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1.  Changes in Scottish suicide rates during the Second World War 
BMC Public Health  2006;6:167.
Background
It is believed that total reported suicide rates tend to decrease during wartime. However, analysis of suicide rates during recent conflicts suggests a more complex picture, with increases in some age groups and changes in method choice. As few age and gender specific analyses of more distant conflicts have been conducted, it is not clear if these findings reflect a change in the epidemiology of suicide in wartime. Therefore, we examined suicide rates in Scotland before, during and after the Second World War to see if similar features were present.
Methods
Data on deaths in Scotland recorded as suicide during the period 1931 – 1952, and population estimates for each of these years, were obtained from the General Register Office for Scotland. Using computer spreadsheets, suicide rates by gender, age and method were calculated. Forward stepwise logistic regression was used to assess the effect of gender, war and year on suicide rates using SAS V8.2.
Results
The all-age suicide rate among both men and women declined during the period studied. However, when this long-term decline is taken into account, the likelihood of suicide during the Second World War was higher than during both the pre-War and post-War periods. Suicide rates among men aged 15–24 years rose during the Second World War, peaking at 148 per million (41 deaths) during 1942 before declining to 39 per million (10 deaths) by 1945, while the rate among men aged 25–34 years reached 199 per million (43 deaths) during 1943 before falling to 66 per million (23 deaths) by 1946. This was accompanied by an increase in male suicides attributable to firearms and explosives during the War years which decreased following its conclusion.
Conclusion
All age male and female suicide rates decreased in Scotland during World War II. However, once the general background decrease in suicide rates over the whole period is accounted for, the likelihood of suicide among the entire Scottish population during the Second World War was elevated. The overall decrease in suicide rates concealed large increases in younger male age groups during the War years, and an increase in male suicides recorded as due to the use of firearms. We conclude that the effects of war on younger people, reported in recent conflicts in Central Europe, were also seen in Scotland during the Second World War. The results support the findings of studies of recent conflicts which have found a heterogeneous picture with respect to age specific suicide rates during wartime.
doi:10.1186/1471-2458-6-167
PMCID: PMC1526726  PMID: 16796751
2.  The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic 
Antiviral research  2009;85(1):1.
In the last 25 years, HIV-1, the retrovirus responsible for the Acquired Immunodeficiency Syndrome (AIDS), has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir® (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including 1.) the life-long duration of therapy; 2.) the ultimate role of pre-exposure prophylaxis (PrEP); 3.) the cardiometabolic side effects or other toxicities of long-term therapy; 4.) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); 5.) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and 6.) the continued pace of new HIV-1 infections in many parts of the world. All of these factors make refining current therapies and developing new therapeutic paradigms essential priorities, topics covered in articles within this special issue of Antiviral Research. Fortunately, there are exciting new insights into the biology of HIV-1, its interaction with cellular resistance factors, and novel points of attack for future therapies. Moreover, it is a short journey from basic research to public health benefit around the world. The current science will lead to new therapeutic strategies with far-reaching implications in the HIV-1/AIDS pandemic. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
doi:10.1016/j.antiviral.2009.10.002
PMCID: PMC2815149  PMID: 20018391
HIV-1; AIDS; antiretroviral therapy; zidovudine; nucleoside reverse transcriptase inhibitors
3.  Prevalences of sexually transmitted infections in young adults and female sex workers in Peru: a national population-based survey 
The Lancet Infectious Diseases  2012;12(10):765-773.
Summary
Background
We assessed prevalences of seven sexually transmitted infections (STIs) in Peru, stratified by risk behaviours, to help to define care and prevention priorities.
Methods
In a 2002 household-based survey of the general population, we enrolled randomly selected 18–29-year-old residents of 24 cities with populations greater than 50 000 people. We then surveyed female sex workers (FSWs) in these cities. We gathered data for sexual behaviour; vaginal specimens or urine for nucleic acid amplification tests for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; and blood for serological tests for syphilis, HIV, and (in subsamples) herpes simplex virus 2 (HSV2) and human T-lymphotropic virus. This study is a registered component of the PREVEN trial, number ISRCTN43722548.
Findings
15 261 individuals from the general population and 4485 FSWs agreed to participate in our survey. Overall prevalence of infection with HSV2, weighted for city size, was 13·5% in men, 13·6% in women, and 60·6% in FSWs (all values in FSWs standardised to age composition of women in the general population). The prevalence of C trachomatis infection was 4·2% in men, 6·5% in women, and 16·4% in FSWs; of T vaginalis infection was 0·3% in men, 4·9% in women, and 7·9% in FSWs; and of syphilis was 0·5% in men, 0·4% in women, and 0·8% in FSWs. N gonorrhoeae infection had a prevalence of 0·1% in men and women, and of 1·6% in FSWs. Prevalence of HIV infection was 0·5% in men and FSWs, and 0·1% in women. Four (0·3%) of 1535 specimens were positive for human T-lymphotropic virus 1. In men, 65·0% of infections with HIV, 71·5% of N gonorrhoeae, and 41·4% of HSV2 and 60·9% of cases of syphilis were in the 13·3% who had sex with men or unprotected sex with FSWs in the past year. In women from the general population, 66·7% of infections with HIV and 16·7% of cases of syphilis were accounted for by the 4·4% who had been paid for sex by any of their past three partners.
Interpretation
Defining of high-risk groups could guide targeting of interventions for communicable diseases—including STIs—in the general Peruvian population.
Funding
Wellcome Trust-Burroughs Wellcome Fund Infectious Disease Initiative and US National Institutes of Health.
doi:10.1016/S1473-3099(12)70144-5
PMCID: PMC3459082  PMID: 22878023
4.  The Scientific Conferences Organized During War Time (1992-1995) in Sarajevo 
Materia Socio-Medica  2011;23(4):238-248.
Author of this paper spent 1479 days in the siege of Sarajevo, during the period of war time in Bosnia and Herzegovina (B&H). This siege, lasting from 1992 to 1995 (e.g. Dayton Piece agreement was signed in November, 1995) represents the longest siege in the history of the world. Besides usual daily work, as the associate professor of Health education, Medical deontology and Medical informatics for the students of the Faculty of medicine, Faculty of dental medicine, Faculty of Pharmacy and Nursing college of University of Sarajevo, the author organized by himself and contributors, 10 scientific conferences in a sieged Sarajevo. All presented papers at those conferences are published in Proceedings abstract books, as the proof of continuing scientific work, in Sarajevo and other cities in B&H. Additionally, the author continued to publish, in that time, unique PubMed/MedLine indexed journal, - Medical Archives, (i.e. established in 1947) and, in 1993 formed a new journal named - “Acta Informatica Medica” (AIM) , as the Journal of the Bosnian Society of Medical informatics. Bosnian Society of Medical Informatics, thus became the first scientific association from Bosnia and Herzegovina, included in 1994, in the European Federation of Medical Informatics (EFMI) and the International Medical Informatics Assiciation (IMIA) , which was “miracle” from the besieged Sarajevo and war time result of aggression on Bosnia and Herzegovina. It should be noted that the importance of maintaining these academic gatherings, in the circumstances of war, was multifaceted. First of all, thanks to these meetings, the continuity of scientific meetings and activities in the besieged city of Sarajevo was not broken, as well as the continuity of scientific publication, which was crucial for the maintenance of the teaching staff at the university and, finally, in the expansion of the “scientific truth” about what happened in Sarajevo and B&H in these difficult times. All of this was critical to the “survival” of B&H and its people. Some of the published articles, especially in the Medical Archives journal, which even in difficult war conditions did not break the continuity of its publication, and then it was the only scientific journal indexed in B&H, having been consequently cited in the major biomedical data bases in the world. Many scientists abroad have had the opportunity to learn about some of the wonders of Sarajevo “war medicine”, thanks to this journal. Finally, despite the fact that it is another way of expressing its resistance to the aggression on B&H, the organized symposia in the war represented the continuity of the scientific research activities. Bosnia and Herzegovina and Sarajevo under siege, in this way, kept in touch with the civilized world and modern achievements, despite the fact that they were victims of medieval barbarism. In addition, these meetings sent a powerful message to the world about the willingness to register and systematize all the war experiences, especially those related to medicine and medical practice, in terms of what Europe has not known, since the Second World War. Partially, we succeeded in that. The total number of 286 presentations were presented in seven war Conferences, as quantitative and qualitative contribution to the scientific activities, despite the inhuman conditions, in which these articles emerged. These presentations and Conferences testify to the enthusiasm of B&H community and academic institutions that have collaborated with it. Authors and co-authors presented the “war” articles that deserve to be mentioned in the monograph “1479 days of the siege of Sarajevo”. Unfortunately, many of these brave authors are not alive and cannot read this. The task for us remains to remember them by their own good. Old Persian proverb says; “The event which is not recorded is as like it had never happened”. Sapienti sat.
doi:10.5455/msm.2011.23.238-248
PMCID: PMC3633541  PMID: 23678305
Bosnia and Herzegovina; siege; scientific meetings during wartime.
