I’ve Got a (lot of) Little (check)lists

PLOS Medicine Editorial Director, Virginia Barbour, reflects on the publication of the CONSORT and PRISMA guidelines and reminds us of the importance of checklists to medical publishing.

Image credit: Oliver Tacke, Flickr.

Image credit: Oliver Tacke, Flickr.

Gilbert and Sullivan’s Lord High Executioner has, sadly given lists a bad name. Rather than tools of revenge, lists in healthcare, however, have the power to do much good. Atul Gawande’s book on lists has explained why they should be core to medical practice. I’d argue that in medical publishing too they are critical.

When Robert Boyle, one of the founders of the UK’s Royal Society, wrote the Spring of the Air he was probably the first to write in such a way that allowed other men (it was only men then of course) to repeat and test his findings.  In this way he was in turn one of the first to legitimize research by making it reproducible.

More than 300 years later we have a fully reproducible literature with everything fully reported, right? Wrong. There is a current crisis of confidence in research, with increasing and appropriate concern that many results, especially the most dramatic, often cannot be trusted. Contributing fundamentally  (but not exclusively, obviously) to this problem is that whole swathes of the medical and scientific literature are not described in sufficient detail that anyone else can even test. In medicine this crisis literally is life threatening; patients given treatments as a result of inadequately described studies may at best be treated sub-optimally, at worst harmed or killed.

However, in one important corner of the research endeavor a group of individuals, have, for many years now, been making a determined effort to change this poor reporting and PLOS Medicine is proud to have played its part in it. The CONSORT reporting guidelines for clinical trials and the PRISMA guidelines for Systematic Reviews and Meta-Analyses are, I’d argue two of the most important papers the journal has ever published. The premise behind both of these documents, and the checklists in them and the many other guidelines that we and other PLOS journals have published is very simple: tell us what you did so others can test it.


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Category: 10th Anniversary | Leave a comment

Voluntary Male Circumcision as HIV Prevention in Africa

PLOS Medicine Associate Editor Linda Nevin discusses the landmark publication, and striking impact, of the first randomized clinical trial of voluntary medical male circumcision, published in PLOS Medicine in 2005.

Image credit: (left) Sgt. Adam Fischman, US Army Africa & (right) Sterling Riber, MFDI for Jhpiego/Tanzania.

Image credit: (left) Sgt. Adam Fischman, US Army Africa & (right) Sterling Riber, MFDI for Jhpiego/Tanzania.

Since the 1980s, observational studies have shown that HIV infection rates in African tribal or ethnic groups that practice male circumcision are lower than rates in groups that do not. HIV protection by male circumcision has biologic plausibility; the removal of the foreskin reduces the covered, moist space in which the virus can incubate after sex. However, because ecological studies can never establish causality, the potential benefits of promoting male circumcision in African communities remained unclear past the year 2000. In 2005, Bertran Auvert and colleagues at the Hôpitaux de Paris, Boulogne, France published the first randomized clinical trial (RCT) of circumcision for HIV prevention, conducted in Orange Farm, a semiurban region close to Johannesburg, South Africa. In this trial, about 3,000 young, heterosexual uncircumcised men were randomly allocated to be circumcised upon enrollment, or 21 months later. In a planned interim analysis 17 months after the study was initiated, the authors observed a striking difference in incidence of HIV infection in the uncircumcised group (49 cases of 1582 participants) compared with the newly circumcised men (20 cases of 1546). The difference represented a statistically significant protection of 60% (95% confidence interval 32%–76%). At the request of the trial’s data and safety monitoring board, the trial was immediately stopped and all interested participants were circumcised.

This was broadly considered a landmark study in the field of HIV research. Its publication initiated robust debate about trial controls, blinding, covariates analyzed, and ethics; the paper has been cited in 998 scientific publications, and collected 99,867 page-views to date. At the time of publication, two other trials– in Kenya and Uganda– were underway, and researchers in the field waited on tenterhooks to see if the Orange Farm RCT results would be corroborated. They were. However, questions remained on the pragmatic front. Would a larger roll-out of a male circumcision program be effective across the diverse communities of Eastern and Southern Africa? Would circumcised men engage in risk compensation, the increase in unsafe behavior due to perceived protection?

Based on trial findings, Auvert and colleagues began a community-wide scale-up of voluntary male circumcision in Orange Farm in 2008. Their results from the 2008-2011 study period, published in PLOS Medicine in 2013, were a second landmark achievement. They observed an increased prevalence of circumcision (from 12% to 53%), a roughly 60% reduction in risk of contracting HIV among circumcised compared to uncircumcised men (consistent with the RCT), and no detectable increase in risky sexual behaviors among circumcised men. Using these numbers, the authors estimated that the VMMC scale-up reduced the 2011 prevalence of HIV in the community from a projected ~15% to ~12%.


