Takayasu arteritis (TA) is a large vessel vasculitis that usually affects young female patients during the second and third decades of life, but has been reported in children as young as 24 months of age. Aim of this report was to describe four children (two girls) with TA, as well as summarizing main published studies. The mean age at presentation of our cases was 11 years (range 8–15). Three patients were Caucasians and one Asian. Arterial hypertension was the commonest mode of presentation followed by systemic symptoms. Other related symptoms were due to ischemia and consisted of abdomen, chest, and limb pain. An abdominal bruit was noted in only one patient. Inflammation markers were always abnormal. Angiography was performed in all cases; left subclavian artery and common carotid artery were more frequently involved. Renal artery stenosis was observed in two patients. One boy was diagnosed as having an associated immune deficiency (Wiskott-Aldrich syndrome). Treatment modalities included prednisone (n = 4), methotrexate (n = 3), and mycophenolate mofetil (MMF) (n = 1). Surgery was required in two patients. Follow-up ranged from 3 to 10 years since diagnosis. In three cases antihypertensive drugs and methotrexate were stopped, and prednisone was reduced to 7.5 mg/day. Takayasu arteritis (TA) is a large vessel vasculitis affecting mainly the aorta and its major branches. TA occurs most commonly in female patients in the second and third decades of life, but has also been reported in children as young as 24 months of age . The disThe aim of the present report was to describe four cases of pediatric TA seen in a French tertiary pediatric rheumatology center, with an emphasis on both medical and surgical management, as well as providing a recent review of the literature. A representative clinical history is detailed below, while Table PH, male, with unremarkable family or past medical history, at the age of 11 years was admitted for the occurrence of arterial hypertension (180/100 mm Hg) with the presence of headache and vomiting for the previous 2 days. His parents reported a history of fatigue, myalgia, frontal headache and weight loss (9 kg) for the previous 2 months. On admission he was alert, afebrile and in no acute distress. BP was 170/105 mm Hg. All his pulses were felt and symmetric. Fundoscopy was normal. No abdominal bruit was present. The rest of his physical examination was normal. Investigations on admission revealed anemia (Hb 79 g/L), thrombocytosis (platelet count 738 G/L), ESR 125 mm/h, CRP 80 mg/L. The rest of laboratory investigations, including serum creatinine, electrolytes, autoantibodies, and urinalysis, were normal, as well as ECG and chest X-ray. An echocardiogram showed mild thickening of the left ventricle. A renal color Doppler ultrasound examination revealed a right renal artery stenosis with a small ipsilateral kidney (70 mm vs 104 mm for the left kidney). An angio-MRI demonstrated a thrombosis in the left common carotid artery, a 70% stenosis of the left subclavian artery, a 80% stenosis of the brachiocephalic artery, a thrombosis in the descending thoracic aorta, and a right renal artery thrombosis and stenosis , together with nonspecific symptoms . Symptoms due to ischemia, which are frequent in adults, have been seldom reported in children. However, although true claudication (upon effort) was present only in one patient, we have observed ischemic findings  in three of our four patients. The disease is also called 'pulseless disease', since peripheral pulses are often absent due to vascular obstruction; however, this feature was present only in one of our patients. In addition, an abdominal bruit can often help in the diagnosis, but this was noted in only 1/4 of our cases.The largest series of TA in children has been reported by Hong et al., who described 70 cases ; the malThe diagnosis of TA is based on characteristic findings of diseased aorta and its major branches seen on angiography. This is demonstrated by luminal abnormalities such as stenosis or aneurysmal dilatation of the aorta, its major branches, and the pulmonary arteries. With regard to imaging studies, traditionally the angiographic patterns have been divided in: type I, affecting the aortic arch; type II, the thoracic and abdominal aorta; type III, the aorta both above and below the diaphragm; and type IV, the aorta and the pulmonary arteries. In our cases type I was the predominant pattern, whereas in two series type II was the predominant one ,9.Ultrasonography and positron emission tomography are new, promising techniques to assess large-vessel vasculitides. Color-coded Doppler sonography can facilitate an accurate diagnosis of Takayasu arteritis by the characteristic appearance. Homogeneous circumferential intima-media thickening of the common carotid arteries is a specific ultrasonographic finding in patients with Takayasu arteritis -12. MoreWith regard to treatment, in our series corticosteroids have been used in all cases, with the adjunction of methotrexate in three cases and MMF in one. Although the numbers are small and the retrospective nature of this report does not allow to draw firm conclusions, our patients have obtained clinical and laboratory remission with this regimen of early immunosuppression. Our patients were followed from 2 to 10 years since diagnosis  and medications at the last visit included only low-dose prednisone in three cases (one of whom still needed MMF and anti-hypertensives), while the fourth patient is now only on low-dose aspirin. Bypass surgery was required in two patients because of severe vascular occlusion, with excellent results as well. One bypass was carried out between the ascending aorta and the right carotid artery, the other one between the lower thoracic aorta and infra-renal aorta; in the latter a reimplantation of left renal artery and auto transplantation of right renal artery to common iliac was also performed.Due to the rarity of the disease, there are no controlled studies of medical treatment of children with TA. An interesting new possibility is represented by the use of sildenafil, that has been recently reported in a 8-year old girl . We haveTA has been associated with other autoimmune diseases such as systemic lupus erythematosus, juvenile idiopathic arthritis, anterior uveitis, sarcoidosis, seronegative spondyloarthropathy, Crohn's disease, Wegener's granulomatosis, and Sweet syndrome -26. One TA is a disease with severe prognosis, mortality rate being reported in children from 35 to 40% by five years . It is tWe conclude that TA is not such a rare disease in a pediatric rheumatology setting, and also that it has to be considered in cases of unexplained arterial hypertension or unexplained inflammatory syndromes without signs of localization. A thorough physical examination can lead to the correct diagnosis if pulses cannot be felt or if an abdominal bruit is heard, even if these are not constant findings. Since the disease can be progressive and life-threatening, an early recognition is vital in order to start immunosuppression, which proved to be very successful in our patients.The authors declare that they have no competing interests.SAA and RC wrote the manuscript, MFD and LD retrieved data from charts, and XB and PC conceived and supervised the study. All authors read and approved the final manuscript.