5.  Lifetime Prevalence of Mental Disorders in Lebanon: First Onset, Treatment, and Exposure to War  
PLoS Medicine  2008;5(4):e61.
Background
There are no published data on national lifetime prevalence and treatment of mental disorders in the Arab region. Furthermore, the effect of war on first onset of disorders has not been addressed previously on a national level, especially in the Arab region. Thus, the current study aims at investigating the lifetime prevalence, treatment, age of onset of mental disorders, and their relationship to war in Lebanon.
Methods and Findings
The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation study was carried out on a nationally representative sample of the Lebanese population (n = 2,857 adults). Respondents were interviewed using the fully structured WHO Composite International Diagnostic Interview 3.0. Lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder was 25.8%. Anxiety (16.7%) and mood (12.6%) were more common than impulse control (4.4%) and substance (2.2%) disorders. Only a minority of people with any mental disorder ever received professional treatment, with substantial delays (6 to 28 y) between the onset of disorders and onset of treatment. War exposure increased the risk of first onset of anxiety (odds ratio [OR] 5.92, 95% confidence interval [CI] 2.5–14.1), mood (OR 3.32, 95% CI 2.0–5.6), and impulse control disorders (OR 12.72, 95% CI 4.5–35.7).
Conclusions
About one-fourth of the sample (25.8%) met criteria for at least one of the DSM-IV disorders at some point in their lives. There is a substantial unmet need for early identification and treatment. Exposure to war events increases the odds of first onset of mental disorders.
In a survey of 2,857 adults in Lebanon, Elie Karam and colleagues found a lifetime prevalence of any DSM-IV psychiatric disorder of 25.8%.
Editors' Summary
Background.
Mental illnesses—persistent problems with thinking, with feelings, with behavior, and with coping with life—are very common. In the UK about a quarter, and in the US, almost half, of people have a mental illness at some time during their life. Depression, for example, persistently lowers a person's mood and can make them feel hopeless and unmotivated. Anxiety—constant, unrealistic worries about daily life—can cause sleep problems and physical symptoms such as stomach pains. People with impulse-control disorders, have problems with controlling their temper or their impulses which may sometimes lead to hurting themselves or other people. These and other mental illnesses seriously affect the work, relationships, and quality of life of the ill person and of their family. However, most people with mental illnesses can lead fulfilling and productive lives with the help of appropriate medical and nonmedical therapies.
Why Was This Study Done?
Recent epidemiological surveys (studies that investigate the factors that affect the health of populations) have provided important information about the burden of mental disorders in some industrialized countries. However, little is known about the global prevalence of mental disorders (the proportion of people in a population with each disorder at one time) or about how events such as wars affect mental health. This information is needed so that individual countries can provide effective mental-health services for their populations. To provide this information, the World Mental Health (WMH) Survey Initiative is undertaking large-scale psychiatric epidemiological surveys in more than 29 countries. As part of this Initiative, researchers have examined the prevalence and treatment of mental disorders in Lebanon and have asked whether war in this country has affected the risk of becoming mentally ill.
What Did the Researchers Do and Find?
The researchers randomly selected a sample of nearly 3,000 adults living in Lebanon and interviewed them using an Arabic version of the World Health Organization's “Composite International Diagnostic Interview” (CIDI 3.0). This interview tool generates diagnoses of mental disorders in the form of “DSM-IV codes,” the American Psychiatric Association's standard codes for specific mental disorders. The researchers also asked the study participants about their experience of war-related traumatic events such as being a civilian in a war zone or being threatened by a weapon. The researchers found that one in four Lebanese had had one or more DSM-IV disorder at some time during their life. Major depression was the single most common disorder. The researchers also calculated that by the age of 75 years, about one-third of the Lebanese would probably have had one or more DSM-IV disorder. Only half of the Lebanese with a mood disorder ever received professional help; treatment rates for other mental disorders were even lower. The average delay in treatment ranged from 6 years for mood disorders to 28 years for anxiety disorders. Finally, exposure to war-related events increased the risk of developing an anxiety, mood, or impulse-control disorder by about 6-fold, 3-fold, and 13-fold, respectively.
What Do These Findings Mean?
These findings indicate that the prevalence of mental illness in Lebanon is similar to that in the UK and the US, the first time that this information has been available for an Arabic-speaking country. Indeed, the burden of mental illness in Lebanon may actually be higher than these findings suggest, because the taboos associated with mental illness may have stopped some study participants from reporting their problems. The findings also show that in Lebanon exposure to war-related events greatly increases the risk of developing for the first time several mental disorders. Further studies are needed to discover whether this finding is generalizable to other countries. Finally, these findings indicate that many people in Lebanon who develop a mental illness never receive appropriate treatment. There is no shortage of health-care professionals in Lebanon, so the researchers suggest that the best way to improve the diagnosis and treatment of mental disorders in this country might be to increase the awareness of these conditions and to reduce the taboos associated with mental illness, both among the general population and among health-care professionals.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050061.
Read a related PLoS Medicine Perspective article
IDRAAC has a database that provides access to all published research articles related to mental health in the Arab World
The UK charity Mind provides information on understanding mental illness
The US National Institute of Mental Health provides information on understanding, treating, and preventing mental disorders (mainly in English but some information in Spanish)
MedlinePlus provides a list of useful links to information about mental health
Wikipedia has a page on DSM-IV codes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Mental Health Survey Initiative and the Lebanese WHM study are described on the organizations' Web pages
doi:10.1371/journal.pmed.0050061
PMCID: PMC2276523  PMID: 18384228
6.  ‘Saving the lives of our dogs’: the development of canine distemper vaccine in interwar Britain 
This paper examines the successful campaign in Britain to develop canine distemper vaccine between 1922 and 1933. The campaign mobilized disparate groups around the common cause of using modern science to save the nation's dogs from a deadly disease. Spearheaded by landed patricians associated with the country journal The Field, and funded by dog owners and associations, it relied on collaborations with veterinary professionals, government scientists, the Medical Research Council (MRC) and the commercial pharmaceutical house the Burroughs Wellcome Company (BWC). The social organization of the campaign reveals a number of important, yet previously unexplored, features of interwar science and medicine in Britain. It depended on a patronage system that drew upon a large base of influential benefactors and public subscriptions. Coordinated by the Field Distemper Fund, this system was characterized by close relationships between landed elites and their social networks with senior science administrators and researchers. Relations between experts and non-experts were crucial, with high levels of public engagement in all aspects of research and vaccine development. At the same time, experimental and commercial research supported under the campaign saw dynamic interactions between animal and human medicine, which shaped the organization of the MRC's research programme and demonstrated the value of close collaboration between veterinary and medical science, with the dog as a shared object and resource. Finally, the campaign made possible the translation of ‘laboratory’ findings into field conditions and commercial products. Rather than a unidirectional process, translation involved negotiations over the very boundaries of the ‘laboratory’ and the ‘field’, and what constituted a viable vaccine. This paper suggests that historians reconsider standard historical accounts of the nature of patronage, the role of animals, and the interests of landed elites in interwar British science and medicine.
doi:10.1017/S0007087413000344
PMCID: PMC4014013  PMID: 24941736
7.  Conflicts of Interest at Medical Journals: The Influence of Industry-Supported Randomised Trials on Journal Impact Factors and Revenue – Cohort Study 
PLoS Medicine  2010;7(10):e1000354.
Andreas Lundh and colleagues investigated the effect of publication of large industry-supported trials on citations and journal income, through reprint sales, in six general medical journals
Background
Transparency in reporting of conflict of interest is an increasingly important aspect of publication in medical journals. Publication of large industry-supported trials may generate many citations and journal income through reprint sales and thereby be a source of conflicts of interest for journals. We investigated industry-supported trials' influence on journal impact factors and revenue.
