PHOENIX Ultrasound-guided radiofrequency ablation (RFA) delivered better and faster results than did laser ablation (LA)

) in patients with large benign thyroid nodules, a randomized study has found. The results, the first head-to-head comparison of LA with RFA in large nodules, were presented on May 5 by Roberto Valcavi, MD, director of the endocrine unit and thyroid diseases center, Santa Maria Nuova Hospital, Reggio Emilia, Italy, in a latebreaker session at the American Association of Clinical Endocrinologists (AACE) 2013 Scientific & Clinical Congress. Dr. Valcavi told Medscape Medical News that the current practice for large benign thyroid nodules is open surgery, and at present laser and radiofrequency are the only thermal-ablation techniques available. "The future impact of ultrasound-assisted thermal-ablation techniques should be a reduction of open surgeries," he said. This study showed several distinct advantages of RFA the most important the absence of the characteristic charring (carbonization) seen nearly universally with laser-ablation procedures as a result of overheating, he noted. Session moderator Daniel Duick, MD, a past AACE president now in private practice in Phoenix, Arizona, told Medscape Medical News, "It's a tremendous advance. The difference between laser and a cool-tip radiofrequency is that we don't burn tissue. We don't have to vent tissue. We don't have to smell like the kitchen is on fire." RFA: Faster, Cleaner, and Cheaper Than LA Another distinct advantage of RFA is that it can be accomplished in a single session, whereas LA often requires multiple procedures with large nodules. In this study, however, both techniques were performed in single sessions, Dr. Valcavi noted. The trial randomized 108 consecutive outpatients with symptomatic, cytologically benign large (> 30 mL) thyroid nodules to either ultrasound-guided LA (54 patients, mean age, 51 years) or ultrasound-guided RFA (54 patients, mean age, 47 years). At baseline, nodule volumes were 39.3 mL in the LA group and 40.4 mL for the RFA patients, not significantly different.

Mean total energy delivered was 9624 J for LA vs 60,122 J with RFA. Carbonization, seen as a hyperechoic irreversible mark on ultrasound, occurred in all of the LA patients and none of the RFA patients. "RFA permitted the delivery of greater energy to obtain larger ablations without carbonization," Dr. Valcavi observed. At 1 month following the procedure, nodule volumes had dropped to 31.9 mL with LA vs 28.9 mL with RFA (P < .03 for the difference between the 2 procedures). By 3 months, the difference was 27.8 mL vs 26.6 mL (P < .04), and by 6 months, volumes had dropped even further, to 22.6 mL vs 16.9 mL (P < .01). "We had a faster and greater effect with RFA, of about 70% at 6 months vs 50% with laser," Dr. Valcavi noted. At 6 months, compressive symptoms as rated on the visual analog scale had been reduced from 5.1 to 2.5 with LA, compared with 5.3 to 0.8 with RFA (P < .01). Levels of thyroid-stimulating hormone and thyroid hormone were unaffected by the procedure in either group. "Volume reduction of large benign thyroid nodules was greater, faster, and more homogenous after RFA than LA therapy," Dr. Valcavi concluded, adding that reduced cost is yet another RFA advantage: "RFA is a more promising and less expensive thermal-ablation technique than LA." Results May Aid Expansion of RFA Beyond Radiology Dr. Duick told Medscape Medical News that the primary use of RFA in the United States has been by interventional radiologists to treat liver tumors and nodules in other tissues. It is used to treat thyroid nodules too, thus far only through radiological facilities, however, he added. Of course, data such as these could advance the field. "When you look at efficacy, it's very self-evident It's a very important procedure," Dr. Duick said.

Neither Dr. Valcavi nor Dr. Duick has reported any relevant financial relationships. American Association of Clinical Endocrinologists 2013 Scientific & Clinical Congress. Abstract 1100, presented May 5, 2013.

Ambrisentan was ineffective in treating idiopathic pulmonary fibrosis (IPF) and was linked with an increased risk for disease progression and respiratory hospitalizations, according to Ganesh Raghu, MD, from the Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, Seattle, and colleagues.

The researchers report the findings from a randomized, placebocontrolled trial in an article published in the May 7 issue of the Annals of Internal Medicine.

"Due to the increased risk of death and/or disease progression, ambrisentan must not be used in patients with IPF with or without secondary pulmonary hypertension (PH)," Diego Macas Saint-Gerons, PharmD, MPH, from the Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Medicines and Healthcare Products Agency in Madrid, Spain, told Medscape Medical News when asked about the study. "Stratified analyses suggest that the presence of IPF and concomitant PH could be associated with a similar (or higher) risk of disease progression and/or hospitalization than in patients without PH."

IPF is a progressive, fatal lung disease associated with irreversible scarring around both lungs. Currently, there are no approved treatments in the United States. In IPF, endothelin 1 stimulates lung fibroblast proliferation and contractile activity via the endothelin A receptor.

The hypothesis tested in the double-blind Randomized, PlaceboControlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF (ARTEMIS-IPF) trial was that ambrisentan, an endothelin A receptorselective antagonist, might decrease time to disease

progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.

Study Terminated Early At academic and private hospitals, patients with IPF, aged 40 to 80 years, who had minimal or no honeycombing on high-resolution computed tomography scans received ambrisentan, 10 mg/day, or placebo.

After enrollment of 492 patients (75% of intended enrollment), the investigators terminated the study because interim analysis showed a low probability of efficacy by the scheduled study end. Mean duration of exposure to study medication was 34.7 weeks.

Patients receiving ambrisentan were more likely to meet prespecified criteria for disease progression compared with those receiving placebo (90 [27.4%] vs 28 [17.2%] patients; P = .01; hazard ratio, 1.74; 95% confidence interval [CI], 1.14 - 2.66). Patients receiving ambrisentan also fared worse in terms of lung function decline (55 [16.7%] vs 19 [11.7%]; P = .11), respiratory hospitalizations (44 [13.4%] vs 9 [5.5%]; P = .007), and deaths (26 [7.9%] vs 6 [3.7%]; P = .10).

Results were similar for analysis stratified by the presence of pulmonary hypertension at baseline (10% of patients in each group).

