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Rodríguez Villa, M.J. Ruiz Rodríguez, M. Vargas Pabón" "autores" => array:3 [ 0 => array:2 [ "nombre" => "S." "apellidos" => "Rodríguez Villa" ] 1 => array:2 [ "nombre" => "M.J." "apellidos" => "Ruiz Rodríguez" ] 2 => array:2 [ "nombre" => "M." 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Díaz-Rodríguez, R. Abreu-González, R. Dolz-Marco, R. Gallego-Pinazo" "autores" => array:4 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Díaz-Rodríguez" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Abreu-González" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "Dolz-Marco" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Gallego-Pinazo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669116302350" "doi" => "10.1016/j.oftal.2016.11.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365669116302350?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579417300579?idApp=UINPBA00004N" "url" => "/21735794/0000009200000007/v1_201706250033/S2173579417300579/v1_201706250033/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Bio-environmental factors associated with myopia: An updated review" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "307" "paginaFinal" => "325" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "V. Galvis, A. Tello, P.A. Camacho, M.M. Parra, J. Merayo-Lloves" "autores" => array:5 [ 0 => array:3 [ "nombre" => "V." "apellidos" => "Galvis" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 1 => array:4 [ "nombre" => "A." "apellidos" => "Tello" "email" => array:1 [ 0 => "alejandrotello@gmail.com" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "P.A." "apellidos" => "Camacho" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "M.M." "apellidos" => "Parra" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "J." "apellidos" => "Merayo-Lloves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Centro Oftalmológico Virgilio Galvis, Floridablanca, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Fundación Oftalmológica de Santander FOSCAL, Floridablanca, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Facultad de Salud, Universidad Autónoma de Bucaramanga, Bucaramanga, Colombia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Fundación de Investigación Oftalmológica Fernández-Vega, Oviedo, Asturias, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Los factores bioambientales asociados a la miopía: una revisión actualizada" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In 2011, it was estimated that there were about 1.5 billion myopic people, or 23 per cent of the world's population, which will increase to an estimated 2.5 billion people by the year 2020.<a class="elsevierStyleCrossRefs" href="#bib0960"><span class="elsevierStyleSup">1,2</span></a> Since the late 1950s important genetic factors have been identified and estimates of heritability, that is, the proportion of the phenotypic variation that is attributable to genetic variation for refractive errors in twins is in the range of 75 to 90%.<a class="elsevierStyleCrossRefs" href="#bib0970"><span class="elsevierStyleSup">3–7</span></a> Familial studies have generally produced estimations between 15 and 70%.<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">7</span></a> However, as members of a family frequently share a common environment, said inheritance calculations could be overestimated.<a class="elsevierStyleCrossRefs" href="#bib0990"><span class="elsevierStyleSup">7–9</span></a> On the other hand, the identification of over 40 genetic loci associated to the appearance of myopia supports the genetic contribution to said disease.<a class="elsevierStyleCrossRefs" href="#bib0985"><span class="elsevierStyleSup">6,7,10–12</span></a> In addition, an important predictor of myopia is myopia history in parents<a class="elsevierStyleCrossRefs" href="#bib0995"><span class="elsevierStyleSup">8,13–20</span></a> (Jones LA, Sinnott L, GL Mitchell, et al. <span class="elsevierStyleItalic">How well do parental history and near sighted work predict myopia?</span> E-Abstract # 5452 ARVO, 2006). In a cohort study in Singapore on myopia risk factors (<span class="elsevierStyleItalic">Singapore cohort study of the risk factors for myopia</span>), Saw et al. found that children in school age with both parents being myopic had 1.6 times greater risk of being myopic than children without myopic parents.<a class="elsevierStyleCrossRefs" href="#bib0990"><span class="elsevierStyleSup">7,8,13,21,22</span></a> According to recently published results of the study Growing up in Singapore towards healthy outcomes, Chua et al. pointed out that genetic factors could have a greater contribution to the early development of refractive errors than environmental factors. In multivariate regression models, 3-year-old children with 2 myopic parents had higher probabilities of higher myopic spherical equivalents, longer axial length and greater propensity to myopia than children whose parents were not myopic.<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">23</span></a> However, other researchers explain that, even though said correlations are consistent with the idea of a genetic background for myopia, this background is not definitively established because, as mentioned above, parents and children also share environmental factors.<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">9</span></a> In addition, the influence of parental myopia in refractive error of school children and teenagers is not a universal finding. In 2004, Quek et al. reported in Singapore the absence of a statistically significant difference in the incidence of myopia between students aged 15–19 in accordance with the myopic history of their parents. However, they recognized that a shortcoming of this study was that the parental refractive state was established by interviewing the teenagers instead of their parents.<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">24</span></a> In a study covering three generations of children in Hong Kong and northern China, Wu and Edwards found that the influence of parental history (at least one of the parents being myopic) in the probabilities of having myopia was greater in the second generation, i.e., in the generation of parents, than in the 3<span class="elsevierStyleSup">rd</span> generation, i.e., the generation of the children. This finding supports greater effect of environmental vis-à-vis inheritance factors.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,20</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Current evidence, including experimental studies, seems to support the premise that the development of juvenile myopia is driven both by genetic and environmental factors<a class="elsevierStyleCrossRefs" href="#bib0995"><span class="elsevierStyleSup">8,17,21,25–27</span></a> (Guggenheim JA. <span class="elsevierStyleItalic">Genetic susceptibility to myopia induced by the visual environment</span>. E-Abstract # 5243 ARVO, 2015). However, the mechanisms through which the genes identified as responsible for experimental myopia determine the appearance of refractive error are yet to be defined.<a class="elsevierStyleCrossRefs" href="#bib1040"><span class="elsevierStyleSup">17,25,28</span></a> Now, as Mutti et al. asserted in their classic work of 1996 (an assertion that seems to have been backed up by the results of research over the past 20 years): in the debate between nature and environment, which traditionally had a posture of an option versus the other one, the fundamental question today seems to have changed to how much of each of these factors weighs on the onset of myopia.<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">29</span></a> In addition, as indicated by Morgan and Rose in their influential paper published in 2005, high inheritability does not establish any limit in the possibilities of environmentally induced change. At the time, said authors indicated that the concept that Eastern Asian populations had an intrinsically higher prevalence of myopia had the counter argument of the low prevalence reported in rural areas of some countries of the region as well as the high prevalence of myopia reported for other ethnic groups (such as Indians having different genetic information) that migrated to Southeast Asia.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,30–33</span></a> Examples of low prevalence in Asian population groups include the report by Chang et al., who referred to a study carried out by Chen in Taiwanese students of non-aboriginal ethnicity carried out in the 80s, which found only 9.7% of prevalence of myopia.<a class="elsevierStyleCrossRef" href="#bib1115"><span class="elsevierStyleSup">32</span></a> Also in Taiwan in the decade of the 80s, Lin et al. found 20% myopia rate among native schoolchildren.<a class="elsevierStyleCrossRef" href="#bib1110"><span class="elsevierStyleSup">31</span></a> More recent findings in China and Singapore also seem to support that people in Southeast Asia do not clearly have a significantly higher genetic predisposition to being myopic than other ethnic groups, as estimates of low prevalence have also been reported in some population groups from those countries.<a class="elsevierStyleCrossRefs" href="#bib1125"><span class="elsevierStyleSup">34–37</span></a> In addition, the premise that the genetic basis of Southeast Asian inhabitants may make them more susceptible to risk factors does not appear to be valid in light of the findings of a significant increase in myopia in young adults of Indian origin living in Singapore during a 13-year period (1996–1997 and 2009–2010), recently reported by Ko et al. The increased prevalence was greater in Indian individuals than in Singapore residents of the same age of another ethnic group (Chinese and Malaysian).<a class="elsevierStyleCrossRef" href="#bib1145"><span class="elsevierStyleSup">38</span></a> It is striking that, on the other hand, there is a much lower prevalence of myopia in India than that presented by these inhabitants of Singapore of Indian ethnic origin.<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">39</span></a> These findings, as recently explained by Morgan and Rose, support the argument that environmental conditions (including intensive education and diminished outdoors exposure) are directly related to higher myopia rates in all ethnic groups in Singapore, which in turn indicates that the effect of genetic influence might not be as important.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,30,31,37</span></a> Accordingly, a propensity to develop myopia in “myopigenic environments” seems to be a characteristic shared by all, or at least a majority, of human beings.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,29,37</span></a> Complete reviews on the genetics of myopia, as well as two genome-wide association studies (GWAS) with a high number of participants, have been published recently (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib1005"><span class="elsevierStyleSup">10,11,17,25,40–43</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Since the late 1970s, with the pioneering studies by Wiesel and Raviola and later those by Wallman et al., it was confirmed that deprivation of visual stimuli caused myopia in young animals of a variety of species.<a class="elsevierStyleCrossRefs" href="#bib1175"><span class="elsevierStyleSup">44,45</span></a> These experiments demonstrated the effect of the environment on the refractive condition of eyes in animals, although this does not necessarily mean that human myopia is largely secondary to environmental conditions.<a class="elsevierStyleCrossRefs" href="#bib1175"><span class="elsevierStyleSup">44–47</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Recently, the surprising observation of the large increase in the prevalence of myopia over the course of a few decades, in many parts of the world (including Southeast Asia and China), in the span of only one or two generations, has attracted attention on the crucial effect of environmental factors. On its own, genetics cannot explain this rapid change and it is clear that environmental influences could play a role as there seems to be evidence indicating that humans are sensitive to several external factors such as increased educational pressure and that these are associated to higher prevalence of myopia.