Methods and Findings
We sampled six major medical journals (Annals of Internal Medicine, Archives of Internal Medicine, BMJ, JAMA, The Lancet, and New England Journal of Medicine [NEJM]). For each journal, we identified randomised trials published in 1996–1997 and 2005–2006 using PubMed, and categorized the type of financial support. Using Web of Science, we investigated citations of industry-supported trials and the influence on journal impact factors over a ten-year period. We contacted journal editors and retrieved tax information on income from industry sources. The proportion of trials with sole industry support varied between journals, from 7% in BMJ to 32% in NEJM in 2005–2006. Industry-supported trials were more frequently cited than trials with other types of support, and omitting them from the impact factor calculation decreased journal impact factors. The decrease varied considerably between journals, with 1% for BMJ to 15% for NEJM in 2007. For the two journals disclosing data, income from the sales of reprints contributed to 3% and 41% of the total income for BMJ and The Lancet in 2005–2006.
Conclusions
Publication of industry-supported trials was associated with an increase in journal impact factors. Sales of reprints may provide a substantial income. We suggest that journals disclose financial information in the same way that they require them from their authors, so that readers can assess the potential effect of different types of papers on journals' revenue and impact.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Medical journals publish many different types of papers that inform doctors about the latest research advances and the latest treatments for their patients. They publish articles that describe laboratory-based research into the causes of diseases and the identification of potential new drugs. They publish the results of early clinical trials in which a few patients are given a potential new drug to check its safety. Finally and most importantly, they publish the results of randomized controlled trials (RCTs). RCTs are studies in which large numbers of patients are randomly allocated to different treatments without the patient or the clinician knowing the allocation and the efficacy of the various treatments compared. RCTs are best way of determining whether a new drug is effective and have to be completed before a drug can be marketed. Because RCTs are very expensive, they are often supported by drug companies. That is, drug companies provide grants or drugs for the trial or assist with data analysis and/or article preparation.
Why Was This Study Done?
Whenever a medical journal publishes an article, the article's authors have to declare any conflicts of interest such as financial gain from the paper's publication. Conflict of interest statements help readers assess papers—an author who owns the patent for a drug, for example, might put an unduly positive spin on his/her results. The experts who review papers for journals before publication provide similar conflict of interest statements. But what about the journal editors who ultimately decide which papers get published? The International Committee of Medical Journal Editors (ICMJE), which produces medical publishing guidelines, states that: “Editors who make final decisions about manuscripts must have no personal, professional, or financial involvement in any of the issues that they might judge.” However, the publication of industry-supported RCTs might create “indirect” conflicts of interest for journals by boosting the journal's impact factor (a measure of a journal's importance based on how often its articles are cited) and its income through the sale of reprints to drug companies. In this study, the researchers investigate whether the publication of industry-supported RCTs influences the impact factors and finances of six major medical journals.
What Did the Researchers Do and Find?
The researchers determined which RCTs published in the New England Journal of Medicine (NEJM), the British Medical Journal (BMJ), The Lancet, and three other major medical journals in 1996–1997 and 2005–2006 were supported wholly, partly, or not at all by industry. They then used the online academic citation index Web of Science to calculate an approximate impact factor for each journal for 1998 and 2007 and calculated the effect of the published RCTs on the impact factor. The proportion of RCTs with sole industry support varied between journals. Thus, 32% of the RCTs published in the NEJM during both two-year periods had industry support whereas only 7% of the RCTs published in the BMJ in 2005–2006 had industry support. Industry-supported trials were more frequently cited than RCTs with other types of support and omitting industry-supported RCTs from impact factor calculations decreased all the approximate journal impact factors. For example, omitting all RCTs with industry or mixed support decreased the 2007 BMJ and NEJM impact factors by 1% and 15%, respectively. Finally, the researchers asked each journal's editor about their journal's income from industry sources. For the BMJ and The Lancet, the only journals that provided this information, income from reprint sales was 3% and 41%, respectively, of total income in 2005–2006.
What Do These Findings Mean?
These findings show that the publication of industry-supported RCTs was associated with an increase in the approximate impact factors of these six major medical journals. Because these journals publish numerous RCTs, this result may not be generalizable to other journals. These findings also indicate that income from reprint sales can be a substantial proportion of a journal's total income. Importantly, these findings do not imply that the decisions of editors are affected by the possibility that the publication of an industry-supported trial might improve their journal's impact factor or income. Nevertheless, the researchers suggest, journals should live up to the same principles related to conflicts of interest as those that they require from their authors and should routinely disclose information on the source and amount of income that they receive.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000354.
This study is further discussed in a PLoS Medicine Perspective by Harvey Marcovitch
The International Committee of Medical Journal Editors provides information about the publication of medical research, including conflicts of interest
The World Association of Medical Editors also provides information on conflicts of interest in medical journals
Information about impact factors is provided by Thomson Reuters, a provider of intelligent information for businesses and professionals; Thomson Reuters also runs Web of Science
doi:10.1371/journal.pmed.1000354
PMCID: PMC2964336  PMID: 21048986
8.  Alcohol consumption and cognitive performance in a random sample of Australian soldiers who served in the Second World War. 
BMJ : British Medical Journal  1997;314(7095):1655-1657.
OBJECTIVE: To examine the association between the average daily alcohol intake of older men in 1982 and cognitive performance and brain atrophy nine years later. SUBJECTS: Random sample of 209 Australian men living in the community who were veterans of the second world war. Their mean age in 1982 was 64.3 years. MAIN OUTCOME MEASURES: 18 standard neuropsychological tests measuring a range of intellectual functions. Cortical, sylvian, and vermian atrophy on computed tomography. RESULTS: Compared with Australian men of the same age in previous studies these men had sustained a high rate of alcohol consumption into old age. However, there was no significant correlation, linear or non-linear, between alcohol consumption in 1982 and results in any of the neuropsychological tests in 1991; neither was alcohol consumption associated with brain atrophy on computed tomography. CONCLUSION: No evidence was found that apparently persistent lifelong consumption of alcohol was related to the cognitive functioning of these men in old age.
PMCID: PMC2126835  PMID: 9180067
9.  When to start: as soon as possible 
Debate regarding “When to start” antiretroviral (ARV) therapy has raged since the introduction of zidovudine in 1987. Based on the entry criteria for the original Burroughs Wellcome (002) study, the field has been anchored to “CD4 counts” as the prime metric to indicate ARV treatment initiation for asymptomatic HIV-positive individuals. The pendulum has swung back and forth, based mostly on the efficacy and toxicity of available regimens. In today's world, several factors have converged that compel us to initiate therapy as soon as possible: (i) The biology of viral replication (1 to 10 billion viruses/day) screams that we should be starting early. (ii) Resultant inflammation from unchecked replication is associated with earlier onset of multiple co-morbid conditions. (iii) The medications available today are more efficacious and less toxic than in years past. (iv) Clinical trials have demonstrated benefit for all but the highest CD4 strata (>450 to 500 cells/µL). (v) Some cohort studies have demonstrated clear benefit of ARV therapy at any CD4 count, and almost all cohort studies have demonstrated no detrimental effects of early treatment. (vi) In addition to the demonstrated and inferred benefits to the individual patient, we now have a public health benefit of earlier intervention: treatment is prevention. Finally, from a practical/common sense perspective, we are talking about life-long therapy. Whether we start at a CD4 count of 732 or 493/µL, the patient will be on therapy for over 40 to 50 years! There does not seem to be much benefit in waiting, and there is likely to be significant long-term harm. Treat early!
doi:10.7448/IAS.15.6.18070
PMCID: PMC3512539
10.  When to start antiretroviral therapy: as soon as possible 
BMC Medicine  2013;11:147.
Background
The debate regarding ‘When to Start’ antiretroviral therapy has raged since the introduction of zidovudine in 1987. Based on the entry criteria for the original Burroughs Wellcome 002 study, the field has been anchored to CD4 cell counts as the prime metric to indicate treatment initiation for asymptomatic individuals infected with Human Immunodeficiency Virus. The pendulum has swung back and forth based mostly on the relative efficacy, toxicity and convenience of available regimens.