"Ambrisentan should not be used to treat patients with IPF," the authors write.

Study limitations include early termination, which was necessary because of the findings of harm associated with ambrisentan. In addition, the investigators recommend that results of the PH-stratified analysis be interpreted cautiously because the subset of patients with PH was inadequately powered to examine all end points.

Generalizability may also be limited to patients with IPF with minimal or absent honeycombing.

"This is the largest and longest clinical trial published with ambrisentan and the third published clinical trial of an [endothelin A receptor] for the treatment of IPF to date," Dr. Macas Saint-Gerons said. "IPF was well characterized and the stratified randomization of pulmonary hypertension at baseline resulted in well-balanced groups and avoided a possible effect modification on IPF outcomes."

Dr. Macas Saint-Gerons, who was not involved in the current trial, recommended additional research and vigilance regarding other uses of ambrisentan.

"Pulmonary hypertension is a recognized comorbid condition of IPF," he concluded. "These results raise safety concerns for ambrisentan beyond IPF, especially in the long-term use of the drug."

This study was supported by Gilead Sciences Inc. Dr. Raghu has reported receiving a grant from the University of Washington; consulting and travel fees from Gilead Sciences; travel fees from InterMune-EU; consulting fees from Actelion, Boehringer-Ingelheim, Bayer, Centocor (Johnson & Johnson), Stromedix (Biogen), Takeda, Sanofi, and Fibrogen; fees from the US Department of Justice for acting as an expert witness; and grants from the National Institutes of Health. Full disclosure information is available on the journal's Web site. Dr. Macas Saint-Gerons has disclosed no relevant financial relationships.

Ann Intern Med. 2013;158:641-649. Abstract

Elementary-school-aged children who spend more time playing outdoors are less likely to develop myopia than their peers who sometimes prefer to stay indoors during school recesses, according to a report by Taiwanese researchers published in the May issue of the journal Ophthalmology.

In a separate article published in the same issue, researchers who studied myopic children in Denmark found that seasonal changes in the mean number of daylight hours correlated significantly with 3 indicators of myopia progression: eye elongation (P = .00), myopia progression (P = .01), and corneal power change (P = .00). The figures increased in winter, when daylight is present for about 7 hours in Denmark, the study reports. During the 17.5hour days of summer, myopic progression still occurred, but the increases were not as large, the report said. The 2 studies are part of a worldwide boom in myopia research that has occurred during the last decade. The research began with the aim of illuminating the causes of large increases in prevalence of this refractive disorder during the second half of the 20th century. Myopia prevalence has increased in the United States from 25% in 1971-1972 to 41.6% in 1999-2004, according to a 2009 report from scientists at the National Eye Institute. However, the prevalence has increased even more dramatically in Asia. "Myopia has become very high in the last 30 years in Taiwan. It is a very severe public health problem," explained lead author Pei-Chang Wu, MD, PhD, in an interview with Medscape Medical News. "Ninety percent of college students in Taiwan have myopia. But in previous generations, the prevalence was about 10%." Dr. Wu is director of ophthalmology at the Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan. In the comparative, 1-year study Dr. Wu and colleagues performed autorefractions and measured axial length in 571 students at 2 elementary schools in a suburban area and collected other data on the children and their families via a parent questionnaire. The myopia prevalence in the 7- to 11year-old children was nearly 50% at both schools.

After baseline measurements, one school began a simple intervention with its students (n = 333): They turned off classroom lights and encouraged children go outdoors during their 80 minutes of recess from class each day (6.7 hours per week). In the control school, there were no special recess programs, and children were allowed to stay indoors during recess periods. Both groups had 2 hours of outdoor physical education per week. At the end of a year, the researchers retested the children's eyes. The measurements showed significantly fewer new cases of myopia in the test group (8.41% vs 17.65%; P < .001). There also was less myopic shift in the intervention group (0.25 D/year vs 0.38 D/year; P = .029). Bright, Natural Light Needed These outcomes demonstrate how small changes might be able to expose children to the bright, natural light that their eyes apparently need to grow normally, Dr. Wu told Medscape Medical News. "Kids spend a lot of time in school. Therefore, if the educational design could change a little bit, we might get a change in myopia prevalence," he concluded. In the Danish study, investigators looked for correlations between a surrogate measure of daylight exposure (the total number of daylight hours during winter and summer periods of 6 months each) and myopic progression in 235 myopic children between 8 and 14 years of age. The scientists confirmed that lower total hours of daylight correlated with higher numbers in the 3 parameters they tested, and vice versa. With an average of 1681 hours of daylight over the course of 6 months, axial eye growth was a mean 0.19 0.10 mm, myopia progression was 0.32 0.27 D, and the corneal power change was 0.04 0.08 D. This compared with axial eye growth of 0.12 0.09 mm, myopia progression of 0.26 0.27 D, and corneal power change of 0.05 0.10 D during summer with 2782 hours of daylight.

Dongmei Cui, MD, PhD, the study's first author and an associated professor of ophthalmology at State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Peoples Republic of China, says it still is not clear what the light is actually triggering in the eye to arrest growth. However, it is not too early for parents of children with myopia to heed the common underlying message of the 2 studies. "I suggest the parents make sure their children spend an adequate amount of time in outdoor activities," she said. Kate Johnson, BAppSc(Optom)Hons, GradCertOcTher, a Brisbane, Australia, optometrist who fits myopic children with orthokeratology contact lenses because of recent research indicating that they slow down progression, said she routinely asks parents about their children's myopia risk factors, including how much time they spend on outdoor activities. "If they spend all their time on an iPad, if they spend spent less than 1.5 hours outside every day, they're at risk," she said. The Taiwanese study was supported by the Chang Gung Medical Research Project Research Grants from Kaohsiung Chang Gung Memorial Hospital, Taiwan. The Danish study was supported by the National Natural Science Foundation of China and by the Fundamental Research Funds of State Key Laboratory of Ophthalmology, in Guangzhou, People's Republic of China. Dr. Wu, Dr. Ciu and Johnson have disclosed no relevant financial relationships. Mutations in a gene that controls copper metabolism in parts of the eye are linked to the severe, high-grade form of the myopia, according to results from a study published in the May 2 issue of the American Journal of Human Genetics. High-grade myopia, with refractive error exceeding 6.00 D, runs in families and affects approximately 2% of the 33.1% of adults in the United States with

