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Perspectives20 May 2003Medical Professionalism in the New Millennium: A Physician Charter 15 Months LaterFREELinda Blank, Harry Kimball, MD, Walter McDonald, MD, and Jaime Merino, MD, for the ABIM Foundation, ACP Foundation, and European Federation of Internal Medicine (EFIM)*Linda BlankFrom ABIM Foundation and ACP Foundation, Philadelphia, Pennsylvania; and European Federation of Internal Medicine, Maastricht, the Netherlands., Harry Kimball, MDFrom ABIM Foundation and ACP Foundation, Philadelphia, Pennsylvania; and European Federation of Internal Medicine, Maastricht, the Netherlands., Walter McDonald, MDFrom ABIM Foundation and ACP Foundation, Philadelphia, Pennsylvania; and European Federation of Internal Medicine, Maastricht, the Netherlands., and Jaime Merino, MDFrom ABIM Foundation and ACP Foundation, Philadelphia, Pennsylvania; and European Federation of Internal Medicine, Maastricht, the Netherlands., for the ABIM Foundation, ACP Foundation, and European Federation of Internal Medicine (EFIM)*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-138-10-200305200-00012 SectionsAboutVisual AbstractAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail AbstractFor a list of members of these organizations, see the Appendix.As we mark the 15-month anniversary of the physician charter that was published simultaneously in Annals of Internal Medicine and The Lancet in 2002 (1, 2), the members of the Medical Professionalism Project are pleased by the level of interest and activity the charter has engendered. Several hundred U.S. and international newspapers cited the charter in related stories; more than 70 radio, television, and online interviews have been conducted with individual project members; over 65 000 reprints have been requested from around the world; and, collectively, the Annals, Medical Professionalism Project and European Federation of Internal Medicine (EFIM) Web sites have logged more than 70 000 related visits. In addition, this issue of Annals features a collection of provocative Letters about the charter. Building on this level of responsiveness, the ABIM (American Board of Internal Medicine) Foundation and the ACP (American College of Physicians) Foundation will sponsor phase II of the Project, planned as a 2-year initiative. Phase II will encompass reviewing the charter's initial impact and, within that context, explore the opportunity to define the health rights and responsibilities of patients, physicians, and society.Background and RationaleThe Medical Professionalism Project, jointly sponsored by the ABIM Foundation and the ACP Foundation, began in November 1999 as a collaborative effort designed to raise the concept of professionalism within the consciousness of internal medicine, both in the United States and Europe. The two foundations, in partnership with the European Federation of Internal Medicine, are well positioned to influence the ethical and professional standards of medicine and encourage the profession to reaffirm its civic commitment.Impetus for the Project stemmed from the following question: Why is raising awareness about the core values of medical professionalism important? As the pace of change in health care accelerated and the future of medical practice became increasingly uncertain, the ABIM and ACP Foundations and European Federation of Internal Medicine saw the need to convene this collaborative project because medical professionalism is universally endangered. Physician unionization, waning ability to self-regulate, medical errors, bioterrorism, compromised access and health care delivery, conflicts of interest precipitated by managed care and for-profit medicine, and the pharmaceutical industry's role in patient care and medical education reflect the range of issues that challenge the medical profession globally. At this crossroads, the medical profession urgently needs a united front to influence and inform the culture and context of both clinical practice and medical training. The charter's three fundamental principles and set of professional responsibilities are intended to encourage such dedication and debate (Table).Table. Charter on Medical Professionalism: Fundamental Principles and Professional Responsibilities PublicationsTo date, in addition to Annals of Internal Medicine and The Lancet, the charter has been published in the following journals: Clinical Medicine (formerly Journal of the Royal College of Physicians), European Journal of Internal Medicine, American Journal of Obstetrics and Gynecology, The American Journal of Surgery, Journal of the American College of Dentists, Annals of the Royal College of Physicians and Surgeons of Canada, Canadian Medical Association Journal, The Medical Journal of Australia, Bollettino Ordine Provinciale Medici Chirurghi e Odontoiatri-Milano, La Revue de Mdecine Interne, and La Radiologia Medica. The charter has been translated into Italian, French, Spanish, Portuguese, German, and Polish. The Health Ministry of Italy also published the charter and distributed it to every medical student and faculty member throughout the country. Translations into Dutch, Swedish, Japanese, and Turkish should lead to future publication in journals written in these languages.PresentationsSince the charter's publication, project members and others have collectively given more than 100 related presentations in a variety of formats: named lectures, grand rounds, medical school graduation addresses, plenary sessions at national and international meetings, workshops, and seminars. National meetings have included those of the Association of American Medical Colleges, ACP, American College of Obstetricians and Gynecologists, American Medical Association, Arnold P. Gold Foundation, Council of Medical Specialty Societies, Accreditation Council for Graduate Medical Education, American Board of Medical Specialties, American College of Surgeons, Association for Hospital Medical Education, and Federation of State Medical Boards. International meetings have included those of the Association for Medical Education in Europe and the European School of Internal Medicine; the European Federation of Internal Medicine Congresses in Edinburgh and Berlin; the International Society of Internal Medicine Congress in Kyoto; and the Association of Canadian Medical Colleges, Ottowa Conference, and Royal College of Physicians and Surgeons of Canada.EndorsementsTo date, the following 90 professional associations, colleges, societies, and certifying boards have endorsed the charter: Accreditation Council for Graduate Medical Education; American Academy of Allergy, Asthma & Immunology; American Academy of Dermatology; American Academy of Family Physicians; American Academy of Neurology; American Academy