going to solve the problem of early childhood caries.”

References:

1. Arch Pediatr Adolesc Med. 2009;163[7]:601-607.
2. AArch Pediatr Adolesc Med. 2009;163[7]:667-668.

Compared to Conventional Risk Factors, Certain Biomarkers May Have Limited Added Benefit For Predicting Cardiovascular Events

Use of several older and newer biomarkers appears to offer minimal added benefit in the prediction of cardiovascular events compared to conventional risk factors such as high cholesterol and high blood pressure, according to a study in the July 1 issue of JAMA.

“Cost-effective cardiovascular prevention relies on the accurate identification of individuals at risk. However, a large proportion of individuals with cardiovascular events have 1 or fewer of the conventional risk factors, including smoking, diabetes, hypertension, or hyperlipidemia,” the authors write. As a result, the use of recently identified biomarkers to supplement standard risk algorithms has attracted increasing attention in recent years. However, prior studies have reached differing conclusions regarding the usefulness of biomarkers for cardiovascular risk prediction, according to background information in the article.

Olle Melander, M.D., Ph.D., of Lund University, Malmö, Sweden, and colleagues assessed several cardiovascular biomarkers, individually and in combination, regarding their usefulness in predicting future cardiovascular events, compared with conventional risk factors. The study included 5,067 participants (average age, 58 years; 60 percent women) without cardiovascular disease from Malmö, Sweden, who were examined at the beginning of the study, between 1991 and 1994. Participants underwent measurement of older biomarkers (C-reactive protein [CRP] and N-terminal pro-B-type natriuretic peptide [N-BNP]) and newer biomarkers (cystatin C, lipoprotein-associated phospholipase-2 [Lp-PLA2], midregional proadrenomedullin [MR-proADM], and midregional proatrial natriuretic peptide [MR-proANP]. There was follow-up until 2006, using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmö register for first cardiovascular events (heart attack, stroke, coronary death). During median (midpoint) follow-up of 12.8 years, there were 418 cardiovascular events and 230 coronary events.

When considered individually, 5 of 6 biomarkers predicted future cardiovascular events and 3 (cystatin C, MR-proADM, and N-BNP) predicted future coronary events in models adjusting for conventional risk factors. “The best combinations of biomarkers were CRP and N-BNP for predicting cardiovascular events and MR-proADM and N-BNP for predicting coronary events. The use of multiple biomarkers minimally improved the accuracy of risk prediction models over and above conventional cardiovascular risk factors and did not reclassify a substantial proportion of individuals to higher or lower risk categories,” the authors write.

The researchers add that what may be relevant to clinical care, however, is not whether changes in predicted probabilities are statistically significant but whether they result in reclassification of individuals to new, clinically meaningful risk categories. “Our data indicate that a relatively small proportion of individuals are moved to new risk categories by the addition of biomarkers—8 percent or fewer when both upward and downward risk category movement are included and fewer than 1 percent when only the movements likely to lead to changes in therapy according to the Adult Treatment Panel III [cholesterol] guidelines are included. Furthermore, these reclassifications result in only modest improvements in the overall concordance between risk categories and actual event rates, as measured by the net reclassification improvement.”

“The challenge will be to find new cardiovascular biomarkers that alone or in combination with existing biomarkers can bring about improvements in risk assessment that are not just statistically significant but clinically significant as well,” the authors conclude.

JAMA. 2009;302[1]:49-57.

Findings of Genetics Study Does Not Support Causal Association of C-Reactive Protein With Coronary Heart Disease

An analysis of the association between genetic variations of the inflammation biomarker C-reactive protein (CRP) with coronary heart disease failed to support a causal association, according to a study in the July 1 issue of JAMA.1

Coronary heart disease (CHD) is the leading cause of death worldwide. Inflammation plays a key role in the development of CHD at every stage, from initiation to progression and rupture of plaque. CRP is currently the most widely used biomarker of inflammation, according to background information in the article. “There is considerable interest in establishing whether CRP has a causal role in CHD or whether CRP is merely a marker of underlying atherosclerosis,” the authors write.

Paul Elliott, F.R.C.P., of Imperial College London, and colleagues conducted a genetic association study to identify common genetic loci (the specific site of a particular gene on its chromosome) that influence CRP levels and used the concept of mendelian randomization (the randomized allocation of alleles—an alternative form of a gene at a locus—at conception) to examine the possible causal relationship of CRP levels with CHD. First a genome-wide association (n = 17,967) and replication study (n = 13,615) were conducted to identify genetic loci associated with plasma CRP concentrations.

Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. The researchers then carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. These findings were compared with findings predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease.

The researchers found: “The present genome-wide association study confirms the associations of common genetic variants in the LEPR, IL6R, CRP, and HNF1A loci and APOE-CI-CII cluster with CRP levels. However, the minor allele of SNP rs7553007 and other variants in the CRP locus included in our mendelian randomization study were not associated with CHD risk.”

The authors write that the variants included in their mendelian randomization study are associated with approximately 20 percent lower CRP levels, corresponding to a 6 percent reduction in CHD risk predicted by the meta-analysis of observational studies of CHD risk. “The lack of association with CHD of genetic variants in the CRP locus suggests that the observational data linking CRP levels and CHD may be confounded [factors that can influence outcomes] by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship.”

“In summary, our mendelian randomization study of more than 28,000 cases and 100,000 controls found no association of variants in the CRP locus and CHD, arguing against a causal role for CRP in atherosclerosis. Moreover, this study suggests that development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful,” the researchers conclude.

In an accompanying editorial, Svati H. Shah, M.D., M.H.S., of Duke University Medical Center, Durham, N.C., and James A. de Lemos, M.D., of the University of Texas Southwestern Medical Center, Dallas, comment on the two studies in this week’s JAMA that examine the use of biomarkers for predicting cardiovascular disease.

