To quarantine the spreading possibility of HIV virus to general population boosting public awareness is must. But the proper awareness level is substantially low in Bangladesh. This paper aims to identify the factors associated with the awareness regarding HIV/AIDS through a bivariate and multivariate analysis using the data extracted from Bangladesh Demography and Health Survey (BDHS) 1999–2000.The findings of both techniques show that education, occupation, socioeconomic status, status of household food consumption, area of residence and media exposure have significant (p < 0.001) contribution in determining HIV/AIDS awareness level. It also reveals that media, particularly TV, and education play the leading role regarding this issue while the others have an indirect relationship. The odds of awareness among higher educated women and men were 4.69 and 77.73 times of no educated women and men respectively. In addition, both women and men those who regularly watch TV were 8.6 times more likely to be aware about AIDS compared to those who never watch TV. This phenomenon holds true for both women and men.At this instant it is urgent to give emphasis on education, alleviation of poverty, ensuring electronic media exposure, head to head communication program, institutional based sex education and necessary information to learn about HIV/AIDS for the young, adult and adolescents all over the country. Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV) has created a major global health crisis and its impact on a country is tremendous -3. The wThe data for this study were obtained from the 1999–2000 Bangladesh Demographic and Health Survey (BDHS). It is a cross-sectional survey that have been carried out once in every two years since 1993 among a nationally representative samples of women as done in many other countries. The BDHS is part of the worldwide Demographic and Health Surveys (DHS) programme which collects information on a number of areas such as demographic characteristics, reproductive history and family planning. The survey was conducted during the period from November 1999 to March 2000, under the authority of the National Institute of Population Research and Training (NIPORT), Bangladesh. A nationally representative two-stage probability sample design was used for the sample survey in which a total of 10544 currently married women and 2556 currently married men were successfully interviewed. Details of the methodologies adopted in BDHS can be found elsewhere . This stSince a cure or vaccine is unlikely in the near future, efforts to prevent the HIV epidemic must focus on public awareness. Several countries, including Thailand and Uganda, have successfully decreased the spread of HIV by aggressive efforts in this regard . KeepingAppendix Table Bivariate results for female respondents showed that other than woman's current working status, number of visit by family planning field worker (FPFW) and health field worker (HFW), all the other variables included in this analysis had statistically significant relationship with the level of HIV/AIDS awareness Table . NeverthAwareness regarding HIV/AIDS was highest among higher educated women and lowest among the illiterate women. Women with no education only 12.4% ever heard AIDS. As the education level increases the percent of the respondents who aware about AIDS also increases. Women with education secondary or more belongs to highest percent, 72.0%, of awareness. Often awareness of the women relies on their husbands' education and occupation. The findings shows that the wives of the husbands with education secondary plus are more conscious, 54.1%, than those having the husbands with no education, 12.9%. In relative sense the odds of awareness among the women with education level higher were 4.68 times of the women with no education. In addition, wives of the educated husbands know better about AIDS than the wives of the uneducated husbands and this difference is about 85% more in the literate group.Wives of the husbands employed in agriculture and/or does manual work bear least knowledge as to AIDS than wives of the husbands employed as professional , technical expert and managerial work. Among the wives of the agricultural self-employees only 14.7% learnt about AIDS, followed by agricultural employee or manual work, 25.6%. The percentage is high in the category like professional/technical/managerial, 49.1% and didn't work, 45.4%.Household economic status determined by assets owned has a positive affect on awareness. Women belonging to the households with 7–12 items have the awareness more, 56.6% and less in the group having 0–3 items, 14.5%. In the comparative sense the women of the households with 7 or more items were 2.8 times more alert than the households with 3 or less items.Women of the households with food surplus or equal are more conscious, 45.3%, than the women of the households with food deficit sometimes, 22.4% or deficit in the whole year, 14.5%. In addition, the odds of awareness was 1.2 times among women of the household with food surplus or equal compare to those women of the household with food deficit in the whole year.It is usual to have awareness among the people who retain themselves in close contact to mass media/electronic media like radio, TV. Women who listen to radio everyday possess the highest percent, 52.1%, in awareness and 45.6% who listen often and 21.0% who listen never. Of everyday female TV watchers 77.1% were alert about AIDS, 38.5% of those who watch TV sometimes and only 21.0% of those who never do so. In comparative sense, the odds of awareness were 1.9 and 1.5 times among the women who had listen radio every day and listen sometimes respectively compare to those who had never listen radio. Correspondingly the odds of awareness among regular TV viewers and moderate viewers were 8.6 and 2.9 times respectively of those never watch TV.It is usual to expect that urban people are more alert than their rural counterparts. Urban people enjoy more amenities like TV, telephone, radio, newspaper, magazine etc. than rural people. They are closer to the information highway than the rustics. Women living in the urban areas have more awareness, 64.3%, than those who live in the rural areas, 22.6%. In relative sense, urban women were 3.93 times more aware compare to its rural counterpart.Bivariate results for male respondents on the other hand showed statistically significant relationship between education, occupation, household economic status as measured by assets owned, household food consumption, media like radio and TV, area of residence and AIDS awareness Table . LogistiEducated males also have more awareness in comparison to males with no education. Among males with education higher secondary or more, 82% heard about AIDS. The figures are 39%, 25% and 20% for the males with secondary, primary and no education respectively. In comparative sense, the odds of awareness among the men with higher education, secondary education and primary education were 77.7, 9.0 and 2.1 times respectively of those who have no education.Occupation determines largely the social status of an individual. Awareness level varies with their professions. Of the male respondents with professions like teaching, managing and technical 72% heard about AIDS and the percentage is less in agricultural employees and manual workers, 30.6%. On the other hand, Professionals like teachers, engineers, managers etc. are 1.95 times more aware than agricultural self employed males.On the other hand, household possessions reflect the socioeconomic index of a household, which relates the consciousness as well as AIDS awareness. The more the household items the more the percentage of people who have heard AIDS. In addition, the odds of consciousness among the men of household with 7 or more items was 8.5 times of those men who belonging the household with three or less items while the odds was 3.2 times among men whose household contained 4–6 items. The awareness as to HIV/AIDS also indirectly related to food consumption pattern. It is found that households with food deficiency in the whole year have one-fifth awareness in comparison to the households with food surplus or break-even point as well as households with food deficiency hardly or off and on.Media like radio and TV also have a strong positive relationship with awareness. Everyday male listeners of radio have highest-level awareness, 67.0%, followed by the moderate listeners compared to 37.5%, who had never listen radio. In addition, the odds of awareness among regular listeners and moderate listeners were 2.0 and 1.5 times of those who had never listen radio.TV watching have more direct impact on awareness of male. Among everyday watchers 83.2% are concerned of AIDS. This figure is far away than those who did never, 26.5%. In relative sense, the odds of consciousness were 8.6 and 2.9 times among the men who watch TV regularly and watch sometimes respectively compared to those men who never watch TV. Men living in the urban area were also more aware than its rural counterpart.From both bivariate and multivariate techniques, the study has identified the factors exposure of electronic media, education of the respondent, partner's education, area of residence, occupation, socioeconomic status determined by household possessions, and food consumption pattern that were associated with the level of awareness about HIV/AIDS. This phenomenon holds true for both male and female respondents.Broadcast media like radio, TV have tremendous reach and influence and play a vital role to build up awareness against HIV/AIDS in the community ,18. AccoAnalogous statistics have also been reported in the United States and United Kingdom and elsewhere in the world ,19. ThisEducation is an event of human life that carries out a significant role in determining his/her social status. In the context of Bangladesh, high education indicates better occupation, better income and better income eases media access. More exposure in media signifies more awareness about HIV. Again socioeconomic status determined by existent household assets including radio/TV and household food consumption, also has a contribution to determine HIV/AIDS awareness level. It is found from the study that poor people, determine by household's food deficiency in the whole year and/or number of household items, are less likely to be aware of AIDS as likely as its counter rich peoples. It is due to the facts that poor people have less education and less media exposure than rich people. Thus, poverty alleviation would be another strategy to increase awareness.In Bangladesh urban areas are much more developed than rural areas in terms of socioeconomic factors like education, occupation, income, media exposure, health service facility etc. Findings of the study show that both urban male and female are much more aware about HIV/AIDS than rural counterparts. Therefore, more socioeconomic development indicates more awareness. But in context of developing country like Bangladesh, the rural peoples have less media contact. Since about 76% people live in rural area with less media coverage, it should give special attention to develop socioeconomic condition of rural people, which may meet people to media, and as a result there will be a remarkable change in awareness level. In contrast, as the use of mass media such as radio, TV is very limited in Bangladesh especially in rural areas as compared to urban areas, some additional programs such as face-to-face communication and sexual education at institutions may be effective in raising awareness in Bangladesh.Therefore, now is the time to emphasize more on education, alleviation of poverty, ensuring electronic media exposure, head to head communication program, institutional based sex education and necessary information to learn about HIV/AIDS for the young, adult and adolescents all over the country. On the other hand, for effective use of mass media, it requires careful planning, audience research, message development, pre-testing, dissemination strategy, evaluation, co-ordination with existing services, and linking mass media with interpersonal communication. The role of international health and development organizations in promoting, supporting and advocating the use of well-planned mass media campaigns can also make a significant difference . All pos


