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1.  Towards evidence based medicine for paediatricians 
In order to give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format which has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, through they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching,2 and gaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best quality evidence to answer the question.4 A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as number needed to treat, NNT) books by Sackett5 and Moyer6 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the Instructions for Authors at www.archdischild.com. Three topics are covered in this issue of the journal:
Does neonatal BCG vaccination protect against tuberculous meningitis?
Does dexamethasone reduce the risk of extubation failure in ventilated children?
Should metformin be prescribed to overweight adolescents in whom dietary/behavioural modifications have not helped?
REFERENCES
1. Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2. Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3. Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4. http://cebm.jr2.ox.ac.uk/docs/levels.htm (accessed July 2002).
5. Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
6. Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
How to read your journals
Most people have their journals land, monthly, weekly, or quarterly, on their desk, courtesy of their professional associations. Then they sit, gathering dust and guilt, for a period of time. When the layer of either is too great for comfort (or the desk space is needed for some proper work), the wrapper is removed and the journal scanned. But does how people read reflect their information needs or their entertainment requirements?
It is not uncommon to find people straying from the editorial introduction to the value added sections (like obituaries, Lucina‐like summary pages, and end‐of‐article fillers) rather than face the impenetrable science that sits between them. I think that this is probably unhelpful, and would urge readers to do one more thing before placing the journal in the recycling. Scan the table of contents; if it mentions a systematic review or a randomised trial, then read at least the title and the abstract's conclusions. If you agree, pat yourself warmly on the back for being evidence based and up‐to‐date. If you disagree, ask if it will make any impact on your clinical (or personal) life. If it might, run through the methods and quickly appraise them. Does it supply higher quality evidence than that you already possess? If it does, it's worth reading. If it doesn't, don't bother too much.
There are new innovations which might aid the tedious task of consuming research effort. The on‐line Précis section of the Archives provides a highly readable version of the contents page to whet one's appetite. Finally, it's worth mentioning that evidence based summary materials (like Archimedes, or Journal Watch) are always worth reading—and if you didn't think that you wouldn't be here, would you?
PMCID: PMC2082933
Archimedes; evidence based medicine
2.  Towards evidence‐based medicine for paediatricians 
To give the best care to patients and families, paediatricians need to integrate the highest‐quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence‐based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format that has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, although they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence‐based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching2 and gaining answers.3) A brief report of the search used follows—this has been carried out in a hierarchical way, to search for the best‐quality evidence to answer the question (http://www.cebm.net/levels_of_evidence.asp). A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal and the measures of effect (such as number needed to treat), books by Sackett et al4 and Moyer et al5 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Electronic‐only topics that have been published on the BestBets site (www.bestbets.org) and may be of interest to paediatricians include:
Are meningeal irritation signs reliable in diagnosing meningitis in children?
Is immobilisation effective in Osgood‐Schlatter's disease?
Do all children presenting to the emergency department with a needlestick injury require PEP for HIV to reduce HIV transmission?
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still has not been answered, feel free to submit your summary according to the Instructions for Authors at www.archdischild.com. Three topics are covered in this issue of the journal.
Is lumbar puncture necessary for evaluation of early neonatal sepsis?
Does the use of calamine or antihistamine provide symptomatic relief from pruritus in children with varicella zoster infection?
Is supplementary iron useful when preterm infants are treated with erythropoietin?
Is more research needed?
“More research is needed” is a phrase you might have read before. But is more research really needed? Two situations are offered to us in Archimedes this month where clinical questions are, as yet, unanswered. Is iron supplementation really necessary for premature infants treated with erythropoietin, and do antihistamines and calamine lotion help in children with chicken pox? How can we decide if these questions really do “need” research? It may be worth thinking of how likely benefits and harms may be, what the importance of these outcomes are and finally, how much would you consider reasonable to pay for the answer? For example, what chance is there that antihistamines work in chickenpox? What is the chance that side effects will occur? What is the relative severity of side effects versus the delight of being itch free? If we pay for research and spend hours and hours of time pressing through the increasing regulatory frameworks for clinical trials to define the answer to this question, what will be the opportunity cost? What would we fail to do by looking at this? The same questions can be asked of iron supplementation in premature infants, the salvage treatment of relapsing systemic histocytosis or the promotion of car‐seat use in low‐income families. Such value judgements are important; they will have different answers from different perspectives; they will be subject to political influences from pressure groups; being aware of them might stop us from frequently expounding “more research is needed”.
References
1Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
5Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
doi:10.1136/adc.2006.105379
PMCID: PMC2083019
3.  Predicting Outcome after Traumatic Brain Injury: Development and International Validation of Prognostic Scores Based on Admission Characteristics 
PLoS Medicine  2008;5(8):e165.
Background
Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors.
Methods and Findings
Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial.
Conclusions
Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.
Ewout Steyerberg and colleagues describe a prognostic model for the prediction of outcome of traumatic brain injury using data available on admission.