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The Truth about Standardized Packaging? Blow Some My Way

PLOS Medicine Associate Editor, Linda Nevin, discusses how a 2014 research article by Selda Ulucanlar and colleagues deconstructed advocacy documents submitted to the UK government by tobacco companies, and catches up with one of the authors for a Q&A.

Image credit: Rachel Chapman, Flickr

Image credit: Rachel Chapman, Flickr

As researchers, what is our duty to respond when corporate interests distort scientific evidence to influence policy? In a 2014 PLOS Medicine research article, Selda Ulucanlar and colleagues from the UK Centre for Alcohol and Tobacco Studies, University of Bath, used the lens of epistemology to search for truth, misleading arguments, and anything in between in expert testimony submitted to the UK government by British American Tobacco (BAT) and Japan Tobacco Inc (JTI). The testimony was submitted in response to a 15-question government survey issued in April 2012, inviting interested citizens, businesses and organisations to comment on a range of health and economic implications of standardised packaging (SP)—the strict specification of visual and physical pack attributes—of tobacco products. In their study, the authors checked the transnational tobacco companies’ (TTC) reference-based claims against the original sources to ascertain preservation of meaning, and assessed the scientific validity of TTC critiques of the evidence on SP. They found that the TTC reports misrepresented the evidence base in three ways: misquoting, mimicked scientific critique, and evidential landscaping (for explanation of these tactics, see the Editor’s Summary).

Much of the transnational tobacco companies’ (TTC’s) testimony was directed toward a seminal and influential paper in the field: Crawford Moodie and colleagues’ systematic review of 37 behavioural studies which, in sum, indicated that SP reduces the attractiveness and appeal of tobacco, increases the noticeability and effectiveness of health messages, and reduces the ability of manufacturers to mislead consumers about harmfulness to health. In the TTC critique of this review and the studies therein, Ulucanlar and colleagues explained, “Individual studies were examined in depth to determine whether any—on its own—constituted a warrant for SP and, following systematic deconstruction, none was found to be good enough to justify SP.” Based on this finding, the authors make an inspiring distinction between scientist and advocate: “In court, each piece of evidence (i.e., each study and the Moodie review) is treated as a separate piece of evidence and each needs to be undermined and discredited in turn until no evidence remains that could damage one’s client’s case. By contrast, in scientific work, it is essential that the extant research is synthesised and greater confidence in the findings established through the cumulative ‘weight of the evidence’.”


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“Pulling Back the Curtain” on Lethal Injection

PLOS Medicine Associate Editor, Thomas McBride, reflects on the 2007 research article that investigated whether lethal injection consistently induces a painless death.

Image credit: Joseph Kranak, Flickr

Image credit: Joseph Kranak, Flickr

The December 7, 1982 execution of Charles Brooks Jr. in Texas marked the first use of lethal injection, conceived as a painless and more “humane” alternative to the electric chair. With the patient laying on a gurney, heart monitored by an ECG and an IV drip in arm, the new procedure certainly looked like a controlled death delivered by medical science. Over the next three decades lethal injection would become the most common form of execution in the United States and worldwide. But when reports of complications arose, the public and lawmakers began to question whether inmates were being forced to needlessly suffer. By 2006, 11 states had suspended executions while they considered changing the protocol. In a 2007 PLOS Medicine research article, Leonidas Koniaris and colleagues asked whether lethal injection truly delivers a consistently painless execution.

The article was an interesting choice for a medical journal. Despite appearances, lethal injection is anything but a controlled medical environment. Ending the life of a physically healthy person against his or her will is antithetical to medicine, which is why the technician who attaches the IV is not a doctor or nurse. The protocol was designed not based on experimental evidence, but the personal experience of Oklahoma state medical examiner Jay Chapman. Academic editor Clifford Woolf recalls the decision to publish was a “tough call, since it could be argued the paper better belonged in journal specializing in ethical or legal issues.” In an Editorial that ran in the same issue, the PLOS Medicine Editors expressed hopes that the data presented in the research article would convince US lawmakers that execution is inhumane.

The topic was also a departure from the norm for Koniaris and his colleagues, primarily cancer researchers. Lead author Teresa Zimmers recalls it was difficult to fit this research around their “day jobs” but that despite the sacrifices, they were “excited to add knowledge about the process and to help shape the debate.”


