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vigilance through screening and treatment, ROP-induced blindness in highincome countries is falling and now accounts for less than 10% of childhood blindness. However, in middle-income countries where babies do not have access to ROP screening, this figure can be as high as 60%.2 With increased survival, and expansion of neonatal care, the problem is increasing. The diagnosis of this potentially blinding but treatable retinopathy, as well as that of diabetic retinopathy, is made by ophthalmoscopically visible signs. Recent advances in digital imaging allow these signs to be captured by non-medical personnel and transmitted to a physician expert for grading. Since only a very small proportion of preterm babies screened require treatment (2% in the UK3), a telemedicine approach could greatly reduce the number of examinations done by ophthalmologists, and greatly increase coverage in countries where screening is not currently available. Research is progressing apace so that semiautomatic analysis of the salient features in both diabetic retinopathy4 and ROP5 is a virtual certainty in the very near future. This eventuality will reduce the amount of experts’ time spent, so improving cost-effectiveness. It is a common misconception that telemedicine entails transmission of medical information or communication across substantial distances. But remoteness is relative. Thus, the baby with sight-threatening ROP who is only a mile or so from a too-busy ophthalmologist is equally remote from care. To have a real and sustainable effect that will make sense to clinicians and healthservice providers, telemedicine needs not only to work afar, but must also contribute something to routine medical care that enables local teams to work better and in a way that is currently not possible. We declare that we have no conflict of interest.
*Alistair R Fielder, Clare Gilbert, Anna Ells, Graham E Quinn a.fi
[email protected]
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Department of Optometry and Visual Science, City University, London EC1V 0HB, UK (ARF); International Centre for Eye Health, London School of Hygiene and Tropical Medicine, London, UK (CG); Department of Ophthalmology, University of Calgary, Calgary, Alberta, Canada (AE); and Department of Ophthalmology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA (GEQ) 1 2
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Kumar S, Yogesan K. Internet-based eye care: VISION 2020. Lancet 2005; 366: 3244–45. Gilbert C, Fielder A, Gordillo L, et al, on behalf of the International NO-ROP Group. Severe retinopathy of prematurity in middle and lowincome countries: implications for screening programmes. Pediatrics 2005; 115; e518–25. Haines L, Fielder AR, Pollock JI, Wilkinson AR. Retinopathy of prematurity in the UK: the organisation of services for screening and treatment. Eye 2002; 16: 33–38. Sinthanayothin C, Boyce JF, Williamson TH, et al. Automated detection of diabetic retinopathy on digital fundus images. Diabet Med 2002; 19: 105–12. Swanson CR, Cocker KD, Parker KH, Moseley MJ, Fielder AR. Semi-automated computer analysis of retinal vessels in infants with acute-phase retinopathy of prematurity. Br J Ophthalmol 2003; 87: 1474–77.
Transfer of mouse embryonic stem cells to sheep myocardium Claudine Ménard and colleagues (Sept 17, p 1005)1 transplanted cardiaccommitted mouse embryonic stem cells into chronically infarcted sheep myocardium, and described their differentiation after implantation, in particular within the infarcted ventricular wall and infarct border zone. Histological analysis of the tissue 1 month after transplantation revealed that the embryonic stem cells were transformed into either fibroblasts or contractile cardiac myocytes expressing the MHC proteins. Ménard and colleagues report that after transplantation there was cellular expression of connexin 43 in the previously infarcted myocardium and within the infarct border zone, suggesting that the engrafted differentiated embryonic stem cells were expressing connexin 43. However, Ménard and colleagues could not discern whether the expression of these myocardial connexins was due to interactions between fibroblasts and myocytes, fibroblasts and fibroblasts, or
myocytes and myocytes. In any of these scenarios, there could be an increased risk of arrhythmias, resulting from the creation of zones of heterogeneous conduction. We suggest that fibroblasts could have a role in cardiac electrical stability after infarction.2 From our own unpublished preclinical data from rabbits, we have found that the expression of smooth muscle actin—a biomarker for increased expression of myofibroblasts—is associated with increased induction of monomorphic ventricular tachycardia via programmed electrical stimulation. In particular, increased expression of myofibroblasts at the infarct border zone seems to increase the risk. Communication between fibroblasts or myofibroblasts and cardiac myocytes via connexins could promote abnormal conduction.2,3 Immunohistochemical staining for connexin is difficult on fibroblasts and myofibroblasts.4 Therefore, if connexin 43 is being expressed and visualised, it is likely to be on cardiac myocytes. However, as Ménard and colleagues note, one cannot rule out connexin expression by fibroblasts. Across many animal species after experimental chronic infarction, connexins are usually downregulated and remain so. From our own experimental studies in rabbits, connexin 43 is downregulated in ventricular regions remote from the infarct, and is absent at the infarct border and within the infarct scar. Other species such as the dog also have an observable reduction in connexin 43 within the infarct border zone.5 Whether this reduction in connexin 43 confers an electrical safety factor has not yet been determined. However, with respect to the study by Ménard and colleagues, the fact that connexin 43 and possibly fibroblast expression are being manipulated after embryonic stem cell transplantation would suggest that cardiac electrical stability remains to be thoroughly explored before clinical trials can be recommended. We declare that we have no conflict of interest.