of Ophthalmology; American Academy of Orthopaedic Surgeons; American Academy of OtolaryngologyHead and Neck Surgery; American Academy of Pediatrics; American Academy of Physical Medicine and Rehabilitation; American Board of Medical Specialties; American Board of Allergy and Immunology; American Board of Anesthesiology; American Board of Colon and Rectal Surgery; American Board of Dermatology; American Board of Emergency Medicine; American Board of Family Practice; American Board of Internal Medicine; American Board of Medical Genetics; American Board of Neurological Surgery; American Board of Nuclear Medicine; American Board of Obstetrics and Gynecology; American Board of Ophthalmology; American Board of Orthopedic Surgery; American Board of Otolaryngology; American Board of Pathology; American Board of Pediatrics; American Board of Physical Medicine and Rehabilitation; American Board of Plastic Surgery; American Board of Preventive Medicine; American Board of Psychiatry and Neurology; American Board of Radiology; American Board of Surgery; American Board of Thoracic Surgery; American Board of Urology; ABIM Foundation; American College of Dentists; American College of Medical Genetics; American College of Obstetricians and Gynecologists; ACP; American College of Radiology; American College of Surgeons; ACP Foundation; American Psychiatric Association; American Society of Anesthesiologists; American Society of Clinical Pathologists; American Society of Plastic Surgeons; American Urological Association; Association of Academic Physiatrists; Association of Physicians of Ireland; Association of Physicians of Malta; Austrian Society of Internal Medicine; Belgian Society of Internal Medicine; College of Physicians and Surgeons of British Columbia; Council of Deans, Association of Canadian Medical Colleges; Council of Medical Specialty Societies; Czech Society of Internal Medicine; Danish Society of Internal Medicine; Estonian Society of Internal Medicine; European Federation of Internal Medicine; Federation of Royal Colleges of Physicians of United Kingdom; Federation of State Medical Boards; Finnish Society of Internal Medicine; French Society of Internal Medicine; German Society of Internal Medicine; Hellenic Society of Internal Medicine; Hungarian Society of Internal Medicine; Israeli Society of Internal Medicine; Italian Society of Internal Medicine; Latvian Society of Internal Medicine; Lithuanian Society of Internal Medicine; Luxembourg Society of Internal Medicine; Ministero della Salute; Netherlands Society of Internal Medicine; Polish Society of Internal Medicine; Portuguese Society of Internal Medicine; Royal Australasian College of Physicians and Surgeons; Royal College of Physicians of Edinburgh; Royal College of Physicians of Ireland; Royal College of Physicians of London; Royal College of Physicians and Surgeons of Canada; Slovak Society of Internal Medicine; Slovenian Society of Internal Medicine; Society of Neurological Surgeons; Society of Nuclear Medicine; Society of Thoracic Surgeons; Spanish Society of Internal Medicine; Swedish Society of Internal Medicine; Swiss Society of Internal Medicine; and Turkish Society of Internal Medicine. During the remainder of the year, additional endorsements will be sought from state medical societies, educational organizations, and other national and international medical associations.Future ActivitiesThe ABIM Foundation has launched a series of targeted activities to promote the charter: 1) an attractive charter publication for distribution at medical school and residency orientation, white coat ceremonies, and graduation; 2) a charter wall poster suitable for framing; 3) Putting the Charter into Practice [small seed grants for implementation were awarded to McGill University; New York University School of Medicine; University of California, San Francisco; University of Michigan Medical School; and University of Texas Medical Branch, Galveston]; 4) Medical Professionalism Project colloquia and conferences; 5) professionalism portfolios designed to promote self-reflection and use of self-assessment tools; 6) inclusion of the charter with each ABIM diplomate's Board certificate; 7) a proposed charter series in peer-reviewed journals; and 8) a proposed award recognition program. The past, present, and future activities stimulated by the charter are being chronicled and will be essential in determining its short- and long-term impact toward promoting and empowering an action agenda for the profession of medicine that is universal in scope and purpose.Appendix: Project MembersABIM Foundation: Troyen Brennan, MD, JD (Project Chair); Linda Blank (Project Staff); Jordan Cohen, MD; Harry Kimball, MD; and Neil Smelser, PhD.ACP Foundation: Robert Copeland, MD; Risa Lavizzo-Mourey, MD, MBA; and Walter McDonald, MD.European Federation of Internal Medicine: Gunilla Brenning, MD; Chris Davidson, MA, MB, FRCP; Philippe Jaeger, MB, MD; Alberto Malliani, MD; Hein Muller, MD, PhD; Daniel Sereni, MD; and Eugene Sutorius, JD.Special Consultants: Richard Cruess, MD; Sylvia Cruess, MD; and Jaime Merino, MD.References1. Medical professionalism in the new millennium: a physician charter. Ann Intern Med. 2002;136:243-6. [PMID: 11827500] LinkGoogle Scholar2. Medical professionalism in the new millennium: a physicians' charter. Lancet. 2002;359:520-2. [PMID: 11853819] CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From ABIM Foundation and ACP Foundation, Philadelphia, Pennsylvania; and European Federation of Internal Medicine, Maastricht, the Netherlands.Disclosures: None disclosed.Corresponding Author: Linda Blank, ABIM Foundation, 510 Walnut Street, Suite 1700, Philadelphia, PA 19106; e-mail, [email protected]org.Current Author Addresses: Ms. Blank and Dr. Kimball: ABIM Foundation, 510 Walnut Street, Suite 1700, Philadelphia, PA 19106.Dr. McDonald: ACP Foundation, 190 N. Independence Mall West, Philadelphia, PA 19106.Dr. Merino: Depart. Medicina y Psiquiatria, Universidad Miguel Hernandez, Campus de San Juan, Cta. 332 Alicante-Valencia Km. 87, 03550 San Juan de Alicante, Spain. 