myopia. It is associated with increased risk for retinal detachment, glaucoma, cataracts, and disease of the macula. Khanh-Nhat Tran-Viet, MS, laboratory manager at the Duke Center for Human Genetics in Durham, North Carolina, and colleagues used next-generation exome sequencing of 4 members of an 11-member, 3-generation family of European descent. Nine members of the family have autosomal-dominant, nonsyndromic high-grade myopia, with an average spherical refractive error of 22.00 D. The 4 sequenced exomes shared rare gene variants at 49 loci. The investigators then used Sanger-sequencing to analyze the variants in the other family members, including the remaining 5 affected individuals. The relatives with high-grade myopia share a nonsense mutation in SCO2, a gene that encodes a cytochrome c oxidase assembly protein, which functions in the mitochondrial respiratory chain. Substitution of glutamine with a stop codon at position 53 truncates the protein, eliminating the catalytic domain. The researchers then used polymerase chain reaction sequencing to analyze SCO2 in 140 unrelated cases and found 3 additional mutations. In contrast, the team found no similar mutations in 1000 control DNA samples from nonmyopic individuals. The SCO2 protein normally carries copper in the mitochondria, and its malfunction enables reactive oxygen species to accumulate and damage DNA and ocular tissues. The phenotype affects the retina because of its high energy requirement. Damage to the retina, in turn, alters refractive development, the researchers write. Follow-up studies further implicated the gene. The researchers tracked SCO2 gene expression in relevant structures that contribute to myopia and discovered decreased expression of the gene in eyes made myopic with artificial lenses in mice.

Alternate Guise: Infantile Cardiomyopathy The team's identification of a defect in a copper-binding protein made sense, although they did not set out with any specific candidate genes in mind. "The connection was fortuitous. The literature shows individuals who have copper deficiency tend to become nearsighted, and we found a gene that has to do with copper metabolism," Terri L. Young, MD, MBA, professor of ophthalmology, pediatrics and medicine at the Duke Eye Center and principal investigator, told Medscape Medical News. The finding is consistent with the observation that depriving certain animal models, such as rats, of copper leads to ocular abnormalities. Moreover, compound heterozygotes for missense mutations in the SCO2 gene have fatal infantile cardioencephalomyopathy, a more severe phenotype than that of the individuals with a single nonsense mutation. The cardiomyopathy syndrome includes retinal ganglion neuronal loss and globular distension of the photoreceptors. The infants die too soon to investigate refractive error. The SCO2 gene did not emerge in other studies of causes of high-grade myopia, such as those that identified a zinc finger protein. "[O]ur findings provide evidence that SCO2 may play an important role in eye growth and development, particularly in those who become highly myopic," the researchers conclude. Because the SCO2 form of high-grade myopia may be a very rare subtype, screening for it alone does not make sense, Dr. Young said. "We're developing a panel of genes implicated in syndromic and nonsyndromic myopia," she added, such as screens for the 18 genes that cause Leber congenital amaurosis. She also suggested that copper supplements may help prevent some forms of myopia. The work on this rare genetic subtype of a common condition has broader implications, according to Dennis J. Thiele, PhD, George Barth Geller professor in the Department of Pharmacology and Cancer Biology at Duke

University, who was not part of the study. "It clearly implicates copper homeostasis in myopia and suggests that in the absence of mutations, dietary copper deficiency could be in part responsible for myopia," he told Medscape Medical News. He cautioned that although copper is an essential micronutrient, too much is toxic. Shalom Kieval, MD, associate clinical professor of ophthalmology at Albany Medical College in New York, places the work in perspective. "Myopia development is a complex process that emerges from the interplay of both genetic and environmental factors," he said, citing recent work suggesting that lack of sunlight contributes to myopia in children. "As we deepen our understanding of the mechanisms that induce myopia, we can expect to develop clinical and public health interventions to reduce the great social and economic burden of the disease," he added. This research was funded by the National Institutes of Health, the Lew Wasserman Award from Research to Prevent Blindness, and a DukeNational University of Singapore core grant. One coauthor was supported by the Toulouse Hospital Young Researcher Fellowship, the Fondation pour la Recherche Mdicale, and Fondation de France. The animal model experiments were supported by the National Medical Research Council of Singapore. The commentators have disclosed no relevant financial relationships.
Adults with amblyopia who played a video game binocularly and under conditions that reduced the visual stimulus to their better-seeing eye showed gains in stereopsis and in visual acuity (VA, logMAR units) in the amblyopic eye. The researchers saw much smaller improvements in participants who played the game monocularly. In an article published in the April 22 issue of Current Biology, an international research group led by Jinrong Li, MD, PhD, from the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China, reports that after 10 hours of dichoptic training with the video game Tetris, stereopsis improved by a factor of 4 (P = .03); monocular training, in which the participants had 1 eye patched, had little effect.

After 8 weeks of training, VA in the amblyopic eyes improved from a mean of 0.51 logMAR (standard deviation [SD], 0.09) to 0.34 logMAR (SD, 0.09; P < .001) in the dichoptic group. Monocular play of the game resulted in minimal change in the mean VA, which went from 0.52 logMAR (SD, 0.09) to 0.48 (SD, 0.09; P < .05). When the participants in the control group switched to binocular game playing for an additional 8 weeks, the investigators saw improvements similar to those initially assigned to binocular play (from a mean baseline of 0.48 logMAR [SD, 0.09] to a postintervention mean of 0.3 [0.11] logMAR). These results indicate that even in adults, the brain's plasticity enables it to learn how to blend competing images from both eyes into a single view, the researchers conclude. In addition, they note, the study supports an emerging view that amblyopic eyes cannot learn to see because signals to the visual cortex are suppressed by the contralateral eye. This explanation of amblyopia's underlying neurobiology challenges the conventional view of amblyopic eyes as "lazy" eyes that must be forced to work, study coauthor Robert F. Hess, DSc, told Medscape Medical News. The study has caught the interest of the Pediatric Eye Disease Investigator Group, which currently is planning a multicenter clinical trial of dichoptic video game playing as a treatment for children with amblyopia. Dr. Hess is helping with the trial design. "We've said the main problem is the 2 eyes don't work together," explained Dr. Hess, who directs the Research Department of Ophthalmology at the Research Institute of the McGill University Health Centre in Montreal, Canada. "We believe that the reason why the eye isn't working is not because it's lazy, but because it's actively inhibited by the fellow, sighted eye." In the current study, 18 adult participants used special video-display goggles to play the video game Tetris for 10 hours, 1 hour per session, over the course of 2 weeks. The researchers rigged the goggles so that in the dichoptic group (n = 9), both eyes saw different, complementary images. One eye saw colorful squares falling across the display, and the other eye viewed stacks of squares at the bottom. However, the image sent to the better-seeing eye was low-contrast,