The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC , which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as “zero-inflated data” and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms. Each participant was scanned twice consecutively, and the results from the two scans were averaged to provide a more accurate estimation. The amount of calcium was quantified with the Agatston scoring method http://www.mesa-nhlbi.org. Study presented in this article has been approved by the Human Subjects Research Review Committee at Yale University.The MESA study has been approved by the Human Subjects Research Review Committee at University of Washington and all six sites. Detailed information is available at the MESA website K covariates of interest.The distribution of CAC is highly skewed. We make the logarithm transformation and study Consider two-part models, where in the first part, we model the occurrence of a nonzero CAC value. More specifically, considerWe determine the link function K regression coefficients, and Parametric, proportional covariate effects:K regression coefficients, and there is no proportionality constraint on Parametric, nonproportional covariate effects:m unknown regression coefficients, K-m unknown nonparametric covariate effects, and Semiparametric, proportional covariate effects:m unknown regression coefficients, Semiparametric, nonproportional covariate effects:Models(i) and (ii) are parametric, whereas models (iii) and (iv) are semiparametric. There is a rich literature on the advantages and disadvantages of parametric and semiparametric models Most existing two-part models share a similar spirit with models (ii) and (iv) in that there is no constraint on the covariate effects With a statistical model, we are interested in its two closely related but distinct properties. The first is the estimation property, where the goal is to fully describe the relationship between covariates and response variable. The second is the prediction property, where the goal is to accurately predict values of the response variable for subjects that are not used in model building. Theoretically speaking, there exists a true data generating model. This model not only provides the best description of the relationship between covariates and response but also has the best prediction performance. However, in practice with finite sample data, the true model is not known, and the models most suitable for estimation and prediction may differ.With a simple linear regression model (M1): 2SE =  for subjects not used in model building. This quantity can be decomposed into two components. The first is a bias component, and the second is a variance component. Model (M2) is misspecified, so it may have the bias component larger than that of (M1). However, model (M2) has fewer unknown parameters and can be more accurately estimated. So the variance component for (M2) may be smaller than that for (M1). Thus, because of the bias-variance tradeoff, the misspecified (M2) can be more suitable for prediction. In studies of statistical models for CAC, the two aspects of model fitting have not been well distinguished, and the best estimation models have been used for prediction without rigorous justification, or vice versa. Our study shows that, for CAC in MESA, the models most suitable for estimation and prediction are in fact different.We also consider the alternative model (M2): n iid observations. Denote With a normally distributed random error, up to a constant, the log-likelihood function for a single observation isWith models (i) and (ii), we consider the maximum likelihood estimates (MLE), which are defined as the maximizers of With model (iii), we further assume that With model (iv), we adopt a similar estimation strategy and consider the PMLE defined as the maximizer of With parametric models (i) and (ii), inference can be based on the asymptotic normality result and the Fisher information matrix. However, with semiparametric models (iii) and (iv), such an approach involves smoothed estimation and is very difficult to employ. We propose the following bootstrap approach for inference of all parameters in all models: (a) Fit the model and compute the MLEs (PMLEs); (b) With the observed covariate values, generate random errors from the normal distribution with mean zero and variance We collect measurements on the following covariates, which have been suggested as possibly associated with CAC in various publications: gender , race/ethnicity , former smoker (binary indicator), current smoker (binary indicator), diabetes (binary indicator), SBP (systolic blood pressure), DBP (diastolic blood pressure), age, BMI (body mass index), LDL cholesterol, and HDL cholesterol. We consider the following parametric models: (i.1) model (i) with linear effects for all covariates; (i.2) model (i) with linear effects for all covariates plus quadratic effects for LDL and HDL; (ii.1) model (ii) with linear effects for all covariates; and (ii.2) model (ii) with linear effects for all covariates plus quadratic effects for LDL and HDL. Models (i.1) and (ii.1) are more commonly adopted in practice, whereas models (i.2) and (ii.2) have been motivated by the nonproportional semiparametric model, i.e, the “biggest model”, and suggested by a reviewer. In semiparametric models (iii) and (iv), among the 13 covariates, 7 are binary, which naturally have parametric effects. Our preliminary analysis also suggests parametric covariate effects for SBP and DBP. Thus, there are 9 parametric covariate effects and 4 nonparametric ones. There are a total of six models considered.For Among the six models, models (i.1)-(iii) are special cases of model (iv). model (iv) can be simplified as (i.1) versus model (iv) cannot be simplified.We consider the likelihood ratio test statistic to fully describe the relationship between CAC and risk factors, the semiparametric nonproportional model (iv) is needed. Based on the above results, we conclude that, To evaluate the prediction performance, ideally, two independent datasets (one training set and one testing set) from studies with comparable designs are needed. We are not able to find a study fully comparable to MESA. As an alternative, we consider the following Monte Carlo-based approach. (a) Randomly split the data in to a training set and a testing set with equal sizes; (b) Estimate the unknown parameters using the training set only; (c) Make predictions for subjects in the testing set. Specifically, for a subject, first predict the probability of a nonzero CAC using the logistic regression model. Dichotomize the predicted probability at 0.5 and create the binary CAC status (zero or nonzero). If a nonzero CAC status is obtained, predict its actual value using the linear regression model; and (d) To avoid bias caused by an extreme split, repeat Steps (a)–(c) 500 times. Compute summary statistics.In Step 1, we use random partition to generate independent training and testing sets. To avoid an extreme partition, multiple partitions are carried out. In the prediction evaluation, we are interested in the probability of correctly predicting the binary CAC status (zero or nonzero) as well as the overall mean squared error (MSE), which measures the ability to predict the actual CAC values. Under the six models, the mean error rates for predicting zero versus nonzero CAC areThe above results suggest that, despite their significantly different estimation results, all models have similar prediction performance. It is interesting to note that model (i.2), which has parametric proportional covariate effects, has prediction performance better than all of the other models . As model (i.2) is a submodel of model (iv), this finding may seem counterintuitive. However, as discussed above, it can be explained by the bias-variance tradeoff. Although the prediction performance of model (i.2) is only slightly better than that of the other models, it has fewer unknown parameters than four of the alternative models and is easy to estimate. Thus, we conclude that model (i.2) is the most suitable for the purpose of prediction.In the above sections, interesting findings include the nonlinear relationships found in model (iv) and the discrepancy between the models most suitable for estimation and prediction. Examination of As discussed in Models (i) and (iii) assume that the two covariate effects are perfectly proportional, whereas models (ii) and (iv) assume no proportionality. There are intermediate, partially proportional models with some covariate effects being proportional and the others not. Such models are as difficult to interpret and estimate as nonproportional models and hence not pursued. Our conclusions on the CAC models are based on the analysis of MESA. There are a few other studies examining similar cardiovascular problems, including the CHICAGO study Coronary artery calcification is an important predictor of cardiovascular disease events. Our literature review suggests certain limitations of existing CAC modeling studies. In this article, we analyze the MESA data and systematically investigate various CAC models. Building on existing studies including


Controversies exist regarding the indications for unicompartmental knee arthroplasty. The objective of this study is to report the mid-term results and examine predictors of failure in a metal-backed unicompartmental knee arthroplasty design.2), diagnosis, Knee Society scores and patella arthrosis with failure.At a mean follow-up of 60 months, 80 medial unicompartmental knee arthroplasties (68 patients) were evaluated. Implant survivorship was analyzed using Kaplan-Meier method. The Knee Society objective and functional scores and radiographic characteristics were compared before surgery and at final follow-up. A Cox proportional hazard model was used to examine the association of patient's age, gender, obesity . However, none of the factors assessed was independently associated with failure based on the results from the Cox proportional hazard model.Gender, pre-operative diagnosis, preoperative objective and functional scores and patellar osteophytes were not independent predictors of failure of unicompartmental knee implants, although high body mass index trended toward significance. The findings suggest that the standard criteria for UKA may be expanded without compromising the outcomes, although caution may be warranted in patients with very high body mass index pending additional data to confirm our results.Level of Evidence: IV Unicondylar knee arthroplasty (UKA), in addition to total knee arthroplasty (TKA) and high tibial osteotomy (HTO), is a common surgical treatment for monocompartmental knee disease. The initial pain relief and function restoration achieved by UKA appear to be comparable to TKA and HTO . CompareHowever, the use of UKA has remained controversial since the 1970s because of differences in the success rates reported. Patient selection is believed to considerably influence the success of UKA . As seleThe objective of this study was to examine the clinical and radiographic outcomes, the survivorship, and the predictors of failure of a metal-backed UKA design. The results from this study may lead to a better understanding of selection criteria for patients receiving UKA to help improve the