Letters
thrombocytopenia following histone infusion into mice1,2 and suggest that, if confirmed, circulating histones may be valuable in predicting or monitoring thrombocytopenia in patients who are critically ill. Yasir Alhamdi, MBChB, PhD Simon T. Abrams, PhD Steven Lane, PhD Guozheng Wang, MD, PhD Cheng-Hock Toh, MD Author Affiliations: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (Alhamdi, Abrams, Wang, Toh); Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (Lane). Corresponding Author: Cheng-Hock Toh, MD, Institute of Infection and Global Health, University of Liverpool, Ronald Ross Building, 8 West Derby St, Liverpool L69 7BE, United Kingdom ([email protected]). Author Contributions: Drs Alhamdi and Toh had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Alhamdi, Wang, Toh. Acquisition, analysis, or interpretation of data: Alhamdi, Abrams, Lane, Wang, Toh. Drafting of the manuscript: Alhamdi, Toh. Critical revision of the manuscript for important intellectual content: Alhamdi, Abrams, Lane, Wang, Toh. Statistical analysis: Alhamdi, Abrams, Lane. Obtained funding: Wang, Toh. Administrative, technical, or material support: Wang. Study supervision: Wang, Toh. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: This work was funded by the National Institute of Health Research, British Heart Foundation, and the Royal Liverpool & Broadgreen University Hospitals NHS Trust. Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-3714. 2. Abrams ST, Zhang N, Dart C, et al. Human CRP defends against the toxicity of circulating histones. J Immunol. 2013;191(5):2495-2502. 3. Alhamdi Y, Abrams ST, Cheng Z, et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10): 2094-2103. 4. Abrams ST, Zhang N, Manson J, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2): 160-169. 5. De Labriolle A, Bonello L, Lemesle G, et al. Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors. Eur Heart J. 2010;31 (9):1079-1087. 6. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318-1321.
COMMENT & RESPONSE
School-Based Myopia Prevention Effort To the Editor The school-based myopia prevention trial conducted by Dr He and colleagues1 supports what has been noted in observational studies2 that more time spent outdoors rejama.com
duces the risk of myopia in children. However, one important issue regarding this finding has not been fully addressed by the authors. Longitudinal cohort studies have indic ated that more time spent outdoors has a significant protective effect on myopia onset, but not its progression.3,4 In other words, spending more time outdoors is only effective in children without myopia, but not in children with existing myopia. In their analysis of 3-year changes in spherical equivalent refraction, which is an indicator for the progression of myopia, the effect size of the intervention was small and marginally significant (P = .04), consistent with current epidemiological data. Therefore, strategies for preventing myopia and retarding its progression should be different. Further studies are warranted to investigate how to control myopia progression, which is important in reducing the burden of pathological myopia and other myopia-related ocular complications.5 Chen-Wei Pan, MD, PhD Hu Liu, MD, PhD Author Affiliations: School of Public Health, Medical College of Soochow University, Suzhou, China (Pan); Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Liu). Corresponding Author: Chen-Wei Pan, MD, PhD, School of Public Health, Medical College of Soochow University, 199 Ren Ai Rd, Suzhou 215123, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. He M, Xiang F, Zeng Y, et al. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA. 2015;314(11):1142-1148. 2. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology. 2008;115(8):1279-1285. 3. Li SM, Li H, Li SY, et al; Anyang Childhood Eye Study Group. Time outdoors and myopia progression over 2 years in Chinese children: the Anyang Childhood Eye Study. Invest Ophthalmol Vis Sci. 2015;56(8):4734-4740. 4. Jones-Jordan LA, Sinnott LT, Cotter SA, et al; CLEERE Study Group. Time outdoors, visual activity, and myopia progression in juvenile-onset myopes. Invest Ophthalmol Vis Sci. 2012;53(11):7169-7175. 5. Pan CW, Cheung CY, Aung T, et al. Differential associations of myopia with major age-related eye diseases: the Singapore Indian Eye Study. Ophthalmology. 2013;120(2):284-291.