and the amblyopic eye's image was 100% contrast. "[The participants] can really succeed only if the information is combined between the 2 eyes," Dr. Hess said. Other versions of the test system use a special screen filter to create the dichoptic video display on a handheld iPod Touch or an iPad, Dr. Hess said. "This is a very promising new approach to treating amblyopia, because it doesn't involve patching the fellow eye or atropine drops to the fellow eye," Jonathan M. Holmes, MD, professor of ophthalmology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. Dr. Holmes is also network chair of the Pediatric Eye Disease Investigator Group, a North American coalition of university-based and community pediatric ophthalmologists that has sponsored large interventional clinical trials of treatments for amblyopia for more than a decade. "The Pediatric Eye Disease Investigator Group is now working with Dr. Hess to design a large multicenter randomized clinical trial to further evaluate the effectiveness of this new binocular treatment for decreased visual acuity caused by amblyopia," Dr. Holmes added. The study was funded by national research grants in Canada, China, and New Zealand and by a Thrasher Research grant to Dr. Li. Dr. Hess and a coauthor are listed as inventors on a patent owned by McGill University, and they might receive financial compensation if commercialization occurs. Dr. Holmes has received unrestricted grants from Research to Prevent Blindness; his work with the Pediatric Eye Disease Investigator Group is funded by the National Eye Institute. Curr Biol. 2013;23:R308-R309. Abstract

Cataract surgery yields excellent visual outcomes for the majority (61.3%) of patients, according to results from a large database study. The greatest influence on visual outcome was found to be short-term postoperative complications, ocular comorbidity, surgical complications, and complex surgery. Age and sex also influenced visual outcomes.

Mats Lundstrom, MD, PhD, from Lund University in Sweden, and colleagues published the results of the study in the May issue of the Journal of Cataract & Refractive Surgery. The data (some self-reported) were drawn from the European Registry of Quality Outcomes for Cataract and Refractive Surgery. The multinational database included information on 368,256 cataract extractions. The authors found that 94.3% of patients achieved a postoperative corrected distance visual acuity (CDVA) of 0.5 (20/40) or better, and 61.3% had CDVA of 1.0 (20/20) or better. Even patients who experienced less-than-ideal results usually experienced a visual improvement after surgery. However, the researchers did find 5.7% of patients whose vision was unchanged after surgery and 1.7% of patients who experienced worse CDVA after surgery. The investigators also found that patients with an ocular comorbidity were most likely to experience a CDVA that was less than 0.5 (odds ratio, 3.8). The conditions that were most likely to require a complex surgery were also those that were most likely to compromise surgical outcomes. "Some clinics use a risk scoring before surgery. In such a scoring system, a brown cataract, pseudoexfoliation, miosis, high age, etc, give [a] higher score...which means need for an experienced surgeon," explained Dr. Lundstrom in an email interview with Medscape Medical News. This approach might help in matching complex surgeries with the appropriate surgeon. Although surgical complications did demonstrate a weak contribution to surgical outcomes, postoperative complications were more likely to predict a worse postoperative CDVA than that seen before surgery. The study also revealed another, surprising, predictor of outcome: preoperative CDVA. Dr. Lundstrom described the take-home message for physicians: "In general terms, the outcome is very good. However, if the preoperative visual acuity is very good, there is a risk for poorer vision after surgery. This is obvious if we study patients with a preoperative visual acuity of 1.0 (20/20). [In particular,]

patients with good preoperative visual acuity and an ocular comorbidity in the surgery eye have a high risk for deterioration after surgery." Dr. Lundstrom noted that he was surprised to discover that patients with good preoperative vision and previous corneal refractive surgery were likely to have a poor outcome after a cataract extraction. Rishi P. Singh, MD, from the Cole Eye Institute of the Cleveland Clinic in Ohio, was also surprised to read about the outcomes for patients with 20/20 vision but thought the rest of the results were more expected. "The study validates that cataract surgery outcomes are quite good for the majority of patients. The risk factors for poorer outcomes are consistent with previous studies and thoughts," he told Medscape Medical News in an email interview. Dr. Singh, who was not involved in the study, also described some of the limitations of the study, explaining that it relied on a registry that did not have mandatory participation. Therefore, it is possible that bad surgeons would not participate. Dr. Singh also felt that the study provides a local view of the European Union and that it would be difficult to extrapolate the results to the rest of the world. The authors and Dr. Singh have disclosed no relevant financial relationships. BOSTON, Massachusetts What most assume is common practice screening 3-, 4-, and 5-year-old children for vision problems is not universal, a new study reveals. To get an accurate snapshot of preschool vision screening, Suzanne Johnston, MD, from Boston Children's Hospital in Massachusetts, and her team randomly selected the charts of 450 children from an electronic medical record system used by 72 private pediatrician practices in Massachusetts. Overall, 63% of children had undergone visual acuity screening and 38% had undergone stereovision testing, Dr. Johnston toldMedscape Medical

News here at the American Association for Pediatric Ophthalmology and Strabismus 39th Annual Meeting. Pediatrician practices are not equally adept at vision screening. "We found a statistically significant difference; larger practices tend to do a better job than smaller practices," she reported. The researchers also found that patient age plays a significant role. When they compared 3 age groups (n = 150 each), older children were more likely to undergo amblyopia screening. "Older children are generally more cooperative than younger children. A 3-year-old, for example, might have a harder time sitting still for testing," Dr. Johnston explained. Table. Visual Acuity Screening by Practice Size and Age Group
Variable Practice size* Small (1 or 2 physicians) Medium (3 to 5 physicians) Large (6 or more physicians) Age group* 3 years 4 years 5 years
*P < .0001

Proportion Screened, %

41.4 60.5 76.8

42.2 70.5 77.2

Once a potential visual problem is identified, is that child getting referred? "My general impression is that referrals are low," said Dr. Johnston. The researchers found that for children who failed any portion of the vision test or for whom there was no documentation of a completely normal visual acuity and stereovision test, only 11.3% had evidence of a referral to an ophthalmologist or optometrist.