outcomes of this procedure.2 . The mean follow-up was 60 months . Obese patients, defined as a BMI of 30 kg/m2 or over, accounted for 28% of the cohort. The majority of the knees  were diagnosed with osteoarthritis and the remainder  were diagnosed with osteonecrosis. An overview of the patient demographics can be found in Table Sixty-eight patients (80 knees) treated with a metal-backed unicondylar knee prosthesis at our institution were followed prospectively. There were 39 women and 29 men, who had a mean age of 72 years  and a mean body mass index (BMI) of 27 kg/mAll patients were evaluated clinically and radiographically pre-operatively, as well post-operatively at approximately 3 months, 6 months, 1 year, and annually thereafter. Clinical evaluation was performed with use of the Knee Society (KSS) rating system . Patient®  metal-backed unicompartmental prosthesis was used in all cases. Unicompartmental prostheses represent approximately 5% of the total number of knee arthroplasties performed by this surgeon in any given year. The skin incisions ranged from 10 to 15 centimeters. The patella was displaced laterally at the start of the procedure to inspect the patellofemoral joint and the lateral compartment, to evaluate the patella for the presence of osteophytes, and to confirm that the anterior and posterior cruciate ligaments (ACL and PCL) were intact. Inspection was done in both flexion and extension.All surgeries were performed by a single surgeon (P.M.B.) using a medial parapatellar approach. An M/GVarus releases were performed. Intramedullary instrumentation was used to make a distal femoral cut in 4 degrees of valgus orientation. The tibia was resected using an extramedullary alignment jig, with a minimum of 2 millimeters of bone removed in the greatest depth of deformity. A reciprocating saw was then used to make the center cut just medial to the ACL footprint and this bone fragment was removed. The leg was brought into extension to assess alignment. Next, femoral cuts were made and sized relative to the tidemark to avoid patellofemoral impingement. Finally, the chamfer, posterior, and peg cuts were made.The tibia was sized in both the anterior-posterior (AP) and medial-lateral (ML) dimensions to optimize coverage while avoiding implant overhang. A keel cut and two peg cuts were made. Trial components were used to achieve 1 to 2 millimeters of laxity in full extension, with balanced flexion. Occasionally, additional soft tissue releases were required to achieve this aim.Next, the metal implants were cemented into position, starting with the tibial component followed by the femoral prosthesis. A polyethylene trial was then placed on the tibial tray, and the leg was brought into full extension to allow the cement to harden. The trial was then removed, and the residual cement was removed with an osteotome. The final polyethylene spacer was then implanted, and balancing and alignment of the knee was confirmed throughout the full range of motion of the knee Figure .2), diagnosis, and presence of preoperational patella osteophytes) between the two groups. Similarly, Wilcoxon matched-pair signed-rank tests and chi-squared tests were used to compare continuous and categorical variables, respectively, before and after the operations. Seven factors were evaluated for association with implant failure: patient age, gender, obesity (BMI ≥ 30 kg/m2), pre-operative diagnosis (osteonecrosis or osteoarthritis), pre-operative Knee Society objective and functional scores, and the presence of patellar osteophytes prior to surgery. A Cox proportional hazard model was used to examine whether any of these factors were associated with the risk of failure of UKA, with a hazard ratio over one indicating that the factor was an independent predictor of a higher risk of failure of UKA. Patients that died or were lost to follow-up were excluded from this analysis.Failure of UKA was defined as a revision to total knee arthroplasty (TKA). In our center we do not treat symptomatic aseptic loosening with implantation of a new UKA prosthesis; all these patients are revised to a TKA. The Kaplan-Meier method was used to estimate the survivorship of the prosthesis used in the study cohort. The Wilcoxon rank sum test was used to compare continuous variables  between the failure and non-failure groups; a chi-squared or Fisher exact test was used to compare categorical variables  and 48 points (SD = 10), respectively Table . Both scRadiographic analysis revealed that the femoral angle increased by a mean of 0.9 degrees postoperatively (p < 0.01). However, there was no significant change in tibial angle. Medial joint space also increased significantly from a mean of 1.0 mm preoperatively to 3.0 mm postoperatively. At final follow-up, stable non-progressive lucent lines less than 2 mm in size were present in five of the unrevised patients (7%). One patient had a lucent line >2 mm in size but was asymptomatic and doing well at the most recent follow-up, with Knee Society pain and function scores of 92 and 90 points, respectively. One patient had progressive lucent lines in more than one zone and was judged to have an impending component failure. A revision was recommended to this patient but she refused as she was asymptomatic at most recent follow-up with Knee Society pain and function scores of 99 and 100 points respectively. A complete description of radiographic characteristics can be found in Table Of the 80 knees that were treated with UKA, nine (11%) were revised to a TKA over the follow up period. Two cases were due to component loosening, and three were attributed to patellofemoral/lateral pain Figures  and 3B. There were differences in some patient factors between the failure and non-failure groups, but no independent predictors of failure were identified. There was a significant difference in the mean age at index arthroplasty  between the non-failure and failure groups, respectively. There was a higher proportion of obese patients in the failure group compared to the non-failure group (44% versus 20%) but this difference was not significant (p = 0.11). Although the age difference was significant between the failure and non-failure groups, the hazard ratio of age was 0.94 , suggesting that age did not independently affect the risk of failure of UKA. Consistent with the descriptive analysis, obesity had a high hazard ratio of 2.12 but the 95% CI included a hazard ratio of 1.0. A more detailed comparison of the failure and non-failure groups can be found in Table Although patient selection is thought to influence the success of UKA, controversy remains over which specific factors affect the outcome of this procedure. Patient age, gender, and weight have been examined in previous studies without conclusive findings. Other factors, such as pre-operative diagnosis Knee Society function scores and patellar arthritis, have rarely been studied in relation to failure of UKA implant. This study used prospectively collected data to examine seven factors that may be associated with failure of UKA implants. We followed 80 knees for an average of 60 months. The survivorship of the UKA implants was 84% at 10 years follow up which is comparable to those reported in the literature ,10. Overet al. examined the survival of 1,047 knee arthroplasties in patients aged 55 years old or younger using a community registry and did not find an association between age groups and survival rate [et al. followed 28 knees in 28 patients who had a mean age of 52 years; only two knees were revised over a maximum of six years follow up [et al. reported a survival rate of 92% at 10 years in a group of younger patients [Traditionally, UKA was recommended for patients aged 60 years or over with a sedentary lifestyle . Howeverval rate . Althougollow up . Similarpatients . Tabor apatients -16. Addipatients ,16. The To date, gender has not been used as an inclusion/exclusion criterion for UKA, though some studies have found a difference in outcomes between male and female patients ,17,18. Het al. reported mean BMIs in the failure and non-failure groups of 33 kg/m2 and 25 kg/m2, respectively [Weight and obesity are other factors to consider when UKA is applied. A multi-center investigation by Heck ectively . Howeverectively ,15. One ectively . In addiectively . Despiteectively , such cret al. studied 31 osteonecrotic knees receiving UKA with a minimum follow up of three years and reported the survival rate of 96.7% at 12 years [et al. reported that there is no difference in survival rate based on diagnosis [Although most UKAs are performed to in patients with osteoarthritis, it is not the only indication for UKA. Osteonecrosis can be treated with UKA with good results. Parratte 12 years . The autiagnosis .Preoperative Knee Society objective and functional scores, and patellar osteophytes have rarely been studied as predictors for UKA failure. Although anterior knee pain is a relative contradiction for UKA based on conventional surgical criteria, a recent study found that it did not affect the success of UKA using the Oxford phase 3 device . Our finUKA is an effective treatment for unicompartmental knee disease. In addition to its clinical advantages, it may be more cost-effective when compared to TKA . OpponenSeveral limitations are noted in this study. First, the sample size is relatively small. Certain patient factors, notably obesity, trended towards significance in our analysis of independent predictors of failure, and it is possible that a larger study group would provide additional power to better define the associations between the factors and risk of failure of UKA. Additionally, because of the small and diverse number of failures, we did not attempt to assess hazard ratios for each individual cause for revision. It is possible that such an analysis would reveal variability in independent associations for some modes of failure. Finally, the follow up time is relatively short compared to some other studies on UKA. The average length of follow up was five years, which affects the survival rate in this study. In addition, long-term outcomes could not be assessed.Young age, gender, obesity, diagnosis, pre-operative objective and functional scores and patella osteophytes were not predictors of failure of a unicondylar knee implant, although increased obsesity was association with a high hazard ratio. The findings suggest that the standard criteria for UKA may be expanded without compromising the outcomes, although caution may be warranted in patients with very high body mass index pending additional data to confirm our results.No external financial support was received in support of this study.MAM is a consultant for Stryker Orthopaedics and Wright Medical Technologies, and receives royalties from Stryker Orthopaedics. PMB is a consultant for Stryker Orthopaedics, and receives royalties from Stryker, Arthrocare, Biomet, and Synthes.None of the other authors have any financial or non-financial competing interests to disclose.TMS, MAM, LPL, JX, PMB designed the study. LPL, DRM, PMB collected the data. TMS, LPL, JX, DRM, MGZ, analyzed the data. TMS, MAM, DRM, MGZ, prepared the manuscript. MAM, JX, MGZ, PMB ensured the accuracy of the data and analysis. All authors have read and approved the final manuscript.