Editors' Summary
Background.
Traumatic brain injury (TBI) causes a large amount of morbidity and mortality worldwide. According to the Centers for Disease Control, for example, about 1.4 million Americans will sustain a TBI—a head injury—each year. Of these, 1.1 million will be treated and released from an emergency department, 235,000 will be hospitalized, and 50,000 will die. The burden of disease is much higher in the developing world, where the causes of TBI such as traffic accidents occur at higher rates and treatment may be less available.
Why Was This Study Done?
Given the resources required to treat TBI, a very useful research tool would be the ability to accurately predict on admission to hospital what the outcome of a given injury might be. Currently, scores such as the Glasgow Coma Scale are useful to predict outcome 24 h after the injury but not before.
Prognostic models are useful for several reasons. Clinically, they help doctors and patients make decisions about treatment. They are also useful in research studies that compare outcomes in different groups of patients and when planning randomized controlled trials. The study presented here is one of a number of analyses done by the IMPACT research group over the past several years using a large database that includes data from eight randomized controlled trials and three observational studies conducted between 1984 and 1997. There are other ongoing studies that also seek to develop new prognostic models; one such recent study was published in BMJ by a group involving the lead author of the PLoS Medicine paper described here.
What Did the Researchers Do and Find?
The authors analyzed data that had been collected prospectively on individual patients from the 11 studies included in the database and derived models to predict mortality and unfavorable outcome at 6 mo after injury for the 8,509 patients with severe or moderate TBI. They found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and characteristics on the CT scan, including the presence of traumatic subarachnoid hemorrhage. A core prognostic model could be derived from the combination of age, motor score, and pupillary reactivity. A better score could be obtained by adding CT characteristics, secondary problems (hypotension and hypoxia), and laboratory measurements of glucose and hemoglobin. The scores were then tested to see how well they predicted outcome in a different group of patients—6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial.
What Do These Findings Mean?
In this paper the authors show that it is possible to produce prognostic models using characteristics collected on admission as part of routine care that can discriminate between patients with good and poor outcomes 6 mo after TBI, especially if the results from CT scans and laboratory findings are added to basic models. This paper has to be considered together with other studies, especially the paper mentioned above, which was recently published in the BMJ (MRC CRASH Trial Collaborators [2008] Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 336: 425–429.). The BMJ study presented a set of similar, but subtly different models, with specific focus on patients in developing countries; in that case, the patients in the CRASH trial were used to produce the models, and the patients in the IMPACT database were used to verify one variant of the models. Unfortunately this related paper was not disclosed to us during the initial review process; however, during PLoS Medicine's subsequent consideration of this manuscript we learned of it. After discussion with the reviewers, we took the decision that the models described in the PLoS Medicine paper are sufficiently different from those reported in the other paper and as such proceeded with publication of the paper. Ideally, however, these two sets of models would have been reviewed and published side by side, so that readers could easily evaluate the respective merits and value of the two different sets of models in the light of each other. The two sets of models are, however, discussed in a Perspective article also published in PLoS Medicine (see below).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050165.
This paper and the BMJ paper mentioned above are discussed further in a PLoS Medicine Perspective article by Andrews and Young
The TBI Impact site provides a tool to calculate the scores described in this paper
The CRASH trial, which is used to validate the scores mentioned here, has a Web site explaining the trial and its results
The R software, which was used for the prognostic analyses, is freely available
The MedlinePlus encyclopedia has information on head injury
The WHO site on neurotrauma discusses head injury from a global perspective
The CDC's National Center for Injury Prevention and Control gives statistics on head injury in the US and advice on prevention
doi:10.1371/journal.pmed.0050165
PMCID: PMC2494563  PMID: 18684008
4.  Towards evidence based medicine for paediatricians 
In order to give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence‐based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format which has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, though they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence‐based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching2 and gaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best‐quality evidence to answer the question. (http://www.cebm.net). A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as number needed to treat), books by Sackett et al4 and Moyer et al5 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Electronic‐only topics that have been published on the BestBets site (www.bestbets.org) and may be of interest to paediatricians include:
When is a second course of indomethacin effective for PDA in neonates?
Does delayed cord clamping prevent sepsis?
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the Instructions for Authors at www.archdischild.com. Three topics are covered in this issue of the journal:
In children aged <3 years does procalcitonin help exclude serious bacterial infection in fever without focus?
Does avoidance of breast feeding reduce mother‐to‐infant transmission of hepatitis C virus infection?
Should children under treatment for juvenile idiopathic arthritis receive flu vaccination?
CAN gambling with other people's children
When we use tests to “rule out” a condition, we generally accept that we are left with a small risk of being wrong. (I think we have all discharged a child with an “upper respiratory tract infection” on a Friday to be greeted with them on antibiotics for pneumonia the following Monday.) How much faith we place in a test result is a product of two things: our initial assumption about the likelihood of the diagnosis (pretest probability) and our opinion as to how effective the test is (accuracy), but our actions do not just reflect these factors.