"It is not surprising that a higher percentage of the older preschoolers were screened because it is much easier to test these children. The percentage of children receiving a screening was decent, considering that repeat screenings are offered throughout childhood," said Katherine Lee, MD, a pediatric ophthalmologist at St. Luke's Children's Hospital in Boise, Idaho, who was asked by Medscape Medical News to comment on the findings. Dr. Lee, who took interested attendees on a guided poster tour during the meeting, added that "the percentage of children who had evidence of referral following failed or missed screening was poor. This is certainly an area in need of attention in screening programs." Dr. Johnston agrees, and noted that future research should examine the rate of follow-through with referrals. She added that although this study was retrospective all participants were screened during well-child visits in 2010 one of its strengths is the large number of patients and practices. The private practices participating in the study are all members of the Pediatric Physicians' Organization, which is affiliated with Boston Children's Hospital. The ramifications of this research likely go beyond providing a snapshot of current screening prevalence, Dr. Johnston noted. "The practices involved have shown an interest in using these data to improve their vision screening, and data can provide an impetus to change practice.... It is satisfying that [the results] will have a practical effect." This study was funded by a Prevention of Blindness Grant sponsored by the Maternal & Child Health Bureau, the US Department of Health and Human Services. Dr. Johnston and Dr. Lee have disclosed no relevant financial relationships. American Association for Pediatric Ophthalmology and Strabismus (AAPOS) 39th Annual Meeting: Abstract 81. Presented April 6, 2013.

SEATTLE, Washington Antioxidant and omega-3 supplements do not reduce the risk for advanced macular degeneration, according to results from the highly anticipated AgeRelated Eye Disease Study (AREDS2). Although the primary results are disappointing, important clinical messages emerged during its presentation here at the Association for Research in Vision and Ophthalmology 2013 Annual Meeting. The results were published online May 5 in theJAMA: The Journal of the American Medical Association to coincide with their presentation. The new data point to ways to change the nutritional formulation from the initial AREDS trial to reduce potential risks without sacrificing benefit for people at high risk for advanced agerelated macular degeneration (Arch Ophthalmol.2001;119:1417-1436). "AREDS resulted in a formulation of vitamin C, beta carotene, zinc, and vitamin E that reduced the risk of progression of advanced disease by 25%" at 5 years, Emily Chew, MD, from the National Eye Institute in Bethesda, Maryland, told Medscape Medical News. "We wanted to see if we could tweak it a bit by adding components to it." Bolstered by promising evidence from animal and observational studies, Dr. Chew and her team sought to determine if the addition of the carotenoids lutein and zeaxanthin and/or the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) could further forestall progression to advanced macular degeneration. It didn't work. "In the overall analysis, using 3 treatment groups, we found no significant difference in rates of macular degeneration," Dr. Chew said. In fact, risk was not significantly reduced with any treatment, compared with placebo (hazard ratio [HR], 0.90; 98.7% confidence interval [CI], 0.76 - 1.07;P = .04), over a median of 4.9 years of follow-up. A total 4203 participants were randomized to placebo with no additional supplementation or to 1 of 3 treatment groups. The first group received a tablet of 10 mg lutein plus 2 mg zeaxanthin both antioxidants found in green leafy vegetables. The second group received a gel cap with 350 mg DHA plus 650 mg EPA. The third group received both the tablet and gel cap on a daily basis. Risk for Advanced Age-Related Macular Degeneration

Treatment Group Placebo (n = 1012) Antioxidants (n = 1044) Omega-3 fatty acids (n = 1068) Both supplements (n = 1079)

5-Year Progression (%) 31 29 31 30

Reduced Risk (Hazard Ratio) 0.90 0.97 0.89

When asked by Medscape Medical News to comment on the findings, Abdhish Bhavsar, MD, said, "I was quite surprised to see that AREDS2 did not show any difference between the primary outcome treatment groups. However, the study involved a very complex clinical trial design and tried to answer some difficult questions on lutein plus zeaxanthin and DHA plus EPA." Dr. Bhavsar, a retinal surgeon, is director of clinical research at the Retina Center in Minneapolis, Minnesota, and national clinical spokesperson for the American Academy of Ophthalmology. Although no significant additional overall benefit emerged, a subanalysis showed that lutein plus zeaxanthin supplementation might help some patients. When stratified by dietary intake of these antioxidants at baseline, participants in the lowest quintile who took the supplements showed a 26% risk reduction against progression to advanced macular degeneration (HR, 0.74; 95% CI, 0.59 - 0.94; P = .01). "That is not exactly small," Dr. Chew said. "People who are not eating enough show a benefit." Silver Lining Another secondary analysis of the data yielded a 10% risk reduction in progression to advanced macular degeneration in patients who took lutein plus zeaxanthin, compared with those who did not. "So this appeares to have an effect," Dr. Chew said. "Secondary-level analyses seem to point in the direction that lutein and zeaxanthin are associated with a reduction in progression to advanced and neovascular age-related macular

degeneration," Dr. Bhavsar said. "Thus, at the present time although based on secondary analyses it seems that the best medical evidence points to considering lutein and zeaxanthin in addition to the AREDS formula."