Mary Moran and colleagues survey global investment into research and development of new pharmaceutical products to prevent, manage, or cure diseases of the developing world. The need for new pharmaceutical tools to prevent and treat neglected diseases is widely accepted . The creThere is little consensus on what constitutes a neglected disease or what new products are required . Health Specific R&D investment data are available for some neglected diseases—including annual surveys of HIV/AIDS and TB funding since 2000 and 2005, respectively , and a ohttp://www.thegeorgeinstitute.org/prpppubs).In order to address these information deficits, the Bill & Melinda Gates Foundation commissioned the George Institute for International Health to conduct five sequential annual surveys of global investment into R&D of new pharmaceutical products to prevent, manage, or cure diseases of the developing world. This article summarises key data from the first G-FINDER report ; by investments in platform technologies with shared Western, as well as potential developing country, applications ; or by funding for activities not directly related to product development .The definition of what constituted a “developing-country-specific” investment for each restricted disease and product category was reached through an intensive consultation process over four months with the Advisory Committee. In some cases, views of additional disease experts were sought before consensus could be reached. This resulted in a tailored set of criteria for each restricted disease-product category, reflecting differences in disease and product profiles, research approaches, and products already available. The example of vaccines for bacterial pneumonia and meningitis is given below.Streptococcus pneumoniae and Neisseria meningitidis) should be eligible for inclusion in G-FINDER. Within this, the Committee defined “developing-country-specific” products, for which investments could be included, as those that met the following criteria. For S. pneumoniae, the vaccine should be, at a minimum, designed for use in infants less than two years of age and provide coverage against S. pneumoniae serotypes 1, 5, and 14. For N. meningitidis, the vaccine should provide coverage against N. meningitidis serotype A, be a conjugate rather than a polysaccharide vaccine, be designed for use in infants less than two years of age, and be designed to cost less than a dollar per dose. For multivalent pneumonia vaccines covering Western and developing country strains, only developing-country-specific costs were eligible, defined as trials, registration, and phase IV/pharmacovigilance studies carried out in the target developing countries for the vaccine.  but excluding general research that could also be applied to commercial products. Research into HIV drugs also included only developing-country-specific applications, such as label extensions to paediatric patient groups, fixed dose combinations, and slow release formulations. These restrictions were important to prevent developing-country-specific funding being swamped by the high level of public and private investment into HIV R&D targeted at Western needs.As noted above, G-FINDER sought to provide data that were as consistent and comprehensive as possible across the range of neglected diseases surveyed, in order to enable analysis across diseases, funders, or regions and, as the survey is repeated, over time.In order to achieve this, we followed two core principles. Firstly, only raw primary data reported by the funders, product development partnerships (PDPs), and product developers themselves were included in the survey. If these data were not available, they were not supplemented with secondary data or estimates. Secondly, in order to make the data as comparable and consistent as possible, all raw primary grant data were collected using the same online/offline reporting tool and inclusion/exclusion framework for all survey recipients. The only exception was the NIH, where a proportion of grants could not be collected in this way due to NIH data management system changes (see below on how exceptions were handled).“Core funding of a multi-disease organisation” ;“Platform technologies”, further allocated as investment into diagnostic platforms; adjuvants, and immunomodulators; or delivery device platforms;“Other R&D” for any grants that still could not be allocated.Survey participants were asked to enter every neglected disease grant they had disbursed or received in 2007 into a password-protected online database, including the grant amount, grant identification number, a brief description of the grant, and the name of the funder or recipient of the grant. They were also asked to confirm their organisation details such as role in funding , financial year, currency used, type of organisation , and country where they were located. Each grant was entered using a three-step process where the survey recipient had to choose (1) a specific disease or sub-disease; (2) a product type ; and (3) a research type within the product  according to pre-determined categories as described below.  staff employed on neglected disease programmes, including employment costs and benefits but excluding overheads; and all non-FTE direct project costs according to predefined lists developed by G-FINDER. These lists included typical R&D activities such as screening, medicinal chemistry, batch manufacture, and bioanalysis studies. Companies were asked to allocate their investments by disease, product and research type, according to the same guidelines used for online survey recipients.We note that all participants agreed to provide actual 2007 grant disbursements and investments, as opposed to commitments made but not yet disbursed, or “soft” figures such as in-kind contributions, costs of capital, or funding estimates. Organisations submitted data based on their financial year, rather than the calendar year.This system was varied in the case of the NIH. Due to restructuring of NIH information systems, only the Office of AIDS Research and the intramural arm of the National Institute of Allergy and Infectious Diseases were able to provide raw grant data. Taken together, these represented 68% of NIH 2007 expenditures on neglected disease R&D accounted for in the survey. On the advice of the NIH, the remaining 32% were obtained and filtered from public official databases.Raw grant data for selected diseases were also shared with and between other survey groups  to avoid resurveying funders when possible. Any raw data received from other groups were reviewed, cleaned, and reclassified according to G-FINDER guidelines prior to entry into the database.Data were entered over a 10-week period from July to September 2008, with a final total of 5,116 grants or investments recorded in the database.Survey closure was followed by a three-month period of intensive cleaning, cross-checking, and organising of the complex dataset collected.Prior to commencing cross-checking, foreign currencies were converted to US dollars based on the 2007 average annual exchange rate as reported by the International Monetary Fund . All nonAnalysis was conducted using automated reports constructed to show multiple data cuts from our cleaned and cross-checked database. These included calculating funding by disease, product, and research areas and possible combinations of these; and by funder, geographical region, recipient type, and so forth, with summary findings set out below. Industry figures were analysed at aggregate level, rather than by individual company. This included analysis of multinational pharmaceutical company aggregate contributions and small company aggregate contributions.Public, private, and philanthropic funders in high- and middle-income countries that were part of the Organisation for Economic Cooperation and Development (OECD); all European Union Member States; and other high- and middle-income countries known to have an active research base Public funders in selected innovative developing countries—IDCs .In its first year, G-FINDER sought to capture 2007 data from a wide range of funders and countries including:In subsequent years, the survey will expand to include private sector funding in these two IDCs, as well as public funding in additional IDCs  and other low- and middle-income countries.Potential funders were identified through a number of avenues. The Health Policy Division has been working in the neglected disease field since 2004, during which time we have developed a large internal database of neglected disease