“What are the implications of these 2 important studies? Ideally, biomarkers would also be risk factors and could be used for both risk assessment and to individualize specific therapies. Large collaborative investigations incorporating genome-wide association study and mendelian randomization as highlighted by Elliott et al offer a blueprint for definitive evaluation of the causal role of intermediate traits such as biomarkers.

Similarly, studies such as that by Melander et al exemplify the necessity of comprehensive appraisal of the value of novel biomarkers, including CRP, beyond standard risk factors in specific populations. Studies such as these will help determine which biomarkers are likely to be useful as specific drug targets but also whether they have a potential role in risk assessment or even therapeutic selection. In the future, better biomarkers and more creative strategies for combining them will be needed, along with comprehensive statistical and functional evaluation of causality, to fulfill the promise of biomarkers for personalized medicine.”

References:

1. JAMA. 2009;302[1]:92-93.

2. JAMA. 2009;302[1]:37-48.

Boys With Intermittent Eye Deviation Appear More Likely to Develop Mental Illness

Children and especially boys diagnosed with intermittent exotropia, a condition in which the eye turns outward (away from the nose) only some of the time, appear more likely to develop mental illness by young adulthood than children without strabismus (when the eyes deviate or are misaligned when looking at an object), according to a report in the June issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

“Intermittent exotropia occurs in approximately 1 percent of developmentally healthy children in the United States and, given its predominance over esodeviations [when the eye turns in] among Asian populations, it may be the most prevalent form of strabismus worldwide,” the authors write as background information in the article.

Jeff A. McKenzie, B.A., and colleagues at Mayo Clinic, Rochester, Minn., analyzed the medical records of 183 children younger than 19 in Olmsted County, Minn., who were diagnosed with intermittent exotropia between 1975 and 1994. For each patient, the researchers identified one control child who was the same age but did not have a diagnosis of any type of strabismus. Both groups were followed to an average age of 22.

During the 20-year study period, 97 of the children with intermittent exotropia (53 percent) were diagnosed with a mental health disorder, compared with 55 controls (30.1 percent)—meaning that patients with the condition had an increased risk of developing a psychiatric illness. Mental health disorders were diagnosed in 63 percent of boys (41 of 65) and 47 percent of girls (56 of 118) with intermittent exotropia, compared with 33 percent of boys (22 of 66) and 28 percent of girls (33 of 117) in the control group.

“Additionally, males with intermittent exotropia had a greater use of psychotropic medication, psychiatric emergency department visits, psychiatric hospital admissions, suicide attempts and suicidal ideation than controls, and females with intermittent exotropia had more suicidal ideation than controls,” the authors write.

The reasons underlying these associations remain unclear, the authors note. “Studies regarding the psychosocial impact of strabismus have reported that individuals with intermittent exotropia are not judged more poorly than individuals with orthotropia [the absence of strabismus] by adult observers. However, a negative bias toward people with strabismus has been demonstrated in children,” the authors write.

“Although this study focused on mental illness that was diagnosed by early adulthood, there is also evidence to suggest that the social problems associated with strabismus persist and even intensify into adult life.”

“Further study is needed to determine whether interventions for intermittent exotropia can decrease or otherwise alter the future development of mental illness,” they conclude.

Arch Ophthalmol. 2009;127[6]:743-747.

An Estimated 4 Percent of Older U.S. Men Have Dry Eye Disease

Dry eye disease is common among American men older than 50 and increases with age, high blood pressure, benign prostate disease and the use of antidepressants, according to a report in the June issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

Dry eye is one of the most common eye diseases and reason that older adults seek eye care, according to background information in the article. “It is an important public health problem, causing increased risk of ocular infections and bothersome symptoms of ocular discomfort, fatigue and visual disturbance that interfere with crucial activities such as reading, working on a computer and driving a car,” the authors write.

Debra A. Schaumberg, Sc.D., O.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues estimated the prevalence of and examined risk factors for dry eye disease among 25,444 U.S. men who participated in the Physicians’ Health Study I and II. The men were asked if they had ever been diagnosed with dry eye disease and also whether they had symptoms, including dry or irritated eyes.

Overall, 765 men (3 percent) reported being diagnosed with dry eye, 6.8 percent experienced at least one symptom (dryness or irritation) constantly or often and 2.2 percent reported both symptoms constantly or often. The total age-standardized prevalence of dry eye disease among men 50 and older was estimated to be 4.34 percent. Men 75 years and older were more likely to have the condition—prevalence increased from 3.9 percent among men age 50 to 54 to 7.7 percent among men age 80 and older.

High blood pressure, benign prostatic hyperplasia (a non-cancerous enlargement of the prostate) and the use of medications to treat depression, hypertension or hyperplasia were also associated with an increased risk of dry eye disease.

“The present study estimates that approximately 1.68 million men 50 years and older are affected with dry eye disease in the United States,” the authors write. “These data, derived from studying more than 25,000 men, show a significantly lower prevalence of dry eye disease than was found in a similar study using the same methods in U.S. women, among whom the prevalence was estimated at 3.23 million women.

Nonetheless, there is a significant increase in the prevalence of dry eye disease with age among men, as is the case among women, and there is a predicted growth to 2.79 million U.S. men affected by dry eye disease in 2030.”

“Given the increasing recognition of the adverse visual impact of dry eye disease, and the high level of bother patients report because of its irritative symptoms, we hope that these data from a large and well-characterized group of U.S. men will provide further motivation for clinicians and researchers to understand this disease and develop more effective and targeted interventions for patients,” they conclude.

Arch Ophthalmol. 2009;127[6]:763-768.