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Quantifying the Dirty Nature of War

PLOS Medicine Senior Editor, Amy Ross, discusses the potential impact of the “Dirty War Index”, a tool developed by Madelyn Hsiao-Rei Hicks and Michael Spagat, to minimize civilian harm in areas of armed conflict.

Image Credit: valeyoshino, Flickr

While international humanitarian treaties, such as the Geneva Conventions, have sought to limit the barbarity of war over the past century and violence and deaths due to armed conflict have diminished dramatically in the last few generations, political violence within or between countries is still rife in many parts of the world. Media reports on civilian injuries and deaths in areas of armed conflict emerge on what seems to be a daily basis and, with often biased reporting of such events, it can be difficult to identify who is responsible for the worst of these harms. As data on these civilian deaths have become more readily available, a field of research has developed that attempts to quantify the impact of different war tactics on civilian deaths with the ultimate goal to minimize civilian harm.

In December 2008, PLOS Medicine published a Policy Forum by Madelyn Hsiao-Rei Hicks and Michael Spagat proposing a new tool, called the Dirty War Index (DWI), that was developed to systematically identify “rates of particularly undesirable or prohibited, i.e., “dirty,” war outcomes inflicted on populations during armed conflict”.

It uses a fairly basic calculation:

DWI = Number of “dirty,” i.e., undesirable or prohibited cases / Total number of cases × 100

where high DWI values can indicate indiscriminate warfare, especially dangerous weapons, or targeting of civilians.  As one of several examples in the paper, the researchers apply a “child casualty DWI” (Number of child casualties/ Total number of casualties) to weapons-casualty data from Chechnya between 1994 and 2005, to calculate the following ratios for different explosive devices: antitank landmines (34/223, DWI = 15), antipersonnel landmines (223/1,004, DWI = 22), booby traps (65/214, DWI = 30), and other unexploded ordnance (255/892, DWI = 29). They conclude that unexploded ordnance and booby traps are more dangerous to children than landmines in this setting.


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Outing Wyeth and Their Hired Ghosts

Margaret A. Winker, MD, Senior Research Editor for PLOS Medicine, reflects on the 2010 Policy Forum by Adriane Fugh-Berman that explored the medical literature manipulation behind hormone “replacement” therapy.

The results of the Heart Estrogen/progestin Replacement Study (HERS) and Women’s Health Initiative (WHI) randomized trials stand out as two of the most important and surprising findings in the recent medical literature. The trials showed that hormone “replacement” therapy (HT), which was touted to treat estrogen “deficiency” in menopausal women just as thyroxine is used to treat hypothyroidism, not only did not reduce risk of cardiovascular disease but even increased risk of coronary heart disease, breast cancer, stroke, and pulmonary embolism. These remarkable results were both public and personal: an obstetrics-gynecologist friend on vacation when the news broke was flooded with phone calls from patients who feared their increased risk and wanted to stop HT immediately. My mother, who I had strongly encouraged to take HT given its apparent benefits, had just stopped it after developing endometrial hyperplasia.  Of course, until the trials were published the evidence was observational with the known likelihood of confounding, but researchers had tried to control for those issues as best they could and had still found an association. The huge popularity of HT appeared to result from the available evidence, and the steady stream of papers supporting HT for a multitude of diseases including cardiovascular disease, Alzheimer’s disease, and stroke had seemed to indicate consensus around the importance of HT. Or did they?

Image Credit: David Merz, Flickr.

Image Credit: David Merz, Flickr.

The use of medical ghost writers by pharmaceutical companies was well established when Adriane Fugh-Berman’s paper was published in PLOS Medicine and the documents on which it was based posted (here and here). However, her revelations of Wyeth’s promotion of HT, culled from a collection of documents obtained from litigation brought by more than 14,000 plaintiffs who developed breast cancer while taking Prempro and made public when PLOS Medicine  and the New York Times intervened in the litigation, were remarkable for their breadth and impact, shocking even the most cynical reader. Wyeth used several medical writing firms, but one in particular, DesignWrite, developed and implemented a publication plan on behalf of Wyeth to promote “HRT… a drug in search of a disease” for a number of conditions, ultimately publishing four trial reports and 20 review articles, a total of “over 50 peer-reviewed publications, more than 50 scientific abstracts and posters, journal supplements, internal white papers, slide kits, and symposia.”

Fugh-Berman outlines in excruciating detail the lengths to which DesignWrite went to promote Wyeth’s product. Not only were “authors” enlisted to put their names on the ghostwritten pieces but the ghosts were careful to ensure the “authors’” hesitation about the lack of evidence or misleading messages did not undermine the underlying marketing messages. Responses to peer reviewers who challenged the flawed studies being cited implied that such criticisms were inappropriate: “The review of the current paper is not the appropriate place to criticize the methodologic flaws of published papers”, DesignWrite wrote for the authors.