For instance, a well, afebrile child with a scattering of petechiae over its wrist 8 hours before, is unlikely to have meningococcal disease. If you perform a couple of tests, you can find that it has a low C‐reactive protein and a normal full blood count. What we do with this varies widely; some people would treat this with 48 h of antibiotics, others would discharge the patient home.
It is interesting to reflect on two things: first, what chance of meningococcal disease would you put on this clinical picture (before the test), and what about with the test results? What about your colleagues? You may be surprised by how widely this varies. Second, even those who have the same estimates of risk of disease may have different preferred actions (depending on their attitude to risk).
In looking at the diagnostic test for the ruling out of a disease, we can make our arguments more useful by having some data on the assumptions we make, and then transparently discussing our attitudes to risk. It is only after doing this that we can really decide if a test is good enough for us, regardless of how accurate it might be.
References
1Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
5Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health. Issue 1. London: BMJ Books, 2000.
PMCID: PMC2083694  PMID: 17376947
5.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Background
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Conclusion
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000286.
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
doi:10.1371/journal.pmed.1000286
PMCID: PMC2879408  PMID: 20532236
6.  Epidemiology and Reporting Characteristics of Systematic Reviews 
PLoS Medicine  2007;4(3):e78.
Background
Systematic reviews (SRs) have become increasingly popular to a wide range of stakeholders. We set out to capture a representative cross-sectional sample of published SRs and examine them in terms of a broad range of epidemiological, descriptive, and reporting characteristics, including emerging aspects not previously examined.
Methods and Findings
We searched Medline for SRs indexed during November 2004 and written in English. Citations were screened and those meeting our inclusion criteria were retained. Data were collected using a 51-item data collection form designed to assess the epidemiological and reporting details and the bias-related aspects of the reviews. The data were analyzed descriptively. In total 300 SRs were identified, suggesting a current annual publication rate of about 2,500, involving more than 33,700 separate studies including one-third of a million participants. The majority (272 [90.7%]) of SRs were reported in specialty journals. Most reviews (213 [71.0%]) were categorized as therapeutic, and included a median of 16 studies involving 1,112 participants. Funding sources were not reported in more than one-third (122 [40.7%]) of the reviews. Reviews typically searched a median of three electronic databases and two other sources, although only about two-thirds (208 [69.3%]) of them reported the years searched. Most (197/295 [66.8%]) reviews reported information about quality assessment, while few (68/294 [23.1%]) reported assessing for publication bias. A little over half (161/300 [53.7%]) of the SRs reported combining their results statistically, of which most (147/161 [91.3%]) assessed for consistency across studies. Few (53 [17.7%]) SRs reported being updates of previously completed reviews. No review had a registration number. Only half (150 [50.0%]) of the reviews used the term “systematic review” or “meta-analysis” in the title or abstract. There were large differences between Cochrane reviews and non-Cochrane reviews in the quality of reporting several characteristics.
Conclusions
SRs are now produced in large numbers, and our data suggest that the quality of their reporting is inconsistent. This situation might be improved if more widely agreed upon evidence-based reporting guidelines were endorsed and adhered to by authors and journals. These results substantiate the view that readers should not accept SRs uncritically.
Data were collected on the epidemiological, descriptive, and reporting characteristics of recent systematic reviews. A descriptive analysis found inconsistencies in the quality of reporting.
Editors' Summary
Background.
In health care it is important to assess all the evidence available about what causes a disease or the best way to prevent, diagnose, or treat it. Decisions should not be made simply on the basis of—for example—the latest or biggest research study, but after a full consideration of the findings from all the research of good quality that has so far been conducted on the issue in question. This approach is known as “evidence-based medicine” (EBM). A report that is based on a search for studies addressing a clearly defined question, a quality assessment of the studies found, and a synthesis of the research findings, is known as a systematic review (SR). Conducting an SR is itself regarded as a research project and the methods involved can be quite complex. In particular, as with other forms of research, it is important to do everything possible to reduce bias. The leading role in developing the SR concept and the methods that should be used has been played by an international network called the Cochrane Collaboration (see “Additional Information” below), which was launched in 1992. However, SRs are now becoming commonplace. Many articles published in journals and elsewhere are described as being systematic reviews.
Why Was This Study Done?
Since systematic reviews are claimed to be the best source of evidence, it is important that they should be well conducted and that bias should not have influenced the conclusions drawn in the review. Just because the authors of a paper that discusses evidence on a particular topic claim that they have done their review “systematically,” it does not guarantee that their methods have been sound and that their report is of good quality. However, if they have reported details of their methods, then it can help users of the review decide whether they are looking at a review with conclusions they can rely on. The authors of this PLoS Medicine article wanted to find out how many SRs are now being published, where they are being published, and what questions they are addressing. They also wanted to see how well the methods of SRs are being reported.