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To write what is worth publishing, to find honest people to publish it, and get sensible people to read it, are the three great difficulties in being an author. Charles Caleb Colton Each year, the annual Journal Impact Factors (JIFs) published by the Institute for Scientific Information (ISI) are awaited with almost equal amounts of trepidation and anticipation by editors of peer-reviewed journals. Since the JIF is widely acknowledged as 1 key indicator of a journal's quality,1–4 a significant rise or fall on the JIF-ranked table can affect journal prestige and may influence a variety of quality measurements such as subscription figures or the number and quality of submitted manuscripts. The ISI JIF is calculated for each year by establishing the number of citations in that year to articles published in the preceding 2 years and dividing this figure by the total number of substantive articles published in the same 2-year period. The 2004 JIF value for the Journal of Cataract & Refractive Surgery (JCRS) is 1.937.5 In a year in which many ophthalmic journals experienced a reduction in their JIF, this is an improvement on the 2003 JIF (1.877) and cements a high-ranking mean JIF of 2.013 for the journal during the period 1999 to 2004. As highlighted in a contemporary review of journal citation by Cartwright and McGhee in this issue,6 of more than 100 periodicals in the ophthalmology and vision-science arena, two thirds might be considered peer reviewed but only 42 have the appropriate scientific qualities that enable the Science Citation Index to calculate a journal impact factor.5 For several years, a debate has flourished around whether the JIF is truly a definitive measure of quality that readers, researchers, and editors should consider when evaluating scientific journals.7–10 Although many would agree that it is the only readily available quantitative value with which to gauge relative journal quality, there are many limitations and potential misuses of the JIF.6 Unfortunately, other possible measures of journal quality or influence such as circulation or electronic access of articles are less readily available and may be influenced by factors other than journal quality per se. Nonetheless, the most frequently electronically accessed articles may be representative of the interest of the general readership7 and therefore an indicator of journal quality and influence. Perneger11 has noted that the papers receiving the most "electronic hits" on the British Medical Journal web site were subsequently cited more frequently than less accessed papers. Frank12 evaluated the criteria used by authors in selecting journals, and the top 3 factors that influenced the author's choice of submission journal were, in descending order, journal's prestige, makeup of the journal's readership, and whether the journal usually published articles on the topic. While prestige and quality are ultimately judgments that can be made only by careful peer review, to a large extent we live in a number-biased electronic age in which some form of citation analysis, be that JIF or other citation parameters, will be used as a surrogate measure of journal quality. The Journal of Cataract & Refractive Surgery publishes quality peer-reviewed articles relating to its 2 main topic areas of cataract and refractive surgery. The 2004 ISI Journal Citation Reports,5 which include the JIF, were published in June 2005. Subsequent to the release of these data, an analysis via the ISI Web of Science (July 2005)13 revealed more than 6500 articles falling under the broad heading "cataract surgery." If one considers the top 500 most-cited articles in this field, it is notable that more than 70% of these were published in only 5 journals: 117 (23.4%) were in JCRS, 21.8% in Ophthalmology, 12.2% in Archives of Ophthalmology, and 6.6% each in the British Journal of Ophthalmology and the American Journal of Ophthalmology (AJO). No other journal published more than 4.0% of the 500 top-cited articles. In relation to refractive surgery, laser in situ keratomileusis (LASIK) has become an outstandingly successful procedure over the past decade and a major research topic in the field of refractive surgery. A similar search of the ISI Web of Science demonstrates that LASIK has been the subject of more than 2040 articles. Once more we can use these data to examine journal influence both in relation to the number of articles published in specific journals and, perhaps more importantly, the relative number of the 500 most-cited articles published in each journal. In respect to the top 500 most commonly cited articles, almost one third (31.2%) were published in JCRS and the majority of the others were published in the Journal of Refractive Surgery (26.8%), Ophthalmology (18.6%), Cornea (6.4%), AJO (4.0%), and Investigative Ophthalmology and Visual Science (IOVS) (1.8%). The JIF is a measure of journal quality, not a measure of individual articles, and a relatively small number of heavily cited articles can contribute to the JIF, whereas many articles in the same journal may be cited rarely or not at all.14 In 2004, the top 3 JIF-ranked ophthalmology journals were Progress in Retinal and Eye Research (Progress), IOVS, and Survey of Ophthalmology (Survey), respectively. Two of these 3 journals, Progress and Survey, primarily publish review articles, which are typically referenced more frequently than original research.14 In the 2004 JIF analysis period, although Progress was the top-ranked journal, with a JIF of 5.345, it published only 29 articles in 2003 compared with 702 published by the second-ranked, but arguably much more influential original research journal, IOVS (JIF 3.577). Ultimately, a journal is only as good as the quality of the scientific papers it publishes. The Journal of Cataract & Refractive Surgery serves an international readership with a focus on the twin domains of cataract surgery and refractive surgery. Although the United States is the source of around 50% of the world's ophthalmic and vision science literature,15 it behooves any international journal to provide a suitable platform for quality research from around the world. To this end, JCRS publishes original clinical and scientific studies for an international readership from a diverse and representative international authorship originating from more than 50 countries including the U.S. (23.4%), Japan (5.9%), England (5.7%), Germany (5.7%), Austria (3.5%), India (3.2%), Spain (3.1%), Italy (2.8%), Turkey (2.3%), and Canada (2.1%). The 2004 JIF continues a strong trend that has maintained JCRS' position in the top 12 JIF-ranked ophthalmology journals over the past 5 years. However, while the JIF is 1 useful indicator of journal quality, it does not comprehensively define the relative quality of a journal. Indeed, the preceding analysis of the ISI Web of Science citation data demonstrates that JCRS publishes a greater number of top-cited articles in the fields of cataract surgery and refractive surgery (LASIK) than any other journal. The journal also readily fulfils Frank's criteria12 of prestige, appropriate readership, and publication in key areas for researchers in the related areas of cataract and refractive surgery. Both authorship and readership are broad and international and, with the publication of the 2004 citation indices, the editorial board should be heartily congratulated on maintaining JCRS as the premier journal in this field.