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Category: 10th Anniversary | 1 Comment

PLOS Medicine’s Big Food Series: Shining a Spotlight on Industry’s Influence on Health

PLOS Medicine Deputy Editor, Paul Simpson, reflects on the PLOS Medicine Series on Big Food, which was published in 2012.

‘The Food Industry is Ripe for Scrutiny’ is the clarion call of the lead editorial that announced PLOS Medicine’s Big Food series. The series of eight commissioned articles was the brainchild of PLOS Medicine’s then Senior Magazine Editor, Jocalyn Clark (@jocalynclark), alongside guest editors for the series Marion Nestle (@marionnestle) and David Stuckler (@davidstuckler), and was published over three weeks in June and July 2012.

Image Credit: Todd Hryckowian, Flickr

Image Credit: Todd Hryckowian, Flickr

While the field of medicine has had a long interest in how global corporations influence human health, particularly the tobacco and pharmaceutical industries, the editors were inspired to commission the series because they noted a dearth of critical perspectives in the medical literature on the food industry’s role and competing interests in human health. This seemed especially pertinent as the global health community were and are increasingly focused on the health impact of two billion of the planets population being obese or overweight, while at the same time one billion people on the planet are hungry.

David Stuckler and Marion Nestle’s Essay, Big Food, Food Systems, and Global Health, clearly set the scene for the series by noting that, “food systems are not driven to deliver optimal human diets but to maximize profits.”  They highlighted three positions that public health advocates could adopt in relation to the food industry: The first is to do nothing and let the industry regulate itself; the second is to work in partnership with the industry; and the third is to take the view that there are inherent conflicts of interest between corporations that profit from unhealthy food and public health collaborations. Few in the field of public health would agree that self-regulation is likely to be optimal from a health perspective, others may see some merit in working alongside the food industry but in their essay the authors plant their flag firmly in the ground: “[W]e find no evidence for an alignment of public health interest in curbing obesity with that of the food and beverage industry.”


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Category: 10th Anniversary | 1 Comment

A Little Furry Test for Human Toxicity

PLOS Medicine Associate Editor Laureen Connell discusses a research article from 2014 in which Gary Peltz and colleagues described a new mouse model with a humanized liver that can replicate human-specific toxicity and improve safety of clinical trials.

Image credit: Rama, Wikimedia Commons.

Image credit: Rama, Wikimedia Commons.

In 1993, fialuridine (a nucleoside analogue used to treat hepatitis B virus infection) was tested in humans in a phase II trial after earlier preclinical testing in animals suggested the drug was safe. Some participants had a variety of severe reactions to the drug, including liver failure, lactic acidosis, and steatosis, which led to the death of five participants. Human-specific drug toxicity is a potential problem that requires screening early in drug development.  The development of accurate models in the lab to test drugs for toxicity before serious side effects arise during clinical trials in humans is an important part of developing therapeutics.  Also, more nucleoside analogues are being developed as therapeutics, and therefore improved screening tools are needed for human-specific toxicity. Peltz and colleagues recently explored this problem when they investigated whether testing fialuridine in a new mouse model would have predicted the problems found in humans during clinical trials.

Chimeric TK-NOG mice with humanized livers were generated in 2011 and have been used to predict human-specific drug metabolism and interactions with other drugs. These chimeric TK-NOG mice have been transplanted with human liver cells in order to establish a long-lived mature “human organ.” Previous mouse models used for testing drug toxicity in humans had many limitations and did not accurately predict toxicity in humans. The TK-NOG chimeric mouse was generated by expressing a herpes simplex virus type 1 thymidine kinase (TK) transgene within the liver of a highly immunodeficient mouse strain (NOG).  The mouse’s liver cells expressing the transgene were ablated by exposure to an antiviral drug, allowing transplanted human liver cells to develop into a humanized liver, with a three-dimensional architecture and gene expression pattern characteristic of mature human liver and containing only a small percentage of mouse liver cells.


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Category: 10th Anniversary | 2 Comments

Happy Birthday to PLOS Medicine

On the 10th anniversary of our first issue, the PLOS Medicine Editors reflect on some of our most interesting and influential articles.

Image Credit: Larry Peiperl

Image Credit: Larry Peiperl

This week PLOS Medicine celebrates the 10th anniversary of our first issue. Don’t worry, you don’t need to get us a present. Instead, you can celebrate with us by taking a stroll down memory lane and reading some of the most exciting and interesting articles from the past decade.

We’ve chosen eight articles and one collection that highlight the breadth and influence of PLOS Medicine, from publishing ethics to public health policy to translational medical advances and more.