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,12,38,46,48–50</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Systematic review methodology</span><p id="par0025" class="elsevierStylePara elsevierViewall">Relevant articles and chapters of books discussing the impact of environmental factors in the appearance and progression of myopia were identified. The studied articles, published up to April 2, 2016, were obtained from journals through the PubMed database without restrictions related to language or publication date. The following English keywords were utilized for the search (restricted to the title or abstract of articles, with the number of found documents indicated in parenthesis): “myopia progression” (303); “myopia onset” (49); “myopia environmental factors” (295); and “myopia prevention” (19). After reviewing the titles, the articles deemed to have potential interest were selected for reading of abstracts. If the abstract included relevant information about appearance, progression and prevention of myopia, the full text was accessed. In addition, all the articles, books or chapters thereof identified as relevant within the references cited in said articles were also searched. In addition, the website of the Association for the Research in Vision and Ophthalmology (ARVO) was searched for articles and abstracts of presentations (using the keyword “myopia” and restricted to the title, 2136 publications were identified). The final result was that 191 articles were included.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Environmental factors related to myopia</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Education level</span><p id="par0030" class="elsevierStylePara elsevierViewall">As early as 1813 in London, Ware stated that myopia affected the higher classes more than the lower ones.<a class="elsevierStyleCrossRef" href="#bib1210"><span class="elsevierStyleSup">51</span></a> Different education could have played a role at that time because lower social classes had little if any access to education. Later on, other researchers who carried out incipient systematic studies during the 19<span class="elsevierStyleSup">th</span> century found higher prevalence of myopia among population groups with higher education.<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In the last decades, many studies carried out in the 5 continents have confirmed that higher education levels or achievements equates to higher myopia prevalence.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,52–58</span></a> In addition, a correlation was found between myopia and higher academic results.<a class="elsevierStyleCrossRefs" href="#bib1025"><span class="elsevierStyleSup">14,55,59,60</span></a> A study carried out in Australia and published in 1999 found that individuals who had completed higher education exhibited greater prevalence of myopia than those who had not finished secondary education (29.5 and 12.3%, respectively) and this was not influenced by age.<a class="elsevierStyleCrossRef" href="#bib1220"><span class="elsevierStyleSup">53</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">An effective interaction between myopia genes and education is still an unresolved issue. In 2008, Dirani et al. published the results of their myopia genetic research (<span class="elsevierStyleItalic">Genes in myopia</span>), a study on twins also carried out in Australia. The objective was to establish the relative contribution of genetics on education levels as well as assessing shared genetic and environmental factors between education levels and refraction by means of structural equation models. They found that the education level was significantly associated with myopia but, in accordance with their estimations, the education level only explained 4.4% of the total variance in refraction. In addition, aggregate genetic effects explained 69% of variations in education levels, whereas common and unique environmental factors accounted for 20% and 11% of said variance, respectively. The authors reached the conclusion that the education level was strongly influenced by genes and accordingly could not be considered only as an environmental risk factor.<a class="elsevierStyleCrossRef" href="#bib1260"><span class="elsevierStyleSup">61</span></a> In two independent cohorts of the population-based Rotterdam study, a significant biological interaction was found between education and the genetic risk of myopia. Subjects with high genetic risk in combination with high education levels had higher risk of myopia than those who only had one of these two factors.<a class="elsevierStyleCrossRefs" href="#bib1005"><span class="elsevierStyleSup">10,62</span></a> On the other hand, in 2014 Mirshahi et al. published the results of their analysis of the association between myopia and education level in a cohort of European adults (Gutenberg health study) that included genetic analysis. The multivariate analysis found that college and professional education levels were associated with higher myopic error, regardless of sex. The authors also analyzed genetic polymorphism, which is related to the multiple forms of a gene, i.e., with differences in DNA sequences that can be relatively common in a population. In general, it is considered that, for polymorphism to exist, the least common allele (that is, each of the alternative forms the gene can have) must have a frequency of at least 1%. If said frequency is lower, the allele is regarded as a mutation. Single-nucleotide polymorphism (SNP) is a genetic polymorphism characterized by variation (either deletion, insertion or exchange) of a single nucleotide in a specific position. Mirshahi et al. found a small effect of age and polymorphisms of an SNP, but the latter only accounted for 0.01 D in spherical equivalent. The association between prevalence and magnitude of myopia and levels of academic education as well as professional training after formal education remained significant after being adjusted for age, sex and the SNPs currently known as being associated to myopia in multivariate models.<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">63</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Recently, in 2015, Williams et al. published a meta-analysis of cross-sectional population-based studies of the European Eye Epidemiology (E3) Consortium, with data from 61,946 participants (median age range 44–78 years) from 15 population studies conducted between 1990 and 2013. The level of education was significantly associated with myopia in all age brackets (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001) in the 13 studies which had said data available (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>60,125 participants). The prevalence of standardized myopia for age for those participants who had completed primary school (defined as those who left school before age 16), secondary school (those who dropped out of school until the age of 19) and education (those who dropped out of school at age 20 or later) was 25.4; 29.1 and 36.6%, respectively. In age brackets between 35 and 84, the prevalence of participants with higher education levels was approximately twice than those who had primary education only. However, a cohort effect was also observed, that is, an increase in the prevalence of myopia related to a more recent date of birth in all the educational groups. Even though the younger group was more likely to achieve higher education levels, per se this did not explain the cohort effect of the increased myopia. The association of the education level and the birth cohort had an additive effect on the prevalence of myopia. The authors believed that said cohort effect was multifactorial and reached the conclusion that, even though the expansion of higher education could be an explanation, it appeared to be only one of several factors that bear on the increased prevalence of myopia (in the second half of the past century the use of computers increased together with the duration of education hours per day and afterschool courses, diminishing time spent outdoors).<a class="elsevierStyleCrossRef" href="#bib1275"><span class="elsevierStyleSup">64</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Recently, utilizing a Mendelian randomization analysis to estimate the causal effect of education in refractive errors (measured as spherical equivalent) with the use of genetic predisposition to education as an instrumental variable, Cuellar-Partida et al. estimated in a meta-analysis that each increase in the z score in education (approximately 2 years of education) produce a myopic change of 0.92<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.29 D. This estimated effect of educational myopia was higher than in 3 observational studies, after adjusting for sex and age, calculated by the authors at 0.25<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.03<span class="elsevierStyleHsp" style=""></span>D myopization for each increase in the <span class="elsevierStyleItalic">z</span> score. This finding implies that observational studies could in fact underestimate the actual effect. The results of this Mendelian randomization analysis are among the most solid evidence published supporting the concept that the educational level exhibits a causal relationship with refractive error.<a class="elsevierStyleCrossRef" href="#bib1280"><span class="elsevierStyleSup">65</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In short, higher education levels seem to be an important factor that influences the increased prevalence of myopia. This concept is supported by the results of a recent study that utilized Mendelian randomization analysis.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,14,52–60,64,65</span></a> However, the cohort effect observed in several studies appears to be multifactorial, and educational achievements seem to be only one of several factors that bear on myopia.<a class="elsevierStyleCrossRefs" href="#bib1260"><span class="elsevierStyleSup">61,62,64</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Near work and accommodation</span><p id="par0060" class="elsevierStylePara elsevierViewall">Reading and other near vision tasks have been associated with myopia for centuries. Traditionally, several mechanisms related to accommodation have been proposed. In the 17<span class="elsevierStyleSup">th</span> century, Kepler proposed the “near work” hypothesis to explain myopia and indicated that studying and carrying out visual tasks at shorter distances during childhood accustomed eyes to adapt to near objects.<a class="elsevierStyleCrossRefs" href="#bib1285"><span class="elsevierStyleSup">66–68</span></a> Cohn published a book in 1886 indicating that focusing the eyes on nearby objects for long periods of time, above all with poor lighting, promoted the appearance of myopia.<a class="elsevierStyleCrossRef" href="#bib1300"><span class="elsevierStyleSup">69</span></a> In the following decades it was generally accepted that prolonged accommodation and convergence periods required by near sight work were the main contributing factor not only for myopia but also for the progression thereof in susceptible individuals who had additional predisposing factors.<a class="elsevierStyleCrossRefs" href="#bib1305"><span class="elsevierStyleSup">70,71</span></a> At the time, accommodation was seen as the most significant factor. However, even today it is not clear which is the exact mechanism by means of which accommodation could increase the prevalence and progression of myopia. Experimental evidence against accommodation as an isolated and necessary factor in the etiology of myopia includes the fact that myopia due to visual deprivation can be induced in primates even after the destruction of the ciliary ganglion or the Edinger–Westphal nucleus.<a class="elsevierStyleCrossRef" href="#bib1315"><span class="elsevierStyleSup">72</span></a> In addition, in 1993 McBrien et al. demonstrated that a small mammal (gray squirrel) did not need to have a functional accommodation system to induce experimental myopia.<a class="elsevierStyleCrossRef" href="#bib1320"><span class="elsevierStyleSup">73</span></a> The same authors, in the same year, also found that in chickens, which do not have M3 receptors in the ciliary body, atropine slowed the development of experimental myopia, which indicates that a non-accommodation mechanism was involved in the appearance and progression of experimental myopia.<a class="elsevierStyleCrossRef" href="#bib1325"><span class="elsevierStyleSup">74</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">However, accommodation could be related to the development of myopia in humans through several mechanisms proposed by different researchers. In the late 19<span class="elsevierStyleSup">th</span> century, Cohn and Fuchs proposed the theory according to which continued accommodation efforts produced a kind of spasm that remained active even after finishing the near sight task.<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">69,70</span></a> This theory was recently revived.<a class="elsevierStyleCrossRefs" href="#bib1330"><span class="elsevierStyleSup">75,76</span></a> Its proponents point out that myopic retinal unfocusing or blur can also be myopigenic, a premise that is not clearly supported by experimental results in animals.