Takayasu arteritis (TAK) is a vasculitis mainly affecting the aorta and its large branches.1 TAK predominantly affects young women and 90% of TAK patients are females. While many patients with TAK have been found in Asian countries, this disease is reported from all over the world. TAK is, however, seen more commonly in Indian subcontinent, Japan, China, Korea and southeast Asian countries amongst the APLAR nations as well as in Turkey, Brazil, Mexico and south Africa. Reports from western world including Iceland and USA also do exist in literature. Much about Dr. Mikito Takayasu, who was the first to report a patient with TAK, is not widely known. In this essay, Chikashi Terao from Kyoto would like to introduce the history of TAK and Dr. Takayasu. In April 1908, Dr. Mikito Takayasu (Fig. 1), a professor of ophthalmology at the current Kanazawa University, at the 12th Annual Meeting of Japanese Ophthalmology Society held in Fukuoka, reported a case of a 22-year-old woman. He described ‘a case of peculiar changes in the central retinal vessels’.2 He saw the female patient for the first time in May 1905. She had felt lowering and blurring of her vision since September 1904. She sometimes developed redness of conjuctiva. While the symptoms transiently improved by medication, they recurred in March 1905 and she visited Dr. Takayasu. She did not have a history of severe medical or gynecological diseases. While he described that she looked as if she suffered from tuberculosis (TB), he and his colleagues in the Department of Internal Medicine did not find any evidence of infection, including TB or syphilis. Her pupils were slightly dilated and the light reflex was damaged. He found eminent abnormalities in retinal vessels. Retinal vessels branched 2–3 mm away from the optic disc and the branches formed anastomosis with one another to create circularity around the disc. The branches branched further radially and the peripheral portions were narrow. The distal parts of the branches made aneurysms, anastomosis with other branches to form circularity, or terminated in a blind end. The optic disc was severely congested and hemorrhage was found around the disc. While these abnormalities were mainly found in arteries, veins anastomosed with arteries and venous blood flowed into the lesions. While he found these abnormalities in the oculus dexter, similar findings were reported in the oculus sinister. She was admitted and took medications. During the first admission, she was found to have cataracts and underwent an operation. However, her vision did not improve. She stopped visiting the hospital for several years after discharge. She revisited Dr. Takayasu's clinic in February 1908. She developed retinal detachment and her left pupil was remarkably dilated. Dr. Takayasu had no choice but to tell her that there was no effective treatment. He described that the anastomosis and aneurysmal changes should be the primary findings and that the others should be the secondary findings. After his presentation at the Congress, Dr. Yoshiakira Ohnishi, a professor at Kyushu University, mentioned another female case resembling the case presented by Dr. Takayasu. He described that he could not sense her pulse at the bilateral radial arteries. This case report by Dr. Takayasu was published in June in the same year in the Journal of the Juzen Medical Society in Kanazawa University (Fig. 2). In this manuscript, he presented an image of the arteries that he beautifully hand-sketched himself (Fig. 3). While it is often regarded that it was Dr. Takayasu who first reported a patient with TAK, there are other prior potential case reports of patients with TAK. Giovanni Battista Morgagni, an Italian anatomist, described a 40-year-old woman suffering from pulseless disease.3 In 1830, Rokushu Yamamoto described a 45-year-old man suffering from fever.4 After 1 year, the patient became pulseless in the right radial artery and had a very weak pulse in the left radial artery. The patient developed pulseless disease in both carotid arteries and died 11 years after the first visit. He described two other cases reported by another doctor. In 1856, Savory5 reported a 22-year-old woman presenting with pulseless disease in both upper extremities and left neck. The patient lost her vision. However, whether these cases truly suffered from TAK is uncertain. Numano4 suspected the case reported by Savory should be explained by other diseases since the patient had a corneal ulcer leading to invasion of scalp and brain. Dr. Minoru Nakajima in 1921 compared his cases with previous reports and proposed that they should be regarded as one disease. He characterized this disease by the following four criteria: (i) affecting bilateral eyes in young women; (ii) arteriovenous anastomosis around the optic disc and microaneurysm formation in retinal vessels; (iii) lowering of vision complicated with cataract; and (iv) unpalpable radial artery. He proposed to call this disease ‘Takayasu disease’. After his proposal, Japanese ophtalmologists paid attention to this disease and many cases were reported. In 1946, Frövig6 proposed that the diseases presenting pulselessness should be called ‘aortic arch syndrome’. In 1948, Drs Kentaro Shimizu and Keiji Sano, brain surgeons at the University of Tokyo, proposed to give an alias name of ‘pulseless disease’. In 1951, this disease was reported by these doctors outside of Japan for the first time, by reviewing a total of 25 cases.7 Since 1951, there have been case reports from a number of foreign countries. In 1952, Caccamise and Whitman8 reported the primary occidental case report. In 1962, Judge et al.9 described ‘Takayasu's arteritis’. In Japan, many doctors proposed acronyms of TAK. Drs Maekawa and Kakei called it ‘occlusive coagulant aortic syndrome’.10 Dr. Nasu11 called it ‘obstructive productive arteritis’. In 1965, Riehl et al.12 analyzed this disease from pathological and immunological aspects and proposed the concept that this disease is an autoimmune disease. Since 1990 when the American College of Rheumatology published a classification criteria of TAK13 and described ‘Takayasu