Discussion
In today’s world, several factors have converged that compel us to initiate therapy as soon as possible: 1) The biology of viral replication (1 to 10 billion viruses per day) strongly suggests that we should be starting early. 2) Resultant inflammation from unchecked replication is associated with earlier onset of multiple co-morbid conditions. 3) The medications available today are more efficacious and less toxic than years past. 4) Clinical trials have demonstrated benefits for all but the highest CD4 strata (>500 cells/μl). 5) Some cohort studies have demonstrated the clear benefit of antiretroviral therapy at any CD4 count and no cohort studies have demonstrated that early therapy is more detrimental than late therapy at the population level. 6) In addition to the demonstrated and inferred benefits to the individual patient, we now have evidence of a Public Health benefit from earlier intervention: treatment is prevention.
Summary
From a practical, common sense perspective we are talking about life-long therapy. Whether we start at a CD4 count of 732 cells/μl or 493 cells/μl, the patient will be on therapy for over 40 to 50 years. There does not seem to be much benefit in waiting and there likely is significant long-term harm. Do not wait. Treat early.
The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/148.
doi:10.1186/1741-7015-11-147
PMCID: PMC3682940  PMID: 23767762
HIV infection; CD4 lymphocyte count; When to start; Antiretroviral therapy; Early treatment
11.  Strongyloidiasis in Allied ex-prisoners of war in south-east Asia 
British Medical Journal  1980;280(6214):598-601.
One hundred and sixty ex-servicemen who had been prisoners of war in south-east Asia during 1942-5 were investigated for infection with Strongyloides stercoralis. Larvae were found in 44 (27·5%) of the men, who had therefore been infected for 34-37 years. Direct microscopy of the faeces was the most successful diagnostic method, giving a positive result in 37 cases (84%); multiple examinations were often necessary. Faecal culture was positive in 30 cases (68%), but examination of duodenal fluid obtained with the string test gave a positive result in only 17 (39%). The mean blood eosinophil count and mean serum IgE concentration were higher in the infected men, though normal values were often found in individual cases. Clinical manifestations of isolated strongyloides infection were analysed by comparing the infected men with control groups of ex-prisoners in south-east Asia without proved strongyloidiasis and ex-prisoners in Europe. Twenty-nine infected men (66%) complained of non-specific urticaria, and 13 (30%) had pathognomonic larva currens. Gastrointestinal symptoms significantly more common in the infected group were diarrhoea, indigestion, lower abdominal pain, pruritus ani, and weight loss (p <0·05-p <0·0005).
The study group was thought to be reasonably representative of Allied ex-servicemen imprisoned in south-east Asia during the second world war. Probably there are many thousands of infected persons in several countries. The worm has an unusual ability to multiply, and larvae may spread throughout the body in immunosuppressed subjects.
PMCID: PMC1600761  PMID: 7370602
12.  Do childhood cognitive ability or smoking behaviour explain the influence of lifetime socio-economic conditions on premature adult mortality in a British post war birth cohort?☆ 
Social Science & Medicine (1982)  2009;68(9):1565-1573.
Poor childhood and adult socio-economic conditions, lower childhood cognitive ability and cigarette smoking are all associated with adult mortality risk. Using data on 4458 men and women aged 60 years from a British birth cohort study, we investigated the extent to which these risk factors are part of the same pathway linking childhood experience to adult survival. Compared with women from non-manual origins, men from non-manual origins, women and men from manual origins, and those with missing data on father's social class had about double the risk of mortality between 26 and 60 years. Cox proportional hazards models showed that these differences were reduced but remained significant after adjusting for childhood cognitive ability, adult socio-economic conditions and smoking. Higher childhood ability increased survival chances by securing better adult socio-economic conditions, such as home ownership, which was strongly associated with survival. These findings were similar for cardiovascular and cancer mortality.
doi:10.1016/j.socscimed.2009.02.006
PMCID: PMC3504657  PMID: 19269077
Mortality; Socio-economic conditions; Childhood cognitive ability; Cigarette smoking; Birth cohort study; Life course; UK
13.  “Working the System”—British American Tobacco's Influence on the European Union Treaty and Its Implications for Policy: An Analysis of Internal Tobacco Industry Documents 
PLoS Medicine  2010;7(1):e1000202.
Katherine Smith and colleagues investigate the ways in which British American Tobacco influenced the European Union Treaty so that new EU policies advance the interests of major corporations, including those that produce products damaging to health.
Background
Impact assessment (IA) of all major European Union (EU) policies is now mandatory. The form of IA used has been criticised for favouring corporate interests by overemphasising economic impacts and failing to adequately assess health impacts. Our study sought to assess how, why, and in what ways corporations, and particularly the tobacco industry, influenced the EU's approach to IA.
Methods and Findings
In order to identify whether industry played a role in promoting this system of IA within the EU, we analysed internal documents from British American Tobacco (BAT) that were disclosed following a series of litigation cases in the United States. We combined this analysis with one of related literature and interviews with key informants. Our analysis demonstrates that from 1995 onwards BAT actively worked with other corporate actors to successfully promote a business-oriented form of IA that favoured large corporations. It appears that BAT favoured this form of IA because it could advance the company's European interests by establishing ground rules for policymaking that would: (i) provide an economic framework for evaluating all policy decisions, implicitly prioritising costs to businesses; (ii) secure early corporate involvement in policy discussions; (iii) bestow the corporate sector with a long-term advantage over other actors by increasing policymakers' dependence on information they supplied; and (iv) provide businesses with a persuasive means of challenging potential and existing legislation. The data reveal that an ensuing lobbying campaign, largely driven by BAT, helped secure binding changes to the EU Treaty via the Treaty of Amsterdam that required EU policymakers to minimise legislative burdens on businesses. Efforts subsequently focused on ensuring that these Treaty changes were translated into the application of a business orientated form of IA (cost–benefit analysis [CBA]) within EU policymaking procedures. Both the tobacco and chemical industries have since employed IA in apparent attempts to undermine key aspects of European policies designed to protect public health.
Conclusions
Our findings suggest that BAT and its corporate allies have fundamentally altered the way in which all EU policy is made by making a business-oriented form of IA mandatory. This increases the likelihood that the EU will produce policies that advance the interests of major corporations, including those that produce products damaging to health, rather than in the interests of its citizens. Given that the public health community, focusing on health IA, has largely welcomed the increasing policy interest in IA, this suggests that urgent consideration is required of the ways in which IA can be employed to undermine, as well as support, effective public health policies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The primary goal of public health, the branch of medicine concerned with the health of communities, is to improve lives by preventing disease. Public-health groups do this by assessing and monitoring the health of communities, by ensuring that populations have access to appropriate and cost-effective health care, and by helping to formulate public policies that safeguard human health. Until recently, most of the world's major public-health concerns related to infectious diseases. Nowadays, however, many major public-health concerns are linked to the goods made and marketed by large corporations such as fast food, alcohol, tobacco, and chemicals. In Europe, these corporations are regulated by policies drawn up both by member states and by the European Commission, the executive organ of the European Union (EU; an economic and political partnership among 27 democratic European countries). Thus, for example, the tobacco industry, which is widely recognized as a driver of the smoking epidemic, is regulated by Europe-wide tobacco control policies and member state level policies.
Why Was This Study Done?
Since 1997, the European Commission has been required by law to assess the economic, social (including health), and environmental consequences of new policy initiatives using a process called an “impact assessment” (IA). Because different types of IA examine the likely effects of policies on different aspects of daily life—a health impact assessment, for example, focuses on a policy's effect on health—the choice of IA can lead to different decisions being taken about new policies. Although the IA tool adopted by the European Commission aims to assess economic, environmental and social impacts, independent experts suggest this tool does not adequately assess health impacts. Instead, economic impacts receive the most attention, a situation that may favour the interests of large businesses. In this study, the researchers seek to identify how and why the EU's approach to IA developed. More specifically, the researchers analyze internal documents from British American Tobacco (BAT), which have been disclosed because of US litigation cases, to find out whether industry has played a role in promoting the EU's system of IA.
What Did the Researchers Do and Find?
The researchers analyzed 714 BAT internal documents (identified by searching the Legacy Tobacco Documents Library, which contains more than 10 million internal tobacco company documents) that concerned attempts made by BAT to influence regulatory reforms in Europe. They also analyzed related literature from other sources (for example, academic publications) and interviewed 16 relevant people (including people who had worked at the European Commission). This analysis shows that from 1995, BAT worked with other businesses to promote European regulatory reforms (in particular, the establishment of a business-orientated form of IA) that favor large corporations. A lobbying campaign, initiated by BAT but involving a “policy network” of other companies, first helped to secure binding changes to the EU Treaty that require policymakers to minimize legislative burdens on businesses. The analysis shows that after achieving this goal, which BAT described as an “important victory,” further lobbying ensured that these treaty changes were translated into the implementation of a business-orientated form of IA within the EU. Both the tobacco industry and the chemical industry, the researchers argue, have since used the IA to delay and/or weaken EU legislation intended to protect public health.