The best medical evidence points to considering lutein and zeaxanthin in addition to the AREDS formula.
The researchers also performed a secondary randomization of 3036 participants to evaluate refinements in the initial formulation specifically, daily supplementation with lower zinc levels, without beta carotene, or both. Dr. Chew and colleagues responded to concerns from nutritionists that the amount of zinc in AREDS exceeds the absorbable amount. They assessed the potential removal of beta carotene to reduce the risk for lung cancer in smokers that has been seen in other randomized controlled trials (J Natl Cancer Inst. 1996;88:1550-1559 and Am J Clin Nutr. 1995;62:1427S-1430S). Lowering zinc dose did not significantly alter progression to advanced macular degeneration (HR, 1.06; 95% CI, 0.95 - 1.19; P = .32), nor did the removal of the beta carotene (HR, 1.07; 95% CI, 0.94 - 1.20;P = .31). A recommendation to change the zinc dose, therefore, was not made based on the findings. For this reason, smokers were randomized to 1 of 2 formulations without beta carotene in AREDS2. In the second randomization component of AREDS2, more lung cancers still occurred in the beta carotene group than in the no beta carotene group (2.0% vs 0.9%). The vast majority of participants (91%) who developed lung cancer were former smokers, "so former smokers are at risk for lung cancer with beta carotene," Dr. Chew said. "The bottom line is that we have enough data to suggest we can remove the beta carotene in the AREDS formulation and substitute it with the lutein and zeaxanthin," she pointed out. "This way there is one formulation for people to take whether they have ever smoked or not." Researchers enrolled participants in AREDS2 from October 2006 to September 2008 at 82 clinical sites. All were 50 to 85 years of age (mean, 73 years) and at high risk for progression

to advanced macular degeneration because of bilateral large drusen or large drusen in one eye and advanced macular degeneration in the other. Low rates of loss to follow-up (3%) and good adherence to the treatment regimen are strengths of the study. Generalizability of results is a potential limitation, as is the inability to determine if the null findings are attributable to lack of efficacy of the supplements, inadequate dose, inadequate duration, or a combination of these. This study was supported by the National Institutes of Health. Dr. Chew and Dr. Bhavsar have disclosed no relevant financial relationships. JAMA. Published online May 5, 2013. Abstract Association for Research in Vision and Ophthalmology 2013 Annual Meeting. Presented May 5, 2013.

LES DYSLIPIDEMIES
valuation plus fine du risque cardiovasculaire, abaissement des objectifs thrapeutiques de LDL-cholestrol : les dernires recommandations europennes font voluer la prise en charge des dyslipidmies. Selon des donnes 2006-2007, une dyslipidmie est retrouve chez 48 % de la population adulte de 35 64 ans (1). L'hypercholestrolmie est la dyslipidmie la plus frquente : elle concerne 36,9 % des adultes, soit 9,1 millions de personnes. Le profil le plus frquent est l'hypercholestrolmie pure (27,5 %). La seconde anomalie est l'hypercholestrolmie associe une hypo-HDL-cholestrolmie, suivie par lhyperlipidmie mixte. Lhypertriglycridmie pure est observe chez 2,4% des patients. Les dernires recommandations conjointes de la Socit europenne de cardiologie (ESC) et de la Socit europenne d'athrosclrose (EAS) (2) font le point sur les rcentes volutions de la prise en charge.

LE BILAN LIPIDIQUE Pour qui

- Les recommandations europennes prconisent, dans le cadre du dpistage des facteurs de risque cardiovasculaire en population gnrale, de prescrire un bilan lipidique partir de 40 ans chez l'homme et 50 ans chez la femme. - Certaines situations ncessitent de dpister une dyslipidmie indpendamment de l'ge. C'est le cas des patients prsentant une maladie cardiovasculaire tablie ou un diabte de type 2. galement en cas d'antcdents familiaux de maladie cardiovasculaire prcoce, de dyslipidmie familiale, d'hypertension artrielle, de tabagisme, d'obsit (IMC 30 kg/m2) ou d'obsit abdomin ale (tour de taille 94 cm chez l'homme ou 80 cm chez la femme), de maladie rnale chronique. Enfin,

l'existence d'une pathologie inflammatoire chronique auto-immune (polyarthrite rhumatode, lupus rythmateux) ou la prise d'un traitement antiviral ncessitent de connatre le profil lipidique du patient.

Quoi mesurer
- Le bilan repose sur le dosage du cholestrol total (CT), des triglycrides, du HDL -cholestrol (HDLC), et sur le calcul du LDL-cholestrol (LDL-C). Celui-ci est obtenu grce la formule de Friedwald, sous rserve que les triglycrides soient infrieurs 4 g/l (ou &lt; 4,5 mmol/l). Le prlvement sanguin doit tre ralis aprs 12 heures de jene, mais cette prcaution ne vaut en ralit que pour le dosage des triglycrides (donc pour le calcul du LDL-C). Stricto sensu, les dosages du cholestrol total et du HDL-C peuvent tre faits alors que le patient n'est pas jeun. Lorsque les triglycrides sont trop levs pour calculer de faon fiable le LDL-C, le dosage direct de celui-ci est possible. Il est dsormais disponible dans la plupart des laboratoires, mais son utilisation est rserve la seconde intention. - Une alternative consiste doser les apolipoprotines A1 et B (apo A1 et B). L'apo A1 est la principale apolipoprotine des lipoprotines HDL, tandis que l'apo B est la protine majoritaire des lipoprotines LDL et VLDL. La HAS considre que ces deux mesures ne sont pas justifies pour la prise en charge des dyslipidmies courantes (3). Elle rserve leur utilisation de rares situations, toujours en seconde intention aprs une premire exploration lipidique, en cas de dyslipidmie complexe ou de dyslipidmie d'origine gntique, et lorsque le HDL-C est infrieur 0,30 g/l (non fiable pour dterminer l'apo A1) ou les triglycrides trop levs pour permettre le calcul du LDL-C. Les recommandations europennes (2) soulignent de leur ct le bnfice du dosage de l'apo B en cas de dyslipidmie mixte, de diabte, de syndrome mtabolique ou de maladie rnale chronique, et prsentent le rapport apo B / apo A1 comme une mthode alternative au bilan lipidique usuel. Pour le Pr Bruckert, " les renseignements fournis par le dosage des apolipoprotines A1 et B sont aussi pertinents que ceux obtenus par l'exploration classique, mais on se heurte en pratique au problme de l'absence de standardisation des taux dapolipoprotines. Et malgr des progrs cet gard, il est prfrable pour l'heure de s'en tenir au bilan standard des recommandations franaises " . - Une autre option consiste doser le non-HDL-cholestrol (CT HDL-C). "Il tient compte de l'ensemble des lipoprotines athrognes (VLDL + LDL + IDL [intermediate-density lipoprotein]), et donne une meilleure estimation du risque cardiovasculaire, notamment chez les sujets hypertriglycridmiques. Mais l encore, l'utilisation de cette variable n'est pas entre dans les habitudes et n'a pas sa place en premire intention".