funders, intermediaries, and product developers. This knowledge was built through scanning portfolios, media releases, industry reports, conference presentations, personal contacts, and in our role as Expert Advisors on a previous funding survey . Previous neglected disease surveys have also collated lists of funders, intermediaries, and developers working in HIV, TB, and malaria; and we liaised closely with these survey groups, and with our Advisory Committee, to exchange information on known organisations in the field. Collation of this information resulted in a list of 551 organisations in the 43 target countries, who had previously recorded involvement in neglected disease product development. Of these, 134 were funders (the target group for the survey).These 500-plus potential survey recipients were prioritised based on their R&D role , level of funding, and area of disease and product activity.Our top priority, as noted, was to target funders; however, it was known that some funders played a more pivotal role than others. For example, previous surveys had identified that 88% of malaria R&D funding ; 88% of All potential survey recipients were then reviewed for their activity in diseases outside HIV, TB, and malaria, to ensure the survey did not overlook groups who might only be active in other diseases and would therefore not have appeared in previous HIV, TB, and malaria funding surveys. Based on this review, on our internal database, and on advice from our Advisory Committee, we identified known or suspected major funders, PDPs, and product developers  for the remaining 27 G-FINDER diseases. If not already included, these were added to our high priority group.This prioritisation process resulted in three survey strata, as follows. The maximum priority group included 25 organisations known to be major funders (over US$10 million per year) or major private sector developers investing internally in the 30 target neglected diseases. The high priority group of 85 organisations included known significant funders (US$5–US$10 million per year); potential research funders in high-GERD countries; and a range of academic research institutes, PDPs, government research institutes, multilaterals, multinational pharmaceutical firms, and small companies, who collectively provided good coverage of all disease areas. The remaining survey recipients, classified as low priority, were known very small funders or other known grant recipients, including many academic groups and public research institutions. We note that, although data from grant recipients were not included in the survey, they were collected to underpin the cross-checking process and track funding flows through the system. In addition, they provided extremely useful insights into how and where neglected disease research is conducted.The G-FINDER process focused on the 110 organisations included in the maximum and high priority groups, who likely represented the majority of global neglected disease R&D funding. Substantial pro-active effort was put into securing high survey completion and data accuracy rates from these groups. The remaining groups were passively surveyed, but not pro-actively pursued for information.We received complete financial information from 150 organisations. In the maximum priority group, 23 of 25 recipients (92%) provided funding information for 2007. Two maximum priority organisations, Wyeth-Ayerst Lederle and Merck , did not provide data; and one, sanofi-aventis, provided incomplete data (drug but not vaccine data). In the high priority group, 77 organisations (91%) provided full funding information for 2007.Just over US$2.5 billion was invested into R&D of new neglected disease products in 2007.Funding was highly concentrated, with HIV/AIDS, TB, and malaria receiving nearly 80% of the total see . Other eOverall, product R&D investment was heavily focused on drugs and vaccines. Investment in new diagnostics was patchy, while platform technologies applicable to many diseases, for instance vaccine adjuvants, diagnostic platforms, and delivery technologies, received less than 0.4% of total R&D investment.Total R&D funding for HIV/AIDS was US$1.08 billion, with US$692 million (63.9%) directed to vaccines, US$200 million (18.4%) to microbicides, and US$176 million (16.2%) to basic research. Less than US$1 million (0.1%) was invested in development of HIV drugs targeted at developing world needs, such as paediatric formulations and fixed-dose antiretroviral combinations .Total funding for malaria was US$468.5 million, with drug development receiving nearly half this amount (US$214 million or 45.7%). Basic research was the next highest funded category at US$113 million (24.1%), while vaccines received US$88.4 million (18.9%). Vector control products, such as insecticides and biological control measures, received US$17.7 million. Malaria diagnostics received very limited funding of US$1.6 million  .TB funding for 2007 totalled US$410.4 million. As with malaria investments, the bulk of this went to R&D of TB drugs (US$145.1 million or 35.3%), closely followed by basic research at US$132.4 million (32.3%). TB vaccines were funded at similar levels to malaria vaccines in both actual and relative terms, receiving US$82.3 million (20%) of total TB funding. However, TB diagnostics fared dramatically better, receiving 8.5% of global TB investment (US$35 million) .Neglected disease funding remains primarily the realm of public and philanthropic donors, who collectively invested US$2.3 billion or 90% of the total funding in 2007 .Public donors, including government and multilateral groups, provided US$1.78 billion (69%) while philanthropic and not-for-profit funders invested US$538 million (21%). Although only two IDCs were included in year one of the survey, they represented 1% of global spending. IDC figures are expected to be substantially larger in subsequent G-FINDER surveys due to the inclusion of India, China, and Cuba.The private pharmaceutical industry provided around 9% of the global total, with an aggregate investment of US$231.8 million. This collectively made the pharmaceutical industry the third largest global investor in neglected disease R&D behind the NIH and the Bill & Melinda Gates Foundation. Small companies and biotechs represented around 20% of reported industry investment (US$46.2 million), with multinational firms contributing US$185.7 million (80%).The US Government represented nearly three quarters of global public spending with an investment of US$1.25 billion (70%) through its various institutes and departments . EuropeaIt was also illuminating to examine funding from the perspective of individual organisations. This showed that global investment into creating new neglected disease products is heavily reliant on a mere handful of donors. Twelve organisations provided around 80% of global funding, with the NIH and the Bill & Melinda Gates Foundation collectively investing US$1.51 billion or 59.5% of the total .For confidentiality reasons, industry investments were aggregated. However, we note that if this had not been the case, some pharmaceutical companies would have appeared in the list of top 12 funders based on the size of their internal investments.Neglected disease R&D is conducted by a wide variety of organisations, including academic groups, public institutions, and private companies. Some rely entirely on external grants for their neglected disease R&D programmes, while others fund their programmes from their own budgets, and yet others operate on a mix of both.Funders also appeared to increasingly rely on PDPs to manage and allocate funding . Twenty-G-FINDER is, we believe, the most rigorous neglected disease R&D survey conducted to date in terms of its scope, methodology, and breadth of participation. Strenuous efforts were made to reach agreement on definitions of diseases, products, and research activities for inclusion. Equal effort was put into designing a data collection system that provided an identical reporting framework for each organisation, despite differences in currency, financial year, research categorisation, and reporting systems. By collecting primary raw grant and investment data in the same way from all organisations, we believe the G-FINDER survey allows for a more accurate comparison of funding across the range of neglected diseases than has been possible before.public maximum priority funders are close to 100% complete, since all identified public groups provided full data. However, private sector figures are almost certainly under-reported due to the non-participation of two