Feldbaum and colleagues look at evidence on the links between HIV and national security, and evaluate the risks and benefits of addressing HIV/AIDS as a national security issue. Two leaders in the global fight against HIV/AIDS—Richard Feachem, Executive Director of the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and Peter Piot, Executive Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS)—have recently argued that HIV represents an extraordinary national security threat ,2. TheiDespite the high-profile linking of HIV/AIDS and security, including four United Nations Security Council (UNSC) meetings and prominent mention within the United States national security strategy, critical debate about the ways in which public health interacts with the security interests of states are scarce in public health journals. Journals have examined the ways national security issues, including the recent war in Iraq and the Israeli–Palestinian conflict ,4, haveThis paper argues for greater understanding and analysis of the public health–national security nexus to ensure this linkage benefits the fight against HIV/AIDS. Successfully negotiating this nexus is essential because the humanitarian objectives of global health do not fit easily into the state-centered perspective of national security. Global health works to improve the health of all people within and across states, while the national security field works to protect the people, property, and interests of only one state. This article will present the unique national security perspective on the HIV/AIDS pandemic and evidence on the links between HIV/AIDS and national security, and will evaluate the risks and benefits of addressing HIV/ AIDS as a national security issue.National security is traditionally defined as the protection of a state's territory, population, and interests against external threats. While recognizing the humanitarian dimensions of the HIV/AIDS pandemic, national security analyses rely on the human impacts of the disease to be large enough to affect the military, political, and economic interests of a state. For example, a partially declassified US National Intelligence Council estimate argues that infectious diseases threaten American national security because they will “endanger US citizens at home and abroad, threaten US armed forces deployed overseas, and exacerbate social and political instability in key countries and regions in which the United States has significant interests” . This foThree main arguments linking HIV/ AIDS and national security emerge from the security community's analyses of the HIV/AIDS pandemic. The first describes the impact of HIV/AIDS on individuals critical to the maintenance of state and international security: soldiers and peacekeepers. The second argument suggests that the epidemic in some sub-Saharan African nations may cause state instability and failure. The third argument focuses on the security effects of the worsening pandemic on the large, strategically important states of Russia, India, and China see. The eviHIV/AIDS is severely affecting the armed forces of many countries. Accurate data on prevalence of HIV among soldiers is difficult to obtain because affected states either do not collect or do not want HIV prevalence data published. In 1998, UNAIDS estimated that sexually transmitted disease “rates among armed forces are generally 2 to 5 times higher than in civilian populations” . Recent However, the impact of HIV/AIDS on militaries is not limited to Africa. In Russia, 9,000 potential draftees have been rejected for service because of testing HIV positive in the last five years, with 5,000 rejected in the last two years alone . While China and India's large populations provide some insulation against shortages in military personnel, these countries are increasingly monitoring AIDS in their militaries as epidemics in these countries spread [The impact that high HIV prevalence will have on the strategic capabilities of militaries is complex. Most analysts emphasize the negative security implications of increasing rates of HIV infection in militaries. The loss of highly trained, professional soldiers to AIDS will have a major impact on affected armed forces. Trained soldiers are difficult and expensive to replace, and their absence interrupts the training of younger recruits. Armed forces that rely wholly or partially on conscripts face a decreasing pool of healthy recruits as HIV/AIDS continues to spread. Russia's HIV epidemic is already exacerbating an existing shortage of healthy individuals available for military service. It is also argued that armed forces with high HIV prevalence may incur mounting costs to treat soldiers with antiretroviral drugs, leading the military to seek greater proportions of public expenditure while rendering them less able to protect national and international interests ,10.It is important to note that some analyses conflate HIV and AIDS, assuming all soldiers who are HIV positive will not be able to perform their duties because of AIDS. Thus, the security implications of HIV may be less than initially perceived, especially for militaries relying on conscription, because many soldiers who are HIV positive will have completed their duty by the time they develop symptoms of AIDS. Also, contrary to arguments that HIV will worsen national security is the idea that higher rates of HIV among militaries could have a beneficial strategic effect by constraining “offensive military plans in bellicose countries” . DecreasConcern about peacekeepers spreading HIV/AIDS while on missions brought the pandemic to the attention of the UNSC in 2000. Then US Ambassador to the UN Richard Holbrooke argued that it was a cruel irony to send peacekeepers to stop conflict only to find that they have unintentionally spread HIV . Fears tIn addition to peacekeepers directly spreading HIV, high rates of HIV among the militaries in troop-contributing countries may make it more difficult to staff peacekeeping missions ,13. HigA final complication is that countries may object to hosting peacekeepers that come from countries with high HIV/AIDS prevalence . In 2001The effect of HIV/AIDS on state stability is perhaps the least studied, yet also the most feared, potential impact of the disease on security. The US National Intelligence Council argues that high rates of HIV/ AIDS are “likely to have significant economic, social, political, and military implications” in certain countries . If thesThe repercussions of HIV affecting state stability differ depending upon the country and region affected. To date, sub-Saharan Africa has been the most highly affected region, and the pandemic is seen to represent a direct national security threat to countries in this region . DespiteEvidence does exist that suggests AIDS is undermining the capacity of communities in Southern Africa to cope with food crises, producing a new variant of famine created by AIDS . A numbeThe consideration of sub-Saharan Africa on the Western security agenda is new. Before the events of 9/11, the huge human toll of HIV/AIDS in sub-Saharan Africa was insufficient to seriously engage Western security communities. The experience of 9/11, when terrorists attacked the US from a safe harbour within the failed state of Afghanistan, demonstrated the threat that failed states pose to powerful countries. The 2002 US national security strategy states clearly that “America is now threatened less by conquering states than we are by failing ones” . The 200The final argument linking HIV/AIDS and national security has focused on more traditional national security concerns by arguing that a “second wave” of HIV could destabilize powerful countries and regions critical to the US and, by extension, global strategic interests ,24. TheRussia has rejected HIV positive individuals from military service.Nicholas Eberstadt estimates that intermediate-to-severe epidemics in Russia, India, and China could account for between 193 and 259 million new cases of HIV by 2025— more than six times the global total of people living with HIV/AIDS today [From the perspective of the Russian, Indian, and Chinese governments, the link between HIV/AIDS and security raises internal security challenges. India and China have vast populations and small HIV epidemics as a proportion of the total population, making them less vulnerable than sub-Saharan Africa to shortages in workers and military recruits. Russia has rejected individuals who are HIV positive from military service since 2003, compounding its shortage of conscripts due to tuberculosis, drug use, alcoholism, and age demographics  . The AIDThis combination of drug trafficking and use, commercial sex, and growing HIV epidemics in separatist areas are major challenges for the Chinese, Indian, and Russian governments. Programs to prevent and control HIV/ AIDS in these regions may fail due to lack of trust, while doing nothing may result in further political tensions and even accusations of genocide . China aThe available evidence to date on the links between HIV/AIDS and security suggests real, and potentially significant, risks to national, regional, and global security from the pandemic. In sub-Saharan Africa, the HIV/AIDS pandemic is already having a substantial impact on militaries and peacekeepers. In the strategically important states of Russia, India, and China, HIV/AIDS may contribute to medium- to long-term risks of state and regional instability. However, far more evidence is needed to support such claims.What is clear is that arguments linking HIV/AIDS to national security have succeeded in elevating the disease to the highest levels of international politics, resulting in greater political commitment and funding. The chronic lack of resources to fight the disease and the neglect of the humanitarian crisis in sub-Saharan Africa seem to justify this strategic appeal to the “higher order” values of national interests and self-preservation that define the security community.Nonetheless, it is also important to recognize that there are a number of potential risks in adopting a national security approach to fight HIV/AIDS. Countries classifying information on HIV/AIDS in their armed forces as national security secrets hinder the targeting, operation, and evaluation of HIV prevention and treatment programs for both soldiers and civilian populations that interact with them. A primary focus on the national security implications of the pandemic could cause an inappropriate redirection of HIV/AIDS resources toward strategically important countries or those supportive of the “War on Terror.” Conversely, a security community could conclude that higher rates of HIV/AIDS in certain militaries would actually benefit its own national interests because of a reduced ability by affected countries to launch offensive attacks. In Russia, India, and China, the security implications of HIV/AIDS involve vulnerable populations such as injection drug users, sex workers, and ethnic minorities in separatist areas. Addressing their health needs using a security-based rationale could lead to repression or increased stigmatization of persons living with HIV/AIDS, both counterproductive to effective public health practice. Finally, the security community seeking to win “hearts and minds” through health initiatives clouds the traditionally humanitarian role of public health and could lead to a loss of trust in the motives of public health professionals working on HIV/AIDS, an issue already fraught with sensitivities. The Soviet KGB disinformation campaign, suggesting that the US deliberately developed and spread HIV/AIDS, is an early example of the mixing of HIV/AIDS and security politics that still haunts public health activities today ,32.Strengthening the evidence on the links between HIV/AIDS and national security is essential.Successfully negotiating these risks is critical to ensuring that the public health–national security nexus benefits the fight against HIV/AIDS. Strengthening the evidence base on the links between HIV/AIDS and national security is essential. This includes better data on the epidemiology of HIV/AIDS among soldiers and peacekeepers, and the complex relationship between the disease and state stability. Equally important is the ability of the health community to appropriately harness the political clout and resources of the security community. Foremost is the need to demonstrate how proven principles and practices in public health must be maintained. The security community must be convinced of their value, notably a human rights–based approach, to national security interests. It is only with this starting point that the shared goal of effectively tackling the HIV/AIDS pandemic can be achieved together.