What Did the Researchers Do and Find?
They picked one month and looked for all the SRs added to the main list of medical literature in that month. They found 300, on a range of topics and in a variety of medical journals. They estimate that about 20% of reviews appearing each year are published by the Cochrane Collaboration. They found many cases in which important aspects of the methods used were not reported. For example, about a third of the SRs did not report how (if at all) the quality of the studies found in the search had been assessed. An important assessment, which analyzes for “publication bias,” was reported as having been done in only about a quarter of the cases. Most of the reporting failures were in the “non-Cochrane” reviews.
What Do These Findings Mean?
The authors concluded that the standards of reporting of SRs vary widely and that readers should, therefore, not accept the conclusions of SRs uncritically. To improve this situation, they urge that guidelines be drawn up regarding how SRs are reported. The writers of SRs and also the journals that publish them should follow these guidelines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040078.
An editorial discussing this research article and its relevance to medical publishing appears in the same issue of PLoS Medicine
A good source of information on the evidence-based approach to medicine is the James Lind Library
The Web site of the Cochrane Collaboration is a good source of information on systematic reviews. In particular there is a newcomers' guide and information for health care “consumers”. From this Web site, it is also possible to see summaries of the SRs published by the Cochrane Collaboration (readers in some countries can also view the complete SRs free of charge)
Information on the practice of evidence-based medicine is available from the US Agency for Healthcare Research and Quality and the Canadian Agency for Drugs and Technologies in Health
doi:10.1371/journal.pmed.0040078
PMCID: PMC1831728  PMID: 17388659
7.  Reporting Guidelines for Survey Research: An Analysis of Published Guidance and Reporting Practices 
PLoS Medicine  2011;8(8):e1001069.
Carol Bennett and colleagues review the evidence and find that there is limited guidance and no consensus on the optimal reporting of survey research.
Background
Research needs to be reported transparently so readers can critically assess the strengths and weaknesses of the design, conduct, and analysis of studies. Reporting guidelines have been developed to inform reporting for a variety of study designs. The objective of this study was to identify whether there is a need to develop a reporting guideline for survey research.
Methods and Findings
We conducted a three-part project: (1) a systematic review of the literature (including “Instructions to Authors” from the top five journals of 33 medical specialties and top 15 general and internal medicine journals) to identify guidance for reporting survey research; (2) a systematic review of evidence on the quality of reporting of surveys; and (3) a review of reporting of key quality criteria for survey research in 117 recently published reports of self-administered surveys. Fewer than 7% of medical journals (n = 165) provided guidance to authors on survey research despite a majority having published survey-based studies in recent years. We identified four published checklists for conducting or reporting survey research, none of which were validated. We identified eight previous reviews of survey reporting quality, which focused on issues of non-response and accessibility of questionnaires. Our own review of 117 published survey studies revealed that many items were poorly reported: few studies provided the survey or core questions (35%), reported the validity or reliability of the instrument (19%), defined the response rate (25%), discussed the representativeness of the sample (11%), or identified how missing data were handled (11%).
Conclusions
There is limited guidance and no consensus regarding the optimal reporting of survey research. The majority of key reporting criteria are poorly reported in peer-reviewed survey research articles. Our findings highlight the need for clear and consistent reporting guidelines specific to survey research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Surveys, or questionnaires, are an essential component of many types of research, including health, and usually gather information by asking a sample of people questions on a specific topic and then generalizing the results to a larger population. Surveys are especially important when addressing topics that are difficult to assess using other approaches and usually rely on self reporting, for example self-reported behaviors, such as eating habits, satisfaction, beliefs, knowledge, attitudes, opinions. However, the methods used in conducting survey research can significantly affect the reliability, validity, and generalizability of study results, and without clear reporting of the methods used in surveys, it is difficult or impossible to assess these characteristics and therefore to have confidence in the findings.
Why Was This Study Done?
This uncertainty in other forms of research has given rise to Reporting Guidelines—evidence-based, validated tools that aim to improve the reporting quality of health research. The STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) Statement includes cross-sectional studies, which often involve surveys. But not all surveys are epidemiological, and STROBE does not include methods' and results' reporting characteristics that are unique to surveys. Therefore, the researchers conducted this study to help determine whether there is a need for a reporting guideline for health survey research.
What Did the Researchers Do and Find?
The researchers identified any previous relevant guidance for survey research, and any evidence on the quality of reporting of survey research, by: reviewing current guidance for reporting survey research in the “Instructions to Authors” of leading medical journals and in published literature; conducting a systematic review of evidence on the quality of reporting of surveys; identifying key quality criteria for the conduct of survey research; and finally, reviewing how these criteria are currently reported by conducting a review of recently published reports of self-administered surveys.