<a class="elsevierStyleCrossRefs" href="#bib0980"><span class="elsevierStyleSup">5,76</span></a> However, some studies have demonstrated that undercorrection of myopia for distance vision in young people produced greater progression of myopia. This would support that myopic defocus would cause the axial length to increase.<a class="elsevierStyleCrossRefs" href="#bib1340"><span class="elsevierStyleSup">77–80</span></a> Ciuffreda is of the opinion that there is sufficient evidence in humans to state that any type of blur, either myopic as well as hyperopic, is myopigenic, and that the results of studies in animals cannot be transferred directly (Ciuffreda KJ. Personal communication, March 21, 2016).<a class="elsevierStyleCrossRefs" href="#bib1335"><span class="elsevierStyleSup">76–80</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Another mechanism that could affect the quality of images in the retina could be related to defective accommodation during near work, that would cause a significant accommodation lag. This was proposed in Russia in the late 60s.<a class="elsevierStyleCrossRefs" href="#bib1360"><span class="elsevierStyleSup">81,82</span></a> In the presence of an accommodation lag, the accommodative stimuli generated by divergent beams coming from a near object exceeds the accommodative response in a certain value of diopters, and therefore the eye cannot focus with precision the near object image on the fovea, which leads to a hyperopic defocus during near sight work. If we make an analogy with experimental studies in animals, this would in turn lead to myopia due to stimulating axial length growth. Over two decades ago it was found that myopic children in the United States had longer accommodative lag than emmetropes, which matches the conclusions of this theory.<a class="elsevierStyleCrossRefs" href="#bib1370"><span class="elsevierStyleSup">83–85</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">However, even though several studies in humans have indicated that the increase in accommodative lag occurs prior to the appearance of myopia,<a class="elsevierStyleCrossRefs" href="#bib1370"><span class="elsevierStyleSup">83,86,87</span></a> others have found that the increase in hyperopic defocus of the accommodative lag could be a consequence instead of a cause of myopia.<a class="elsevierStyleCrossRef" href="#bib1395"><span class="elsevierStyleSup">88</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In turn, epidemiological studies have found contradictory results about near sight work and myopia. Several studies have found that said work is related to higher prevalence and magnitude of myopia.<a class="elsevierStyleCrossRefs" href="#bib1025"><span class="elsevierStyleSup">14,89–96</span></a> It has also been found that children who read continuously or at short distances were more susceptible to be myopic and that less near sight activity could potentially be associated with a greater likelihood of stabilization of myopia at age 15.<a class="elsevierStyleCrossRefs" href="#bib1425"><span class="elsevierStyleSup">94,97,98</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In contrast, the results of other studies did not support a significant effect of near sight work.<a class="elsevierStyleCrossRefs" href="#bib1025"><span class="elsevierStyleSup">14,15,21,22,95,99–101</span></a> In the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) study, a multicenter research carried out in the United States, Jones et al. found that near sight activities (reading, watching TV, studying and the use of computers or video games) was not a significant risk factor in children who became myopic.<a class="elsevierStyleCrossRef" href="#bib1460"><span class="elsevierStyleSup">101</span></a> In the Singapore cohort study of the risk factors for myopia, Saw et al. exhaustively evaluated near sight activities (books read per week, hours per day of reading, use of computers, video games and television) and also found that none of these variables was a significant risk factor for myopia.<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">21</span></a> Very recently, Zadnik et al. determined the best set of predictors for myopia in CLEERE in the United States (including Caucasian, Afro-American, Hispanic and Asian children) and found that near sight vision did not exhibit association with the appearance of myopia neither in univariate nor in multivariate models.<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">15</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">A relationship between an occupation requiring near sightwork and myopia has been found during decades.<a class="elsevierStyleCrossRefs" href="#bib1465"><span class="elsevierStyleSup">102–107</span></a> However, it is not entirely clear if this association is simply a correlation or if a causal relationship indeed exists.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In a meta-analysis recently published by Huang et al., the authors examined the magnitude of the association between time used in near sight work and myopia, and found that the longer time periods dedicated to near sight work were associated with higher probabilities of myopia (odds ratio [OR]<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.14; IC<span class="elsevierStyleHsp" style=""></span>95%: 1.08–1;20) and also found an increase of 2% in the probability of myopia for each additional diopter-hour spent on near sight work per week (one diopter-hour being the integral calculation of exposure to near sight activities, related to the accommodative stimuli in accordance with the working distance of each task in accordance with the following formula: 3<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h reading<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h studying <span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h watching videos or using a computer<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h watching TV). These results add evidence to the association between near sight work and myopia. However, the authors recommend additional longitudinal studies and controlled randomized trials to confirm whether near sight work is actually a risk factor for the development of myopia. The authors considered that inconsistent evidence on the effects of near sight work on myopia could be related to differences in study designs, the diversity of ethnic origins of children, differences in the definition of myopia and near sight work, limited precision of the reports referred by children or parents about the time dedicated to near sight activities and the quality of collected data.<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">22</span></a> According to Mutti (DO Mutti. Personal communication, December 13, 2015), Huang et al. did a very good job when separating cross-sectional from longitudinal studies because these two designs make fundamentally different questions. A cross-sectional study asks whether myopes do more near sight work. They found that 10 out of 15 cross-sectional studies showed that myopes in fact do carry out more nearsight work. However, the most important question is asked by a longitudinal study, i.e., does near sight work increase the risk of a child to go from ametropia to myopia? Huang et al. examined six longitudinal studies and found that only two showed some increases in the risk of myopia related to near sight vision. One of these was the CLEERE report published in 2011.<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">108</span></a> However, in that study near sight work was significantly greater only one year prior to the appearance of myopia in children who became myopic. In fact, the authors of said CLEERE report argued that one year was too short a time to be significant and Mutti, one of the authors of the CLEERE study, believed that Huang et al. could have misinterpreted results in what concerns the effect of near sight work (DO Mutti. Personal communication, December 13, 2015). As described above, the new results of the CLEERE study demonstrated that near sight vision was not a significant risk factor, both in univariate as well as a multivariate analyses.<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Even though the links between near sight work and myopia have been identified for a long time, the biological connection between both was not consistently supported by recent evidence, besides the fact that a likely mechanism is not clear either.<a class="elsevierStyleCrossRef" href="#bib1500"><span class="elsevierStyleSup">109</span></a> As discussed, several epidemiological studies have failed to find proof that near sight activities are a risk factor for myopia.<a class="elsevierStyleCrossRefs" href="#bib1030"><span class="elsevierStyleSup">15,21,22,99</span></a> However, collected evidence on the link between education and myopia also seem to support an association between near sight work and myopia. Even though there are few quantitative data, it seems to be a very plausible, nearly obvious, affirmation that those who have completed more years of academic study and have obtained better results in exams are more likely to have spent more hours reading. On the other hand, some expert researchers (such as Mutti and Zadnik) have stated that an almost constant effort would be required to significantly alter the growth of the human eye (e.g., the exceptional experience of Orthodox rabbi students who spent 16<span class="elsevierStyleHsp" style=""></span>h per day of study, which is clearly not the norm nowadays<a class="elsevierStyleCrossRefs" href="#bib1400"><span class="elsevierStyleSup">89,99</span></a>). In summary, the concept that near sight work is an important risk factor for myopia has lost strength within the scientific community in recent years.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Lifestyle and urbanization</span><p id="par0105" class="elsevierStylePara elsevierViewall">Living in urban instead of rural areas is another factor that influences the prevalence of myopia. It has been found in several countries that populations with very similar genetic antecedents and who live in different environments exhibit significantly different myopia rates. Individuals who grow up in rural environments generally have lower prevalence of myopia.<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">9,110–112</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">It is not easy to establish a causal relationship between growing up in an urban environment and the presence of myopia, as several other factors can play a role. For instance, the educational level, the socioeconomic index, outdoor activities and exposure to natural light. Educational pressure tends to be greater in cities than in towns, even if the minimum schooling formal requirements are equivalent.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Historically, we have some examples of a significant increase in myopia when people change their lifestyle. In the late 60s, the Eskimo population (Inuit) experienced significant increases in the prevalence of myopia after moving to new settlements and adopting a westernized lifestyle.<a class="elsevierStyleCrossRefs" href="#bib1520"><span class="elsevierStyleSup">113,114</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Studies of some immigrant groups have demonstrated the same tendency. The Study of Latin Eyes in Los Angeles found that the second generation of Latino immigrants (born and bred in the United States) had higher myopia prevalence than those born in other countries (22.66 against 13.99%) and that a higher level of adoption of the new culture, measured with a 9-item questionnaire, increased the risk of myopia.<a class="elsevierStyleCrossRef" href="#bib1530"><span class="elsevierStyleSup">115</span></a> Similar results were obtained in Singapore in the analysis of the first generation of Indian immigrants and comparing them with the second generation who descended from the first but were already born in Singapore. The prevalence of myopia was higher in the latter group (30.2 against 23.4%).<a class="elsevierStyleCrossRef" href="#bib1535"><span class="elsevierStyleSup">116</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A recent study carried out in China found significant differences when comparing myopia prevalence and predictors in two provinces, one with median income (Shaanxi) and the other with lower income (Gansu). Researchers found that the prevalence of myopia was nearly double in the medium income than in the lower income population (22.9 against 12.7%). The authors explained that, even after adjusting for differences in factors such as near sight work, school performance and time spent outdoors, they were unable to explain a large proportion of the different prevalence of clinically significant myopia between the medium and lower income populations.