maximum priority multinational pharmaceutical companies and provision of incomplete data by another. We note that at least one of these companies has a late-stage pneumonia vaccine programme for commercial markets; however, this may have included some investment in developing country studies that will have been missed. One of the three firms also had a late-stage HIV vaccine in development, which will have led to significant under-reporting of AIDS vaccine investments.However, it is also important to note the limitations of the survey. The greatest limitation is survey non-completion, particularly by maximum priority groups who are by definition major funders or play a significant R&D role in a specific disease-product area. We believe that data from A second area where missing private sector data are likely to distort results is that of diagnostics, where smaller companies play an active role. A total of 150 small firms were identified as having neglected disease R&D activity, many of them working in the diagnostic field, particularly HIV and TB diagnostics; however, only 28 of these provided data for the survey. The plethora of small firms in the diagnostic field is likely to reflect the substantially lower development cost and time of bringing new diagnostics to market, compared to developing new drugs and vaccines. Low participation rates by these small firms mean diagnostic investments are likely to be under-reported, particularly in HIV and TB. As a result, the diagnostic funding reported in G-FINDER for these two diseases needs to be treated with caution.It is also important to note other factors that are likely to have led to under-estimation of the value of industry investments. Companies who participated in the survey agreed to exclude costs that were difficult to quantify in order to avoid degrading the quality of data—for instance, costs of capital, infrastructure costs, and the value of in-kind contributions. Although difficult to quantify, these inputs nevertheless have a substantial value and represent a substantial unrecognised cost to companies.Differing level of responsiveness between organisations and countries may also skew findings. For instance, it is possible that the Australian location of the G-FINDER group led to high levels of responsiveness from Australian funders, or that funders in non-English-speaking settings were less enthusiastic in their levels of response. This is not known to be the case, but is simply noted as a possible factor.Finally, G-FINDER can only report the data that were given to us. Although strenuous efforts were made to check the classification, accuracy, and completeness of grants, in a survey this size it is likely that some data will still have been incorrectly entered or that donors may have accidentally omitted some grants. The requirement to use public official databases for some NIH data, as opposed to raw grant data, also means these figures may contain inaccuracies or omissions that we were unable to detect. We believe, however, that the checks and balances built into the G-FINDER process mean that such mistakes, if present, will have a minor impact.The G-FINDER survey is intended to report accurate, comparable R&D investment figures across the spectrum of neglected diseases. We are not seeking to analyse whether investment is best spent, or to make recommendations on funding allocation; nor are we attempting the task of ascertaining how much R&D funding is “enough”. Although we acknowledge the importance of these questions, it would require a research effort of equal or greater scope to the task undertaken here. The G-FINDER report is simply the first step in the process, providing information to allow discussion and decision-making to begin.We therefore restrict ourselves to a few observations. The first is that research funding is highly concentrated and has little correlation with burden of disease, as measured by DALYs.For instance, HIV, TB, and malaria accounted for 125 million DALYs in low- and middle-income countries in 2004  and receThis observation should not be construed as a statement or belief that funding levels can or should be based only on disease DALYs. DALYs are the most widely accepted quantitative indicator of burden of disease, but remain an imperfect measure. For some diseases, such as Buruli ulcer, reliable DALYs are virtually nonexistent; correct estimates can be difficult to obtain in regions with weak data; and DALYs do not reflect the impact of co-morbidities, such as HIV and TB. The DALY comparison is noted here chiefly to give a sense of the differences in scale of funding for different diseases.It is important to note, however, that funding levels reflect many factors beyond DALYs. The current state of science for a given disease plays a role, since many would-be investors in product development look at feasibility as well as need. Conversely, other investors may specifically choose to invest in areas where science is lacking, believing their best contribution will be funding a breakthrough discovery to unlock the path to new products.Funders may also look at the state of existing therapies, preferring to focus on areas where no safe effective treatments exist  to areas where treatments exist even though they may be limited or sub-optimal . Funders may also want to focus on diseases with a higher relative or absolute mortality, such as dengue or meningitis, rather than diseases with lower relative mortality but a higher DALY burden.The type of R&D needed in a given disease area is also a crucial factor in interpreting the data, since R&D costs vary dramatically depending on the kind of product being developed and how far down the development pathway that product is. Vaccines are far more expensive to develop than drugs, and drugs than diagnostics. Clinical development is also far more expensive than pre-clinical or discovery research. For instance, out-of-pocket development cost of a diagnostic test can be in the low tens of millions; while clinical development cost of a novel fixed-dose combination anti-malarial is estimated at US$30 million, and of a malaria vaccine at just over US$100 million . Thus, fDespite this, the concentration of funding on AIDS, TB, and malaria nevertheless suggests that investment decisions are not only influenced by scientific or epidemiological considerations, but may also be influenced by factors such as the presence of PDPs or civil society groups with active advocacy, fundraising, and investment activities; by funder perceptions or preferences; or by the presence of policy frameworks and funding mechanisms that prioritise specific diseases.The predominance of research into new products for HIV/AIDS, malaria, and TB is understandable—and the generosity of funding in these areas is a credit to donors—however, other high-burden, high-mortality diseases remain badly under-funded: pneumonia and the diarrhoeal illnesses stand out in this regard. The tendency to focus on drugs and vaccines over diagnostics, platform technologies, and developing-country-specific products is also of concern, particularly as these latter categories can represent a highly effective use of resources since any advance will be applicable to many neglected diseases and products.A second observation relates to the concentration of funding. The participation of so many organisations and countries in development of new neglected disease products is a remarkable and welcome change from past decades of inertia and neglect. It is clear, however, that these efforts are not evenly distributed, with several major OECD governments missing in action from the top 10, top 20, or even the top 50 funders of R&D for neglected diseases. It is also remarkable that investment by some private firms is now rivalling or exceeding spending by many public organisations, and indeed many G7 and OECD countries. While we commend these companies and philanthropists, their efforts are meant to support, not replace, those of wealthy governments around the world.A broadening of funding efforts so that all who are able to contribute do so, and all diseases receive the attention they deserve, would lead to a dramatic positive impact on the health of developing country patients afflicted with these diseases. We very much hope that the information presented in the G-FINDER report will contribute to this process.Text S1(40 KB DOC).Click here for additional data file.Text S2(41 KB DOC).Click here for additional data file.Text S3(288 KB PDF).Click here for additional data file.Text S4(617 KB DOC).Click here for additional data file.