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*Craig S McLachlan, Brett Hambly, Zakaria Almsherqi, Reida El Oakley, Mark A McGuire
[email protected] Department of Medicine, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia (CSM); Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (BH); National University of Singapore, Singapore (ZA); King Fahd Medical City, Riyadh, Saudi Arabia (REO); and Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (MAM). 1
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Ménard C, Hagege AA, Agbulut O, et al. Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study. Lancet 2005; 366: 1005–12. Rudy Y. Conductive bridges in cardiac tissue: a beneficial role or an arrhythmogenic substrate? Circ Res 2004; 94: 709. Driesen RB, Dispersyn GD, Verheyen FK, et al. Partial cell fusion: a newly recognized type of communication between dedifferentiating cardiomyocytes and fibroblasts. Cardiovasc Res 2005; 68: 37–46. Rook MB, van Ginneken AC, de Jonge B, el Aoumari A, Gros D, Jongsma HJ. Differences in gap junction channels between cardiac myocytes, fibroblasts, and heterologous pairs. Am J Physiol 1992; 263: C959–77. Ohara T, Ohara K, Cao JM, et al. Increased wave break during ventricular fibrillation in the epicardial border zone of hearts with healed myocardial infarction. Circulation 2001; 103: 1465–72.
Towards a science of community engagement The implementation of HIV prevention trials in developing countries is a crucial component of combating the most devastating pandemic in modern history. The closures of several trials across the globe—including tenofovir trials in Cambodia, Cameroon, and Nigeria—suggest that it might be prudent to devote as much effort to addressing the complex community challenges of successful trial implementation as we dedicate to the formidable biomedical challenges of developing new forms of HIV chemoprophylaxis. In this regard, Kimberly Page-Shafer and colleagues—the investigators on the ill-fated tenofovir trial among Cambodian sex workers—should be lauded for their willingness to share their experiences, and particularly in a non-combative and conciliatory tone
(Oct 22, p 1499).1 Their openness to considering that there might have been alternatives to the way in which the trial was implemented is a good start. Page-Shafer and colleagues identify mistrust among intended participants as a crucial issue and a likely obstacle to trial implementation. They document early difficulties in engaging sex workers in a community advisory group. The description of trial consultation also suggests a disjunction between formative research, ostensibly focused on refining informed consent processes, recruitment and retention procedures, and translation of study materials, and the equally important processes of ongoing community engagement. Local stakeholders’ reported feelings of lack of power and the perceived absence of a forum for dialogue with the investigators also suggests gaps in community engagement. Rather than lament the failure of further ex-post-facto, trial-and-error attempts to redress complex social, cultural, and behavioural pitfalls of clinical trial implementation among vulnerable communities, we might seize the lessons learned from recent clinical trial shutdowns and treat future trials as an opportunity to apply our best science not only to product development, but to the community dimensions of clinical trial planning and implementation. Engaging vulnerable community stakeholders in medical research is less of a controlled and predictable science than we might wish. Nevertheless, it seems curious that we invest millions of dollars in product development, clinical training, design and building of facilities, etc, but often leave vital processes of community engagement largely to trial and error. Rigorous qualitative research methods, including focus groups and key informant interviews,2 and ethnographic investigations3 could provide an empirical basis for theory-based interventions (eg, diffusion of innovations4) and social marketing strategies5 to support successful fieldwork and preparation on the part
of trial investigators and to develop best practices in engagement with local communities. Do such measures guarantee success? No more than a product’s reaching a phase III trial guarantees success. But it would be unheard of—moreover unethical and illegal—to launch a candidate for HIV chemoprophylaxis in a phase III trial without rigorous science, including phase I and II trials behind it. We might similarly aspire to evidence and rigour in designing and initiating strategies for community engagement, which is crucial to successful trial implementation. Not only might we fare better in implementing and sustaining HIV chemoprophylaxis trials, but we might learn valuable lessons for the much greater challenges of future microbicide and HIV vaccine dissemination among vulnerable communities worldwide. I declare that I have no conflict of interest.
Peter A Newman
[email protected] University of Toronto, Centre for Applied Social Research, 246 Bloor Street West, Toronto, Ontario M5S 1A1, Canada 1
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Page-Shafer K, Saphonn V, Sun LP et al. HIV prevention research in a resource-limited setting: the experience of planning a trial in Cambodia. Lancet 2005; 366: 1499–503. Newman PA, Duan N, Cunningham W, et al. HIV vaccine trial participation among ethnic minority communities: challenges for recruitment and implementation. J Acquir Immune Defic Syndr (in press). Streefland PH. Introduction of a HIV vaccine in developing countries: social and cultural dimensions. Vaccine 2003; 21: 1304–09. Rogers EM. Diffusion of innovations, 4th edn. New York: Free Press, 1995. Newman PA, Duan N, Rudy ET, et al. Challenges for HIV vaccine dissemination and clinical trial recruitment: if we build it, will they come? AIDS Pt Care STDs 2004; 18: 691–701.
Department of Error Sazawal S, Black RE, Ramsan M, et al. Effect of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting. Lancet 2006; 367: 133–43—In this Article (Jan 14), the penultimate sentence of the fifth paragraph of the Discussion (p 141) should read: “The Gera and Sachdev review did not assess separately studies from malaria-endemic areas or studies in different age groups.”
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