<a class="elsevierStyleCrossRef" href="#bib1540"><span class="elsevierStyleSup">117</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Ramessur et al. recently published a study in couples of homozygote twins who were discordant in subjective refraction (with a difference ≥2.00 D in spherical equivalent) as well as discordant in the class of refractive defect. Considering that monozygot twins have identical genotypes, the difference in one given risk factor between a couple of twins with a discordant spherical equivalent implies that it is a separate risk factor, independent of genetic effects. When comparing individuals with myopia with those with ametropia/hypermetropia, those who lived in urban areas exhibited a significant difference.<a class="elsevierStyleCrossRef" href="#bib1545"><span class="elsevierStyleSup">118</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary, urbanization holds some evidence of an albeit weak link with myopia. Accordingly, urbanization seems to be an unlikely explanation for the extraordinary increase in the prevalence of myopia in recent decades in Southeast Asia, because a valid counterargument is that Europe has had large cities for centuries without a documented myopia epidemic.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Outdoor activities</span><p id="par0140" class="elsevierStylePara elsevierViewall">In the late 19th century, Cohn stated that lighting at schools was of the utmost importance for preventing myopia. Later on, in the early 20th century Wiener pointed out that myopics needed to spend more time outdoors and exercise more.<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">69,119–121</span></a> The speculative conjectures of these authors have been supported in the past two decades by many studies that have demonstrated that children who carry out more outdoor activities, including physical exercise or not, exhibit lower risk of developing myopia.<a class="elsevierStyleCrossRefs" href="#bib1025"><span class="elsevierStyleSup">14,22,46,93,122,123</span></a> Even though as early as 1993, Pärssinen and Lyyra analyzed the effect of time spent in sports and outdoor activities in the progression of defects in myopic children, they did not carry out a study on the appearance of myopia.<a class="elsevierStyleCrossRef" href="#bib1565"><span class="elsevierStyleSup">122</span></a> In 2002, Mutti et al. reported that less time spent doing sports was a risk factor associated to myopia, although they did not correlate that finding with outdoor activities.<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">14</span></a> Later on, in 2007, the same group of researchers was the first to report an association between time spent doing outdoor activities and lower risk of myopia when they discovered differences in the 3<span class="elsevierStyleSup">rd</span> grade of the primary school between children who would become myopic and those who would not, based on the number of hours spent per week “doing outdoor sports and activities”. However, the survey filled in by parents did not differentiate “sports” and “outdoor activities” because the question comprised both items. Accordingly, as pointed out by said authors, it is possible that the protective effect could have been related more to participation in any outdoor activity and not specifically with the practice of sports.<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">13</span></a> The direct relationship with time spent outdoors instead of physical activities was emphasized in 2008 by Rose et al. who, in a cross-sectional study of schoolchildren in Sydney (Australia), has already found that more time spent outdoors was associated to lower prevalence of myopia, and also reported their comparative study of Chinese children who had grown up in Australia and Singapore.<a class="elsevierStyleCrossRefs" href="#bib1575"><span class="elsevierStyleSup">124,125</span></a> Despite the fact that both groups of children presumptively shared a similar genetic predisposition to myopia, the prevalence was significantly lower in Sydney (3.3%) than in Singapore (29.1%), even though those living in Australia read more books per week and carried out more near sight activities. A notable difference was that the Chinese children living in Sydney spent more time in outdoor activities, which was the most important factor associated to the disparity in the prevalence of myopia between both groups.<a class="elsevierStyleCrossRef" href="#bib1580"><span class="elsevierStyleSup">125</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A prospective CLEERE cohort study in the United States demonstrated that children who became myopic spent less time in outdoor activities or practicing sports than emmetropics before, during and after the appearance of myopia. The difference between emmetropics and children who became myopic after spending less time in outdoor activities and sports was significant, taking into account that 4 years before and up to 4 years after the appearance of myopia, the children who ended up being myopic had spent between 1.1 and 1.8<span class="elsevierStyleHsp" style=""></span>h less per week in outdoor activities and sports.<a class="elsevierStyleCrossRef" href="#bib1495"><span class="elsevierStyleSup">108</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">However, a negative association between the amount of time spent by children outdoors and myopia has not been universally observed. In China in 2009, utilizing regression models, Lu et al. found that time spent doing outdoor activities was not associated with myopia adjusting for age, sex and education of parents. Even so, over 80% of subjects in the sample of this study were myopic and spent only an average of 6.1<span class="elsevierStyleHsp" style=""></span>h per week outdoors, which could be below the protective effect threshold of outdoors exposure as indicated by French et al., as in the other studies children generally spent over 10<span class="elsevierStyleHsp" style=""></span>hours per week outdoors.<a class="elsevierStyleCrossRefs" href="#bib1585"><span class="elsevierStyleSup">126,127</span></a> Similar results were found in the study by Zhang et al., who reported that higher population densities seem to be associated to the risk of myopia, regardless of time spent outdoors. In that study, children reported an average of only 5.6–5.7<span class="elsevierStyleHsp" style=""></span>h per week spent outdoors.<a class="elsevierStyleCrossRef" href="#bib1595"><span class="elsevierStyleSup">128</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Low et al. found in Chinese children in Singapore (6–72 months of age) that, while familial antecedents of myopia was the most important factor associated to preschool myopia, neither near sight work or outdoor activities were associated with myopia in this preschooler population.<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">16</span></a> On the other hand, in 2012 Jones-Jordan et al. published the results of the CLEERE study on the progression of myopia. Despite the protective effect of time spent doing outdoor activities in the risk of myopia demonstrated in the same CLEERE study, these outdoor activities or sports were not associated with lower progression of myopia once it appeared in a multivariate model.<a class="elsevierStyleCrossRefs" href="#bib1455"><span class="elsevierStyleSup">100,108</span></a> In 2015, a new report of the same study demonstrated that the protective effect of time spent doing outdoor activities was significant in a univariate model although not significant in a multivariate analysis.<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">15</span></a> Mutti, co-author of the CLEERE study, believed that the effect of the difference of time spent outdoors did not achieve significance in a multivariate analysis because the baseline refraction error was per se excessively important as a predictor (DO Mutti. Personal communication, December 13, 2015). Zadnik, another co-author of said study, similarly commented that time invested in outdoor activities had some protective effect and for this reason it was evident in the univariate analysis, but its contribution to the protection of the appearance of myopia was small compared to the baseline refraction of children (Zadnik<span class="elsevierStyleHsp" style=""></span>K. Personal communication, June 20, 2016).</p><p id="par0160" class="elsevierStylePara elsevierViewall">In 2014, another group of researchers who evaluated the association between outdoor activities at baseline and the stabilization of myopia at age 15 in the Correction of Myopia Evaluation Trial (COMET) reported that time invested in outdoor activities in childhood did not appear to be related to said stabilization.<a class="elsevierStyleCrossRef" href="#bib1445"><span class="elsevierStyleSup">98</span></a> However, in a meta-analysis about the association of outdoor time and myopia published in 2012, Sherwin et al. demonstrated a small but significant protective effect of increased time spent outdoors against myopia in observational studies.<a class="elsevierStyleCrossRef" href="#bib1600"><span class="elsevierStyleSup">129</span></a> Seven cross-sectional studies were combined and, after adjusting covariants, the OR grouped for myopia showed a 2% reduction of the probability of myopia for each additional hour of time spent in outdoors activities per week. The magnitude of the effect was relatively small, but this is related to the measure units included in the studies. On the other hand, the 25–50% reduction indicated in several studies refers to the difference in the development of myopia, on the basis of the presence or absence of myopia as a dichotomic variable and on an arbitrary threshold.<a class="elsevierStyleCrossRefs" href="#bib1605"><span class="elsevierStyleSup">130,131</span></a> Not all the studies could be combined because the authors of the meta-analysis were not able to include some of the data due to the heterogeneous measures of variables.<a class="elsevierStyleCrossRef" href="#bib1600"><span class="elsevierStyleSup">129</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Several intervention studies have been made after publishing this meta-analysis. In 2013, Wu et al. reported the results of a prospective study carried out in Taiwan that included 333 children in school age as the intervention group and 238 in the control group (age 7–11). The groups were comparable in baseline age, sex, baseline refraction, prevalence of myopia and proportion of children receiving pharmacological treatment for myopia (atropine). The proportion of children receiving atropine treatment was 28.93% in the intervention group and 19.66% in the control group. The intervention consisted in motivating children to go out of the classroom and engage in outdoor activities during the break (weekly break time, approximately 6.7<span class="elsevierStyleHsp" style=""></span>h). The estimated time spent outdoors after school was not significantly different between both groups (2.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.0<span class="elsevierStyleHsp" style=""></span>h per week in the intervention group and 2.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.2<span class="elsevierStyleHsp" style=""></span>h per week in the control group). However, due to the intervention the study group children spent more estimated time in outdoor activities (approximately 11.2<span class="elsevierStyleHsp" style=""></span>h per week) than the control group children (about 7.6<span class="elsevierStyleHsp" style=""></span>h). After 12 months, the new myopia cases (spherical equivalent of at least −0.5<span class="elsevierStyleHsp" style=""></span>D) were significantly less frequent in the intervention group (8.41 against 17.65%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). In addition, the myopic progression was significantly lower (−0.25 against −0.38<span class="elsevierStyleHsp" style=""></span>D/year; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.029) when comparing both groups in their entirety. However, said different myopic progression was mainly determined on the basis of the difference between non-myopic subjects at baseline. The progression of myopic children at baseline was not significantly different between the intervention and the control group. In addition, when comparing myopic subjects that were on atropine treatment with those who were not, the mean progression of myopia was not significantly different either. This lack of effect of atropine was observed both in the intervention and the control group. The authors indicated that a possible explanation was poor compliance with the treatment or a rebound effect after interrupting medication. However, as the use of atropine was not an intervention variable, the data required for defining this variable were not available because it was not evaluated.