The researchers found that 154 of the 165 journals searched (93.3%) did not provide any guidance on survey reporting, even though the majority (81.8%) have published survey research. Only three of the 11 journals that provided some guidance gave more than one directive or statement. Five papers and one Internet site provided guidance on the reporting of survey research, but none used validated measures or explicit methods for development. The researchers identified eight papers that addressed the quality of reporting of some aspect of survey research: the reporting of response rates; the reporting of non-response analyses in survey research; and the degree to which authors make their survey instrument available to readers. In their review of 117 published survey studies, the researchers found that many items were poorly reported: few studies provided the survey or core questions (35%), reported the validity or reliability of the instrument (19%), discussed the representativeness of the sample (11%), or identified how missing data were handled (11%). Furthermore, (88 [75%]) did not include any information on consent procedures for research participants, and one-third (40 [34%]) of papers did not report whether the study had received research ethics board review.
What Do These Findings Mean?
Overall, these results show that guidance is limited and consensus lacking about the optimal reporting of survey research, and they highlight the need for a well-developed reporting guideline specifically for survey research—possibly an extension of the guideline for observational studies in epidemiology (STROBE)—that will provide the structure to ensure more complete reporting and allow clearer review and interpretation of the results from surveys.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001069.
More than 100 reporting guidelines covering a broad spectrum of research types are indexed on the EQUATOR Networks web site
More information about STROBE is available on the STROBE Statement web site
doi:10.1371/journal.pmed.1001069
PMCID: PMC3149080  PMID: 21829330
8.  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
9.  Patient-Safety-Related Hospital Deaths in England: Thematic Analysis of Incidents Reported to a National Database, 2010–2012 
PLoS Medicine  2014;11(6):e1001667.
Sukhmeet Panesar and colleagues classified reports of patient-safety-related hospital deaths in England to identify patterns of cases where improvements might be possible.
Please see later in the article for the Editors' Summary
Background
Hospital mortality is increasingly being regarded as a key indicator of patient safety, yet methodologies for assessing mortality are frequently contested and seldom point directly to areas of risk and solutions. The aim of our study was to classify reports of deaths due to unsafe care into broad areas of systemic failure capable of being addressed by stronger policies, procedures, and practices. The deaths were reported to a patient safety incident reporting system after mandatory reporting of such incidents was introduced.
Methods and Findings
The UK National Health Service database was searched for incidents resulting in a reported death of an adult over the period of the study. The study population comprised 2,010 incidents involving patients aged 16 y and over in acute hospital settings. Each incident report was reviewed by two of the authors, and, by scrutinising the structured information together with the free text, a main reason for the harm was identified and recorded as one of 18 incident types. These incident types were then aggregated into six areas of apparent systemic failure: mismanagement of deterioration (35%), failure of prevention (26%), deficient checking and oversight (11%), dysfunctional patient flow (10%), equipment-related errors (6%), and other (12%). The most common incident types were failure to act on or recognise deterioration (23%), inpatient falls (10%), healthcare-associated infections (10%), unexpected per-operative death (6%), and poor or inadequate handover (5%). Analysis of these 2,010 fatal incidents reveals patterns of issues that point to actionable areas for improvement.
Conclusions
Our approach demonstrates the potential utility of patient safety incident reports in identifying areas of service failure and highlights opportunities for corrective action to save lives.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Being admitted to the hospital is worrying for patients and for their relatives. Will the patient recover or die in the hospital? Some seriously ill patients will inevitably die, but in an ideal world, no one should die in the hospital because of inadequate or unsafe care (an avoidable death). No one should die, for example, because healthcare professionals fail to act on signs that indicate a decline in a patient's clinical condition. Hospital mortality (death) is often regarded as a key indicator of patient safety in hospitals, and death rate indicators such as the “hospital standardized mortality ratio” (the ratio of the actual number of acute in-hospital deaths to the expected number of in-hospital deaths) are widely used to monitor and improve hospital safety standards. In England, for example, a 2012 report that included this measure as an indicator of hospital performance led to headlines of “worryingly high” hospital death rates and to a review of the quality of care in the hospitals with the highest death rates.
Why Was This Study Done?
Hospital standardized mortality ratios and other measures of in-patient mortality can be misleading because they can, for example, reflect the burden of disease near the hospital rather than the hospital's quality of care or safety levels. Moreover, comparative data on hospital mortality rates are of limited value in identifying areas of risk to patients or solutions to the problem of avoidable deaths. In this study, to identify areas of service failure amenable to improvement through strengthened clinical policies, procedures, and practices, the researchers undertake a thematic analysis of deaths in hospitals in England that were reported by healthcare staff to a mandatory patient-safety-related incident reporting system. Since 2004, staff in the UK National Health Service (the NHS comprises the publicly funded healthcare systems in England, Scotland, Wales, and Northern Ireland) have been encouraged to report any unintended or unexpected incident in which they believe a patient's safety was compromised. Since June 2010, it has been mandatory for staff in England and Wales to report deaths due to patient-safety-related incidents. A thematic analysis examines patterns (“themes”) within nonnumerical (qualitative) data.