What Do These Findings Mean?
These findings suggest that BAT and its corporate allies have fundamentally altered the way in which EU policy is made by ensuring that all significant EU policy decisions have to be assessed using a business-orientated IA. As the authors note, this situation increases the likelihood that the EU will produce policies that favor big business rather than the health of its citizens. Furthermore, these findings suggest that by establishing a network of other industries to help in lobbying for EU Treaty changes, BAT was able to distance itself from the push to establish a business-orientated IA to the extent that Commission officials were unaware of the involvement of the tobacco industry in campaigns for IA. Thus, in future, to safeguard public health, policymakers and public-health groups must pay more attention to corporate efforts to shape decision-making processes. In addition, public-health groups must take account of the ways in which IA can be used to undermine as well as support effective public-health policies and they must collaborate more closely in their efforts to ensure effective national and international policy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/0.1371/journal.pmed.1000202.
Wikipedia has a page on public health (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information on the European Union (in several languages), on public health in the European Union, and on impact assessment by the European Commission is available
The Legacy Tobacco Documents Library is a public, searchable database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The World Health Organization provides information about the dangers of tobacco (in several languages)
The Smoke Free Partnership contains more information about smoking prevalence in Europe and about European policies to tackle the public health issues associated with tobacco use
For more information about tobacco industry influence on policy see the 2009 World Health Organization report on tobacco industry interference with tobacco control
doi:10.1371/journal.pmed.1000202
PMCID: PMC2797088  PMID: 20084098
14.  Managing automation developrent in harmony with the rest of an international company—a QC laboratory manager's perspective 
Significant opportunities and challenges are presented when transitioning from managing laboratory automation development of pharmaceutical products at a single site to collaborative management with multiple domestic and international sites. Prior to integrating Glaxo and Burroughs Wellcome about two years ago, each company had expertise in laboratory automation, but neither had a strategy for consistent business-justified laboratory automation. The approach for international harmonization of automation development of pharmaceutical test methods that the integrated company has adopted is presented. Some items to consider before undertaking a company-wide automation development harmonization programme are offered for consideration. Experiences encountered and future planned benefits are discussed.
doi:10.1155/S1463924698000121
PMCID: PMC2548148  PMID: 18924823
15.  Biochemical mechanisms of the antileishmanial activity of sodium stibogluconate. 
Pentavalent antimonial agents such as sodium stibogluconate (Pentostam; Burroughs Wellcome Co., London, United Kingdom) are the drugs of choice for the treatment of leishmaniasis, but their biochemical mechanisms of action are virtually unknown. The viability of Leishmania mexicana (WR 227) promastigotes and amastigotes was decreased 40 to 61% by a 4-h exposure to 500 micrograms of Sb (in the form of stibogluconate) per ml. Such exposure also resulted in a 51 to 65% decrease in incorporation of label into DNA, RNA, and protein; a 56 to 65% decrease in incorporation of label into purine nucleoside triphosphate; and a 34 to 60% increase in incorporation of label into purine nucleoside monophosphate and diphosphate. It is postulated that the apparent decrease in ATP and GTP synthesis from ADP and GDP contributes to decreased macromolecular synthesis and to decreased Leishmania viability. Further experiments suggested that inhibition of glycolysis and the citric acid cycle may partially explain the inability to phosphorylate ADP.
PMCID: PMC180186  PMID: 2411217
16.  Horizontal transmission of hepatitis B virus amongst British 2nd World War soldiers in South-East Asia. 
Postgraduate Medical Journal  1991;67(783):39-41.
Infection with hepatitis B virus (HBV) is much more common in tropical than in temperate countries. Visitors to the tropics are thus at risk from HBV, though the degree of risk, and the routes of infection involved are uncertain. We report serological markers of HBV in two groups of 2nd World War soldiers, who served in the Thai/Burma jungles. The groups comprised 100 ex-prisoners of the Japanese (POW), and 100 Burma Campaign Veterans (BCV). Surface antigen to HBV (HbsAg) was positive in 0% of POW and 2% of BCV (P = not significant). Surface antibody (anti-HBs) and core antibody (anti-HBc) were both positive in 40% POW and 13% BCV (P less than 0.001). Quoted UK prevalence rates for these markers are 0.1% for HBsAg, 1.5% for anti-HBs and 0.7% for anti-HBc. Both groups thus show very high rates of past HBV infection. For the POW there were many possible reasons, including contaminated surgical instruments and needles, blood transfusions, and multiple beatings with common weapons. None of these factors operated significantly for BCV. Malarial transmission was, however, intense in both groups, though more so in POW. The data thus again raise the possibility of horizontal transmission of HBV by biting insects in tropical countries.
PMCID: PMC2398940  PMID: 1711690
17.  Mortality in Iraq Associated with the 2003–2011 War and Occupation: Findings from a National Cluster Sample Survey by the University Collaborative Iraq Mortality Study 
PLoS Medicine  2013;10(10):e1001533.
Based on a survey of 2,000 randomly selected households throughout Iraq, Amy Hagopian and colleagues estimate that close to half a million excess deaths are attributable to the recent Iraq war and occupation.
Please see later in the article for the Editors' Summary
Background
Previous estimates of mortality in Iraq attributable to the 2003 invasion have been heterogeneous and controversial, and none were produced after 2006. The purpose of this research was to estimate direct and indirect deaths attributable to the war in Iraq between 2003 and 2011.
Methods and Findings
We conducted a survey of 2,000 randomly selected households throughout Iraq, using a two-stage cluster sampling method to ensure the sample of households was nationally representative. We asked every household head about births and deaths since 2001, and all household adults about mortality among their siblings. We used secondary data sources to correct for out-migration. From March 1, 2003, to June 30, 2011, the crude death rate in Iraq was 4.55 per 1,000 person-years (95% uncertainty interval 3.74–5.27), more than 0.5 times higher than the death rate during the 26-mo period preceding the war, resulting in approximately 405,000 (95% uncertainty interval 48,000–751,000) excess deaths attributable to the conflict. Among adults, the risk of death rose 0.7 times higher for women and 2.9 times higher for men between the pre-war period (January 1, 2001, to February 28, 2003) and the peak of the war (2005–2006). We estimate that more than 60% of excess deaths were directly attributable to violence, with the rest associated with the collapse of infrastructure and other indirect, but war-related, causes. We used secondary sources to estimate rates of death among emigrants. Those estimates suggest we missed at least 55,000 deaths that would have been reported by households had the households remained behind in Iraq, but which instead had migrated away. Only 24 households refused to participate in the study. An additional five households were not interviewed because of hostile or threatening behavior, for a 98.55% response rate. The reliance on outdated census data and the long recall period required of participants are limitations of our study.
Conclusions
Beyond expected rates, most mortality increases in Iraq can be attributed to direct violence, but about a third are attributable to indirect causes (such as from failures of health, sanitation, transportation, communication, and other systems). Approximately a half million deaths in Iraq could be attributable to the war.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
War is a major public health problem. Its health effects include violent deaths among soldiers and civilians as well as indirect increases in mortality and morbidity caused by conflict. Unlike those of other causes of death and disability, however, the consequences of war on population health are rarely studied scientifically. In conflict situations, deaths and diseases are not reliably measured and recorded, and estimating the proportion caused, directly or indirectly, by a war or conflict is challenging. Population-based mortality survey methods—asking representative survivors about deaths they know about—were developed by public health researchers to estimate death rates. By comparing death rate estimates for periods before and during a conflict, researchers can derive the number of excess deaths that are attributable to the conflict.
Why Was This Study Done?
A number of earlier studies have estimated the death toll in Iraq since the beginning of the war in March 2003. The previous studies covered different periods from 2003 to 2006 and derived different rates of overall deaths and excess deaths attributable to the war and conflict. All of them have been controversial, and their methodologies have been criticized. For this study, based on a population-based mortality survey, the researchers modified and improved their methodology in response to critiques of earlier surveys. The study covers the period from the beginning of the war in March 2003 until June 2011, including a period of high violence from 2006 to 2008. It provides population-based estimates for excess deaths in the years after 2006 and covers most of the period of the war and subsequent occupation.