<a class="elsevierStyleCrossRefs" href="#bib1605"><span class="elsevierStyleSup">130,132</span></a> In summary, the intervention involving increased outdoor activity during break time at school demonstrated a protective effect against the onset of myopia and also in myopic refractive changes considering the full group of children (including non-myopic), but did not show any effect on the progression of myopia in children who were myopic at baseline. Outdoor activities did not help to increase the effect of atropine for controlling the progression of myopia.<a class="elsevierStyleCrossRefs" href="#bib1605"><span class="elsevierStyleSup">130,132</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Recently published results of two larger trials in China with similar interventions also demonstrated a significant protective effect of outdoor activity. In Guangzhou, Southern China, the addition of a supplementary daily class (40<span class="elsevierStyleHsp" style=""></span>min) after school involving children in structured outdoor activities was associated to diminished aggregate incidents of myopia in children (6–7 years old) at 3 years follow-up: 39.5% in the control group (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>951) in comparison with 30.4% in the intervention group (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>952). The study also found a significant difference in spherical equivalent refraction at 3 years for the intervention group (−1.42 D) in comparison with the control group (−1.59 D) (a difference of 0.17 D [IC 95%: 0.01–0.33 D]; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.04).<a class="elsevierStyleCrossRef" href="#bib1610"><span class="elsevierStyleSup">131</span></a> Likewise, schoolchildren between 6 and 14 years of age in the Sujiatun, Northeastern China, were allowed access to two additional recess programs involving 20 additional minutes out of the classroom during one year. When comparing the intervention group (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.735) with the control group (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.316), the appearance of new myopia cases and myopic progression during the period of the study were significantly lower: 3.70 against 8.50% and −0.10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.65 against −0.27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.52 D/year.<a class="elsevierStyleCrossRef" href="#bib1620"><span class="elsevierStyleSup">133</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In contrast, the <span class="elsevierStyleItalic">Anyang Childhood Eye Study</span> (ACES), a cohort study also carried out in China that included 1997 children between 10 and 15 years of age (average of 12.7 years) and published in 2015 found that outdoor time was not significantly associated to changes in refraction errors or axial length during a 2-year period. In children who were not myopic at study baseline, axial length elongation rate was lower in those who spend more time outdoors. However, this did not translate into lower tendency toward myopic refraction, possibly due to insufficient statistical power to detect such a small effect. On the other hand, the axial elongation rate was not associated with time spent outdoors in children who were myopic at baseline.<a class="elsevierStyleCrossRef" href="#bib1625"><span class="elsevierStyleSup">134</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In summary, according to multiple studies it is possible to state that an increased exposure to natural light and time spent outdoors associate with a lower prevalence of new cases of myopia, and the aggregate evidence of this protective effect has progressively increased. However, this defect has not been identified universally. In addition, quantitative objective biomarkers of ocular exposure to the sun have been found (conjunctival ultraviolet autofluorescence photography) that exhibit an inverse correlation with myopia.<a class="elsevierStyleCrossRefs" href="#bib1630"><span class="elsevierStyleSup">135,136</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Once myopia is present, progression is a different matter.<a class="elsevierStyleCrossRefs" href="#bib1640"><span class="elsevierStyleSup">137,138</span></a> Initially, in a study carried out in Finland in 1993, Pärssinen and Lyyra reported that the amount of time spent outdoors was clearly related to lower progression of myopia among children.<a class="elsevierStyleCrossRef" href="#bib1565"><span class="elsevierStyleSup">122</span></a> In a recent publication of the same group of patients who were followed up during 23 years, Pärssinen et al. found that the factors predicting faster progression of myopia included less time dedicated to sports and outdoor activities in childhood.<a class="elsevierStyleCrossRef" href="#bib1650"><span class="elsevierStyleSup">139</span></a> However, the same author commented that even though they found links between myopia and outdoor entities, surprisingly watching more television had a protective effect. Accordingly, Pärssinen concluded that it is improbable that exposure to sunlight or more time spent outdoors will per se diminish the progression of myopia, and the link between lower final myopia magnitude and increased time spent outdoors could be simply based on the fact that, being outdoors, the subject is far from reading and working in near vision (Pärssinen O. Personal communication, July 17, 2016). Some years earlier, in 2011, Yi and Li had published their findings on the progression of myopia in school children aged 7–11 in China. They also found a connection between slower progression of myopia and more time spent outdoors or more exposure to natural light.<a class="elsevierStyleCrossRef" href="#bib1655"><span class="elsevierStyleSup">140</span></a> On the contrary, time spent outdoors did not affect the progression rate of myopia in myopic children who participated in the CLEERE study in the United States.<a class="elsevierStyleCrossRef" href="#bib1455"><span class="elsevierStyleSup">100</span></a> In addition, as discussed above, increasing outdoor activities of myopic children in China did not cause a significant difference in progression<a class="elsevierStyleCrossRef" href="#bib1605"><span class="elsevierStyleSup">130</span></a> and it was not found that increased time dedicated to outdoor activities was related to refractive error changes and axial length in the following 2 years in another group of myopic schoolchildren in China.<a class="elsevierStyleCrossRef" href="#bib1625"><span class="elsevierStyleSup">134</span></a> In conclusion, even though several studies have identified a protective effect produced by exposure to natural light to slow down the progression of myopia after its onset, it is a subject of debate because this has not been supported by the results of other groups of researchers.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Contradictory results were also reported after studying the effects of seasons on the progression of myopia. Several studies have found slower progression rates during summer holidays.<a class="elsevierStyleCrossRefs" href="#bib1660"><span class="elsevierStyleSup">141–145</span></a> In Japan, however, the progression of myopia did not seem to be affected by the season despite the fact that axial length increase slightly diminished in summer.<a class="elsevierStyleCrossRef" href="#bib1685"><span class="elsevierStyleSup">146</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Several mechanisms can account for the fact that staying outdoors can influence the appearance of myopia. Whether the protective effect of time spent outdoors is the result of longer focus of vision or brighter light typical of outdoor sunlight is still the subject of controversy.<a class="elsevierStyleCrossRef" href="#bib1580"><span class="elsevierStyleSup">125</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In 2008, Rose et al. were the first to propose that stimulating the release of dopamine from the retina, which is known to act as an inhibitor for the growth of the eye, could be the mechanism that produces the protective effect of exposure to light.<a class="elsevierStyleCrossRefs" href="#bib1575"><span class="elsevierStyleSup">124,125</span></a> The release of dopamine is increased in the retina in response to sunlight, and it has been demonstrated that dopamine inhibits the elongation of the axial length in experimental deprivation myopia in chickens and prevents scleral thinning induced by deprivation in rabbits.<a class="elsevierStyleCrossRefs" href="#bib1690"><span class="elsevierStyleSup">147–149</span></a>. In addition, the protective effect of exposure to intense light in chickens to prevent the development of experimental myopia can be blocked with intravitreal injection of a dopamine antagonist.<a class="elsevierStyleCrossRef" href="#bib1705"><span class="elsevierStyleSup">150</span></a> Cohen et al. measured the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), a dopamine metabolite in chicken, as an indicator of the release of dopamine in the retina and arrived at the conclusion that under cycles of light and darkness, low concentrations of DOPAC in the vitreous were associated to the development of myopia. In addition, under continuous light, high DOPAC concentrations in the vitreous were associated to the development of hyperopia. In their study, using both alternatives (light-darkness cycles and continuous light), environmental lighting stimulated the dopamine release rate and refractive changes in the eyes of chickens.<a class="elsevierStyleCrossRefs" href="#bib1710"><span class="elsevierStyleSup">151,152</span></a> If ultraviolet light (UV) played a role in the protective effect against the appearance and development of experimental myopia, this effect could be related to vitamin D levels. However, there are contradictory arguments. The controversy about the role of vitamin D in the appearance and progression of myopia is not new. Knapp (cited by Prangen in 1939) affirmed that the administration of vitamin D and calcium produced improvements in some myopia cases, whereas Laval in 1938 published results indicating that said treatment had no effect at all.<a class="elsevierStyleCrossRef" href="#bib1720"><span class="elsevierStyleSup">153</span></a> The debate is not irrelevant because, if vitamin D provides said protection, and knowing that this vitamin is produced in the skin through the action of UV light during outdoor exposure, in order to prevent myopia subjects should refrain from protecting their skin and the increase of skin cancer risk would be a problem.<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">46</span></a> However, some authors have proposed that daily exposure to sunlight could eliminate the risk of sporadic or intermittent exposure during weekends and holiday periods and could in fact also be a protective effect against melanoma.<a class="elsevierStyleCrossRefs" href="#bib1725"><span class="elsevierStyleSup">154,155</span></a> On the other hand, if the protective effect of time spent outdoors is not related to UV light, efficient skin protection could be applied, and this has demonstrated to be successful in countries with high UV exposure rates such as Australia.<a class="elsevierStyleCrossRefs" href="#bib1735"><span class="elsevierStyleSup">156,157</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">In 2011, Mutti et al. found in a case control study that SNPs within the vitamin D receptor (VDR) in 12q13.11 and GC in 4q12-13 appears to be associated with low-moderate magnitudes of myopia.<a class="elsevierStyleCrossRef" href="#bib1745"><span class="elsevierStyleSup">158</span></a> In 2011, Mutti and Marks reported that in 22 subjects (14 myopic and 8 non-myopic), and after adjusting for differences in diet intake variables, myopics seemed to have lower overall average levels of vitamin D in blood than non-myopics (approximately 20%).<a class="elsevierStyleCrossRef" href="#bib1750"><span class="elsevierStyleSup">159</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">In 2014 Choi et al. published their results which showed that lower concentrations levels of 25 (OH) D were associated to the prevalence of myopia in Korean teenagers. The authors found that this relationship was particularly notable in adolescents with high myopia.<a class="elsevierStyleCrossRef" href="#bib1755"><span class="elsevierStyleSup">160</span></a> In 2014, in Australia Yazar et al. also found a significantly higher prevalence of myopia in subjects with vitamin D deficiency when compared to individuals with normal vitamin D levels.<a class="elsevierStyleCrossRef" href="#bib1760"><span class="elsevierStyleSup">161</span></a> However, after analyzing also in 2014 data of children in the United Kingdom, Guggenheim et al. did not find statistical evidence to support the hypotheses that the elevation of vitamin D levels is the mechanism through which outdoor exposure protects against myopia.