L'EVALUATION DU RISQUE CARDIOVASCULAIRE GLOBAL

- La prise en charge dbute toujours par l'valuation du risque card iovasculaire global. L'ESC et l'EAS prconisent le recours au modle de risque SCORE (Systemic Coronary Risk Estimation), qui estime la probabilit de survenue 10 ans d'un premier vnement cardiovasculaire fatal (infarctus du myocarde, accident vasculaire crbral, mort subite d'origine cardiaque) (2). "En pratique clinique, l'valuation du risque peut toujours tre ralise par la mthode de sommation des risques propose par l'Afssaps en 2005 (4). Mais certains patients, notamment ceux entre 50 et 70 ans ayant au moins un facteur de risque autre que la dyslipidmie, atteignent trs rapidement un haut niveau de risque

cardiovasculaire. Afin de ne pas ngliger cette ventualit, un calcul plus prcis du risque est ncessaire, ce qui lgitime l'utilisation du systme SCORE." Rappelons que les facteurs de risque lists par l'Afssaps sont l'ge (homme de 50 ans ou plus, femme de 60 ans ou plus), les antcdents familiaux de maladie coronaire prcoce, le tabagisme actuel ou arrt depuis moins de 3 ans l'hypertension artrielle traite ou non, le diabte de type 2 trait ou non, et un HDL-cholestrol &lt; 0, 40 g/l quel que soit le sexe. Un HDL-C suprieur 0,60 g/l est considr comme un facteur protecteur. - Certains sujets sont d'emble considrs comme tant haut ou trs haut risque cardiovasculaire : sujets ayant une maladie cardiovasculaire connue, diabte de type 2 ou diabte de type 1 avec microalbuminurie, maladie rnale chronique avec dbit de filtration glomrulaire infrieur 60 ml/min/1,73 m2, risque calcul selon SCORE 10 %, cumul de facteurs de risque cardiovasculaire un niveau lev (2). Pour ces patients, lutilisation de la grille SCORE est inutile. - Pour tous les autres sujets, le systme SCORE tient compte de la prsence de c ertains facteurs de risque et de leur valeur (voir figure 1). On distingue d'abord les pays bas risque cardiovasculaire (Belgique, France, Grce, Italie, Luxembourg, Espagne, Suisse, Portugal), et les pays haut risque cardiovasculaire (autres rgions europennes). Les autres variables prendre en compte sont l'ge ( partir de 40 ans), le sexe, le tabagisme, la pression artrielle systolique et le cholestrol total, auxquelles s'ajoute, dans cette dernire version des recommandations europennes, le HDL-cholestrol. Quatre groupes de HDL-C ont t dfinis, selon que la variable est gale 0,8 mmol/l (~ 0,30 g/l), 1 mmol/l (~ 0,40 g/l), 1,4 mmol/l (~ 0,54 g/l) ou 1,8 mmol/l (~ 0,70 g/l). Le niveau de HDL-C modifie en effet de faon importante le niveau de risque cardiovasculaire (voir exemples figures 1, 2 et 3). L'existence d'antcdents familiaux prcoces de maladie cardiovasculaire n'apparat pas dans les grilles, mais dans ce cas, le rsultat obtenu doit tre multipli par 1,7 chez la femme et 2 chez l'homme. - Quatre niveaux de risque sont dfinis : 1) Le trs haut risque cardiovasculaire ( 10%) ; 2) Le haut risque, qui regroupe les sujets ayant des facteurs de risque majeurs ou particulirement levs (hypercholestrolmie familiale, HTA svre) et ceux dont le score se situe entre 5 et 10 % ; 3) Le niveau de risque modr, qui concerne les patients dont le score est compris entre 1 et 5 % ; 4) Le bas risque, qui regroupe les sujets dont le score est infrieur 1 % (2). L'hypertriglycridmie quant elle constitue un facteur de risque indpendant, mais dont le poids reste modeste."Cependant, les sujets hypertriglycridmiques cumulent volontiers d'autres facteurs de risque : HDL-C bas, obsit abdominale, diabte, HTA. Ce qui explique qu'ils soient souvent haut risque cardiovasculaire, en dpit du faible niveau de risque confr par l'hypertriglycridmie" .

QUI TRAITER
- Seuls les sujets faible risque cardiovasculaire et dont le LDL -C initial est infrieur 1,0 g/l se voient dispenss de prise en charge.

- Dans tous les autres cas, les mesures hygino-dittiques font partie du traitement, constituant parfois le seul mode d'intervention. - S'agissant du traitement pharmacologique, tous les patients trs haut risq ue doivent recevoir un hypolipmiant ds lors que le LDL-C excde 0,70 g/l. Mme chose pour les sujets haut risque lorsque le LDL-C dpasse 1,0 g/l. Lorsque le risque est modr ou faible, le traitement pharmacologique n'est envisag que lorsque la valeur cible de LDL-C n'est pas atteinte par les seules mesures hygino-dittiques.