Recent investigation of Cullin 4 (CUL4) has ushered this class of multiprotein ubiquitin E3 ligases to center stage as critical regulators of diverse processes including cell cycle regulation, developmental patterning, DNA replication, DNA damage and repair, and epigenetic control of gene expression. CUL4 associates with DNA Damage Binding protein 1 (DDB1) to assemble an ubiquitin E3 ligase that targets protein substrates for ubiquitin-dependent proteolysis. CUL4 ligase activity is also regulated by the covalent attachment of the ubiquitin-like protein NEDD8 to CUL4, or neddylation, and the COP9 signalosome complex (CSN) that removes this important modification. Recently, multiple WD40-repeat proteins (WDR) were found to interact with DDB1 and serve as the substrate-recognition subunits of the CUL4-DDB1 ubiquitin ligase. As more than 150–300 WDR proteins exist in the human genome, these findings impact a wide array of biological processes through CUL4 ligase-mediated proteolysis. Here, we review the recent progress in understanding the mechanism of CUL4 ubiquitin E3 ligase and discuss the architecture of CUL4-assembled E3 ubiquitin ligase complexes by comparison to CUL1-based E3s (SCF). Then, we will review several examples to highlight the critical roles of CUL4 ubiquitin ligase in genome stability, cell cycle regulation, and histone lysine methylation. Together, these studies provide insights into the mechanism of this novel ubiquitin ligase in the regulation of important biological processes. Ubiquitin-mediated proteolysis has been established as a key regulatory mechanism governing almost every biological process in the eukaryotic cell. Ubiquitination involves the covalent attachment of a polyubiquitin chain to a lysine residue in a substrate protein, and proceeds via three distinct enzymatic activities. Following ATP-dependent ubiquitin activation by ubiquitin activating enzyme (E1) and ubiquitin transfer to an ubiquitin conjugating enzyme (E2), ubiquitin is attached to substrate with the aid of an ubiquitin ligase, or E3. Since E3s interact with substrate directly, the dynamic regulation of E3 activity and substrate specificity is an area of extensive exploration.Caernorhabditis elegans [Saccharomyces cerevisiae, but present in Schizosaccharomyces pombe (Pcu4), Xenopus laevis, Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana. Ancestral duplication yielded the mammalian-specific CUL4A and CUL4B, which are over 80% homologous [CUL4 is a member of the cullin family of proteins, which share substantial homology to CUL1 originally identified in  elegans . Humans  elegans . CUL4 ismologous , CUL4B pmologous , targeteC. elegans led to massive rereplication of the genome and the accumulation of giant nuclei containing up to 100C DNA content in certain cells. Immunostaining suggested that replication licensing protein CDT1 was inappropriately stabilized in S phase, and loss of one genomic copy of CDT1 suppressed nuclear polyploidy. This suggested that CUL4 might regulate replication licensing through CDT1 degradation. CDT1 is a subunit of the pre-replication complex and is recruited to replication origins by the origin recognition complex (ORC) and Cdc6 [Two studies initially established CUL4 ubiquitin E3 ligase activity as a modulator of key biological processes. Zhong et al.  found thIndependently, Higa et al.  reportedSKP1, CUL1/Cdc53, and an F-box protein [Although CUL4 was implicated in CDT1 degradation and other biological processes (see below), the composition and structure of CUL4 E3 ligase was only recently characterized. However, the homology between cullin E3 ligases suggest that the overall strategy of CUL4 E3 ligase for substrate selection may resemble that of SCF, or CUL1-assembled E3s, which usually serve as an architectural prototype for the rest of cullin family. SCF is named for three of its subunits:  protein . The fouCUL1 organizes the substrate receptor and E2 recruitment modules at its amino (N) and carboxy (C) termini, respectively. Structurally, CUL1 forms a stalk-like structure at its N terminus, linked to a C terminal globular domain . The N tDDB1 was found to interact with CUL4A  and was Unlike every other cullin adaptor protein, DDB1 does not contain the BTB/POZ fold but is formed by a cluster of three beta propellers , spanning 100 angstroms . BPA andS. pombe CDT2 was independently identified as CSN2-associated protein that binds to Pcu4 [Two WD40-repeat proteins, DDB2 and the Cockayne syndrome protein, CSA, have been shown to associate with DDB1, CUL4A, and CSN in mammalian cells . Higa et to Pcu4 . These o to Pcu4  and DDB1 to Pcu4 ,16,18 as to Pcu4 ,18 led t to Pcu4 . The aveCUL4 and DDB1-associated WD40-repeat proteins, or CDWs [The majority of WD40 proteins shown to bind DDB1 bear a tandem repeat containing DXXXR/KXWDXR/K  -18. The  or CDWs   at the extreme N terminus [Although CDT1 is proteolyzed after DNA damage or in S phase, soluble CDT1 can be detected in association with CUL4-DDB1 E3 complex but this pool of CDT1 is not ubiquitinated . CDT1 determinus ,34,42. Pterminus . Followiterminus ,34. Consterminus ,34. CDT1terminus .S. pombe has indicated that CUL4-DDB1-CDT2 is also responsible for CDT1 degradation and is a critical integrator of a DNA damage response pathway distinct from NER and mismatch repair [Work in h repair ,43,44. Th repair ,44.Through its regulation of RNR, Spd1 was identified upstream of translesion synthesis in the moderate stress pathway . In contThe assembly of CUL4-DDB1-ROC1 with two different WD40 repeat proteins, DDB2 and CSA, determines NER pathway activation after UV irradiation . Upon exThe later activation of transcription-coupled repair after UV depends on the assembly of CSA with CUL4-DDB1-ROC1. CSA (Cockayne Syndrome A) and CSB (Cockayne Syndrome B), define the two complementation groups of Cockayne syndrome . CSA beaProgression through the cell cycle depends on the timely and ordered elimination of both positive and negative regulators of cyclin-dependent kinases (CDKs). CDK activation requires its association with a cyclin subunit, and cyclin protein levels are the net result of synthesis and ubiquitin-mediated proteolysis. CDK activation and assembly is also negatively regulated by cyclin-dependent kinase inhibitors (CDKIs) .Kip1, are also subject to control by CUL4-DDB1 [Skp2 can be recapitulated in mammalian cell extracts supplemented with cyclin E/CDK2 [SKP2 and CUL4A-DDB1 act independently [SCF is best characterized for its control of the G1/S transition, and SCF-mediated destruction of both G1 cyclins and CDKIs is evolutionarily conserved . Two keyUL4-DDB1 . Inactivn E/CDK2 . Cell exendently . In contendently . While tendently . Furtherendently , the sigFbw7/Ago and CUL4-DDB1, this suggests that CUL4 deneddylation is particularly critical for proper function in vivo. Third, what degron sequences besides the PIP box, or post-trasnslational modifications, specify CUL4 substrate recruitment? In this regard, a high molecular weight isoform of Drosophila cyclin E accumulates after CUL4 RNAi. Furthermore, Dacapo, but not mammalian p27, contains a PIP box [Besides the identification of the CDW(s) that recognize p27 and cyclin E, several open questions about CUL4 structure and regulation remain. First, what determines whether a substrate is recognized by CUL4A, CUL4B, or both? Secondly, what structural features of CUL4 specify its differential regulation by CAND1, CSN, and neddylation? CAND1 was identified as an inhibitor of SCF assembly ,53, and  PIP box . The Xen PIP box . Finally PIP box ,31,57.CUL4A-DDB1-CDT2-ROC1 also interacts with and targets the tumor suppressor protein p53, which mediates cell cycle arrest or apoptosis in the face of genotoxic stress . In an uChromatin dynamics is determined by two distinct mechanisms: post-translational modification of histone proteins, and ATP-dependent nucleosome remodeling. Both processes act on the nucleosome, the fundamental unit of chromatin that consists of ~146 bp of DNA wrapped around a histone octamer (a tetramer of histone H2A and H2B and a tetramer of histone H3 and H4). The globular domain of histones interacts with DNA, while a flexible tail domain protrudes from the nucleosome and is subject to multiple modifications, including phosphorylation, acetylation, ubiquitination, and methylation . The num1), di- (me2), or tri-methylated (me3), and tri-methylated H3K4 marks almost all active transcription promoters and is part of epigenetic control. Loss of WDR5 severely abrogates H3K4me1 and me3, with less effect on H3K4me2. WDR5 inactivation by siRNA in mammalian cells reduced HOX gene expression, and injection of X. laevis embryos with WDR5 morpholino resulted in severe developmental abnormalities. Consistent with its identification as a specific H3K4me2- and H3K4me3-binding protein, WDR5 is postulated to stimulate the conversion of H3K4me2 to H3K4me3.The WDR proteins WDR5 and RBBP5 are essential components of the MLL (mixed-lineage-leukemia) histone methyltransferase complex specific for histone H3 methylation on lysine 4 (H3K4) . H3K4 ca3 and H3K4me1 [3 but not unmodified H3 peptide in vitro. The interactions between WDR5 or RBBP5 and CUL4-DDB1 and the functional involvement of CUL4-DDB1 ubiquitin ligase in H3K4 methylation support the notion that ubiquitin-dependent proteolysis underlies the dynamic regulation of epigenetic marks at H3K4. The ubiquitin ligase activity of CUL4-DDB1 assembled with WDR5 and RBBP5 may thus target a negative regulator of H3K methylation. On the other hand, the demonstration in this study that distinct WDR proteins, WDR5 and CDT2 (L2DTL), perform distinct biological functions through CUL4-DDB1 ligase supports the notion that CDW identity differentiates the biological processes influenced by CUL4-DDB1-ROC1 ubiquitination. Thus maintenance of CDT1 destruction after DNA damage in WDR5-deficient cells and maintenance of H3K4 methylation in CDT2-silenced cells established that WDR proteins are substrate-targeting subunits of CUL4-DDB1 ubiquitin ligases.Higa et al. (2006) found that CUL4-DDB1 interacts with WDR5 and RBBP5 and regulates histone H3 methylation at K4 . Like WD H3K4me1 . In vivoPolycomb group (PcG) proteins maintain the silenced state of homeotic genes . Higa etS. pombe, where a Pcu4 non-neddylated mutant could not restore gene silencing to Pcu4 null yeast [In fission yeast, Pcu4-Rik1 regulates H3K9 methylation through its recruitment of the Clr4 methyltransferase to chromatin and this is independent of DDB1 . A requill yeast . Potentill yeast  or histoll yeast . Given tll yeast , and CULll yeast . It willll yeast .While our knowledge of CUL4 E3 ligases has expanded significantly, many provocative questions remain. One critical question is whether all WDR proteins or a subset of them bind to CUL4-DDB1 and perform a function in protein ubiquitination. CUL4 function in vivo should also be addressed with genetic analysis in knockout animals or cells.Since CUL4A amplification has been noted in breast and hepatocellular cancer ,72, it wThe author(s) declare that they have no competing interests.L.A.H. and H.Z. both drafted the manuscript and designed the figure. All authors read and approved the final manuscript.