Recent reports of high HIV infection rates among men who have sex with men (MSM) from Asia, Africa, Latin America, and the former Soviet Union (FSU) suggest high levels of HIV transmission among MSM in low- and middle-income countries. To investigate the global epidemic of HIV among MSM and the relationship of MSM outbreaks to general populations, we conducted a comprehensive review of HIV studies among MSM in low- and middle-income countries and performed a meta-analysis of reported MSM and reproductive-age adult HIV prevalence data.A comprehensive review of the literature was conducted using systematic methodology. Data regarding HIV prevalence and total sample size was sequestered from each of the studies that met inclusion criteria and aggregate values for each country were calculated. Pooled odds ratio (OR) estimates were stratified by factors including HIV prevalence of the country, Joint United Nations Programme on HIV/AIDS (UNAIDS)–classified level of HIV epidemic, geographic region, and whether or not injection drug users (IDUs) played a significant role in given epidemic. Pooled ORs were stratified by prevalence level; very low-prevalence countries had an overall MSM OR of 58.4 (95% CI 56.3–60.6); low-prevalence countries, 14.4 (95% CI 13.8–14.9); and medium- to high-prevalence countries, 9.6 (95% CI 9.0–10.2). Significant differences in ORs for HIV infection among MSM in were seen when comparing low- and middle-income countries; low-income countries had an OR of 7.8 (95% CI 7.2–8.4), whereas middle-income countries had an OR of 23.4 (95% CI 22.8–24.0). Stratifying the pooled ORs by whether the country had a substantial component of IDU spread resulted in an OR of 12.8 (95% CI 12.3–13.4) in countries where IDU transmission was prevalent, and 24.4 (95% CI 23.7–25.2) where it was not. By region, the OR for MSM in the Americas was 33.3 (95% CI 32.3–34.2); 18.7 (95% CI 17.7–19.7) for Asia; 3.8 (95% CI 3.3–4.3) for Africa; and 1.3 (95% CI 1.1–1.6) for the low- and middle-income countries of Europe.MSM have a markedly greater risk of being infected with HIV compared with general population samples from low- and middle-income countries in the Americas, Asia, and Africa. ORs for HIV infection in MSM are elevated across prevalence levels by country and decrease as general population prevalence increases, but remain 9-fold higher in medium–high prevalence settings. MSM from low- and middle-income countries are in urgent need of prevention and care, and appear to be both understudied and underserved. From a systematic review, Chris Beyrer and colleagues conclude that men who have sex with men in the Americas, Asia, and Africa have a markedly greater risk of being HIV-infected than does the general population. AIDS (acquired immunodeficiency syndrome) first emerged in the early 1980s among gay men living in New York and California. But, as the disease rapidly spread around the world, it became clear that AIDS also affected heterosexual men and women. Now, a quarter of a century later, 40 million people are infected with human immunodeficiency virus (HIV), the organism that causes AIDS. HIV is most often spread by having unprotected sex with an infected partner and in sub-Saharan Africa, the region most badly hit by HIV/AIDS, heterosexual transmission predominates. However, globally, 5%–10% of all HIV infections are thought to be in men who have sex with men , and in several high-income countries, including the US, male-to-male sexual contact remains the most important HIV transmission route.In the US, the MSM population is visible and there is considerable awareness about the risks of HIV transmission associated with sex between men. In many other countries, MSM are much less visible. They remain invisible because they fear discrimination, stigmatization , or arrest—sex between men is illegal in 85 countries. Consequently, MSM are often under-represented in HIV surveillance systems and in prevention and care programs. If the AIDS epidemic is going to be halted, much more needs to be known about HIV prevalence (the proportion of the population that is infected) among MSM. In this study, the researchers have done a systematic review (a type of research where the results of existing studies are brought together) on published reports of HIV prevalence among MSM in low- and middle-income countries to get a better picture of the global epidemic of HIV in this population.The researchers found 83 published studies that reported HIV prevalence in 38 low- and middle-income countries in Asia, Africa, the Americas, and Eastern Europe. When the results were pooled—in what statisticians call a meta-analysis—MSM were found to have a 19.3-times greater chance of being infected with HIV than the general population. This is described as a pooled odds ratio (OR) of 19.3. The researchers also did several subgroup analyses where they asked whether factors such as injection drug use (another risk factor for HIV transmission), per capita income, geographical region, or the HIV prevalence in the general population were associated with differential risk (increase in odds) of HIV infection compared to the general population. They found, for example, that in countries where the prevalence of HIV in the general population was very low  the pooled OR for MSM compared to the general population was 58.4; where it was high (more than 1 adult in 20 infected), the pooled OR for MSM was 9.6.These findings indicate that MSM living in low- to middle-income countries have a greater risk of HIV infection than the general populations of these countries. The subgroup analyses indicate that the high HIV prevalence among MSM is not limited to any one region or income level or to countries with any specific HIV prevalence or injection drug use level. Although the small number and design of the studies included in the meta-analysis may affect the numerical accuracy of these findings, the clear trend toward a higher HIV prevalence of among MSM suggests that HIV surveillance efforts should be expanded to include MSM in those countries where they are currently ignored. Efforts should also be made to include MSM in HIV prevention programs and to improve the efficacy of these programs by investigating the cultural, behavioral, social, and public policy factors that underlie the high HIV prevalence among MSM. By increasing surveillance, research, and prevention among MSM in low- to middle-income countries, it should be possible to curb HIV transmission in this marginalized population and reduce the global burden of HIV.http://dx.doi.org/10.1371/journal.pmed.0040339.Please access these Web sites via the online version of this summary at world legal map on legislation affecting lesbian, gay, bisexual, and transgendered peopleThe International Lesbian and Gay Association provides a Off the Map: How HIV/AIDS Programming is Failing Same-Sex Practicing People in AfricaThe International Gay and Lesbian Human Rights Commission provides a page called MSM initiative, which is focused on providing support to front-line community groups working on providing services and doing research focused on HIV among MSM in lower income-settingsThe American Foundation for AIDS Research (amfAR) has launched their HIV infection and AIDSInformation is available from the US National Institute of Allergy and Infectious Diseases on HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of organizations that provide information for gay men and MSMHIV, AIDS, and men who have sex with menInformation is available from Avert, an international AIDS charity, on HIV/AIDS and on HIV/AIDS among men who have sex with men (in English and Spanish)The US Centers for Disease Control and Prevention provides information on  Male-to-male sexual contact has been an important route of HIV-1 spread since HIV/AIDS was first identified some 25 years ago. HIV among gay, bisexual, and diversely identified men who have sex with men (MSM) remains a significant or predominant component of HIV epidemics in a number of high-income countries including the United States, Australia, and much of Western Europe . Recent MSM is a term coined in 1994 to reduce stigma against gay, bisexual, transgendered, and self-identified heterosexual men who engage in sex with other men, by describing behaviors rather than social or cultural identities . While tA review of the epidemiologic literature suggests that MSM are inadequately studied in many countries, and that despite well-characterized risks for HIV acquisition and transmission, MSM continue to be under-represented in national HIV surveillance systems, in targeted prevention programs, and in care. Caceres et al.  have pubThe highest rates of HIV infection overall have been seen in sub-Saharan Africa, where heterosexual transmission is the main form of spread . In the To investigate the global epidemic of HIV among MSM and the relationship of outbreaks among MSM to spread in the general population, we conducted a systematic review of HIV studies among MSM in low- and middle-income countries, and performed a meta-analysis of reported HIV prevalence data in MSM and among adults of reproductive age in reviewed countries .OR “Homosexual” which were cross-referenced with the key word (AND) “HIV”  OR the MESH term “Human Immunodeficiency Virus”  and limited to reports in the English language, published between October 3, 2000, and the present date, and pertaining to individuals 15 y of age and older (OR “transgender” (37 abstracts). Of the 779 conference abstracts reviewed, 524 were unique and 49 met all the inclusion and exclusion criteria, though six were later excluded due to the inability to contact the study authors for methodologic clarification, or an inability to retrieve background prevalence of HIV in that country. An additional 16 studies were retrieved from the most recent full report from EuroHIV [We searched both electronic databases and conference proceedings for this review. The databases used included PubMed, EMBASE, EBSCO, and the Cochrane Database of Systematic Reviews on October 3, 2006. All the