arteritis’, the name of TAK prevailed worldwide. Although both ‘Takayasu arteritis’ and ‘Takayasu's arteritis’ are used, in the Online Mendelian Inheritance in Man (OMIM) it is registered as ‘Takayasu arteritis’ and this expression is more commonly used. The case report by Dr. Takayasu is quite suggestive. His report tells us that we should carefully examine and observe patients to find characteristics of the patients. Even if we saw just one case, there is a possibility that many patients exist with the same symptoms. It is impressive that Dr. Takayasu described the first patient as being similar to patients with TB. In fact, there are studies pointing out the overlapping of TB and TAK.14, 15 Geographical prevalence of TAK is similar to that of TB. Although there are many conflicting studies in terms of epidemiology and immunology,16 there is a possibility that exposure to TB triggers the immune reaction to TAK. In fact, my group showed that the susceptibility variant is located in the IL12B region17 and this variant has previously been reported in relation to mycobacterium infection. Dr. Mikito Takayasu was born on 19 July, 1860 in Saga prefecture in Japan as the fourth son of a priest. He graduated from Tokyo foreign language school and entered Tokyo University. He graduated from Tokyo University in 1887 and soon moved to Kanazawa prefecture as a lecturer. He went to Germany for 2 years, where he performed research in Berlin City Hospital, Berlin Charité University Hospital and Leipzig University. He studied under Dr. von Graphe. He showed by means of Sudan dyes that arcus senilis occurs due to fat deposition.18 Until his findings, little was known about the nature of arcus senilis in spite of the high frequency of this phenomenon. He returned to Kanazawa and obtained his PhD degree in 1903 for this research. He then went on to become a professor and principal of the Medical School. In 1923, the Medical School was reorganized as the Medical University and he was appointed Dean. He retired from the University in 1924. After retirement, he opened his own clinic near the University Hospital. To prevent the lowering in numbers of patients in surrounding ophthalmologist clinics, he set a very expensive doctor's fee. Despite the expensive fees, his clinic was very popular because patients highly appreciated his sound character and respected his medical skills, experience and knowledge. It is said that many people believed that water from the small river running by his house was effective for eye diseases. In 1933, he suffered from stroke and moved to Beppu in Kyushu for recovery. He died of rectal cancer in Beppu when he was 78 years old on 20 November, 1938. His bones were transferred to Kanazawa soon after his death and his funeral was conducted at Kanazawa University. His grave has been kept in the Hoenji Temple near Kanazawa University (Fig. 4). His statue was built in Kanazawa University in 2002 (Fig. 5). He had three sons and five daughters. Dr. Akira Takayasu, his second son, was a professor of ophthalmology at Kagoshima University. Dr. Tatsuo Hirose, his great-grandson, is a clinical professor of ophthalmology at Harvard Medical School. Dr. Hirose is a grandson of Ms. Miyako Takayasu Hirose, one of Dr. Takayasu's daughters. According to Dr. Hirose, he had seen a couple of young women with TAK during his 4-year stay in the Ophthalmology Clinic in Kanazawa University. However, he has not seen a single patient with TAK in Boston during his career over 40 years in a tertiary referral retina clinic in Boston. This can be explained by different prevalences of TAK among different populations. I would like to thank Dr. Tatsuo Hirose in the Ophthalmology Department of Harvard Medical School and Dr. Kazuki Kuniyoshi in the Department of Ophthalmology, Kinki University Faculty of Medicine, for allowing me to include information from Dr. Hirose in this essay and for their kind help to obtain information about Dr. Mikito Takayasu. I would like to thank Dr. Kazuhisa Sugiyama in the Ophthalmology Department of Kanazawa University for allowing me to use their photos for this essay.

Purpose: Low- to middle-income nations contain more than 80% of the world's population; however, only 4% of articles in ophthalmology journals belong to these countries. We aim to analyze the global diversity of the editorial boards of ophthalmology journals. Methods: Cross-sectional study, including all journals in the Ophthalmology section of the SCImago Journal & Country Rank (SJR). Journals were classified according to the country of origin, SJR interquartile range (Q1-Q4), impact factor, and open-access policy. Global diversity among journals was determined by the country of affiliation of editors-in-chief and editorial board members. Nations were classified by income according to the World Bank's 2022 system. The association between editorial diversity and the journal's metrics and country of origin was analyzed using the χ2 test and the Mann-Whitney U test. Results: A total of 116 journals were included and 83.6% belonged to high-income nations. Only 18 (13.3%) editors-in-chief and 582 (13.5%) board members were affiliated with middle-income nations. The most prevalent middle-income countries in editorial boards were Brazil (n = 184, 4.26%), India (n = 150, 3.47%), Turkey (n = 42, 0.97%), and Iran (n = 36, 0.83%). Only 40 (1.07%) editorial board members of Q1 journals were affiliated with non-high-income nations, most belonging to India (n = 28, 70%). Journals from middle-income nations had a statistically significant lower prevalence in the first- and second-quartile ranking (P < 0.001) and a higher proportion of open-access policies (P = 0.019). Conclusions: A clear underrepresentation of low- to middle-income nations was observed in ophthalmology journals. Promoting editorial diversity and minimizing the possibility of editorial bias could lead to greater exposure to real-world data from resource-constrained settings. Translational Relevance: The documented underrepresentation of low- to middle-income nations in ophthalmology journals highlights the importance of promoting diversity and inclusion.