For more than two decades, the International Narcotic Control Board (INCB) has tried to stop harm reduction and its HIV prevention programs. This posture is based on a fundamental misunderstanding of their responsibilities and of drug addiction itself – i.e. as a public health and clinical care matter made criminal by decree. A recent focal point for the Board's action has been rejecting the use of supervised injection facilities to reduce morbidity and mortality of drug injectors. They single out individual countries and attempt to bully them into rejecting such programs under the banner of the United Nations  and in the name of international treaties. Their unrelenting and unjustified badgering of signatories to the international treaties that established the INCB is not only unjustified; it is an affront to one of the core purposes of the Board itself: to ensure adequate medical supplies and safe use of controlled substances. The INCB's ill-conceived obsession with intravenousaddiction as a crime flies in the face of the medical view and policies of the World Health Organization and the universally endorsed principles of the General Assembly of the United Nations.Insite, located in the inner city of Vancouver, Canada. Using the power of their office to meddle in matters of public health for individual nations is without medical, scientific or legal justification. But, most importantly, it is a matter of lifeand death for these most marginalized of citizens. The empirical evidence remains that a significant portion of the continued growth of the AIDS pandemic is due to injecting drug use, and the INCB's intrusion will inevitably result in additional deaths due to preventable HIV infections and drug overdoses.The latest target of the INCB is North America's only supervised injection facility, "Closed to Reason: The International Narcotics Control Board and HIV/AIDS" is attached along [see Additional file So we are very pleased to call to our readers' attention to a recent report produced by the Canadian HIV/AIDS Legal Network and the International Harm Reduction Development Program (IHRD) joined by former United Nations Special Envoy for HIV/AIDS in Africa, the respected Canadian statesman Stephen Lewis. The full report, Howmany times must a man look upBefore he can see the skyYes and how many earsMust one man haveBefore he can hear people cry?Yes, and how many deathsWill it take till he knowsThat too many people have died?Bob Dylan It has been over 25 years since physician Michael Gottlieb identified the first clinical cases of AIDS in the San Francisco . But AIDWhile the INCB has, after 20 years of opposition and obstruction of harm reduction measures, now (grudgingly) recognized that needle exchange and substitution treatment are not in conflict with the international conventions under which the INCB established. But the INCB continues, in effect, to demonize needle distribution  by portraying such measures as being at perpetual risk of contradicting the sacred goal of demand reduction. Therefore, needle distribution programs; if they are to exist at all, must be purged of any sign of "encouraging" drug use. It is telling that the INCB concludes its description of needle distribution with the following proclamation:"The Board welcomes the United States Government's unequivocal policy position against any form of legalization of the non-medical use of drugs".  (p. 10).By linking what they call "needle distribution schemes" to drug "legalization", the INCB constructs an ideological barrier to HR programs. Rather than act as an aid in the establishment of widespread needle distribution programs, the INCB continues to undermine them. And if the INCB notes that " governments may, lawfully, implement measures such as needle distribution programs to reduce the spread of HIV/AIDS" it then states, with inherent contradiction typical of its pronouncements, that any "prophylactic measures should not promote and/or facilitate drug abuse"  (p. 1). ""The Board has stated on a number of occasions, including its recent Annual Reports, that the operation of such facilities remains a source of grave concern. The Board reiterates that they violate the provisions of the international drug control conventions.""The Board reiterates that article 4 of the 1961 Convention obliges States to ensure that the production, manufacture, import, export, distribution of, trade in, use and possession of drugs is to be limited exclusively to medical and scientific purposes. Therefore, from a legal point of view, such facilities violate the international drug control conventions."So, then, the INCB appears to begrudgingly allow for needle distribution programs, as long as injecting drug users, many of whom are the most marginalized of citizens, inject drugs furtively and outside of a healthcare setting designed to prevent overdoses and HIV infections.In British Columbia, needle distribution has historically been similarly considered as closely connected to a demand reduction strategy. This meant a kind of "one for one" policy whereby needles were not be given unless injection drug users provided a needle in exchange. This strategy was aimed, in part, at ensuring that people with active addictions satisfactorily disposed of their needles. As well, there was a limit (e.g. six per day) placed on the number of needles that were allowed per injection drug users. This limit was regardless of the persons injecting practices or drug of choice (cocaine users would inject many times per day versus heroin users who would inject less frequently for example). The placing of a limit on the number of syringes allowed embodied a kind of "demand reduction" value inherent in the delivery of the service. This meant that when people required many needles for drug use, they were limited at 6 per day regardless of their need. The needle exchange at that time was a centralized rather than a decentralized. There are those that believe that this implicit "demand reduction" approach to needle "exchange" rather than "distribution" (unlimited syringe access) contributed, in part, to the explosion of HIV and HCV in the IDU population in the region.While the INCB overtly concludes that the NEP are technically allowed this does not mean that the Board, in actuality, entirely supportive of this harm reduction measure. Their stance on Supervised Injection Facilities is indicative of their "true colors" on this life saving matter. These kinds of mediocre stands when it comes to life saving programs like NEP have drastic consequences, on the ground, for marginal IDU populations where local governments struggle to address the AIDS pandemic. What they require is support and leadership, not mixed messages from an international body invested with the prestige of the global community.When it comes to the pandemic of AIDS and Injection Drug Use, what is required is clear leadership with respect to strategies that will save lives. The faint and clarified praise for NEP and rejection of SIFs by INCB is a barrier to implementing critical population health initiatives. The Board's implicit and explicit resistance to harm reduction is especially influential in the minefield of morality within which injection drug use and AIDS are situated. The politics of blame surrounding people living with active addiction make the conditional support of the INCB especially unhelpful and even more damning.In times of sweeping death due to uncontrolled illness, an unsure healthcare intervention is better than no medical intervention at all. Better yet, a healthcare intervention with clear efficacy and evidence base, such as SIFs, even though culturally controversial, demand action rather than clarified and conditional support. Clarified supports are the kind where a population healthcare intervention like a SIS might be possible an "ideal world", when the "trees all grow to heaven" and the populace is blessed with a month of Sundays with eternal sunshine. SIFs cannot wait for this month of Sundays. Their time is now and by opposing their establishment, the INCB is being a part of the problem rather than the solution for the AIDS pandemic.Supervised injection facilities (SIF) are, to a large extent, an HIV prevention initiative that provides clean injection equipment. Vancouver's SIF, Insite, supervises approximately 20,000 injections every month. Every one of these 20,000 occurrences is an injection that is not shared and makes use of a clean syringe. To a large extent, the SIF is a needle distribution program and, for this key feature, as well as its allowance of injection itself under supervised conditions, it has come under condemnatory fire from the International Narcotic Control Board. Of course, everyone, including both the operators and users of the facility, hopes for abstinence and restoration to full health, but for now, the prevention of HIV, HCV and fatal overdoses is a good medical beginning. In medicine, a partial medical intervention, with efficacious outcomes, is better than no intervention at all. Sometimes, rather than shooting for the stars such as eradicating addiction altogether, we have to satisfy ourselves with more earthly outcomes such as preventing an HIV infection.Needle distribution is a hallmark component of an SIF. The efficacy of needle distribution is no longer open for debate in the medical and scientific community. The World Health Organization (WHO) has reviewed the available scientific and medical literature on harm reduction programs and concluded that the evidence overwhelmingly indicates that providing such services for injecting drug users significantly reduces HIV infections:"The studies reviewed in this report present a compelling case that NSPs substantially and cost effectively reduce the spread of HIV among IDUs and do so without evidence of exacerbating injecting drug use at either the individual or societal level. This suggests that authorities responsible for areas threatened by or experiencing an epidemic of HIV infection among IDUs should adopt measures urgently to increase the availability and utilization of sterile injecting equipment and expand implementation to scale as soon as possible. conditions and other approaches better suited in other places and conditions. The important point is to aim to reduce the circulation time of needles and syringes." (p. 30)unanimously publicly declared the importance of harm reduction and needle distribution by reiterating that:In recognition of the need for efficacious and evidenced-based action with respect to the AIDS pandemic, the United Nations General Assembly unanimously adopted an imperative Resolution to address the AIDS on 2 June 2006. In this resolution, the United Nations General Assembly sterile injecting equipment; harm-reduction efforts related to drug use; expanded access to voluntary and confidential counselling and testing; safe blood supplies; and early and effective treatment of sexually transmitted infections;" [emphasis added] (p. 4)And yet, despite the overwhelming evidence and consensus of professional judgment support the importance of harm reduction  another international organization, the International Narcotic Control Board (INCB), has been publicly attacking these health programs. The INCB gains its authority from three treaties, the Single Convention on Narcotic Drugs (1961), the Convention on Psychotropic Substances (1971) and the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988)[8[8] The Incongruously, the INCB has become confused about HIV prevention programs and, as a result, developed a pattern in recent years of speaking out against accepted medical and public health strategies. The 13 person committee governing of the INCB, often mistakenly understood by the public to be synonymous with the United Nations, seems to have decided that it is not accountable to scientific evidence, the opinion of most public health officials, nor to the mounting toll of AIDS due to syringe sharing among injecting drug users. As a result, the INCB is beginning to play a central role in promoting unsafe injection