<a class="elsevierStyleCrossRef" href="#bib1765"><span class="elsevierStyleSup">162</span></a> Vitamin D supplements (300 UI of cholecalciferol), that increase over 30 times on average the serum levels of 25 (OH) D did not prevent the appearance of experimental myopia in tree shrews (Siegwart et al., <span class="elsevierStyleItalic">Vitamin D3 supplement did not affect the development of myopia produced with form deprivation or a minus lens in tree shrews</span>. ARVO E-Abstract 6298. 2011).</p><p id="par0215" class="elsevierStylePara elsevierViewall">Other arguments against the role of UV light have come from other experimental studies. Ashby et al. found that intermittent exposure 15<span class="elsevierStyleHsp" style=""></span>min per day to intense quartz-halogen lighting (15,000<span class="elsevierStyleHsp" style=""></span>lx), with a UV-absorbing glass protecting cover that blocked wavelengths below 400<span class="elsevierStyleHsp" style=""></span>nm delayed the development of form deprivation myopia in chickens. As the said lights do not emit the UV range, this constitutes evidence against the role of those wavelengths in this protective effect.<a class="elsevierStyleCrossRef" href="#bib1705"><span class="elsevierStyleSup">150</span></a> Smith et al. found a comparative effect in rhesus monkeys. High environmental lighting utilizing lamps with filters to eliminate wavelengths below 360<span class="elsevierStyleHsp" style=""></span>nm (with a lighting intensity of approximately 25,000<span class="elsevierStyleHsp" style=""></span>lx) delayed the development of form deprivation myopia.<a class="elsevierStyleCrossRef" href="#bib1770"><span class="elsevierStyleSup">163</span></a> Hammond and Wildsoet did not find any protective effect over the compensation response of chicks for optical defocus, either under white light or UV light with a moderately high intensity (200<span class="elsevierStyleHsp" style=""></span>lx).<a class="elsevierStyleCrossRef" href="#bib1775"><span class="elsevierStyleSup">164</span></a> Recently, Karouta et al. found a significant correlation between the intensity of light and the development of form deprivation myopia in chickens. Said researchers found that exposure to 40,000<span class="elsevierStyleHsp" style=""></span>lx 6<span class="elsevierStyleHsp" style=""></span>h per day almost completely prevented the appearance of form deprivation myopia and, once myopia began, it halted its additional progression. The lighting system comprise a combination of two light sources within a range of 400–650<span class="elsevierStyleHsp" style=""></span>nm and 430–700<span class="elsevierStyleHsp" style=""></span>nm, which did not emit in the infrared or UV.<a class="elsevierStyleCrossRef" href="#bib1780"><span class="elsevierStyleSup">165</span></a> Karouta et al. considered these results as well as those by Ashby et al., Smith et al. and Hammond and Wildsoet as an argument supporting the hypothesis that UV exposure does not modify the compensation response for form deprivation. However, even though this conclusion is feasible, it cannot be drawn on the basis of said data. In order to discard any effect of intense UV light on form deprivation myopia, it would be necessary to carry out an experiment with animals exposed to high levels of UV lighting (above the 200<span class="elsevierStyleHsp" style=""></span>lx applied by Hammond and Wildsoet).<a class="elsevierStyleCrossRef" href="#bib1785"><span class="elsevierStyleSup">166</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">On the other hand, the conclusions about the effect of exposure to light on compensation to optical defocus with lenses have been less definitive with different types of light sources. Ashby and Schaeffel found that exposure to high ambient luminance (15,000<span class="elsevierStyleHsp" style=""></span>lx, wavelength 300–1.000<span class="elsevierStyleHsp" style=""></span>nm, peaking at 700<span class="elsevierStyleHsp" style=""></span>nm) initially decelerated the compensation to the defocus generated by negative lenses in chickens. However, refraction at study endpoint on day 6 did not change.<a class="elsevierStyleCrossRef" href="#bib1705"><span class="elsevierStyleSup">150</span></a> In addition, as discussed above, Hammond and Wildsoet reported that in chickens raised under moderately high light intensity conditions (200<span class="elsevierStyleHsp" style=""></span>lx) with light spectrum close to UV as well as on white light of the same intensity (200<span class="elsevierStyleHsp" style=""></span>lx), did not produce any protective effect against the compensation to the defocus imposed by negative lenses.<a class="elsevierStyleCrossRef" href="#bib1775"><span class="elsevierStyleSup">164</span></a> In monkeys, Smith et al. did not find either that exposure to high light intensities (25,000<span class="elsevierStyleHsp" style=""></span>lx) influenced the degree of myopia induced by the use of a negative lens.<a class="elsevierStyleCrossRef" href="#bib1790"><span class="elsevierStyleSup">167</span></a> However, if the two paradigms of experimental myopia in animals (negative lens induced and form deprivation) share similar mechanisms is an unresolved issue.<a class="elsevierStyleCrossRef" href="#bib1795"><span class="elsevierStyleSup">168</span></a> In 2015, Nickla et al. published the results of a study on chickens that were administered intravitreal injections of muscarinic toxin 3 (MT3) and utilized monocular diffusers or negative lenses. MT3 inhibited myopia in response to formdeprivation but did not inhibit the development of myopiain response to hyperopic defocus. These results apparently support the existence of different muscarinic mechanisms in the excessive growth of the eye, produced on the one hand by the open circuit condition of form deprivation versus on the other hand hyperopic defocus, which is a closed circuit condition.<a class="elsevierStyleCrossRef" href="#bib1800"><span class="elsevierStyleSup">169</span></a> There are also differences in the gene expression patterns between both paradigms. However, it seems a lot more work needs to be done to understand the meaning of the gene expression of the altered retina under these conditions.<a class="elsevierStyleCrossRefs" href="#bib1805"><span class="elsevierStyleSup">170,171</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diet and insulin resistance</span><p id="par0225" class="elsevierStylePara elsevierViewall">In 2002, Cordain et al. pointed out that diet could play a role in the pathogenesis of juvenile myopia onset through the interaction with hormone-mediated regulation that influence the growth of the vitreous chamber.<a class="elsevierStyleCrossRef" href="#bib1815"><span class="elsevierStyleSup">172</span></a> The arguments supporting this environmental effect on myopia, which could eventually be acting on information inherited through epigenetics, as has been proposed by some researchers, are suggested by the differences in the phenotypic expression of myopia in monozygotic twins.<a class="elsevierStyleCrossRef" href="#bib1545"><span class="elsevierStyleSup">118</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">In 1969 it was reported that the myopia rates in 508 recently acculturated Eskimos in Barrow (Alaska, USA) varied significantly depending on age. In subjects over 41 the rate of myopia was very low (1.5%), while the examination of subjects between 11 and 40 indicated a much higher rate of myopia (51.4%).<a class="elsevierStyleCrossRef" href="#bib1820"><span class="elsevierStyleSup">173</span></a> The notorious difference in the myopia rates between both groups could be related to the lifestyle changes: the majority of older adults grew up and lived most of their first years with the traditional customs of aboriginal Eskimos and had very little or no education, whereas many of their children and grandchildren had been educated in the North American style.</p><p id="par0235" class="elsevierStylePara elsevierViewall">In a similar study carried out in 1973, recently acculturated Eskimos and aborigins living in the Yukon and Northwest Territories of Canada exhibited age-dependent reductions in myopia rates similar to those of the Alaska Eskimos.<a class="elsevierStyleCrossRef" href="#bib1825"><span class="elsevierStyleSup">174</span></a> The prevalence of myopia (between 25–35%) in younger subjects was similar to the rates found in totally Westernized countries, whereas the incidence of myopia in older subjects (between 30 and 60 years of age) was closer to the myopia rates of African tribes (between 2 and 7%). This rapid and drastic increase in the prevalence of myopia in a single generation took place too quickly to attribute it to purely genetic causes. Therefore, it is possible that environmental factors epigenetically induced the phenotypic expression of myopia. Increased work in near sight conditions and educational pressure on younger subjects could have influenced the higher myopia rates vis-à-vis the elders. However, other factors such as dietary changes and above all the increase in carbohydrate intake, might have also affected the structure of the growing eyes.<a class="elsevierStyleCrossRefs" href="#bib1545"><span class="elsevierStyleSup">118,175</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">The influence of lifestyle on the refractive status of eyes is possibly supported by the relatively high rate of myopia (18.4%) found in 1993 among urban fishermen in Hong Kong who had never attended school. This supports the participation of other factors related to the Westernized lifestyle (including dietary changes).<a class="elsevierStyleCrossRef" href="#bib1405"><span class="elsevierStyleSup">90</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">In Eskimo groups who underwent Western acculturation the individual consumption of sugar in all its forms went from 11.8<span class="elsevierStyleHsp" style=""></span>kg in 1959 to 47.4<span class="elsevierStyleHsp" style=""></span>kg in 1967, and the consumption per capita of cereals and flour products increased from 71.0 in 1959 to 80.0<span class="elsevierStyleHsp" style=""></span>kg in 1967. This demonstrates the addition of a high load of high glycemic carbohydrates in their diet.<a class="elsevierStyleCrossRef" href="#bib1835"><span class="elsevierStyleSup">176</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">In the past four decades, growing evidence has demonstrated that the consumption of food having high glycemic index increases the risk of acute as well as chronic hyperinsulinemia.<a class="elsevierStyleCrossRefs" href="#bib1840"><span class="elsevierStyleSup">177–179</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Over 10 years ago, Cordain et al. published an excellent review of the small amount of literature published until then about this possible link and formulated an interesting hypothesis about the etiology of myopia in relation to insulin resistance.<a class="elsevierStyleCrossRefs" href="#bib1815"><span class="elsevierStyleSup">172,180</span></a> It was demonstrated that compensatory hyperinsulinemia, promoted by the consumption of refined sugars and starch, suppresses the liver synthesis of the insulin-like growth factor binding protein-one (IGFBP-1). This diminished IGFBP-1 level leads to an increase in the free levels of the insulin-like growth factor-1 (IGF-1) that is produced in the liver. In its free-form, IGF-1 is a potent growth stimulator for all cells, including scleral chondrocytes and fibroblasts in animals, and can thus lead to scleral growth. In addition, hyperinsulinemia diminishes the IGFBP-3 levels and through this mechanism axial elongation could increase.<a class="elsevierStyleCrossRefs" href="#bib1815"><span class="elsevierStyleSup">172,180–182</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">In 2010, Lin et al. reported that, after analyzing the data of 851 healthy Chinese schoolchildren (energy intake, carbohydrates, proteins, overall fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, iron, calcium, vitamins A and C, fiber, starch and sugar), they found that higher intake of saturated fats and cholesterol was associated to longer axial length. However, the total daily intake of all the other analyzed nutrients was not related to more myopic spherical equivalents or longer axial lengths, or with in the presence of myopia.<a class="elsevierStyleCrossRef" href="#bib1870"><span class="elsevierStyleSup">183</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Recently, the authors of this review published a review on the above hypothesis<a class="elsevierStyleCrossRef" href="#bib1875"><span class="elsevierStyleSup">184</span></a> and found that, in general, low and middle-income countries have at present higher prevalence of myopia than higher income countries. This was proposed to be a consequence of less exposure time to a modern “Westernized” lifestyle, involving important changes in dietary habits. This phenomenon could also be related to the rapid increase of cardiovascular and metabolic diseases, such as diabetes, among these populations, changes that are almost parallel to those seen in the prevalence of myopia. Said authors proposed that the interactions between genetics, epigenetics and rapidly changing environmental conditions could be involved in the onset and progression of myopia.