To the Editor In their study on 6-year-old primary school children, Dr He and colleagues1 evaluated the effect of adding 40 extra minutes of outdoor activities to each school day on the 3-year cumulative incidence of myopia. The results showed that the cumulative incidence of myopia was 30.4% in the intervention group and 39.5% in the control group (P < .001). Although the authors studied many potential confounders, they failed to document near-work activity, another important factor in the development of juvenile myopia.2 Several previous studies have established the role of near work on the development of myopia.3,4 Children who are within the ages evaluated in He et al’s study often are (Reprinted) JAMA February 23, 2016 Volume 315, Number 8
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Massachusetts Amherst User on 02/24/2016
819
Letters
engaged in a variety of near-work activities, such as reading, painting, and playing with electronic devices, all of which are usually implemented indoors. Adding a 40-minute per day mandator y outdoor activity may proportionately decrease the daily level of near-work activity by shortening the time spent indoors. This issue has the potential to confound the observed protective effect of outdoor activity as an independent factor for developing myopia. The authors should consider conducting a reanalysis of their data, controlling for near-work activity. M. Hossein Nowroozzadeh, MD Author Affiliation: Poostchi Eye Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Corresponding Author: M. Hossein Nowroozzadeh, MD, Poostchi Eye Research Center, Poostchi Eye Clinic, Zand Street, Shiraz, Iran 7134997446 (norozzadeh @gmail.com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. He M, Xiang F, Zeng Y, et al. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA. 2015;314(11):1142-1148. 2. Goss DA. Nearwork and myopia. Lancet. 2000;356(9240):1456-1457. 3. Saw SM, Chua WH, Hong CY, et al. Nearwork in early-onset myopia. Invest Ophthalmol Vis Sci. 2002;43(2):332-339. 4. Hepsen IF, Evereklioglu C, Bayramlar H. The effect of reading and near-work on the development of myopia in emmetropic boys: a prospective, controlled, three-year follow-up study. Vision Res. 2001;41(19):2511-2520.
In Reply The results of our trial showed a statistically significant reduction in the level of incident myopia and a moderate reduction on overall change in spherical equivalent refraction, but no effect on progression. However, it should be noted that the prevalence of myopia in the study sample was low at baseline, and thus an analysis of progression does not have great statistical power. Drs Pan and Liu suggest that time outdoors does not affect progression, and that other strategies will be needed to control progression. We did not find effects on progression, which is consistent with most of the evidence from longitudinal studies and another clinical trial from Taiwan.1 However, there is conflicting evidence2 and evidence of seasonal effects, which suggest that progression rates can be regulated by environmental factors. Even if it is established that progression is not regulated by time outdoors, delay in onset of myopia is likely to lead to less progression. Progression rates tend to decline with age, and thus a delay in onset should leave less time for progression and at lower rates. Increased time outdoors could be used for public health prevention of incident myopia, with additional clinical strategies, such as low-dose atropine and orthokeratology, to control progression in those who nevertheless develop myopia. Dr Nowroozzadeh raises the question of whether the protective effect seen in the trial resulted from the increase in time spent outdoors or from an associated 820
reduction in time spent on near-work activity. In the trial, the curriculum intervention added one additional 40-minute class of supervised outdoor time at the end of every school day. The trial did not alter any other teaching activities, and the children in the intervention group followed the normal school curriculum. We therefore assume that there was no change in the time these children spent on near work at school. The children in the intervention group had more time outdoors at school and the same amount of time as the children in the control group outside school hours, but we cannot exclude the possibility that they also spent less time on near-work activity outside school hours. However, given the emphasis on homework in China, this is not likely. The epidemiological evidence has also addressed this issue, in which 2 studies3,4 concluded that the protective effect of time outdoors was not due to a substitution effect in which more time outdoors meant less near-work activity. In fact, there were complex interactions between the amount of near-work activity and the amount of time spent outdoors. We are currently studying these nonlinear interactions in more detail. There is also experimental evidence that increased light exposure at intensities similar to those encountered outdoors reduces the development of form-deprivation myopia in animal models,5 so there is reason to believe that increased time outdoors is responsible for at least some of the protective effect observed. Whether a reduction in time spent on near work also contributes to the effect is not clear, but from a preventive perspective, this is not crucial, provided that the intervention works. Nevertheless, future work to clarify these issues is important. Mingguang He, MD, PhD Ian G. Morgan, PhD Author Affiliations: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Corresponding Author: Mingguang He, MD, PhD, Zhongshan Ophthalmic Center, Guangzhou 510060, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr He reported receiving grants from the Fundamental Research Funds of the State Key Laboratory in Ophthalmology, National Natural Science Foundation of China, and University of Melbourne Research at Melbourne Accelerator Program Professorship. No other disclosures were reported. 1. Wu PC, Tsai CL, Wu HL, Yang YH, Kuo HK. Outdoor activity during class recess reduces myopia onset and progression in school children. Ophthalmology. 2013;120(5):1080-1085. 2. Pärssinen O, Lyyra AL. Myopia and myopic progression among schoolchildren: a three-year follow-up study. Invest Ophthalmol Vis Sci. 1993;34 (9):2794-2802. 3. Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger ML, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci. 2007;48(8):3524-3532. 4. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology. 2008;115(8):1279-1285. 5. Ashby R, Ohlendorf A, Schaeffel F. The effect of ambient illuminance on the development of deprivation myopia in chicks. Invest Ophthalmol Vis Sci. 2009; 50(11):5348-5354.
JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Massachusetts Amherst User on 02/24/2016
jama.com
thrombocytopenia following histone infusion into mice1,2 and suggest that, if confirmed, circulating histones may be valuable in predicting or monitoring thrombocytopenia in patients who are critically ill. Yasir Alhamdi, MBChB, PhD Simon T. Abrams, PhD Steven Lane, PhD Guozheng Wang, MD, PhD Cheng-Hock Toh, MD Author Affiliations: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (Alhamdi, Abrams, Wang, Toh); Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (Lane). Corresponding Author: Cheng-Hock Toh, MD, Institute of Infection and Global Health, University of Liverpool, Ronald Ross Building, 8 West Derby St, Liverpool L69 7BE, United Kingdom ([email protected]). Author Contributions: Drs Alhamdi and Toh had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Alhamdi, Wang, Toh. Acquisition, analysis, or interpretation of data: Alhamdi, Abrams, Lane, Wang, Toh. Drafting of the manuscript: Alhamdi, Toh. Critical revision of the manuscript for important intellectual content: Alhamdi, Abrams, Lane, Wang, Toh. Statistical analysis: Alhamdi, Abrams, Lane. Obtained funding: Wang, Toh. Administrative, technical, or material support: Wang. Study supervision: Wang, Toh. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: This work was funded by the National Institute of Health Research, British Heart Foundation, and the Royal Liverpool & Broadgreen University Hospitals NHS Trust. Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-3714. 2. Abrams ST, Zhang N, Dart C, et al. Human CRP defends against the toxicity of circulating histones. J Immunol. 2013;191(5):2495-2502. 3. Alhamdi Y, Abrams ST, Cheng Z, et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10): 2094-2103. 4. Abrams ST, Zhang N, Manson J, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2): 160-169. 5. De Labriolle A, Bonello L, Lemesle G, et al. Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors. Eur Heart J. 2010;31 (9):1079-1087. 6. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318-1321.
COMMENT & RESPONSE
School-Based Myopia Prevention Effort To the Editor The school-based myopia prevention trial conducted by Dr He and colleagues1 supports what has been noted in observational studies2 that more time spent outdoors rejama.com
duces the risk of myopia in children. However, one important issue regarding this finding has not been fully addressed by the authors. Longitudinal cohort studies have indic ated that more time spent outdoors has a significant protective effect on myopia onset, but not its progression.3,4 In other words, spending more time outdoors is only effective in children without myopia, but not in children with existing myopia. In their analysis of 3-year changes in spherical equivalent refraction, which is an indicator for the progression of myopia, the effect size of the intervention was small and marginally significant (P = .04), consistent with current epidemiological data. Therefore, strategies for preventing myopia and retarding its progression should be different. Further studies are warranted to investigate how to control myopia progression, which is important in reducing the burden of pathological myopia and other myopia-related ocular complications.5 Chen-Wei Pan, MD, PhD Hu Liu, MD, PhD Author Affiliations: School of Public Health, Medical College of Soochow University, Suzhou, China (Pan); Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Liu). Corresponding Author: Chen-Wei Pan, MD, PhD, School of Public Health, Medical College of Soochow University, 199 Ren Ai Rd, Suzhou 215123, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. He M, Xiang F, Zeng Y, et al. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA. 2015;314(11):1142-1148. 2. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology. 2008;115(8):1279-1285. 3. Li SM, Li H, Li SY, et al; Anyang Childhood Eye Study Group. Time outdoors and myopia progression over 2 years in Chinese children: the Anyang Childhood Eye Study. Invest Ophthalmol Vis Sci. 2015;56(8):4734-4740. 4. Jones-Jordan LA, Sinnott LT, Cotter SA, et al; CLEERE Study Group. Time outdoors, visual activity, and myopia progression in juvenile-onset myopes. Invest Ophthalmol Vis Sci. 2012;53(11):7169-7175. 5. Pan CW, Cheung CY, Aung T, et al. Differential associations of myopia with major age-related eye diseases: the Singapore Indian Eye Study. Ophthalmology. 2013;120(2):284-291.