What Did the Researchers Do and Find?
Interviewers trained by the researchers conducted the survey between May 2011 and July 2011 and collected data from 2,000 randomly selected households in 100 geographical clusters, distributed across Iraq's 18 governorates. The interviewers asked the head of each household about deaths among household members from 2001 to the time of the interview, including a pre-war period from January 2001 to March 2003 and the period of the war and occupation. They also asked all adults in the household about deaths among their siblings during the same period. From the first set of data, the researchers calculated the crude death rates (i.e., the number of deaths during a year per 1,000 individuals) before and during the war. They found the wartime crude death rate in Iraq to be 4.55 per 1,000, more than 50% higher than the death rate of 2.89 during the two-year period preceding the war. By multiplying those rates by the annual Iraq population, the authors estimate the total excess Iraqi deaths attributable to the war through mid-2011 to be about 405,000. The researchers also estimated that an additional 56,000 deaths were not counted due to migration. Including this number, their final estimate is that approximately half a million people died in Iraq as a result of the war and subsequent occupation from March 2003 to June 2011.
The risk of death at the peak of the conflict in 2006 almost tripled for men and rose by 70% for women. Respondents attributed 20% of household deaths to war-related violence. Violent deaths were attributed primarily to coalition forces (35%) and militia (32%). The majority (63%) of violent deaths were from gunshots. Twelve percent were attributed to car bombs. Based on the responses from adults in the surveyed households who reported on the alive-or-dead status of their siblings, the researchers estimated the total number of deaths among adults aged 15–60 years, from March 2003 to June 2011, to be approximately 376,000; 184,000 of these deaths were attributed to the conflict, and of those, the authors estimate that 132,000 were caused directly by war-related violence.
What Do These Findings Mean?
These findings provide the most up-to-date estimates of the death toll of the Iraq war and subsequent conflict. However, given the difficult circumstances, the estimates are associated with substantial uncertainties. The researchers extrapolated from a small representative sample of households to estimate Iraq's national death toll. In addition, respondents were asked to recall events that occurred up to ten years prior, which can lead to inaccuracies. The researchers also had to rely on outdated census data (the last complete population census in Iraq dates back to 1987) for their overall population figures. Thus, to accompany their estimate of 460,000 excess deaths from March 2003 to mid-2011, the authors used statistical methods to determine the likely range of the true estimate. Based on the statistical methods, the researchers are 95% confident that the true number of excess deaths lies between 48,000 and 751,000—a large range. More than two years past the end of the period covered in this study, the conflict in Iraq is far from over and continues to cost lives at alarming rates. As discussed in an accompanying Perspective by Salman Rawaf, violence and lawlessness continue to the present day. In addition, post-war Iraq has limited capacity to re-establish and maintain its battered public health and safety infrastructure.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001533
This study is further discussed in a PLOS Medicine Perspective by Salman Rawaf.
The Geneva Declaration on Armed Violence and Development website provides information on the global burden of armed violence.
The International Committee of the Red Cross provides information about war and international humanitarian law (in several languages).
Medact, a global health charity, has information on health and conflict.
Columbia University has a program on forced migration and health.
Johns Hopkins University runs the Center for Refugee and Disaster Response.
University of Washington's Health Alliance International website also has information about war and conflict.
doi:10.1371/journal.pmed.1001533
PMCID: PMC3797136  PMID: 24143140
18.  Influence of war on quantitative and qualitative changes in drug-induced mortality in Split-Dalmatia County, Croatia 
Croatian Medical Journal  2011;52(5):629-636.
Aim
To study drug-induced mortality and characteristics of overdose deaths in the war (1991-1995), pre-war (1986-1990), and post-war period (1996-2000) in Split-Dalmatia County.
Methods
We retrospectively searched through Databases of the Department of Forensic Medicine, University Hospital Split, the national register of death records, the archives of the Split-Dalmatia County Police, and the Register of Treated Drug Addicts of the Croatian National Institute of Public Health, covering the period from 1986 to 2000, according to drug poisoning codes IX and X of the International Classification of Diseases. The indicators were statistically analyzed.
Results
There were 146 registered drug-induced deaths, with 136 (93%) deceased being men. The median age of all cases was 27 years (interquartile range 8). Most of them were single (70.6%), unemployed (44.6%), and secondary school graduates (69.2%). In the war period, there were 4.8 times more deaths than in the pre-war period (P = 0.014), and in the post-war period there were 5.2 times more deaths than in the pre-war period (P = 0.008). The most common site of death was the deceased person’s home. The toxicological analyses showed that 59 (61%) deaths were heroin related, alcohol use was found in 62 cases (42.5%), and multi-substance use was found in more than a half of the cases. In 133 (91.1%) cases, deaths were classified as unintentional, whereas 13 (8.9%) were classified as suicides.
Conclusion
The war, along with other risk factors, contributed to unfavorable developments related to drug abuse in Split-Dalmatia County, including the increase in the drug-induced mortality rate.
doi:10.3325/cmj.2011.52.629
PMCID: PMC3195972  PMID: 21990081
19.  Clinical Disorders in a Post War British Cohort Reaching Retirement: Evidence from the First National Birth Cohort Study 
PLoS ONE  2012;7(9):e44857.
Background
The medical needs of older people are growing because the proportion of the older population is increasing and disease boundaries are widening. This study describes the distribution and clustering of 15 common clinical disorders requiring medical treatment or supervision in a representative British cohort approaching retirement, and how health tracked across adulthood.
Methods and Findings
The data come from a cohort of 2661 men and women, 84% of the target sample, followed since birth in England, Scotland and Wales in 1946, and assessed at 60–64 years for: cardio and cerebro-vascular disease, hypertension, raised cholesterol, renal impairment, diabetes, obesity, hypothyroidism, hyperthyroidism, anaemia, respiratory disease, liver disease, psychiatric problems, cancers, atrial fibrillation on ECG and osteoporosis. We calculated the proportions disorder-free, with one or more disorders, and the level of undiagnosed disorders; and how these disorders cluster into latent classes and relate to health assessed at 36 years. Participants had, on average, two disorders (range 0–9); only 15% were disorder-free. The commonest disorders were hypertension (54.3%, 95% CI 51.8%–56.7%), obesity (31.1%, 28.8%–33.5%), raised cholesterol (25.6%, 23.1–28.26%), and diabetes or impaired fasting glucose (25.0%, 22.6–27.5%). A cluster of one in five individuals had a high probability of cardio-metabolic disorders and were twice as likely than others to have been in the poorest health at 36 years. The main limitations are that the native born sample is entirely white, and a combination of clinical assessments and self reports were used.
Conclusions
Most British people reaching retirement already have clinical disorders requiring medical supervision. Widening disease definitions and the move from a disease-based to a risk-based medical model will increase pressure on health services. The promotion of healthy ageing should start earlier in life and consider the individual's ability to adapt to and self manage changes in health.
doi:10.1371/journal.pone.0044857
PMCID: PMC3447001  PMID: 23028647
20.  Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution 
BMJ : British Medical Journal  2002;324(7333):321.
Objectives
To discover whether post-combat syndromes have existed after modern wars and what relation they bear to each other.
Design
Review of medical and military records of servicemen and cluster analysis of symptoms.
Data sources
Records for 1856 veterans randomly selected from war pension files awarded from 1872 and from the Medical Assessment Programme for Gulf war veterans.
Main outcome measures
Characteristic patterns of symptom clusters and their relation to dependent variables including war, diagnosis, predisposing physical illness, and exposure to combat; and servicemen's changing attributions for post-combat disorders.
Results
Three varieties of post-combat disorder were identified—a debility syndrome (associated with the 19th and early 20th centuries), somatic syndrome (related primarily to the first world war), and a neuropsychiatric syndrome (associated with the second world war and the Gulf conflict). The era in which the war occurred was overwhelmingly the best predictor of cluster membership.
Conclusions
All modern wars have been associated with a syndrome characterised by unexplained medical symptoms. The form that these assume, the terms used to describe them, and the explanations offered by servicemen and doctors seem to be influenced by advances in medical science, changes in the nature of warfare, and underlying cultural forces.