What Did the Researchers Do and Find?
By searching the NHS database of patient-safety-related incidents, the researchers identified 2010 incidents that occurred between 1 June 2010 and 31 October 2012 that resulted in the death of adult patients in acute hospital settings. By scrutinizing the structured information in each incident report and the associated free text in which the reporter described what happened and why they think it happened, the researchers classified the reports into 18 incident categories. These categories fell into six broad areas of systemic failure—mismanagement of deterioration (35% of incidents), failure of prevention (26%), deficient checking and oversight (11%), dysfunctional patient flow (10%), equipment-related errors (6%), and other (12%, incidents where the problem underlying death was unclear). Management of deterioration, for example, included the incident categories “failure to act on or recognize deterioration” (23% of reported incidents), “failure to give ordered treatment/support in a timely manner,” and “failure to observe.” Failure of prevention included the incident categories “falls” (10% of reported incidents), “healthcare-associated infections” (also 10% of reported incidents), “pressure sores,” “suicides,” and “deep vein thrombosis/pulmonary embolism.”
What Do These Findings Mean?
Although the accuracy of these findings may be limited by data quality and by other aspects of the study design, they reveal patterns of patient-safety-related deaths in hospitals in England and highlight areas of healthcare that can be targeted for improvement. The finding that the mismanagement of deterioration of acutely ill patients is involved in a third of patient-safety-related deaths identifies an area of particular concern in the NHS and, potentially, in other healthcare systems. One way to reduce deaths associated with the mismanagement of deterioration, suggest the researchers, might be to introduce a standardized early warning score to ensure uniform identification of this population of patients. The researchers also suggest that more effort should be put into designing programs to prevent falls and other incidents and into ensuring that these programs are effectively implemented. More generally, the classification system developed here has the potential to help hospital boards and clinicians identify areas of patient care that require greater scrutiny and intervention and thereby save the lives of many hospital patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001667.
The NHS provides information about patient safety, including a definition of a patient safety incident and information on reporting patient safety incidents
The NHS Choices website includes several “Behind the Headlines” articles that discuss patient safety in hospitals, including an article that discusses the 2012 report of high hospital death rates in England, “Fit for the Future?” and another that discusses the Keogh review of the quality of care in the hospitals with highest death rates
The US Agency for Healthcare Research and Quality provides information on patient safety in the US
Wikipedia has pages on thematic analysis and on patient safety (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001667
PMCID: PMC4068985  PMID: 24959751
10.  Anatomy of the Epidemiological Literature on the 2003 SARS Outbreaks in Hong Kong and Toronto: A Time-Stratified Review 
PLoS Medicine  2010;7(5):e1000272.
Weijia Xing and colleagues reviewed the published epidemiological literature on SARS and show that less than a quarter of papers were published during the epidemic itself, suggesting that the research published lagged substantially behind the need for it.
Background
Outbreaks of emerging infectious diseases, especially those of a global nature, require rapid epidemiological analysis and information dissemination. The final products of those activities usually comprise internal memoranda and briefs within public health authorities and original research published in peer-reviewed journals. Using the 2003 severe acute respiratory syndrome (SARS) epidemic as an example, we conducted a comprehensive time-stratified review of the published literature to describe the different types of epidemiological outputs.
Methods and Findings
We identified and analyzed all published articles on the epidemiology of the SARS outbreak in Hong Kong or Toronto. The analysis was stratified by study design, research domain, data collection, and analytical technique. We compared the SARS-case and matched-control non-SARS articles published according to the timeline of submission, acceptance, and publication. The impact factors of the publishing journals were examined according to the time of publication of SARS articles, and the numbers of citations received by SARS-case and matched-control articles submitted during and after the epidemic were compared. Descriptive, analytical, theoretical, and experimental epidemiology concerned, respectively, 54%, 30%, 11%, and 6% of the studies. Only 22% of the studies were submitted, 8% accepted, and 7% published during the epidemic. The submission-to-acceptance and acceptance-to-publication intervals of the SARS articles submitted during the epidemic period were significantly shorter than the corresponding intervals of matched-control non-SARS articles published in the same journal issues (p<0.001 and p<0.01, respectively). The differences of median submission-to-acceptance intervals and median acceptance-to-publication intervals between SARS articles and their corresponding control articles were 106.5 d (95% confidence interval [CI] 55.0–140.1) and 63.5 d (95% CI 18.0–94.1), respectively. The median numbers of citations of the SARS articles submitted during the epidemic and over the 2 y thereafter were 17 (interquartile range [IQR] 8.0–52.0) and 8 (IQR 3.2–21.8), respectively, significantly higher than the median numbers of control article citations (15, IQR 8.5–16.5, p<0.05, and 7, IQR 3.0–12.0, p<0.01, respectively).