To the Editor In their study on 6-year-old primary school children, Dr He and colleagues1 evaluated the effect of adding 40 extra minutes of outdoor activities to each school day on the 3-year cumulative incidence of myopia. The results showed that the cumulative incidence of myopia was 30.4% in the intervention group and 39.5% in the control group (P < .001). Although the authors studied many potential confounders, they failed to document near-work activity, another important factor in the development of juvenile myopia.2 Several previous studies have established the role of near work on the development of myopia.3,4 Children who are within the ages evaluated in He et al’s study often are (Reprinted) JAMA February 23, 2016 Volume 315, Number 8
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Massachusetts Amherst User on 02/24/2016
819
Letters
engaged in a variety of near-work activities, such as reading, painting, and playing with electronic devices, all of which are usually implemented indoors. Adding a 40-minute per day mandator y outdoor activity may proportionately decrease the daily level of near-work activity by shortening the time spent indoors. This issue has the potential to confound the observed protective effect of outdoor activity as an independent factor for developing myopia. The authors should consider conducting a reanalysis of their data, controlling for near-work activity. M. Hossein Nowroozzadeh, MD Author Affiliation: Poostchi Eye Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Corresponding Author: M. Hossein Nowroozzadeh, MD, Poostchi Eye Research Center, Poostchi Eye Clinic, Zand Street, Shiraz, Iran 7134997446 (norozzadeh @gmail.com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. He M, Xiang F, Zeng Y, et al. Effect of time spent outdoors at school on the development of myopia among children in China: a randomized clinical trial. JAMA. 2015;314(11):1142-1148. 2. Goss DA. Nearwork and myopia. Lancet. 2000;356(9240):1456-1457. 3. Saw SM, Chua WH, Hong CY, et al. Nearwork in early-onset myopia. Invest Ophthalmol Vis Sci. 2002;43(2):332-339. 4. Hepsen IF, Evereklioglu C, Bayramlar H. The effect of reading and near-work on the development of myopia in emmetropic boys: a prospective, controlled, three-year follow-up study. Vision Res. 2001;41(19):2511-2520.
In Reply The results of our trial showed a statistically significant reduction in the level of incident myopia and a moderate reduction on overall change in spherical equivalent refraction, but no effect on progression. However, it should be noted that the prevalence of myopia in the study sample was low at baseline, and thus an analysis of progression does not have great statistical power. Drs Pan and Liu suggest that time outdoors does not affect progression, and that other strategies will be needed to control progression. We did not find effects on progression, which is consistent with most of the evidence from longitudinal studies and another clinical trial from Taiwan.1 However, there is conflicting evidence2 and evidence of seasonal effects, which suggest that progression rates can be regulated by environmental factors. Even if it is established that progression is not regulated by time outdoors, delay in onset of myopia is likely to lead to less progression. Progression rates tend to decline with age, and thus a delay in onset should leave less time for progression and at lower rates. Increased time outdoors could be used for public health prevention of incident myopia, with additional clinical strategies, such as low-dose atropine and orthokeratology, to control progression in those who nevertheless develop myopia. Dr Nowroozzadeh raises the question of whether the protective effect seen in the trial resulted from the increase in time spent outdoors or from an associated 820
reduction in time spent on near-work activity. In the trial, the curriculum intervention added one additional 40-minute class of supervised outdoor time at the end of every school day. The trial did not alter any other teaching activities, and the children in the intervention group followed the normal school curriculum. We therefore assume that there was no change in the time these children spent on near work at school. The children in the intervention group had more time outdoors at school and the same amount of time as the children in the control group outside school hours, but we cannot exclude the possibility that they also spent less time on near-work activity outside school hours. However, given the emphasis on homework in China, this is not likely. The epidemiological evidence has also addressed this issue, in which 2 studies3,4 concluded that the protective effect of time outdoors was not due to a substitution effect in which more time outdoors meant less near-work activity. In fact, there were complex interactions between the amount of near-work activity and the amount of time spent outdoors. We are currently studying these nonlinear interactions in more detail. There is also experimental evidence that increased light exposure at intensities similar to those encountered outdoors reduces the development of form-deprivation myopia in animal models,5 so there is reason to believe that increased time outdoors is responsible for at least some of the protective effect observed. Whether a reduction in time spent on near work also contributes to the effect is not clear, but from a preventive perspective, this is not crucial, provided that the intervention works. Nevertheless, future work to clarify these issues is important. Mingguang He, MD, PhD Ian G. Morgan, PhD Author Affiliations: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Corresponding Author: Mingguang He, MD, PhD, Zhongshan Ophthalmic Center, Guangzhou 510060, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr He reported receiving grants from the Fundamental Research Funds of the State Key Laboratory in Ophthalmology, National Natural Science Foundation of China, and University of Melbourne Research at Melbourne Accelerator Program Professorship. No other disclosures were reported. 1. Wu PC, Tsai CL, Wu HL, Yang YH, Kuo HK. Outdoor activity during class recess reduces myopia onset and progression in school children. Ophthalmology. 2013;120(5):1080-1085. 2. Pärssinen O, Lyyra AL. Myopia and myopic progression among schoolchildren: a three-year follow-up study. Invest Ophthalmol Vis Sci. 1993;34 (9):2794-2802. 3. Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger ML, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci. 2007;48(8):3524-3532. 4. Rose KA, Morgan IG, Ip J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology. 2008;115(8):1279-1285. 5. Ashby R, Ohlendorf A, Schaeffel F. The effect of ambient illuminance on the development of deprivation myopia in chicks. Invest Ophthalmol Vis Sci. 2009; 50(11):5348-5354.
JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Massachusetts Amherst User on 02/24/2016
jama.com