QUEL TRAITEMENT PROPOSER Les valeurs cibles

- La prise en charge reste essentiellement axe sur la baisse du LDL-C. Chaque diminution de 0,40 g/l de ce paramtre est associe une rduction de 22 % de la morbi-mortalit cardiovasculaire. Pour les patients trs haut risque cardiovasculaire, notamment en prvention secondaire et chez les sujets diabtiques, le LDL-C doit tre abaiss en dessous de 0,70 g/l (suprieur 1,8 mmol/l) ou rduit de 50 % par rapport au taux initial sans traitement pharmacologique (si la cible de 0,70 g/l ne peut tre atteinte). Pour la catgorie du haut risque cardiovasculaire, le LDL-C doit tre infrieur 1,0 g/l (suprieur 2,5 mmol/l). Lorsque le risque cardiovasculaire est modr, l'objectif est infrieur 1,15 g/l (suprieur 3,0 mmol/l). - Les valeurs cibles proposes dans les recommandations europennes sont donc globalement infrieures aux objectifs fixs par l'Afssaps en 2005 (ceux-ci allaient de 2,20 g/l en l'absence de facteur de risque associ la dyslipidmie moins d'1 g/l en prvention secondaire, en passant par les valeurs 1,90 g/l, 1,60 g/l et 1,30 g/l). Ce sont les valeurs europennes qui dsormais doivent tre retenues, explique le Pr Bruckert. Cela dit, la discordance entre les textes europen et franais n'est qu'apparente, le seuil de 0,70 g/l pour les sujets trs haut risque cardiovasculaire tant dj prsent comme une option par les recommandations franaises. La diffrence est plus marque lorsqu'on considre les patients risque modr, l'objectif de 1,15 g/l tant relativement exigeant. cet gard, il serait souhaitable d'engager le dbat en France, afin de dfinir les priorits pour cette catgorie de ris que. Quoi quil en soit, l'objectif majeur commun toutes les recommandations reste bien de reprer et de prendre en charge les patients haut et trs haut risque cardiovasculaire, pour lesquels les valeurs de 0,70 g/l et 1,0 g/l constituent dsormais la rfrence. noter que l'objectif de rduction de 50 % du LDL-C en cas de trs haut risque cardiovasculaire a t instaur pour protger les patients des ventuels effets secondaires des associations d'hypolipmiants, souvent ncessaires dans ce contexte. Chez ces patients dont le LDL-C initial est souvent lev, on considre alors que si l'objectif de 0,70 g/l de LDL-C n'est pas atteint en dpit d'une bi- voire trithrapie hypolipmiante et malgr des mesures hygino-dittiques adaptes, il est raisonnable de se contenter d'une baisse de 50 % du taux initial de LDL-C. - Pour le HDL-C et les triglycrides, aucune cible prcise n'a t dtermine. On considre que la triglycridmie jeun doit tre infrieure 1,50 g/l.

En ce qui concerne l'apo B, l'objectif thrapeutique est infrieur 0,80 g/l pour les sujets trs haut risque cardiovasculaire, et infrieur 1 g/l pour la catgorie du haut risque (2).

L'importance de l'hygine de vie

Les mesures hygino-dittiques font systmatiquement partie du traitement, que le patient prenne ou non un traitement pharmacologique. La rduction des taux sriques de cholestrol total et de LDL-C peut tre obtenue par une diminution de la consommation d'acides gras saturs et d'acides gras trans, et par la consommation de fibres et de phytostrols. Les mesures les plus efficaces sur la baisse des triglycrides sont la rduction pondrale, la rduction de la consommation d'alcool et de sucres, ainsi que la lutte contre la sdentarit. La supplmentation en acides gras omga 3 est galement cite par les guidelines europens. Enfin, l'augmentation du niveau d'activit physique, la rduction pondrale et la diminution des apports en graisses saturs et en sucres se sont montrs efficaces pour augmenter le HDL-C.

Le choix du traitement pharmacologique

- Lorsqu'un traitement mdicamenteux est envisag, il convient d'abord de dterminer de combien l'on souhaite rduire le LDL-C, en prenant comme objectifs les valeurs cibles recommandes ( voir tableau 1). De l'importance de cette rduction dpend le bnfice du traitement. - Les statines sont les molcules de choix pour abaisser le LDL-C. Une fois dtermin le degr souhait de rduction du LDL-C, le choix de la statine dpend de la puissance respective de chaque molcule. Cinq statines sont disponibles en France : - Atorvastatine, - Fluvastatine, - Pravastatine, - Rosuvastatine, - Simvastatine. La HAS a rcemment mis des conclusions (1) relatives au choix de la statine la plus efficiente dans chaque situation (le critre defficience prend en compte le bnfice d'un produit de sant et les ressources ncessaires l'obtention de ce bnfice) ( voir tableau 2). "Si l'objectif n'est pas atteint avec une premire statine, les habitudes de prescription nous conduisent augmenter la dose ou passer une autre statine, avant d'envisager une bithrapie". - Concernant les effets secondaires des statines, l'lvation des CPK est tolre jusqu' 5 fois la valeur normale. S'il existe des myalgies sans lvation des CPK et si les symptmes sont tolrables, le traitement peut tre poursuivi. Si les symptmes ne sont pas tolrables ou s'aggravent, il doit tre arrt (2). L'lvation des transaminases hpatiques est tolre jusqu' 3 fois la valeur normale. Enfin, des donnes rcentes confirment l'lvation de l'incidence du diabte sous statine. "Il existe une augmentation du risque de diabte sous statine de 9 % versus placebo, et une lvation additive de

12 % quand on compare les doses usuelles de statines aux doses les plus fortes. Pour autant, ceci ne remet pas en cause la stratgie thrapeutique face une dyslipidmie". - Les molcules recommandes en premire intention en cas d'hypertriglycridmie sont les fibrates. Parmi les autres molcules hypolipmiantes, l'ztimibe (inhibiteur de l'absorption intestinale du cholestrol) est indiqu notamment en association avec une statine lorsque la baisse du LDL-C est insuffisante sous statine seule, ou bien en monothrapie en cas d'intolrance aux statines. On dispose galement des rsines changeuses d'ions et de l'acide nicotinique, mais qui posent tous deux des problmes de tolrance. Dr Pascale Naudin-Rousselle (rdactrice, fmc@legeneraliste.fr) sous la responsabilit scientifique du Pr Eric Bruckert (Service dEndocrinologie-Mtabolisme Hpital La PitiSalptrire, 47-83 bd de l'Hpital, 75 013 Paris ; courriel : eric.bruckert@psl.aphp.fr)