To investigate the frequency of converting a residency dissertation to a journal article in Turkey. To compare the different residency programs and their publications rates; to sub classify of dissertations according to sub-specialties. Ophthalmologists who graduated before 2010 conducted surveys. The surveys questions included graduation year, residency program, topic of the dissertations, type of the study (prospective, retrospective, or experimental), publication rate from the dissertations, and type of journal for published dissertations. Three-hundred-eight ophthalmologists conducted surveys. Fifty seven (18.5%) dissertations were published in SCI-Expanded Indexed journals (39 of them (23%) from the university hospital programs and 17 of them (13%) from state hospital programs (p=0.036)) and 97 of dissertations were published in national journals. 92 of 170 (54%) dissertations from the university based residency programs and 59 of 131 (45%) dissertations from the state hospital based residency programs were published in national journals or international journals indexed in the SCI-Expanded Index (p=0.17). A publication rate from dissertations was similar between big city university programs and small city university programs (23.3%; 22.6%). The most frequently studied topics of dissertations were cataract-refractive surgery (21.5%), followed by retina (21%), glaucoma (21%), cornea-anterior segment (19%), and strabismus (7%). Of the study design, 57% of them were prospective, 32% were retrospective, and 10.5% were experimental study. In this study, it seems to be that lesser than one fifth of Ophthalmology Residency dissertations in Turkey converted to journal articles in SCI-Expanded journals. It is obvious that the overall quality of the dissertations was inadequate to be published in indexed journals and it is necessary to take some measures to increase the scientific quality.

BACKGROUND: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. METHODS: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. FINDINGS: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5-3·0) of age-standardised female deaths and 6·8% (5·8-8·0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2-4·3) of female deaths and 12·2% (10·8-13·6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2·3% (95% UI 2·0-2·6) and male attributable DALYs were 8·9% (7·8-9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0-1·7] of total deaths), road injuries (1·2% [0·7-1·9]), and self-harm (1·1% [0·6-1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2-33·3) of total alcohol-attributable female deaths and 18·9% (15·3-22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0-0·8) standard drinks per week. INTERPRETATION: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk-outcome associations. METHODS: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. FINDINGS: In 2017, 34·1 million (95% uncertainty interval [UI] 33·3-35·0) deaths and 1·21 billion (1·14-1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6-62·4) of deaths and 48·3% (46·3-50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39-11·5) deaths and 218 million (198-237) DALYs, followed by smoking (7·10 million [6·83-7·37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6·53 million [5·23-8·23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4·72 million [2·99-6·70] deaths and 148 million [98·6-202] DALYs), and short gestation for birthweight (1·43 million [1·36-1·51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3-6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. INTERPRETATION: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. FUNDING: Bill & Melinda Gates Foundation.

Objective: The changing criteria for associate professorship in Turkey forced researchers to write more articles to the international journals. In this study, it was aimed to evaluate the number of authors in published articles from Turkey and to evaluate the distribution of institutions in which the study conducted. Material and Methods: For this retrospective, bibliometric analysis, the journals indexed in the 2019 Scientific Citation Index (SCI) for ophthalmology were reviewed. The articles submitted by Turkish researchers were included. The journal's subspecialty, the date of publication, the number of authors, the institution where the study held and whether it was an animal study or not were recorded. Results: Between 01.01.2014 and 01.09.2019, a total of 654 original research articles were published in 31 SCI journals. Compared to 2016 and before, the number of authors decreased significantly in 2017 and after (p<0.000). When the institutions were evaluated, more articles accepted from universities (344, 52.60%). When the articles were classified according to subspecialties, medical retina was the leader (212/654, 32.4%), followed by corneal and ocular surface diseases (170/654, 26.0%). Conclusion: With the change in the criteria of associate professorship in Turkey, articles were written with fewer researchers. Universities were the leaders of the institutions in publishing an article.

BACKGROUND: The clinical management of intermittent exotropia (X(T)) has been discussed extensively in the literature, yet there remains a lack of clarity regarding indications for intervention, the most effective form of treatment, and whether there is an optimal time in the evolution of the disease at which any given treatment should be carried out. OBJECTIVES: The objective of this review was to analyze the effects of various surgical and non-surgical treatments in randomized controlled trials (RCTs) of participants with intermittent exotropia, and to report intervention criteria and determine whether the treatment effect varies by age and subtype of X(T). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 1), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Science Information database (LILACS); the ISRCTN registry; ClinicalTrials.gov, and the WHO ICTRP. The date of the search was 20 January 2021. We performed manual searches of the British Orthoptic Journal up to 2002, and the proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA), and American Association for Pediatric Ophthalmology and Strabismus meeting (AAPOS) up to 2001. SELECTION CRITERIA: We included RCTs of any surgical or non-surgical treatment for intermittent exotropia. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We included six RCTs, four of which took place in the United States, and the remaining two in Asia (Turkey, India). A total of 890 participants with basic or distance X(T) were included, most of whom were children aged 12 months to 10 years. Three of these six studies were from the 2013 version of this review. Overall, the included studies had a high risk of performance bias as masking of participants and personnel administering treatment was not possible. Two RCTs compared bilateral lateral rectus recession versus unilateral lateral rectus recession with medial rectus resection, but only one RCT (n = 197) reported on the primary outcomes of this review. Bilateral lateral rectus recession likely results in little difference in motor alignment at near (MD 1.00, 95% CI -2.69 to 4.69) and distance (MD 2.00, 95% CI -1.22 to 5.22) fixation as measured in pupillary distance using PACT (moderate-certainty evidence). Bilateral lateral rectus recession may result in little to no difference in stereoacuity at near fixation (risk ratio (RR) 0.77, 95% CI 0.35 to 1.71), adverse events (RR 7.36, 95% CI 0.39 to 140.65), or quality of life measures (low-certainty evidence). We conducted a meta-analysis of two RCTs comparing patching (n = 249) with active observation (n = 252), but were unable to conduct further meta-analyses due to the clinical and methodological heterogeneity in the remaining trials. We found evidence that patching was clinically more effective than active observation in improving motor alignment at near (mean difference (MD) -2.23, 95% confidence interval (CI) -4.02 to -0.44) and distance (MD -2.00, 95% CI -3.40 to -0.61) fixation as measured by prism and alternate cover test (PACT) at six months (high-certainty evidence). The evidence suggests that patching results in little to no difference in stereoacuity at near fixation (MD 0.00, 95% CI -0.07 to 0.07) (low-certainty evidence). Stereoacuity at distance, motor fusion test, and quality of life measures were not reported. Adverse events were also not reported, but study authors explained that they were not anticipated due to the non-surgical nature of patching. One RCT (n = 38) compared prism adaptation test with eye muscle surgery versus eye muscle surgery alone. No review outcomes were reported. One RCT (n = 60) compared lateral rectus recession and medial rectus plication versus lateral rectus recession and medial rectus resection. Lateral rectus recession and medial rectus plication may not improve motor alignment at distance (MD 0.66, 95% CI -1.06 to 2.38) (low-certainty evidence). The evidence for the effect of lateral rectus recession and medial rectus plication on motor fusion test performance is very uncertain (RR 0.92, 95% CI 0.48 to 1.74) (very low-certainty evidence). AUTHORS' CONCLUSIONS: Patching confers a clinical benefit in children aged 12 months to 10 years of age with basic- or distance-type X(T) compared with active observation. There is insufficient evidence to determine whether interventions such as bilateral lateral rectus recession versus unilateral lateral rectus recession with medial rectus resection; lateral rectus recession and medial rectus plication versus lateral rectus recession and medial rectus resection; and prism adaptation test prior to eye muscle surgery versus eye muscle surgery alone may confer any benefit.