databases were included to ensure sensitivity, though ultimately there was no study included in the final analysis found in other databases that was not also found on PubMed. Inclusion criteria for studies were determined a priori to be: studies including HIV prevalence data among MSM populations ; publication in a peer-reviewed journal; an abstract at a conference with peer-reviewed blinded abstract selection process; listed details regarding data sampling techniques; data collection started since January 1, 2000; studies in low- and middle-income countries; and studies taking place in countries where UNAIDS has calculated a general population prevalence for 2006. If the studies were not published in a peer-reviewed journal, though commissioned by government-managed epidemiologic monitoring agencies such as European Centre for the Epidemiological Monitoring of AIDS (EuroHIV) or the US Centers for Disease Control and Prevention (CDC), the studies were also included. The following medical subject heading (MESH) terms were used for PubMed, while the same terms were used as keywords in the other databases: “Homosexual, Men” nd older . The exc EuroHIV . This daEconomies are divided according to 2005 gross national yearly income per capita, calculated using the World Bank Atlas method. The groups are: low income, US$875 or less; lower middle income, US$876–3,465; upper middle income, US$3,466–10,725; and high income, US$10,726 or more. For this analysis, we used all countries with a gross national income per capita of less than US$10,725 .This meta-analysis calculates the measure of association between being MSM, the independent variable, and HIV infection, the dependent variable, and presents this relationship in the form of an odds ratio (OR). In addition, individual country prevalence estimates were calculated .HIV epidemics have been characterized by prevalence levels and/or epidemic stages. In defining categories of prevalence, we have used the schema recently proposed by Stover et al., which defines HIV epidemics among adults of reproductive age (those aged 15–49 y) as very low prevalence, <0.5% of adults; low prevalence, 0.5%–1.0%; medium prevalence 1.1%–5%; and high prevalence, >5% of adults . The extGeneral population prevalence was estimated by using reported absolute number of HIV infected adults of reproductive age, 15 y and older, published by UNAIDS in 2006 and, using as the denominator the population estimates of people aged 15–49 y in the respective countries as gathered from the US Census Bureau Population Division International Database . The datThe population estimates calculated by UNAIDS are based on statistical models rather than actual survey data. Since the background population estimates are computed individually, based on the specific dynamics of the HIV epidemic in that country, there is potential for bias in the comparison and pooling of ORs between countries. For very populous and diverse countries such as China and India, different regions of these nations have been classified at different levels of the HIV epidemic . SpecifiUNAIDS defines what is a country according to the criteria used by the United Nations; thus, separate analyses for Taiwan and Puerto Rico are not included. For this meta-analysis, data from Taiwan were coupled with that of mainland China; similarly, data from Puerto Rico would be included with that of the United States, a high-income country.Data regarding prevalence and total sample size were obtained from each of the studies that met inclusion criteria. Aggregate values were calculated for each country by combining the absolute number of MSM with HIV and without HIV. As only raw data were collected from the studies, prevalence estimates of HIV among MSM were determined for each country with 95% confidence intervals (CIs). A combined prevalence estimate was calculated by combining a weighted HIV prevalence among MSM for each country. The pooled estimate was weighted according to the sample size of MSM studied in that country's sampling.Q test [Meta-analyses were completed using the comprehensive statistical software package Stata 9.1 . The ManQ test . The datCountries were stratified by epidemic level and by the presence or absence of IDU predominance to determine whether these play a role in determining the overall odds of having HIV among MSM. Background prevalence estimates were categorized as very low , low (0.1%–0.5%), and medium–high (>0.5%). Pooled estimates were also stratified by whether or not injection drug use played an important role in the transmission of HIV in that country ,31. A suSummary statistics, including ORs, aggregate sample sizes, average prevalence of HIV among MSM, and background prevalence is listed in Using studies from all countries, MSM had a 19.3 (95% CI 18.8–19.8) times higher odds of having HIV compared with background populations . When thThis is to our knowledge the first meta-analysis of HIV survey data collected from MSM participants in low- to middle-income countries. Overall, the odds of having HIV infection are markedly and consistently higher among MSM than among the general population of adults of reproductive age across Asia, Africa, the Americas, and the FSU.There are a number of limitations to this study. MSM in many developing countries are often difficult to access and to study because of criminalization of their behavior, the social stigma associated with their behaviors and identities, participant safety concerns in some settings, and low levels of self-identification among MSM. These barriers likely limited both the number and quality of studies in the literature—only a few lower-income countries, including Mexico, Brazil, Thailand, and Peru, have systematically surveyed MSM. The majority of studies cited in this analysis are convenience samples and cross-sectional in design, and so may not be representative of MSM. To determine a corollary of risk for HIV infection among MSM in low- and middle-income countries, we used UNAIDS general population prevalence estimates for each country as the unexposed population to compute ORs. Because of the lack of controls, issues affecting internal validity could not be formally controlled for in our study. MSM tend to congregate in urban areas, at least partially explaining why the majority of reported studies are urban; again, this may limit generalizability. In very populous countries such as China and India, there may be even more marked differences between urban and rural areas in HIV prevalence and in reporting of MSM behaviors. Publication bias tends to affect the results of meta-analyses, both in the realms of clinical and public health research, and could be partly responsible for the magnitude of associations seen in this study . To miniMSM were likely included in some samples of men in the general reproductive-age population. This is likely the case in those settings where MSM behavior is most hidden. We conducted a sensitivity analysis to assess the importance of this misclassification of MSM. Such an approach is important in assessing the validity of the assumptions made for statistical calculations in meta-analyses . Using tn = 63,538). By calculating a measure of association, such as an OR, one can see that two regions with identical absolute measures, such as HIV prevalence among MSM, may be in very different stages of the HIV epidemic affecting the overall risk status of MSM in that region. Due to the significant heterogeneity  of the ORs of HIV infection among MSM from differing countries, one pooled OR describing the HIV risk of MSM globally is likely not valid as an accurate measure of risk. Rather, the value of these analyses is in the overall trends of the results. These trends of high HIV prevalence among MSM in the context of low-level or concentrated HIV epidemics speak to the urgent need for increased targeted prevention strategies to this at-risk population in low- and middle-income countries.Despite these limitations, this meta-analysis draws its precision strength from the combined estimates of the OR and a large aggregate sample size of MSM , and was even higher in countries with low-level epidemics (OR 24.5) or concentrated epidemics (OR 23.5) . The UNAThe direction of the measure of association among MSM appears to be quite consistent between individual countries, geographic regions, and epidemic states, highlighting the external validity of the individual studies. Eastern Europe appears to be an exception: MSM data are scarce, and the region's HIV epidemics are primarily driven by IDU exposure. No peer-reviewed published report or abstract meeting our inclusion criteria was found in Eastern Europe. The most recent EuroHIV surveillance report served as the primary source for these data. Since an unknown but potentially significant number of MSM in this region may also be IDUs, estimating the attributable risk fraction for these differing behaviors is difficult. What is clear is the need for more effort to characterize the risks for MSM in this region.The stratification of the pooled OR estimate revealed some general differences in risk status between MSM globally. The highest OR for HIV infection was found in the Americas, at 33.3. It was lower, but still extremely high, in Asia at 18.7, lower still in Africa at 3.8, and lowest in Eastern Europe at 1.3. The relatively outlying result from Eastern Europe is likely due, as we have argued, to comparing MSM with populations where IDUs are the main driver of HIV. The very high rates in the Americas and Asia were by far the best evidenced, suggesting that these epidemics among MSM are real, and that these men are indeed at markedly greater risk than heterosexuals in these settings. Data regarding MSM in Africa were the sparsest, but are beginning to emerge. Recent reports of HIV risks (if not rates) among MSM were found from Uganda, Zambia, Sudan, and Nigeria, though not all met inclusion criteria for this analysis –42. ThesThese results constitute a clear call to action on three fronts: surveillance, research, and prevention . The var