practices , and, inadvertently, spreading regional AIDS outbreaks.In marked contrast to the vast majority of the medical and scientific establishment, the INCB sees SIFs as neither medical nor scientific and this is basis of their repeated public grievances about purported infringements on international drug control treaties. In so doing, the board is continuing to chase its imaginary tail with increasing fervor within an unaccountable and unscientific universe of its own construction. This would be allowable if AIDS were not such a serious matter.By showing aggression towards SIFs, the International Narcotics Control Board is undermining HIV prevention initiatives that save lives. The INCB began declaring that SIFs are in breach of international treaties in 2001 and 2002 when they stated:"Establishing drug injection rooms, where drug abusers can inject drugs that they have acquired from illicit sources, is contrary to the international drug control treaties"(p. 70).Since that time, the INCB has repetitively attempted to undermine Vancouver's SIF, Insite, the only such health program in North America. In 2003, from their headquarters in Vienna, the INCB proclaimed that Insite violates international law and attempted to urge the Canadian government to comply with their wishes that the program be closed In 2004,In fact, the international treaty to which the INCB repeated refer is the Single Convention on Narcotics of 1961 (amended in 1972). The Preamble of the Convention begins by highlighting that the signatories are primarily concerned with the wellbeing of humanity and main purpose of the convention is to relieve suffering:"The Parties, concerned with the health and welfare of mankind, recognizing that the medical use of narcotic drugs continues to be indispensable for the relief of pain and suffering and that adequate provision must be made to ensure the availability of narcotic drugs for such purposes" (p. 1).Controlled Drug and Substances Act (CDSA) of Canada.The ensuing section trumpets about the importance of being committed to fighting the forces of evil, language that was indicative of the spirit of the time half a century ago when the agreement was drafted, before highlighting the importance of the drugs in the context of medical and scientific use. In fact, it is precisely for scientific or medical purposes that SIFs are eligible for exemption under Section 56 of the AIDS is a public problem for all of humanity. Similar to when a situation or area is designated as a national disaster, the categorization of an epidemic brings public attention as well as national resources. When a disease outbreak is categorized as an epidemic, it also goes through a social transformation to become a public problem. Not all social problems are declared public problems . For exaCertain words are highly significant, like the word pandemic, and they are moored in significant places in the social space and only certain people are consecrated with the social privilege to employ them . Just asOnly certain societal bodies or individuals such as teachers, priests, doctors or legislators are delegated with the authority to carry out key responsibilities . For exaKey societal institutions, such as the INCB, have the social authority to consecrate certain states of affairs:constitution does in the legal and political sense of the term. An investiture  consists of sanctioning and sanctifying a difference (pre-existent or not) by making it known and recognized; it consists of making it exist as a social difference, known and recognized by the agent invested and everyone else" [17: 119]."To institute, in this case, is to consecrate, that is, to sanction and sanctify a particular state of things, an established order, in exactly the same way that a The institution achieves a kind of social wizardry by anointing the credentials of key individuals, such as Chief Medical Health Officers, Surgeon Generals or Chief Coroners, who have the official qualifications to declare public problems such as epidemics that demand widespread attention and resources.With respect to the historical analysis of epidemics, it is often the case that what was not studied is as revealing as what is studied . With reCanadian HIV/AIDS Legal Network and the International Harm Reduction Development Program (IHRD), joined by former United Nations Special Envoy for HIV/AIDS in Africa, Stephen Lewis, who held a press conference to release "Closed to Reason: The International Narcotics Control Board and HIV/AIDS."[So we are very pleased to call to our readers attention to a recent report produced by the IV/AIDS." The fullIV/AIDS."recommendations are clear and compelling.The new report details the ways in which the INCB, funded and staffed by the UN, has "blocked effective HIV prevention among drug users." The docu"To improve accountability, address the HIV epidemic, and meet its mandate to assess compliance with the UN drug conventions, the INCB must change:• The INCB should regularly assess the supply and adequacy of treatment for chemical dependence. It should provide technical assistance to help countries accurately estimate the need for opiate substitution treatment, support governments that are striving to scale up such treatment, and encourage governments that have yet to provide these life-saving therapies to find safe and effective ways to do so.• The INCB should cite scientific evidence for its observations about drug use and health, and legal grounds for its interpretation of law. It should provide sources of information for its annual reports, and opportunities for UN member states and civil society groups to offer corrections or additional information.• The INCB should provide greater opportunity for exchange with UN member states, UN agencies with relevant mandates, civil society, and HIV/AIDS experts. INCB country missions should include greater opportunities for engagement with these groups.• The World Health Organization, the UN Economic and Social Council (ECOSOC) and UN member states should ensure that INCB members include persons with expertise in HIV/AIDS policy and international law.• The INCB should articulate, and ECOSOC should evaluate, public guidelines to clarify when INCB members are speaking for the Board, and how misstatements of fact can be corrected.• The UN Secretary-General should commission an independent evaluation of the INCB, including a scientific evaluation of the Board's statements on health, and an examination of Board members' independence and expertise, with particular attention to HIV, international law and human rights"(pp. 3–4).If the INCB were to be successful in just one of their foolhardy attempts to bully governments into closing a single SIF as a needle distribution centre, then this organization would, quite simply, have blood on its hands. Which of these 13 people, self-righteously sitting on the INCB, would be willing to face the consequences of their having sacrificed medicine and science on the alter of a 46 year old treaty about which even their legal interpretation is uncertain? Or, which of them, if any, would willing to face the father or mother of the addict who died of a drug overdose in an alleyway? Would they proudly talk of their successful mission from their comfortable office in Vienna to an injection room that they had, through their lobbying efforts, successfully closed down?The Preamble of the Charter of the United Nations as enshrined since 1945, states the peoples of the UN are committed to work towards:"... conditions under which justice and respect for the obligations arising from treaties and other sources of international law can be maintained, and to promote social progress and better standards of life in larger freedom, and for these ends, to practice tolerance and live together in peace with one another as good neighbours, and to unite our strength to maintain international peace and security, and to ensure, by the acceptance of principles and the institution of methods, that armed force shall not be used, save in the common interest, and to employ international machinery for the promotion of the economic and social advancement of all peoples..."Treaties, then, are for the advancement of peoples. Treaties are not to be used to exclude marginalized persons, like injecting drug addicts, from receiving access to basic life saving medical care such as injection facilities and syringe distribution programs. International law is for promoting inclusivity, of everyone, even those with the most comprised social tenure, in the global community.Three years after the establishment of the UN, in 1948, the General Assembly of the United Nations approved the Universal Declaration of Human Rights. Article 25, under the Declaration, states that every person:"has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing and medical care and necessary social services, and the right to security in the event of unemployment, sickness, disability, widowhood, old age or other lack of livelihood in circumstances beyond his control" (p. 5).Every human being, including people living with intravenous drug addictions, has the basic human right to their health and medical care and security of their person. For some people, that inalienable right to health might come through the provision of a clean syringe in an injection facility.While the increasing implementation of SIF medical initiatives throughout the globe appear to be increasing the travel budget for the INCB and the resultant tourist opportunities of its 13 members as they embark on their "missions", it does not appear to be effective in anyway with respect to increasing their knowledge of population health or epidemiological approaches to healthcare. It appears that the International Narcotics Control Board is unwavering in its steadfast determination to drink its own ideological bathwater in spite of the widespread availability of knowledge available from the wellspring of medicine and science. It is clearly time to retire the International Narcotics Control Board in its current configuration as a cloistered and unaccountable body that is impenetrable to evidence based science and medicine. According to the INCB annual report, the Board reports to the Economic and Social Council of the United Nations. The Economic and Social Council, in turn, has a "reporting, cooperating and advising relationship" with the General Assembly of the United Nations[Every injecting drug addict was once someone's son or daughter. They do not deserve to die from AIDS or drug overdose due to a cloak of ignorance about basic medical evidence that has, for too long, shrouded the International Narcotic Control Board. It is the responsibility of the United Nations to protect their health and well-being.It is our opinion that the make-up of the governing body of the INCB needs to be dissolved forthwith in its present capacity as a matter of great public urgency in order to reconstitute the board in order to ensure that its make-up is comprised of HIV, medical and legal experts with respect to intravenous drug addiction as a health issue. According to the founding documentation associated with the INCB, the Single Convention on Narcotic Drugs of 1961, the expenses of the Board are ultimately authorized by the United Nations General Assembly In lightThe time for accountability for the INCB is now. We are calling on the general assembly of the United Nations, the signatory nations to the treaties that created the mandate for the INCB, to take steps to contain the damage done by stopping the deleterious work of the INCB before more injecting drug users needlessly die of AIDS and drug overdoses because of the ill-conceived and obstinately counterproductive efforts of this agency. We cannot allow this public body to continue to function in a way so disconnected from the medical and scientific evidence about drug use and AIDS. In the face of the almost universal condemnation of the INCB by the legal community, the INCB's continued arrogance and intransigence sullies the reputation of the United Nations and violates the humanitarian spirit in which this board and all UN agencies were created. The goals of INCB in this matter should be congruent with those of the United Nations and World Health Organization: to promote rather than hinder public health and, in so doing, save lives – not to bring about unnecessary deaths due to preventable HIV infections and AIDS.Closed to Reason: The International Narcotics Control Board and HIV/AIDS. Report by J. Csete and D. Wolfe of the Canadian HIV/AIDS Legal Network; International Harm Reduction Development Program (IHRD); Open Society Institute (OSI); 2007:1–32.Click here for fileClosed to Reason: The International Narcotics Control Board and HIV/AIDS Key Findings. Russian translation of key findings of the above report.Click here for file"Closed to Reason": Time for Accountability for the International Narcotic Control Board. Russian translation of abstract of the above editorial.Click here for file"Closed to Reason": Time for accountability for the International Narcotic Control Board. Chinese translation of abstract of the above editorial.Click here for file