What is already known on this topicService in the Gulf war is associated with an increased rate of reported symptoms and worsening subjective healthPost-combat syndromes have been described after most modern conflicts from the US civil war onwardsWhat this study addsThere seems to be no single post-combat syndrome but a number of variations on a themeThe ever changing form of post-combat syndromes seems to be related to advances in medical understanding, the developing nature of warfare, and cultural undercurrentsBecause reported symptoms are subject to bias and changing emphasis related to advances in medical science or the discovery of new diseases, the characterisation of individual syndromes has to be treated with cautionAttributions by servicemen are generally consistent with symptom characteristics, though there seems to be a growing reluctance to consider the stress of military service as a cause
PMCID: PMC65292  PMID: 11834557
21.  Interactions between Non-Physician Clinicians and Industry: A Systematic Review 
PLoS Medicine  2013;10(11):e1001561.
In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.
Please see later in the article for the Editors' Summary
Background
With increasing restrictions placed on physician–industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician–industry interactions in clinical practice.
Methods and Findings
We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry “information,” attended sponsored “education,” and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect “promotion” while benefiting from industry “information.” Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature.
Conclusions
Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling health care goods (including drugs and devices) and services is big business. To maximize the profits they make for their shareholders, companies involved in health care build relationships with physicians by providing information on new drugs, organizing educational meetings, providing samples of their products, giving gifts, and holding sponsored events. These relationships help to keep physicians informed about new developments in health care but also create the potential for causing harm to patients and health care systems. These relationships may, for example, result in increased prescription rates of new, heavily marketed medications, which are often more expensive than their generic counterparts (similar unbranded drugs) and that are more likely to be recalled for safety reasons than long-established drugs. They may also affect the provision of health care services. Industry is providing an increasingly large proportion of routine health care services in many countries, so relationships built up with physicians have the potential to influence the commissioning of the services that are central to the treatment and well-being of patients.
Why Was This Study Done?
As a result of concerns about the tension between industry's need to make profits and the ethics underlying professional practice, restrictions are increasingly being placed on physician–industry interactions. In the US, for example, the Physician Payments Sunshine Act now requires US manufacturers of drugs, devices, and medical supplies that participate in federal health care programs to disclose all payments and gifts made to physicians and teaching hospitals. However, other health professionals, including those with authority to prescribe drugs such as pharmacists, Physician Assistants, and nurse practitioners are not covered by this legislation or by similar legislation in other settings, even though the restructuring of health care to prioritize primary care and multidisciplinary care models means that “non-physician clinicians” are becoming more numerous and more involved in decision-making and medication management. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers examine the nature and implications of the interactions between non-physician clinicians and industry.
What Did the Researchers Do and Find?
The researchers identified 15 published studies that examined interactions between non-physician clinicians (Registered Nurses, nurse prescribers, midwives, pharmacists, Physician Assistants, and dieticians) and industry (corporations that produce health care goods and services). They extracted the data from 16 publications (representing 15 different studies) and synthesized them qualitatively (combined the data and reached word-based, rather than numerical, conclusions) into eight outcome domains, including the nature and frequency of interactions, non-physician clinicians' attitudes toward industry, and the perceived ethical acceptability of interactions. In the research the authors identified, non-physician clinicians reported frequent interactions with the pharmaceutical and infant formula industries. Most non-physician clinicians met industry representatives regularly, received gifts and samples, and attended educational events or received educational materials (some of which they distributed to patients). In these studies, non-physician clinicians generally regarded these interactions positively and felt they were an ethical and appropriate use of industry resources. Only a minority of non-physician clinicians felt that marketing influenced their own practice, although a larger percentage felt that their colleagues would be influenced. A sizeable proportion of non-physician clinicians questioned the reliability of industry information, but most were confident that they could detect biased information and therefore rated this information as reliable, valuable, or useful.
What Do These Findings Mean?
These and other findings suggest that non-physician clinicians generally have positive attitudes toward industry interactions but recognize issues related to bias and conflict of interest. Because these findings are based on a small number of studies, most of which were undertaken in the US, they may not be generalizable to other countries. Moreover, they provide no quantitative assessment of the interaction between non-physician clinicians and industry and no information about whether industry interactions affect patient care outcomes. Nevertheless, these findings suggest that industry interactions are normalized (seen as standard) in clinical practice across non-physician disciplines. This normalization creates the potential for serious risks to patients and health care systems. The researchers suggest that it may be unrealistic to expect that non-physician clinicians can be taught individually how to interact with industry ethically or how to detect and avert bias, particularly given the ubiquitous nature of marketing and promotional materials. Instead, they suggest, the environment in which non-physician clinicians practice should be structured to mitigate the potentially harmful effects of interactions with industry.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001561.
This study is further discussed in a PLOS Medicine Perspective by James S. Yeh and Aaron S. Kesselheim
The American Medical Association provides guidance for physicians on interactions with pharmaceutical industry representatives, information about the Physician Payments Sunshine Act, and a toolkit for preparing Physician Payments Sunshine Act reports
The International Council of Nurses provides some guidance on industry interactions in its position statement on nurse-industry relations
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice website, which describes what is required of all registered doctors in the UK
Understanding and Responding to Pharmaceutical Promotion: A Practical Guide is a manual prepared by Health Action International and the World Health Organization that schools of medicine and pharmacy can use to train students how to recognize and respond to pharmaceutical promotion.
The Institute of Medicine's Report on Conflict of Interest in Medical Research, Education, and Practice recommends steps to identify, limit, and manage conflicts of interest
The University of California, San Francisco, Office of Continuing Medical Education offers a course called Marketing of Medicines
doi:10.1371/journal.pmed.1001561
PMCID: PMC3841103  PMID: 24302892
22.  Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study 
PLoS Medicine  2010;7(11):e1000366.
Using three nationwide databases in France, Ludivine Orriols, Emmanuel Lagarde, and colleagues provide evidence that prescribed medicines contribute to the risk of experiencing a road traffic crash.
Background
In recent decades, increased attention has been focused on the impact of disabilities and medicinal drug use on road safety. The aim of our study was to investigate the association between prescription medicines and the risk of road traffic crashes, and estimate the attributable fraction.
Methods and Findings
We extracted and matched data from three French nationwide databases: the national health care insurance database, police reports, and the national police database of injurious crashes. Drivers identified by their national health care number involved in an injurious crash in France, between July 2005 and May 2008, were included in the study. Medicines were grouped according to the four risk levels of the French classification system (from 0 [no risk] to 3 [high risk]). We included 72,685 drivers involved in injurious crashes. Users of level 2 (odds ratio [OR]  = 1.31 [1.24–1.40]) and level 3 (OR  = 1.25 [1.12–1.40]) prescription medicines were at higher risk of being responsible for a crash. The association remained after adjustment for the presence of a long-term chronic disease. The fraction of road traffic crashes attributable to levels 2 and 3 medications was 3.3% [2.7%–3.9%]. A within-person case-crossover analysis showed that drivers were more likely to be exposed to level 3 medications on the crash day than on a control day, 30 days earlier (OR  = 1.15 [1.05–1.27]).
Conclusion
The use of prescription medicines is associated with a substantial number of road traffic crashes in France. In light of the results, warning messages appear to be relevant for level 2 and 3 medications and questionable for level 1 medications. A follow-up study is needed to evaluate the impact of the warning labeling system on road traffic crash prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
About 1.3 million people die each year on the world's road. 90% of road traffic deaths occur in developing countries, with pedestrians, cyclists, and users of two-wheel vehicles (scooters, motorbikes) the most vulnerable road users. Although the use of prescribed benzodiazepines has already been documented to be associated with road traffic accidents in industrialized countries, the effects of other medicines have not been well studied or have inconsistent results (for example opioids and antidepressant medications). In the European Union, it is mandatory for pharmaceutical companies to provide data about the effect of a medicine on ability to drive. In France, a multidisciplinary group of experts was appointed to classify all medicines into four levels of risk (from level 0, no or negligible risk, to level 3, major risk), in terms of their effect on driving performances. In 2006, the International Council on Alcohol, Drugs and Traffic Safety proposed a classification list similar to the French classification system.
Why Was This Study Done? There is a pressing need to understand the association between prescribed medicines and the risk of road traffic crashes and also to have a more accurate picture of the fraction of road traffic crashes that are attributable to the use of prescribed medicines. This large French study aimed to advance knowledge in this important area.