Through history, Arabs and Muslims have made valuable contribution to medicine and science. The main objective of this study was to assess the contribution of Arab researchers to ophthalmology using bibliometric indicators. Published articles in "Ophthalmology" authored by Arab researchers were screened and analyzed using ISI Web of Science database. Worldwide research productivity in ophthalmology was 216,921 documents while that from Arab countries; Israel, Turkey and Iran were 2083, 2932, 3027 and 859 documents respectively. Those from Arab countries were published in 85 peer-reviewed ophthalmology related journals with 280 (13.44%) documents published in Journal Francais d Ophtalmologie. Among Arab countries, Kingdom of Saudi Arabia had the highest (828 (39.75%)) research output followed by Egypt (461 (22.13%)) and Tunisia 210 (10.08). Countries with highest collaboration with researchers in Arab world in ophthalmology research were USA; (397; 19.06%) followed by England (92; 4.42%) and Spain (91; 4.37%). The most research productive organization in Arab countries was King Khalid Eye Specialist Hospital (396; 19.01%). Ophthalmology articles authored or co-authored by an Arab researcher had a total citation f 21098 with an average citation of 10.13 per document and an h-index of 51. In conclusion, the present data show promising increase but relatively low ophthalmology research productivity from Arab countries. Wide variation in research productivity do exists. Compared with other non-Arab countries in the Middle East, Arab countries showed lesser ophthalmology research activity than Israel and Turkey but higher than that in Iran.

BACKGROUND: Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. FINDINGS: Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78-0·92) and 1·2 years (1·1-1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. INTERPRETATION: Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. FUNDING: Bill & Melinda Gates Foundation.

Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis characterized by a generalized reduction in pigmentation of hair, skin and eyes. The prevalence of all forms of albinism varies considerably worldwide and has been estimated at approximately 1/17,000, suggesting that about 1 in 70 people carry a gene for OCA. The clinical spectrum of OCA ranges, with OCA1A being the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment accumulation over time. Clinical manifestations include various degrees of congenital nystagmus, iris hypopigmentation and translucency, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, reduced visual acuity usually (20/60 to 20/400) and refractive errors, color vision impairment and prominent photophobia. Misrouting of the optic nerves is a characteristic finding, resulting in strabismus and reduced stereoscopic vision. The degree of skin and hair hypopigmentation varies with the type of OCA. The incidence of skin cancer may be increased. All four types of OCA are inherited as autosomal recessive disorders. At least four genes are responsible for the different types of the disease (TYR, OCA2, TYRP1 and MATP). Diagnosis is based on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms. Due to the clinical overlap between the OCA forms, molecular diagnosis is necessary to establish the gene defect and OCA subtype. Molecular genetic testing of TYR and OCA2 is available on a clinical basis, while, at present, analysis of TYRP1 and MATP is on research basis only. Differential diagnosis includes ocular albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II. Carrier detection and prenatal diagnosis are possible when the disease causing mutations have been identified in the family. Glasses (possibly bifocals) and dark glasses or photocromic lenses may offer sufficient help for reduced visual activity and photophobia. Correction of strabismus and nystagmus is necessary and sunscreens are recommended. Regular skin checks for early detection of skin cancer should be offered. Persons with OCA have normal lifespan, development, intelligence and fertility.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

OBJECTIVE: To make evidence-based recommendations concerning the evaluation of the child with a nonprogressive global developmental delay. METHODS: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. RESULTS: Global developmental delay is common and affects 1% to 3% of children. Given yields of about 1%, routine metabolic screening is not indicated in the initial evaluation of a child with global developmental delay. Because of the higher yield (3.5% to 10%), even in the absence of dysmorphic features or features suggestive of a specific syndrome, routine cytogenetic studies and molecular testing for the fragile X mutation are recommended. The diagnosis of Rett syndrome should be considered in girls with unexplained moderate to severe developmental delay. Additional genetic studies (e.g., subtelomeric chromosomal rearrangements) may also be considered in selected children. Evaluation of serum lead levels should be restricted to those children with identifiable risk factors for excessive lead exposure. Thyroid studies need not be undertaken (unless clinically indicated) if the child underwent newborn screening. An EEG is not recommended as part of the initial evaluation unless there are historical features suggestive of epilepsy or a specific epileptic syndrome. Routine neuroimaging, with MRI preferred to CT, is recommended particularly if abnormalities are found on physical examination. Because of the increased incidence of visual and auditory impairments, children with global developmental delay may undergo appropriate visual and audiometric assessment at the time of diagnosis. CONCLUSIONS: A specific etiology can be determined in the majority of children with global developmental delay. Certain routine screening tests are indicated and depending on history and examination findings, additional specific testing may be performed.