Conclusions
A majority of the epidemiological articles on SARS were submitted after the epidemic had ended, although the corresponding studies had relevance to public health authorities during the epidemic. To minimize the lag between research and the exigency of public health practice in the future, researchers should consider adopting common, predefined protocols and ready-to-use instruments to improve timeliness, and thus, relevance, in addition to standardizing comparability across studies. To facilitate information dissemination, journal managers should reengineer their fast-track channels, which should be adapted to the purpose of an emerging outbreak, taking into account the requirement of high standards of quality for scientific journals and competition with other online resources.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every now and then, a new infectious disease appears in a human population or an old disease becomes much more common or more geographically widespread. Recently, several such “emerging infectious diseases” have become major public health problems. For example, HIV/AIDS, hepatitis C, and severe acute respiratory syndrome (SARS) have all emerged in the past three decades and spread rapidly round the world. When an outbreak (epidemic) of an emerging infectious disease occurs, epidemiologists (scientists who study the causes, distribution, and control of diseases in populations) swing into action, collecting and analyzing data on the new threat to human health. Epidemiological studies are rapidly launched to identify the causative agent of the new disease, to investigate how the disease spreads, to define diagnostic criteria for the disease, to evaluate potential treatments, and to devise ways to control the disease's spread. Public health officials then use the results of these studies to bring the epidemic under control.
Why Was This Study Done?
Clearly, epidemics of emerging infectious diseases can only be controlled rapidly and effectively if the results of epidemiological studies are made widely available in a timely manner. Public health bulletins (for example, the Morbidity and Mortality Weekly Report from the US Centers from Disease Control and Prevention) are an important way of disseminating information as is the publication of original research in peer-reviewed academic journals. But how timely is this second dissemination route? Submission, peer-review, revision, re-review, acceptance, and publication of a piece of academic research can be a long process, the speed of which is affected by the responses of both authors and journals. In this study, the researchers analyze how the results of academic epidemiological research are submitted and published in journals during and after an emerging infectious disease epidemic using the 2003 SARS epidemic as an example. The first case of SARS was identified in Asia in February 2003 and rapidly spread around the world. 8,098 people became ill with SARS and 774 died before the epidemic was halted in July 2003.
What Did the Researchers Do and Find?
The researchers identified more than 300 journal articles covering epidemiological research into the SARS outbreak in Hong Kong, China, and Toronto, Canada (two cities strongly affected by the epidemic) that were published online or in print between January 1, 2003 and July 31, 2007. The researchers' analysis of these articles shows that more than half them were descriptive epidemiological studies, investigations that focused on describing the distribution of SARS; a third were analytical epidemiological studies that tried to discover the cause of SARS. Overall, 22% of the journal articles were submitted for publication during the epidemic. Only 8% of the articles were accepted for publication and only 7% were actually published during the epidemic. The median (average) submission-to-acceptance and acceptance-to-publication intervals for SARS articles submitted during the epidemic were 55 and 77.5 days, respectively, much shorter intervals than those for non-SARS articles published in the same journal issues. After the epidemic was over, the submission-to-acceptance and acceptance-to-publication intervals for SARS articles was similar to that of non-SARS articles.
What Do These Findings Mean?
These findings show that, although the academic response to the SARS epidemic was rapid, most articles on the epidemiology of SARS were published after the epidemic was over even though SARS was a major threat to public health. Possible reasons for this publication delay include the time taken by authors to prepare and undertake their studies, to write and submit their papers, and, possibly, their tendency to first submit their results to high profile journals. The time then taken by journals to review the studies, make decisions about publication, and complete the publication process might also have delayed matters. To minimize future delays in the publication of epidemiological research on emerging infectious diseases, epidemiologists could adopt common, predefined protocols and ready-to-use instruments, which would improve timeliness and ensure comparability across studies, suggest the researchers. Journals, in turn, could improve their fast-track procedures and could consider setting up online sections that could be activated when an emerging infectious disease outbreak occurred. Finally, journals could consider altering their review system to speed up the publication process provided the quality of the final published articles was not compromised.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000272.
The US National Institute of Allergy and Infectious Diseases provides information on emerging infectious diseases
The US Centers for Control and Prevention of Diseases also provides information about emerging infectious diseases, including links to other resources, and information on SARS
Wikipedia has a page on epidemiology (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization has information on SARS (in several languages)
doi:10.1371/journal.pmed.1000272
PMCID: PMC2864302  PMID: 20454570
11.  Methods of Blinding in Reports of Randomized Controlled Trials Assessing Pharmacologic Treatments: A Systematic Review 
PLoS Medicine  2006;3(10):e425.
Background
Blinding is a cornerstone of therapeutic evaluation because lack of blinding can bias treatment effect estimates. An inventory of the blinding methods would help trialists conduct high-quality clinical trials and readers appraise the quality of results of published trials. We aimed to systematically classify and describe methods to establish and maintain blinding of patients and health care providers and methods to obtain blinding of outcome assessors in randomized controlled trials of pharmacologic treatments.