<a class="elsevierStyleCrossRef" href="#bib1875"><span class="elsevierStyleSup">184</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">According to some experts, it seems to be too early to discard the hypothesis of hyperinsulinemia in the development of myopia (Saw SM. Personal communication, November 15, 2015). The authors agree with this and believe that more and appropriately executed studies are required on diet (with validated eating frequency questionnaires) and myopia.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ambient lighting</span><p id="par0275" class="elsevierStylePara elsevierViewall">In a book published in 1886, Cohn compared the levels of lighting in classrooms with a number of myopic children in them and found a negative correlation between those data: the higher lighting levels, the less number of myopic children. He reached the conclusion that the size of windows in classrooms should be at least a fifth part of its overall surface.<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">69,185</span></a> In a book published in English in 1899, Fuchs stated that factors causing myopia were “approximation of written text” and “the lack of sufficient light” for reading. He recommended doing near sight schoolwork at the furthest possible distance from the eyes, to avoid working with artificial light and interrupting near sight work at frequent intervals to rest the eyes by gazing at longer distances, in addition to increasing outdoor exercising.<a class="elsevierStyleCrossRef" href="#bib1305"><span class="elsevierStyleSup">70</span></a> In the early 20<span class="elsevierStyleSup">th</span> century, “eyesight-saving schools” were established in Europe as well as in North America, which recommended using larger size letters, working with learning tools at a longer distance instead of close to the eyes and to ensure high levels of natural light in classrooms, in the belief that avoiding prolonged accommodation could prevent the appearance or slow down the progression of myopia in childhood. Up to the 1950s, high levels of natural light were a legal requirement in British schools, until the controversy about the actual benefits of natural light compared to artificial lighting came to public awareness, with very little evidence supporting said requirement. Together with conclusions about the genetic influence of myopia, the legal requirement on natural light in classrooms was repealed.<a class="elsevierStyleCrossRefs" href="#bib1310"><span class="elsevierStyleSup">71,186–190</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">However, recent research has revived the issue that the amount of light in schools could influence the appearance and progression of myopia. Hua et al. published in 2015 the results of improvements in artificial lighting systems in several Chinese schools and found that this intervention in lighting seemed to have a protective effect on axial growth both for myopic and non-myopic children. Prior to these changes, classrooms had fluorescent tubes that reached a mean luminance on blackboards and desks below 300 and 500<span class="elsevierStyleHsp" style=""></span>lx, respectively (the authors did not provide the exact data). After said changes, the mean luminance of desks increased to 558<span class="elsevierStyleHsp" style=""></span>lx on average, while the mean luminance of blackboards increased to approximately 440<span class="elsevierStyleHsp" style=""></span>lx. As the intensity of light is not close to outdoor levels (or those of experimental animal models), the mechanism of the presumed protective effect is not clear. As discussed in a previous section, the release of dopamine or achieving a clearer image of the retina could be possible explanations which, however, are not proven.<a class="elsevierStyleCrossRefs" href="#bib1900"><span class="elsevierStyleSup">189,191</span></a> An important shortcoming of said study was that among 1907 potential participants of 4 schools, only 317 children were included (178 in the intervention group and 139 in the control group). It is difficult to draw conclusions from such a small sample. In addition, as the authors admitted, the study lacked random individual allocation, which gave rise to the possibility of selection bias. The study included only children in school age in rural areas, which means that their results cannot be directly extrapolated to urban populations. Lastly, the intervention program was not rigorous in what concerns luminance and uniformity of blackboards.<a class="elsevierStyleCrossRef" href="#bib1900"><span class="elsevierStyleSup">189</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">Recently, a research group in China designed and built a classroom to enable the exposure to natural light at the same intensity as outdoors. The classroom was built with transparent light-diffusing glass with a user-controlled shadow canopy that could be extended in sunny conditions. As expected, said researchers found that lighting was significantly higher than in conventional classrooms as, with the canopy drawn, the experimental classroom reached 80% of outdoor light intensity. Student comfort score in said classroom was significantly higher than in conventional classrooms, while the scores given by teachers were not different when comparing the comfort level between both types of classrooms (Chen et al. <span class="elsevierStyleItalic">Pilot study of a novel classroom designed to prevent myopia by increasing children's exposure to outdoor light.</span> E-Abstract # 2948 ARVO, 2015). The researchers reported that they are planning an intervention study. This field of research is very promising because if said results are confirmed and the results of the lighting intervention can be reproduced in future studies, these measures could be easily applied on over the world. The authors are planning a study of this nature with primary school students in Bucaramanga (Colombia).</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusion</span><p id="par0290" class="elsevierStylePara elsevierViewall">The prevalence of myopia is increasing rapidly in many countries, above all in Southeast Asia. This phenomenon can not be explained only through genetics. Environmental factors play an important role, but we are very far from understanding the complete pathogenesis of myopia. Traditionally, working in near sight conditions and educational pressure had been regarded as the main environmental factors associated to myopic changes in young age, although contradictory evidence has emerged. Interest in other recently proposed factors, such as time spent outdoors and indoor lighting has increased. Considering that even partial prevention of myopic progression could provide substantial benefits, it is essential to continue to define possible environmental factors that may influence the onset and progression of myopia, since a combination of several of these measures showing partial positive effects and few side effects, can be useful.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0295" class="elsevierStylePara elsevierViewall">This paper received partial financial support from the Administrative Department of Science, Technology and Innovation (<span class="elsevierStyleItalic">Departamento Administrativo de Ciencia, Tecnología e Innovación</span>) (Colciencias), a governmental institution of the Republic of Colombia, within the project named “Determination of the prevalence of myopia and its association with environmental factors in urban and rural populations of Colombia, MIOPUR study”. Code 651756933785. Call 569, 2012. Contract 495-2013.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0300" class="elsevierStylePara elsevierViewall">No conflict of interests was declared by the authors.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres856909" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec850954" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres856910" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec850955" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Systematic review methodology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Environmental factors related to myopia" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Education level" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Near work and accommodation" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Lifestyle and urbanization" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Outdoor activities" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Diet and insulin resistance" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Ambient lighting" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 10 => array:2 [ "identificador" => "xack287336" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-07-20" "fechaAceptado" => "2016-11-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec850954" "palabras" => array:6 [ 0 => "Myopia" 1 => "Genetics of myopia" 2 => "Myopia environmental factors" 3 => "Near-vision work and myopia" 4 => "Myopia prevention" 5 => "Exposure to sunlight and myopia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec850955" "palabras" => array:6 [ 0 => "Miopía" 1 => "Genética de la miopía" 2 => "Factores ambientales en miopía" 3 => "Trabajo en visión próxima y miopía" 4 => "Prevención de la miopía" 5 => "Exposición a la luz ambiental y miopía" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Experimental studies in animals, as well as observational and intervention studies in humans, seem to support the premise that the development of juvenile myopia is promoted by a combination of the effect of genetic and environmental factors, with a complex interaction between them. The very rapid increase in myopia rates in some parts of the world, such as Southeast Asia, supports a significant environmental effect. Several lines of evidence suggest that humans might respond to various external factors, such as increased activity in near vision, increased educational pressure, decreased exposure to sunlight outdoors, dietary changes (including increased intake of carbohydrates), as well as low light levels indoors. All these factors could be associated with a higher prevalence of myopia.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Estudios experimentales en animales, así como observacionales y de intervención en humanos parecen apoyar la premisa de que el desarrollo de la miopía juvenil es promovido por una combinación del efecto de factores genéticos y ambientales, con una compleja interacción entre ellos. El muy rápido incremento de las tasas de miopía en algunas partes del mundo, como el sudeste asiático, apoyan un efecto ambiental significativo. Diversas evidencias señalan que los seres humanos podrían responder a diversos factores externos, como el incremento de las actividades en visión próxima, el aumento de la presión educativa, la disminución de la exposición a la luz solar al aire libre, los cambios dietéticos (incluyendo el incremento de la ingesta de hidratos de carbono) y la baja iluminación en interiores, y que esto se podría asociar con una mayor prevalencia de miopía.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Galvis V, Tello A, Camacho PA, Parra MM, Merayo-Lloves J. Los factores bioambientales asociados a la miopía: una revisión actualizada. Arch Soc Esp Oftalmol. 2017;92:307–325.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">GWAS, Genome-wide association study; SNP, single nucleotide polymorphisms.