PLoS Medicine [Two recent articles in Medicine ,2 criticMedicine , and belLancet editorial in March 2005 [The key community groups that have expressed concerns about the tenofovir trial in Thailand are the Thai Drug Users Network (TDN) and the Thai AIDS Treatment Advocacy Group (TTAG), which are described in rch 2005 .Thai Drug Users NetworkTDN, Thailand's only drug users' group, was established in December 2002 in response to the health and human rights crisis facing drug users in Thailand, particularly injectors. TDN's mission is to promote the basic human rights of people who use drugs, in order for them to be able to live with dignity in Thai society. TDN undertakes peer-driven HIV prevention, care, and support for IDUs, has supported the Thai government National Harm Reduction Working Group's activities, and has provided technical input to United Nations Office on Drugs and Crime and World Health Organization consultations. Projects are jointly implemented with other organisations, such as the project Preventing HIV and Increasing Care and Support for IDUs in Thailand, which is funded by the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM).Thai AIDS Treatment Action GroupTTAG was founded in December 2002 by the founding chairman of the Thai Network of People Living with HIV/AIDS (PLHA) in order to promote leadership and advocacy among PLHA.TTAG's mission is to promote equal access to AIDS prevention and treatment for all individuals through policy advocacy and coalition building, and by strengthening the capacity of people living with HIV/AIDS to advocate for their human rights. Projects include Preventing HIV and Increasing Care and Support for IDUs in Thailand, which is funded by GFATM, and the Mekong Region Treatment Preparedness Initiative.Key Objections of TDN andTTAG to the Tenofovir Pre-Exposure Prophylaxis Trial in Thailand in Its Present FormAbsence of community consultation during the trial design and lack of meaningful consultation during its implementation.Best current prophylactic methods unavailable to trial participants.No commitment by trial sponsors to promote the safety of trial participants when accessing services.No commitment by the researchers to work, after the trial, with the Thai Ministry of Public Health towards price reductions of tenofovir.Principle RecommendationsUrgently establish a committee, chaired by the US Centers for Disease Control and Prevention, to address key HIV prevention, treatment, and care issues for Bangkok IDUs in the context of the trial. Members should include two TDN representatives, and Thai Red Cross, government, and nongovernmental representatives.Involve TDN in trial outreach and education, including curriculum development.Develop partnerships to ensure the safety of trial participants when accessing services; for example, the Bangkok Metropolitan Authority should host police training workshops on harm reduction, and TDN should be involved in these activities.Commit to supporting TDN in efforts to ensure at least two years of post-trial tenofovir to trial participants, and to working with the Thai Ministry of Public Health towards price reductions.One major concern about the trial was the failure to provide sterile needles and syringes. Singh and Mills assert that this is consistent with Thai government policy . Long prIn fact, the situation in Thailand is improving, with the National Harm Reduction Working Group, chaired by the Ministry of Public Health, taking steps to increase activities in this domain. In 2004, at the 15th International AIDS Conference in Thailand, the prime minister said, “We are now implementing a harm reduction program to reduce the risk of HIV infection among injecting drug users…the program…will be conducted through concerted collaboration among solo UN agencies, government bodies and non-governmental organizations including the Drug User Network” [The reason clean injection materials are not distributed within the trial is because the United States government, who sponsors the trial, bans federally funded organisations  from supporting needle and syringe exchange.Irrespective of whether a needle exchange exists in Thailand, or what the policies of the trial's funders are regarding needles and syringes, investigators have a duty to respect the Helsinki Declaration requirement that “benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods” .The HIV/AIDS community in Thailand is not naive about the ethics of clinical trials: many have been directly or indirectly affected by previous AIDS drug trials in Thailand that have raised ethical concerns ,8. NeverWe believe that the disagreements surrounding the tenofovir trial in Thailand would have been avoided if the investigators had set out to engage the community more openly, and if the wealth of established knowledge among community members could have contributed enormously to the success of the trial design and implementation. TDN andTTAG have made recommendations see  that rep


Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS. A reflection on the 25 year history of AIDS can begin with no better outline than that provided by the late Jonathan Mann of WHO. A slide he gave to me in the late 1980's divides the history of AIDS into four periods: (see fig. Science and Nature over the past few years from B. Hahn and her colleagues) that the natural reservoir for HIV-1 is a particular subspecies of chimp [There has been considerable attention  were occasionally infected for a long time, but died with their disease. Migration to cities may have been associated with increased prostitution. The movement of the rainforests to the world can be seen as the consequence of post World War II societal changes: increased travel with increased promiscuity, advancing intravenous drug addiction, and blood and blood products moving from one nation to another for medical purposes.Part 2 Fig.  is the ird human retrovirus, and one with the capacity to cause a profound immune disorder? 6) finally, as we began this work somewhat tentatively, I was encouraged by David Baltimore, who independently wondered aloud to me that a retrovirus was probably the origin of AIDS.Along with Max Essex in Boston, I speculated in early 1982 that AIDS would be caused by a retrovirus. This was based on information that some retroviruses, like feline leukemia virus (FeLV), caused not only leukemia, but blood cell deficiencies including those of T cells . The reanew retrovirus, but one in the HTLV family. At the time, there were at least a dozen theories as to the cause of AIDS, including non-infectious causes. Our hypothesis was the one that bore fruit. As we soon learned to our astonishment, HIV would be in a separate family of retroviruses.The idea, however, has sometimes been misunderstood and misrepresented as our hypothesizing that HTLV-1 itself was the cause of AIDS. That is clearly not the case. Our idea was that AIDS would be caused by a related to HTLV-1 and 2. In 1982 and in early 1983, these experiments gave variable results that were sometimes highly positive, other times borderline or even negative. In retrospect, the highly positive samples (with sequences related to HTLV) were due to patients being doubly infected with HTLV-1 or HTLV-2 plus HIV, which occurred in close to 10% of our samples. Negative or borderline RT positive samples were due to our performing the RT assays later than the optimal peak of virus production, which occurs days earlier with HIV than with HTLV. Luc Montagnier was stimulated in part by our ideas brought to France by the French clinician Jacques Leibowitch and, in early 1983, I sent Montagnier IL-2 and antibodies against the HTLV's. He and his co-workers had found evidence of a retrovirus in a patient with lymphadenopathy, and they could distinguish it from the HTLV-1 and with those antibodies [J. Mann's Part 3 of AIDS history are the years 1983–85. He called this the period of intense discovery. It begins with the isolation of HIV. Our approach to find the virus of AIDS was to follow our successful pattern with the HTLV's, namely, the culture of blood cells from patients, activation of the T cells in these samples, growth of the T cells with IL-2, and search for reverse transcriptase actively in the supernatant. If positive, we would look for some cross reactivity with HTLV-1 or HTLV-2 with antibodies to proteins of these viruses. Concomitantly, we probed DNA and RNA of some primary tissues of AIDS patients using cDNA from HTLV-1 under rather relaxed conditions in order to detect sequences that might be tibodies . This watibodies . Importatibodies .This was the necessary breakthrough, because for the first time there would be sufficient virus for detailed characterization and the development of a workable HIV blood test. The blood test (for serum antibodies to HIV), along with the large number of isolates from AIDS patients, were the major convincing results that HIV  was the causative agent of AIDS .second was the numerous infections a patient develops as they present with AIDS. Which one, if any, was the cause? The third was our concerns about verification. For rapid progress, it was essential to have rapid verification, and there were at least two factors that could greatly prolong achieving this goal. (1) Samples from AIDS patients were not only limited, but some institutions had forbade even their entry due to fears of infection. (2) T-cell culture technology, though available in immunology laboratories, was not widely available in virology laboratories. Both of these restrictions made it unlikely that there would be sufficiently rapid and conclusive confirmation by HIV isolation. Consequently, the blood test seemed to us to be particularly urgent for three reasons: 1) it allowed prevention of HIV transmission from contaminated blood; 2) it opened the door to our ability to follow the epidemic from the early period of infection, and 3) it provided for verification of HIV's causative role in AIDS. The test for serum antibodies was simple, inexpensive, safe, rapid, sensitive and accurate. Consequently, verification came rapidly and globally.Demonstrating that HIV was the cause of AIDS provided some special challenges – unlike most viral infections. The first was the long period between infection and the signs of AIDS (5 to 15 years). Physicians and public health officials do not ask a patient what they did a decade earlier, but rather think in terms of days or weeks. The A problem then occurred that enormously hindered our work over the coming years. One of our culture samples became contaminated with virus sent to us by Luc Montagnier. At first we stubbornly refused to believe that this was possible, because the strain of HIV from Paris had different characteristics in cell culture. However, this has now been clarified ,17. MontThen, from all sides and in big doses, came patent suits over royalties to the blood test, lawyers, media, politics and just plain pressure. Meanwhile, there were other