What Did the Researchers Do and Find? The researchers used three data sources to find the information they needed: the national health care insurance database (which covers the whole French population and includes data on reimbursed prescription medicines), police reports, and the national police database of injurious road traffic crashes. Drivers involved in road traffic crashes (identified by their national healthcare number) between July 2005 and May 2008 were included in the study. The researchers used a statistical model to conduct a responsibility analysis, which determined factors associated with each driver responsible for the road traffic crash and each driver who was not responsible (controls). In addition, the researchers compared medicine exposure during a period immediately before the crash (case period) with exposure during an earlier period (control period) for each driver involved in a crash. The researchers retrieved data on reimbursed medicines, dispensed within six months of the road traffic crash, by linking included drivers to the national health care insurance database using their national ID, gender, and date of birth and grouped all prescribed medicines according to the four risk levels of the French classification system.
During the study period, 72,685 drivers involved in injurious road traffic crashes were included. The researchers found that drivers who had been prescribed level 2 and level 3 medicines were at higher risk (odds ratio 1.31 and OR 1.25, respectively) of being responsible for the road traffic crash, an association that remained after the researchers adjusted for the presence of chronic diseases. Furthermore, the researchers found that the fraction of road traffic crashes attributable to the use of (prescriptions for) level 2 and 3 medicines was 3.3% and that drivers were more likely to be exposed to level 3 medicines on the day of the road traffic crash than on a control day.
What Do These Findings Mean? This study provides strong evidence for the contribution of medicines to the risk of experiencing a road traffic crash. The French drug risk classification scheme seems accurate for medicines classified as levels 2 and 3 of risk for road traffic crashes. The effect on driving abilities of level 2 medicines depends both on the pharmacodynamics of the drug and on individual susceptibility, whereas for level 3 medicines, the pharmacodynamic effect seems to be predominant. The effects of level 1 medicines seem to be so dependent on individual susceptibility that effects on driving abilities are rare, which raises questions about the relevance of the labels for these medicines. However, some limitations with the study methodology might affect the interpretation of these findings. For example, the researchers used dispensing dates for medications as a surrogate for ingestion and were not able to check for noncompliance.
However, this study provides some of the strongest evidence to date of the need for health care workers to provide patients with proper information on the potential effect of any medicine that they are prescribed (or take) on their driving abilities.
Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000366.The World Health Organization (WHO) provides information on road traffic accidentsTwo Web sites provide information for drivers about drugs that could affect their ability to driveThe US National Institute on Drug Abuse of the National Institutes of Health has an information sheet on drugged driving
doi:10.1371/journal.pmed.1000366
PMCID: PMC2981588  PMID: 21125020
23.  Social and environmental factors in lung cancer mortality in post-war Poland. 
Poland and other Eastern European countries have undergone heavy industrial development with marked increases in air pollution and occupational exposure in the nearly 50 years since World War II. These countries have also experienced substantial increases in chronic disease mortality in the past three decades. While it is tempting to assume a direct association between these phenomena, more detailed analyses are called for. Poland offers a potentially rich opportunity for comparing geographical patterns of disease incidence and of industrial change. In this paper we 1) elucidate the prospects for attributing lung cancer mortality to industrial emissions in Poland, using an ecological approach based on the hitherto unaddressed geographic differences, and accounting for regional differences in cigarette consumption; 2) propose explanatory hypotheses for the observed geographic heterogeneity of lung cancer; 3) begin systematic testing of the widely accepted but not well-scrutinized notion that pollution in Poland is a major contributor to declining life expectancy. Regions with the highest fraction of cancer that cannot be explained by smoking appear to be highly urbanized, have high population exposure to occupational carcinogens, experience the highest rates of alcoholism and crime, and are associated with the post- World War II population resettlement. Although the analysis does not rule out pollution as a significant contributor to lung cancer mortality, it indicates that other factors such as occupational exposures and various social factors are of at least comparable importance.(ABSTRACT TRUNCATED AT 250 WORDS)
Images
PMCID: PMC1519032  PMID: 7628428
24.  The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan 
PLoS Medicine  2010;7(5):e1000283.
Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria.
Background
The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection.
Methods and Findings
A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06–0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02–0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15–0.94], p = 0.037).
Conclusions
G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Although Plasmodium falciparum is responsible for most malaria deaths, P. vivax is the commonest, most widespread cause of malaria outside sub-Saharan Africa. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a parasitic form known as sporozoites into people where they replicate inside liver cells without causing symptoms. About 8–9 days later, merozoites (another parasitic form) are released from the liver cells and invade red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. This increase in the parasitic burden causes malaria's characteristic symptoms (debilitating and recurring chills and fevers). P. vivax infections are usually treated with chloroquine (although resistance to this drug is now emerging) but patients must also take primaquine, a drug that kills hypnozoites, a form of P. vivax that hibernates in the liver. Hypnozoites can cause a relapse months after the initial bout of malaria and make P. vivax malaria harder to control than P. faciparum malaria.
Why Was This Study Done?
Some mutations (DNA changes) protect their human carriers against specific disease-causing organisms. These mutations occur at high frequencies in populations where these organisms are common. For example, the widespread distribution of mutations that cause a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) mirrors the distribution of malaria and the African (A−) form of G6PD deficiency, a type of G6PD deficiency that is common in people of African origin, is known to provide partial protection against severe P. falciparum malaria—P. falciparum does not thrive in G6PD-deficient red blood cells. In areas where P. vivax malaria is common, Mediterranean and Asian variants of G6PD deficiency are more widespread than A− G6PD, so the question is, do these variants protect against P. vivax malaria? In this case-control study (a study in which the characteristics of people with and without a specific condition are compared), the researchers investigate whether G6PD deficiency protects against P. vivax infection in a population of Afghan refugees living in Pakistan.
What Did the Researchers Do and Find?
The researchers enrolled 372 Afghan refugees who had had P. vivax malaria during the previous two years and 743 refugees who had not had malaria over the same period. They measured G6PD activity in the participants' blood to detect “phenotypic” G6PD deficiency (reduced enzyme activity) and looked for the Mediterranean variant of the G6PD gene in the participants (“genotypic” G6PD deficiency). 5.7% of the controls but only 1.1% of the cases had phenotypic G6PD deficiency. Statistical analyses indicated that participants with reduced G6PD levels were about one-fifth as likely to develop P. vivax malaria as those with normal G6PD levels after allowing for other factors that might affect their susceptibility to malaria, an adjusted odds ratio (AOR) of 0.18. The genetic analysis indicated that the Mediterranean G6PD gene variant provided protection against P. vivax infection in men (AOR 0.12) and in women carrying either one or two defective copies of the G6PD gene (AOR 0.37); because the G6PD gene is on the X chromosome, men have only one copy of the gene but women have two copies.
What Do These Findings Mean?
These findings indicate that Mediterranean-type G6PD deficiency protects against P. vivax malaria infection in this population of Afghan refugees. Although further studies are needed to determine whether other G6PD variants protect against P. vivax malaria, these findings suggest that P. vivax malaria might be responsible for the retention of the G6PD deficiency trait in some human populations. In addition, these findings may have implications for the treatment of P. vivax malaria. Currently, in most places where P. vivax malaria is common, primaquine is not given routinely because primaquine can trigger red blood cell death (hemolytic anemia) in G6PD-deficient people and tests for G6PD deficiency are rarely available. These findings suggest that the risk of exposure to primaquine among people infected with P. vivax might be lower than previously assumed, because G6PD deficiency is less common among P. vivax-infected patients than among the general population. Nevertheless, these findings are unlikely to increase the use of primaquine immediately. Such an increase, the researchers suggest, will only occur if a simple test for G6PD deficiency is developed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000283.
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Wellcome Trust on all aspects of malaria, including a news item about G6PD deficiency protecting against severe P. falciparum malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
Vivaxmalaria provides information about P. vivax
More about G6PD deficiency can be found on KidsHealth from the Nemours Children's Health System
doi:10.1371/journal.pmed.1000283
PMCID: PMC2876136  PMID: 20520804
25.  Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs 
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases.
Author Summary
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (HsNMT1 and HsNMT2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. We have identified eight series of protozoan NMT inhibitors, six having good selectivity for either Plasmodium or Leishmania NMTs over the other orthologues in this study. We believe that all of these series could form the basis of medicinal chemistry programs to deliver drug candidates against either malaria or leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as the UK Medical Research Council and Wellcome Trust can stimulate research for neglected diseases.
doi:10.1371/journal.pntd.0001625
PMCID: PMC3335879  PMID: 22545171

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