The body's autoimmune process is involved in the development of Graves' disease (GD), which is manifested by an overactive thyroid gland. In some patients, autoreactive inflammatory reactions contribute to the development of symptoms such as thyroid ophthalmopathy, and the subsequent signs and symptoms are derived from the expansion of orbital adipose tissue and edema of extraocular muscles within the orbit. The autoimmune process, production of antibodies against self-antigens such as TSH receptor (TSHR) and IGF-1 receptor (IGF-1R), inflammatory infiltration, and accumulation of glycosaminoglycans (GAG) lead to edematous-infiltrative changes in periocular tissues. As a consequence, edema exophthalmos develops. Orbital fibroblasts seem to play a crucial role in orbital inflammation, tissue expansion, remodeling, and fibrosis because of their proliferative activity as well as their capacity to differentiate into adipocytes and myofibroblasts and production of GAG. In this paper, based on the available medical literature, the immunological mechanism of GO pathogenesis has been summarized. Particular attention was paid to the role of orbital fibroblasts and putative autoantigens. A deeper understanding of the pathomechanism of the disease and the involvement of immunological processes may give rise to the introduction of new, effective, and safe methods of treatment or monitoring of the disease activity.

Objectives: To investigate the frequency and distribution of ophthalmic articles with Turkish origin on Pubmed search engine and to compare these data with those of the world’s leading countries in that field. Materials and Methods: Using the words “ophthalmology” and “Turkey”, an online retrospective search was conducted on Pubmed for the period from 1990 to 2013. Additionally, same search was performed for each ophthalmic journal indexed in Science Citation Index Expanded (SCI-E) (n=56) and not indexed in SCI-E (n=8), separately. The articles were divided into two groups (research articles and the other articles as case reports, letters, correspondence, editorials and reviews). Results: A total of 5044 articles in the area of ophthalmology were from Turkey in that period. The United States of America, Japan, and Germany had the maximum number of published articles (25%, 6.8%, and 4.9% of all, respectively). There were 3334 articles on ophthalmic journals. 2822 articles were published in SCI-E journals and of those, 2321 were research articles and 501 were other types of articles. Three SCI-E indexed ophthalmic journals which mostly published Turkish articles are the European Journal of Ophthalmology, Journal of Cataract and Refractive Surgery, and the Ophthalmologica (361, 183, and 152, respectively). Conclusion: In this period, the rate of the published ophthalmic articles originated from Turkey was 1.5%. We observed that the number of Turkish ophthalmic articles has been increasing gradually. (Turk J Ophthalmol 2014; 44: 465-70)

Redox degenerative reactions of the biological system inevitably produce reactive oxygen species (ROS) and their derivatives. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species (ROS), such as hydrogen peroxide, organic hydro peroxides, nitric oxide, superoxide and hydroxyl radicals etc. Information are accumulating steadily, supporting the general importance of oxidative damage of tissue and cellular components as a primary or secondary causative factor in many different human diseases and aging processes. Many of the recent landmarks in scientific research have shown that in human beings, oxidative stress has been implicated in the progression of major health problems by inactivating the metabolic enzymes and damaging important cellular components, oxidizing the nucleic acids, leading to cardiovascular diseases, eye disorders, joint disorders, neurological diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), atherosclerosis, lung and kidney disorders, liver and pancreatic diseases, cancer, ageing, disease of the reproductive system including the male and female infertility etc. The advent of a growing number of in vitro and in vivo models for evaluating the human disease pathology is aiding scientists in deciphering the detailed mechanisms of the point of intersection of the oxidative stress with other cellular components or events in the growing roadmap leading to different human disorders. The toxic effect of reactive oxygen and nitrogen species in human is balanced by the antioxidant action of non-enzymatic antioxidants, as well as by antioxidant enzymes. Such antioxidant defences are extremely important as they represent the direct removal of free radicals (prooxidants), thus providing maximal protection for biological sites. These systems not only assert with the problem of oxidative damage, but also play a crucial role in wellness, health maintenance, and prevention of chronic and degenerative diseases. In this review we have tried to generate a gross picture on the critical role of ROS in deteriorating human health and the importance of antioxidative defense system in ameliorating the toxicity of ROS.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

OBJECTIVE: The British Nutrition Foundation was recently commissioned by the Food Standards Agency to conduct a review of the government's research programme on Antioxidants in Food. Part of this work involved an independent review of the scientific literature on the role of antioxidants in chronic disease prevention, which is presented in this paper. BACKGROUND: There is consistent evidence that diets rich in fruit and vegetables and other plant foods are associated with moderately lower overall mortality rates and lower death rates from cardiovascular disease and some types of cancer. The 'antioxidant hypothesis' proposes that vitamin C, vitamin E, carotenoids and other antioxidant nutrients afford protection against chronic diseases by decreasing oxidative damage. RESULTS: Although scientific rationale and observational studies have been convincing, randomised primary and secondary intervention trials have failed to show any consistent benefit from the use of antioxidant supplements on cardiovascular disease or cancer risk, with some trials even suggesting possible harm in certain subgroups. These trials have usually involved the administration of single antioxidant nutrients given at relatively high doses. The results of trials investigating the effect of a balanced combination of antioxidants at levels achievable by diet are awaited. CONCLUSION: The suggestion that antioxidant supplements can prevent chronic diseases has not been proved or consistently supported by the findings of published intervention trials. Further evidence regarding the efficacy, safety and appropriate dosage of antioxidants in relation to chronic disease is needed. The most prudent public health advice remains to increase the consumption of plant foods, as such dietary patterns are associated with reduced risk of chronic disease.