odd problems such as people who denied the existence of AIDS, others who believed HIV did not exist, groups who believed HIV existed, but didn't cause AIDS, and those who believed HIV existed, caused AIDS, and was developed in a U.S. laboratory to kill African Americans and gay men. Suffice it to say, no scientist is prepared for things like this. Despite these distractions, science progressed with great speed. Mann called it the fastest pace of discovery in medical history from the time of inception of a new disease.To briefly revisit that period, some of the noteworthy advances are listed here. They include discovery of HIV 1983–84) -14; conv83–84 -14These rapid advances led to expectations that AIDS might be quickly solved. However, those scientists with experience in retrovirology knew differently: Unless a successful vaccine was soon available, this would be a long road – an infection that might be permanent in the population as retroviruses are in many species. Furthermore, we knew by mid-1984 that the infection was becoming global. We had tested sera from many countries, and we could follow the evidence for HIV coming into a region (a positive HIV blood test) with subsequent AIDS. However, we could never anticipate the HIV African tragedy.th century [Despite the rapid advances in those years, I think it is still appropriate to ask whether we could have done better. For example, were we as medical scientists, health officials, doctors or simply as members of society prepared? The answer is an interesting mix of opposites! On the one hand, if AIDS had to come, we were lucky that  it came at a very good time. The 1970's saw the revelation of the replication cycle of animal retroviruses (so we had a framework to work by once HIV was established as the cause). We had most modern tools of molecular biology (mainly developed in the 1970's). We had monoclonal antibodies also developed in the 1970's. We had access to technology to grow human T-cells with IL-2 which my colleagues and I developed in the mid-1970's, and we had found other human retroviruses in the 1980's-82 giving the first credence to their presence in humans. However, if AIDS had to come, we could also say it came at the worst of times. It seems that people have a memory span not longer than 25–30 years. Here are three examples of what I mean: First, was the surprise and lack of preparation in 1918–1919 for the great influenza epidemic – forgetting lessons of the late 19 century . Secondl century . It is eNo group was really responsible for unraveling the cause of the new epidemic, except the CDC, but in my view the CDC cannot and does not have expertise in every class of microbes, let alone for all types of viruses, and indeed they had no expertise in animal or human retroviruses. Our group became involved only after I listened to a lecture by the CDC's James Curran, who called for help from virologists. I have suggested that the government provide base support for 10 or more virus centers, covering all types of viruses among the centers. These centers would be responsible for providing needed expertise to the CDC for the etiological agent, diagnostics and possibly therapy and prevention. In accordance with the kind of virus suspected, the center(s) would be activated. Each center might also be required to have close collaborations with at least two groups from developing nations.Though the HIV blood test was brought forward rapidly (early 1985) to large companies that could make the test available on an industrialized scale, I believe we could have still done better. For instance, we could have tested the pooled plasma used for hemophiliacs in 1984 without a large industrial scale production of the test. I don't think anyone was thinking of this. We were advised to return to basic laboratory research and assumed someone would be doing these tests. The lesson here for me is to take more control of things that come from your own work.Where did things go since this early period of 1982–85? Jonathan Mann describes Part 4 ('86) as the time of global mobilization. This means education leading to prevention of infection, and no doubt this was the second major practical advance and it continues today with results that vary in place and even in time. There is proven success in some places, but not all, and sometimes there is only temporary success. It is noteworthy that appropriate education also depends upon the blood test, hence on basic science.There were many other major advances over these next 20 years ('86-06), but none were more important than therapy. This is listed as Part 5 of Mann's summary, but it was added by me as the "period" era of practical advances, but the time lines for these advances are actually from 1984–1995. AZT showed for the first time that a viral disease could be objectively treated (decline in virus levels and lessened signs of AIDS), and there is no need to embellish here on the great advances made with the triple drug therapy in the mid 1990's. This was from contributions of a great number of scientists: those who contributed to our basic understanding of HIV replication, and as a result to targets for therapy, and those who developed the culture systems to grow HIV that could also be used in drug testing, and of course to the pharmaceutical industry, especially those like E. Emini who helped design and develop the protease inhibitors.The other major practical advances in the last two decades have mainly been an extension of the earlier ones: more widespread use of the blood test as well as educational programs; refining therapies; learning about HIV drug resistance and how best to avoid it; better care of patients; and learning about serious co-infections especially of tuberculosis and HCV. A selection of the most important basic science advances will be debatable. In my view, the most important include the following: clarification of the two HIV strain functional extremes – the pure CCR5 tropic viruses and the CXCR4 tropic viruses -42, for New York Times reporting of the Toronto International AIDS Conference) that, at the April 1984 press conference, Secretary of Health, Margaret Heckler stated that a successful vaccine would be available within two years. Transcripts of comments are still available and show that no such claim was made. Rather, it was said that the virus could be continuously produced in large amounts, thereby making trials possible within two years. Indeed, this proved true, because in 1986, Daniel Zagury carried out some phase 1 trials in Africa and in Paris.We have reached the end of the first 25 years of AIDS, and we can safely say that we know as much about HIV as we do of any pathogen and about AIDS as we do any human disease. The remaining problems and needs are evident: bringing therapy and better health infrastructure to poor nations; continuing to develop new treatments because of the need for life-long therapy and the associated drug side effects and HIV resistance; continuing and advancing education; global monitoring of the different strains of HIV for changes in their virulence, transmissibility and drug resistance; and development of a preventive vaccine which provides sterilizing immunity (or close to it) . For a sSeveral encouraging developments provide some optimism for the future, such as the ability of some nations to diminish rates of infection by education, and major new funding sources aimed at practical achievements. One laudable example is President Bush's Emergency Plan for AIDS Relief, which is providing $15 billion for therapy for HIV positive patients in needy nations. We have been impressed that this effort carries out its mission with leadership by university clinical scientists who work with groups with long experience in the specific country. In contrast to alternative plans that simply and rapidly provide funds for the drugs, these programs add to local infrastructure and training, thereby reducing the prospects for creating more multi-drug resistant HIV mutants. Private foundations have also been a new forceful addition; International AIDS Vaccine Initiative (IAVI) for developing vaccine candidates and the Bill and Melinda Gates Foundation for fulfilling many needs.There are also major concerns for the future. We know science is essential for solving the HIV problem and, as noted before, science has been responsible for all the major practical advances in fighting this disease. However, there is a growing distance between scientists and the larger public. John Moore of Cornell Weill Medical School reminded me that C.P. Snow wrote about this in the 1950's, but I think the gap has continued to widen as technology becomes more and more specialized. Sometimes, it leads to tension and even hostility by the larger public toward scientists. This is sometimes evident in AIDS, seemingly so in recent years. Consider a recent CNN program that was a positive educational force, but advertised as one composed of AIDS experts. However, not one scientist was among the experts, and the program ended with a movie actor stating that to solve the problem, we all "had to be together." It was togetherness rather than science that he informed us would solve AIDS.th birthday year.To return to and end on a positive note: it is interesting and useful to remember that there has been some silver lining on the dark AIDS clouds. Consider the many positive spin-offs to science in immunology, cancer biology, basic virology, and even molecular biology along with the leadership and focus AIDS research has provided to therapy of viral infections and to vaccine development. Positive spin-offs have not been limited to science. Consider how AIDS has inspired far greater tolerance (at least in the West) of differences in sexuality and much greater scientific and humanitarian collaborations between developed and less developed nations. Certainly, this is the case for relations between the U.S. and Africa. Let us hope these advances in understanding and in conscience will continue to evolve and grow so that there will be no need for anyone to reflect on AIDS in its 50


If compared with printed media, the prospect for the success of health-related WWW publications lies in the added value of motivation and efficacy, due to the multi-modal coding of contents, in the possibility to provide search facilities and the flexibility of interaction with the user. An important advantage over the off-line distribution of disks or CD-ROMs is the automated diffusion and update of the contents. Whereas more and more medical WWW sites are launched, their acceptance and utilisation, especially in medical education is still unsatisfactory. Obviously, one reason for this phenomenon is the lack of quality. Many authors, developers and software publishers ignore that the design of high-quality electronic publications is a cost-intensive process. As key qualifications we identify: domain competence, software engineering skills, media production proficiency, GUI design competence, and didactic qualifications. On behalf of the German Association of Medical Informatics, Biometry and Epidemiology (GMDS), the authors have co-ordinated the development of a catalogue of "Quality Criteria for Electronic Publications in Medicine". This catalogue defines as Electronic Publications in Medicine any software containing health-related generic knowledge, with WWW publications being an important group. The criteria catalogue is divided into the sections contents, technical aspects, coding of information, ergonomy, dialogue and didactics. According to these items, typical faults and deficiencies of medical electronic publications are elucidated and possible solutions are given. Our criteria are intended to support the formative evaluation during the development of electronic publications, and to provide a basis for the summative evaluation of medical WWW and offline publications. The catalogue of "Quality Criteria for Electronic Publications in Medicine" is available in German, English, Portuguese and Spanish, at: http://www.imbi.uni-freiburg.de/medinf/gmdsqc/.