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author/Year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Strategy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Population \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Findings \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kiefer et al., 2013<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GWAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">45,771 European individuals \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 SNP associated to the appearance of myopia including genes related to extracellular matrix (rs12193446 related to gene LAMA2 (laminina alpha2) in chromosome 6); 2<span class="elsevierStyleHsp" style=""></span>are in or near genes involved in the regeneration of 11-cis-retinal (rs745480 related to gene RGR in chromosome 10 and rs3138142 related to gene RDH5 in chromosome 12); rs7744813 related to gene KCNQ5 in chromosome 6, that codes a potassium channel in RPE and the neurosensory retina; 2<span class="elsevierStyleHsp" style=""></span>are near genes that are known to be involved in the growth and guide of retinal ganglion cells (rs4291789 related to gene ZIC2 in chromosome 13 and rs2137277 related to gene SFRP1 in chromosome 8); and 5<span class="elsevierStyleHsp" style=""></span>are in or near genes involved in neuronal signaling or development (rs6480859 related to gene KCNMA1 in chromosome 10; rs17648524 related to gene RBFOX1 in chromosome 16; rs1381566 related to gene LRRC4<span class="elsevierStyleHsp" style=""></span>C in chromosome 11; rs2155413 related to gene DLG2 in chromosome 11 and rs11145746 related to gene TJP2 in chromosome 9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Verhoeven et al., 2013<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GWAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37,382 individuals of European ancestry and 8376 of Asian ancestry \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 new polymorphisms were identified close to genes related to myopia, identifying different functions: neurotransmission (polymorphism SNP rs11601239 related to gene GRIA4 in chromosome 11), ion transport (rs7744813 related to gene KCNQ5 in chromosome 6), retinoic acid metabolism (rs3138144 related to gene RDH5 in chromosome 12), extracellular matrix remodeling (rs12205363 related to gene LAMA2 in chromosome 6 and rs235770 related to gene BMP2 in chromosome 20) and ocular development (rs1254319 related to gene SIX6 in chromosome 14 and rs1656404 related to gene PRSS56 in chromosome 2). The study also confirmed previously reported associations with polymorphisms SNP rs524952 related to gene GJD2 in chromosome 15 and rs4778879 related to gene RASGRF1 in chromosome 15 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wojciechowski, 2011<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Literature review \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ocular refraction in heritability estimations: 50 to 90% risk of myopia recurrence in siblings (family aggregation studies): from 2 to 5.61<br>Segregation analysis of population-based samples: complex inheritance pattern due to ocular refraction involving several genes or environmental factors.<br>Genetic association studies with myopia or syndromic:<br>16 loci: MYP2-MYP17, associated to high myopia.<br>Genes involved in production and remodeling of extracellular matrix:<br>COL2A1, COL1A1, TGFB1, TGFB2, TGIF1, HGF, CMET, IGF1, MMP1, MMP2, MMP3, MMP9 and LUM. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hysi et al., 2014<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">25</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Literature review \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GWAS:<br>High myopia:<br>- rs577948 located in 11q24.1 near BLID gene<br>- rs6885224 within gene CTNND2 in 5p15.2<br>- rs10034228 within gene MYP1121 in 4q25<br>- rs9318086 within gene MIPEP en13q12<br>- rs8027411 near gene RASGRF1 in 15q25.1<br>- rs634990 near GJD2 gene in 15q14<br>- rs189798 within MYP10 in 8p23 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hawthorne and Young, 2013<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">42</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Literature review \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Loci related with myopia through genetic binding: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP1, Chromosome <span class="elsevierStyleSmallCaps">X</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP2, chromosomes 18, 19 and 20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP3, chromosomes 12, 13 and 14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP4, chromosomes 7, 9 and 10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP5, chromosome 17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP6, chromosome 22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP7, chromosome 11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP8, chromosome 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP9, chromosome 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP10, chromosome 8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP11, chromosome 4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP12, chromosomes 2 and 6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP13, chromosome <span class="elsevierStyleSmallCaps">X</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP14,chromosomes 1, 2, 3, 4, 5 and 6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP15, chromosomes 10 and 12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP16, chromosome 5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP17, chromosomes 7,9 and 14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP18, chromosomes 14, 15, 16 and 17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP19, chromosomes 5 and 6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- MYP21, chromosomes 1 and 2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Genes related to myopia:<br>COL2A1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>12q13,11<br>HGF<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>7q21,11<br>MMP1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>11q22,2<br>MMP2<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>16q12,2<br>PAX6<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>11p13<br>SERPINI2<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span> 3q26,1<br>VDR<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>12q13,11<br>ADORA2A<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>22q11,23<br>BMP2<span class="elsevierStyleHsp" style=""></span>K<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>4q21,21<br>C1QTNF9B<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>13q12,12<br>CHRM1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>11q12,3<br>CHRM2<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>7q33<br>CHRM3<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q43<br>CHRM4<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>11p11,2<br>COL1A1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>17q21,33<br>COL2A1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>12q13,11<br>CRYBA4<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>22q12,1<br>CTNND2<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>5p15,2<br>FMOD<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q32,1<br>GRM6<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>5q35,3<br>HGF<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>7q21,11<br>HLA-DQB1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span> 6p21,32<br>DQ beta 1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>6p21,32<br>IGF1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>12q23,2<br>LAMA1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>18p11,31-p11,23<br>LRPEEL1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>3q28<br>LUM<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>12q21,33<br>LYPLAL1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q41<br>MIPEP<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>13q12,12<br>MYOC<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>bication:<span class="elsevierStyleHsp" style=""></span>1q24,3<br>NYX<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span> Xp11,4<br>OPTC<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q32,1<br>PAX6<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>11p13<br>PRELP<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q32,1<br>RASGRF1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>15q25<br>SLC30A10<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q41<br>TGFB1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>19q13,2<br>TGFB2<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q41<br>TGIF<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>18p11,31<br>UMODL1<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>21q22,3<br>ZC3H11B<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1q41<br>ZNF644<span class="elsevierStyleHsp" style=""></span>location:<span class="elsevierStyleHsp" style=""></span>1p22,2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Zhang, 2015<a class="elsevierStyleCrossRef" href="#bib1170"><span class="elsevierStyleSup">43</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Literature review (only GWAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reviewing the results of 2 large studies with the GWAS approach (the CREAM consortium and the 23anMde database) a significant association was identified between refractive error or myopia onset age and SNP Mia the 12 following genes in both studies:<br>PRSS56 (OMIM <span class="elsevierStyleInterRef" id="intr0005" href="omim:613858">613858</span>)<br>BMP3 (OMIM <span class="elsevierStyleInterRef" id="intr0010" href="omim:112263">112263</span>)<br>KCNQ5 (OMIM <span class="elsevierStyleInterRef" id="intr0015" href="omim:607357">607357</span>)<br>LAMA2 (OMIM <span class="elsevierStyleInterRef" id="intr0020" href="omim:156225">156225</span>)<br>TOX (OMIM <span class="elsevierStyleInterRef" id="intr0025" href="omim:606863">606863</span>)<br>TJP2 (OMIM <span class="elsevierStyleInterRef" id="intr0030" href="omim:607709">607709</span>)<br>RDH5 (OMIM <span class="elsevierStyleInterRef" id="intr0035" href="omim:601617">601617</span>)<br>ZIC2 (OMIM <span class="elsevierStyleInterRef" id="intr0040" href="omim:603073">603073</span>)<br>RASGRF1 (OMIM <span class="elsevierStyleInterRef" id="intr0045" href="omim:606600">606600</span>)<br>GJD2 (OMIM <span class="elsevierStyleInterRef" id="intr0050" href="omim:607058">607058</span>)<br>RBFOX1 (OMIM <span class="elsevierStyleInterRef" id="intr0055" href="omim:605104">605104</span>)<br>SHISA6 (HGNC 34491). \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1447583.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Summary of GWAS studies and recent reviews on the genetics of myopia.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:191 [ 0 => array:3 [ "identificador" => "bib0960" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The economics of myopia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ …4] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0965" "etiqueta" => "2" "referencia" => 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analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pgen.1003299" "Revista" => array:5 [ …5] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib1010" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.2554" "Revista" => array:6 [ …6] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib1015" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular genetics of human myopia: an update" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/OPX.0b013e3181940655" "Revista" 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array:2 [ "doi" => "10.1001/jamaophthalmol.2015.0471" "Revista" => array:6 [ …6] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib1035" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Family history, near work, outdoor activity, and myopia in Singapore Chinese preschool children" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/bjo.2009.173187" "Revista" => array:6 [ …6] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib1040" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nature and nurture: the complex genetics of myopia and refractive error" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1399-0004.2010.01592.x" "Revista" => array:6 [ …6] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib1045" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early childhood refractive error and parental history of myopia as predictors of myopia" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1167/iovs.08-3210" "Revista" => array:6 [ …6] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib1050" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The future of myopia control contact lenses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/OPX.0000000000000762" "Revista" => array:6 [ …6] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib1055" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of having myopic parents: an analysis of myopia in three generations" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib1060" 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governmental institution of the Republic of Colombia, for its support to this research within the project named “Determination of the prevalence of myopia and its association with environmental factors in urban and rural populations of Colombia, MIOPUR study”.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/21735794/0000009200000007/v1_201706250033/S2173579417300464/v1_201706250033/en/main.assets" "Apartado" => array:4 [ "identificador" => "5815" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735794/0000009200000007/v1_201706250033/S2173579417300464/v1_201706250033/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579417300464?idApp=UINPBA00004N" ]