Starting today and over the next week, Speaking of Medicine will be publishing posts written by the editors of PLOS Medicine explaining what each article is about, what makes it exciting and important, and reflecting on its influence on the field since it was published.

Post 1 of 8:

A little furry test for human toxicity” by Laureen Connell, about Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing the 2014 translational study in which Gary Peltz and colleagues described how a new mouse model with a humanized liver can replicate human-specific toxicity and improve safety of clinical trials.

Post 2 of 8:

PLOS Medicine’s Big Food Series: Shining a Spotlight on Industry’s Influence on Health” by Paul Simpson, about the series of eight commissioned articles that considered the various ways food corporations influence global human health.

Post 3 of 8:

Outing Wyeth and Their Hired Ghosts” by Margaret Winker, about The Haunting of Medical Journals: How Ghostwriting Sold “HRT”, Adriane Fugh-Berman’s 2010 Policy Forum that explored a pharmaceutical company’s manipulation of the medical literature to promote a product.

Post 4 of 8:

Quantifying the dirty nature of war” by Amy Ross, about The Dirty War Index: A Public Health and Human Rights Tool for Examining and Monitoring Armed Conflict Outcomes, Madelyn Hsiao-Rei Hicks and Michael Spagat’s 2008 Policy Forum that proposed a new tool to quantify the harm done by certain weapons and warfare tactics on civilians.

Post 5 of 8:

Pulling back the curtain on lethal injection” by Thomas McBride, about Lethal Injection for Execution: Chemical Asphyxiation? the 2007 research article by Leonidas Koniaris and colleagues that investigated whether lethal injection actually produces a consistently painless death.

Post 6 of 8:

The truth about standardized packaging? Blow some my way” by Linda Nevin, about Representation and Misrepresentation of Scientific Evidence in Contemporary Tobacco Regulation: A Review of Tobacco Industry Submissions to the UK Government Consultation on Standardised Packaging, in which Selda Ulucanlar and colleagues deconstructed advocacy documents submitted to the UK and demonstrated a meaningful distinction between scientist and advocate.

Post 7 of 8:

Voluntary Male Circumcision as HIV Prevention in Africa” by Linda Nevin, about the first randomized controlled trial of voluntary medical male circumcision.

Post 8 of 8:

I’ve got a (lot of) little (check)lists” by Virginia Barbour, about CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials and Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. This pair of guidelines, published in 2009 and 2010, presented medical researchers and publishers with standards for reporting to improve the way we read, assess, test, and reproduce science.

 

Category: 10th Anniversary | 1 Comment

Improving the health of pre-adolescent children: The latest update to the Pediatric Medicine Collection

In celebration of PLOS Medicine’s 10th birthday, we announce an exciting update to the Pediatric Medicine Collection, highlighting new articles focusing on the health needs of 5 to 10 year old children globally.

In January 2014 PLOS Medicine launched a call requesting papers on the Health of Pre-Adolescent Children, and in light of PLOS Medicine’s own 10 year anniversary, the theme of the call was chosen with the aim to contribute to a better understanding of children who live beyond their 5th birthday but aren’t yet at adolescence. This resulting collection has brought together a broad range of research and commentary.

pediatric_medicineFeatured work in this latest update

Authors Angela Donin and colleagues invited 9-10 year old children to participate in a study examining risk factors for type 2 diabetes. By measuring the levels of insulin, glucose, and other markers, participants reported how often they ate breakfast. It was concluded that children who ate breakfast infrequently had higher fasting insulin levels and increased insulin resistance than children who ate breakfast every day who displayed a favourable type 2 diabetes profile in comparison.

A recent policy forum by Sumit Gupta and co-authors drew attention to the growing need for national childhood cancer strategies in low- and middle-income countries. Amongst severe resource constraints, deficits in infrastructure and other pressing health needs, pediatric oncology resourcing has yet to be translated through from high-income countries. The authors outline why pediatric cancer should now be considered a global child health priority.

Researchers from New Zealand attempted to evaluate the importance of using hand sanitizer for reducing illness in school children. Following a parallel-group cluster randomised trial across 68 primary schools, Patricia Priest and Joanne E McKenzie and colleagues discovered that the provision of hand sanitizer did not reduce the number of school absences due to a specific illness.

 

Through this collection we hope to provide a broad platform for the dissemination of new high-quality evidence and analysis of conditions that affect pre-adolescent children from around the world.

 

Please visit the collection at: www.ploscollections.org/pediatricmedicine

Or read the Flipboard version: http://flip.it/SzfOB

Category: 10th Anniversary, Collections | 2 Comments