Inappropriate antibiotic use promotes resistance. Antibiotics are generally not indicated for upper respiratory infections (URIs). Our objectives were to describe patterns of URI treatment and to identify patient and provider factors associated with antibiotic use for URIs.This study was a cross-sectional analysis of medical and pharmacy claims data from the Pennsylvania Medicaid fee-for-service program database. We identified Pennsylvania Medicaid recipients with a URI office visit over a one-year period. Our outcome variable was antibiotic use within seven days after the URI visit. Study variables included URI type and presence of concurrent acute illnesses and chronic conditions. We considered the associations of each study variable with antibiotic use in a logistic regression model, stratifying by age group and adjusting for confounders.Among 69,936 recipients with URI, 35,786 (51.2%) received an antibiotic. In all age groups, acute sinusitis, chronic sinusitis, otitis, URI type and season were associated with antibiotic use. Except for the oldest group, physician specialty and streptococcal pharyngitis were associated with antibiotic use. History of chronic conditions was not associated with antibiotic use in any age group. In all age groups, concurrent acute illnesses and history of chronic conditions had only had fair to poor ability to distinguish patients who received an antibiotic from patients who did not.Antibiotic prevalence for URIs was high, indicating that potentially inappropriate antibiotic utilization is occurring. Our data suggest that demographic and clinical factors are associated with antibiotic use, but additional reasons remain unexplained. Insight regarding reasons for antibiotic prescribing is needed to develop interventions to address the growing problem of antibiotic resistance. Upper respiratory tract infections (URIs) are one of the most frequent reasons patients see their physicians.  AntibiotAlthough other studies have explored factors associated with antibiotic use for URIs, few studies have examined the importance of comorbidity -14. In fInternational Classification of Diseases,Ninth Revision, Clinical Modification . Concurrent urinary tract infection  was also associated with antibiotic use. Concurrent acute illnesses in the oldest group (age ≥ 45 years) that were associated with antibiotic use included acute sinusitis , chronic sinusitis , acute sinusitis  and otitis media . A history of chronic comorbid conditions  was not associated with antibiotic use in any of the age groups.The C statistic (area under the ROC curve) was used to assess the ability of the presence of the regression models to discriminate patients who received antibiotics from those who did not. We report the C-statistics for the 'any acute condition' models . These findings are consistent with other similar analyses, which found 44% to 60% prevalence of antibiotic prescribing for colds or URIs%. These ,17,18. TAntibiotic resistance is a worldwide public health issue, resulting in emerging antimicrobial resistance and costing $1.3 billion in the United States in 1992. EvidencTo address prescribing factors, educational and administrative interventions have been proposed -31. AdmiOur findings suggest that the presence of certain concurrent acute illnesses increase the likelihood of antibiotic use for a URI. It is possible those antibiotics were actually prescribed for these other acute conditions and that the URI was a coincidental diagnosis. Hence, it could be argued that for some patients the prescription of antibiotics may have been indicated.However, antibiotic use was highly prevalent (47.8%) even among those without a coincidental diagnosis. In the final regression models coincidental diagnoses only had fair to poor ability to distinguish patients who received an antibiotic from patients who did not, as indicated by the C statistics. Although the presence of illnesses such as otitis media or streptococcal pharyngitis was significantly associated with antibiotic use, they did not help to discriminate patients who received an antibiotic during a URI from those who did not. Thus, the reasons why physicians prescribe antibiotics for URIs is complex and is not fully explained by regression models of this study. Several reasons have been cited for inappropriate prescribing of antibiotics. These include patient expectation, -35 physiThis paper explored predictive factors of antibiotic use for URI in an administrative database namely a Medicaid population. The concurrent presence of an acute illness such as cellulitis or UTI may explain the observed antibiotic prescription that was contemporaneous to a URI episode. In addition, we chose to explore the importance of comorbidity in predicting antibiotic use. For some chronic comorbid conditions, such as chronic malignancy or immunodeficiency, antibiotic use may be medically indicated for URIs. Thus, we chose a limited number of comorbid conditions, that we believe justified antibiotic use. Other studies have used a wider range of comorbid conditions that included diabetes, cardiovascular disease. These additional comorbid conditions may be important risk factors in that they increase antibiotic prescribing. However, we chose not to include these additional conditions because their presence generally does not justify antibiotic use.One limitation of this study was that validation of the medical and prescription claims data against the primary data in the actual medical record was not possible due to limited resources. However, Medicaid prescription claims tend to be a reliable source of drug availability.Reimbursement is linked to accurate billing, though the reliability of the diagnosis on the medical service claim is less certain since diagnosis generally does not influence reimbursement directly. This may result in misclassification of URI-related events due to incorrect data entry or wrong code assignment. For example, we included ICD-9-CM code 490 (bronchitis not otherwise specified) in our definition of URI; this code may also include patients with COPD or acute exacerbation of chronic bronchitis. In addition, the severity of the URI or the actual indication for the antibiotic prescribed cannot be definitively determined from claims data. However, we did attempt to link the antibiotic to the URI episode temporally and control for other potential antibiotic indications in the analysis. Another limitation is that there may be misclassification of chronic disease history. Although we searched the administrative claims for evidence of chronic conditions for one year before the index URI episode, only 64% of subjects were eligible for an entire year. However, when we reran the 'history of chronic conditions' models for only those subjects with one year of eligibility prior to the URI episode, we obtained results to those in Table Finally, these findings may not be generalizable to populations other than Medicaid, since Medicaid patients are differentiated by low economic status, source of care and other factors that may affect drug utilization.This analysis suggests that demographic and clinical factors are associated with the prescription of an antibiotic for a URI, but much of the antibiotic use remains unexplained by acute illnesses and comorbid conditions. More insight into the reasons for antibiotic prescribing needs to be gained, which will lead to novel interventions that may hopefully curb the growing problem of antibiotic resistance.The author(s) declare that they have no competing interests.IZ, EP and AH have made substantial contributions to conception and design, data analysis and interpretation of data, have been involved in drafting the manuscript or revising it critically for important intellectual content and have given final approval of the version to be publishedThe pre-publication history for this paper can be accessed here:


The international AIDS community is being held hostage by a small number of activist groups, argues Lange. One of the great tragedies of our times is the extent to which HIV prevention efforts are falling short. In 2004, more new HIV infections occurred than in any previous year: close to 14,000 a day, 570 per hour, almost ten per minute. The greater part of new infections occurs in young people, over half in persons between 15 and 24 years of age, and over half in women. The increasing feminization of the HIV/AIDS epidemic reflects the vulnerable position of women in many societies [Condoms are highly effective at preventing sexual transmission of HIV, but only if they are available and used . Even ifIn the absence of an effective preventive HIV vaccine , which iPLoS Medicine on the recent interruptions of several tenofovir PREP trials, instigated predominantly by activist groups, including Act Up–Paris [Mills and Singh have written an informative and thoughtful essay for Up–Paris . They prThe fear or trepidation about making a correct diagnosis, or being outspoken about the correct diagnosis, is in this case, as in most other circumstances, counterproductive and may even lead to more harm being done. The fact of the matter is that the investigators of the tenofovir trials did consult intensely with community groups concerned, but this consultative process obviously did not include every activist group in the world.As Co-Chair of last year's XVth International AIDS Conference in Bangkok, Thailand, I became painfully aware of a structural flaw in the system of dealing with the activist community. The governing body of the conference, the Conference Organizing Committee, included three international and one local Community Co-Organizers, who were supposed to have a mandate to speak on behalf of the national and international AIDS community. In the end, though, it turned out that agreements on limiting disruption of speeches and destruction of property, which took endless hours of discussion and which were communicated to attendants, governments, speakers, and sponsors, could not be honored because certain activist groups simply ignored them. Likewise, in clinical research, investigators may end up in situations in which they may have had an intense dialogue and come to an agreement with what they have identified to be the relevant community organizations, and yet a day later are put on the stand by yet another activist group.Life would be simpler if there were an umbrella organization with undisputed leadership among AIDS activists that was mandated to speak and act on behalf of this community; somewhat like labor unions in their heydays. But we are far from that.Activist groups have now managed to derail several PREP trials, arguably the most important studies for those at high risk of acquiring HIV infection around the globe. Similarly, activist groups have endangered the funding and therefore the continuity of the International AIDS Conference . And lately activist groups have prevented clinical trials with the promising and highly needed new class of CCR5-receptor-blocking antiretrovirals from proceeding in several European countries.The methods of these specific activist groups are uninformed demagogy, intimidation, and “AIDS exceptionalism”, the last in the sense that they exploit their HIV-positive status to get away with behavior that would not be accepted from others. Within the international AIDS community, such form of activism is only practiced by a tiny minority, but it has taken us hostage. Those who will suffer the most from the misguided ethical imperialism that derailed the PREP trials do not live in Paris, but as usual in Nairobi, Johannesburg, Phnom Penh, and Calcutta.There is no other area of medicine where activism has been so strong and has accomplished so much as in the HIV/AIDS field. Let's be just a little brave, and stand up to protect that legacy.