Methods and Findings
We undertook a systematic review of all reports of randomized controlled trials assessing pharmacologic treatments with blinding published in 2004 in high impact-factor journals from Medline and the Cochrane Methodology Register. We used a standardized data collection form to extract data. The blinding methods were classified according to whether they primarily (1) established blinding of patients or health care providers, (2) maintained the blinding of patients or health care providers, and (3) obtained blinding of assessors of the main outcomes. We identified 819 articles, with 472 (58%) describing the method of blinding. Methods to establish blinding of patients and/or health care providers concerned mainly treatments provided in identical form, specific methods to mask some characteristics of the treatments (e.g., added flavor or opaque coverage), or use of double dummy procedures or simulation of an injection. Methods to avoid unblinding of patients and/or health care providers involved use of active placebo, centralized assessment of side effects, patients informed only in part about the potential side effects of each treatment, centralized adapted dosage, or provision of sham results of complementary investigations. The methods reported for blinding outcome assessors mainly relied on a centralized assessment of complementary investigations, clinical examination (i.e., use of video, audiotape, or photography), or adjudication of clinical events.
Conclusions
This review classifies blinding methods and provides a detailed description of methods that could help trialists overcome some barriers to blinding in clinical trials and readers interpret the quality of pharmalogic trials.
Following a systematic review of all reports of randomized controlled trials assessing pharmacologic treatments involving blinding, a classification of blinding methods is proposed.
Editors' Summary
Background.
In evidence-based medicine, good-quality randomized controlled trials are generally considered to be the most reliable source of information about the effects of different treatments, such as drugs. In a randomized trial, patients are assigned to receive one treatment or another by the play of chance. This technique helps makes sure that the two groups of patients receiving the different treatments are equivalent at the start of the trial. Proper randomization also prevents doctors from controlling or affecting which treatment patients get, which could distort the results. An additional tool that is also used to make trials more precise is “blinding.” Blinding involves taking steps to prevent patients, doctors, or other people involved in the trial (e.g., those people recording measurements) from finding out which patients got what treatment. Properly done, blinding should make sure the results of a trial are more accurate. This is because in an unblinded study, participants may respond better if they know they have received a promising new treatment (or worse if they only got placebo or an old drug); doctors may “want” a particular treatment to do better in the trial, and unthinking bias could creep into their measurements or actions; the same applies for practitioners and researchers who record patients' outcomes in the trial. However, blinding is not a simple, single step; the people carrying out the trial often have to set up a variety of different procedures that depend on the type of trial that is being done.
Why Was This Study Done?
The researchers here wanted to thoroughly examine different methods that have been used to achieve blinding in randomized trials of drug treatments, and to describe and classify them. They hoped that a better understanding of the different blinding methods would help people doing trials to design better trials in the future, and also help readers to interpret the quality of trials that had been done.
What Did the Researchers Do and Find?
This group of researchers conducted what is called a “systematic review.” They systematically searched the published medical literature to find all randomized, blinded drug trials published in 2004 in a number of different “high-impact” journals (journals whose articles are often mentioned in other articles). Then, the researchers classified information from the published trial reports. The researchers ended up with 819 trial reports, and nearly 60% of them described how blinding was done. Their classification of blinding was divided up into three main areas. First, they detailed methods used to hide which drugs are given to particular patients, such as preparing identically appearing treatments; using strong flavors to mask taste; matching the colors of pills; using saline injections and so on. Second, they described a number of methods that could be used to reduce the risk of unblinding (of doctors or patients), such as using an “active placebo” (a sugar pill that mimics some of the expected side effects of the drug treatment). Finally, they defined methods for blinded measurement of outcomes (such as using a central committee to collect data).
What Do These Findings Mean?
The researchers' classification will help people to work out how different techniques can be used to achieve, and keep, blinding in a trial. This will assist others to understand whether any particular trial was likely to have been blinded properly, and therefore work out whether the results are reliable. The researchers also suggest that, generally, blinding methods are not described in enough detail in published scientific papers, and recommend that guidelines for describing results of randomized trials be improved.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030425.
James Lind Library has been created to help patients and researchers understand fair tests of treatments in health care by illustrating how fair tests have developed over the centuries
ClinicalTrials.gov, a trial registry created by the US National Institutes of Health, has an introduction to understanding clinical trials
National Electronic Library for Health introduction to controlled clinical trials
doi:10.1371/journal.pmed.0030425
PMCID: PMC1626553  PMID: 17076559
12.  Health-related quality of life in breast cancer patients: A bibliographic review of the literature from 1974 to 2007 
Background
Quality of life in patients with breast cancer is an important outcome. This paper presents an extensive overview on the topic ranging from descriptive findings to clinical trials.
Methods
This was a bibliographic review of the literature covering all full publications that appeared in English language biomedical journals between 1974 and 2007. The search strategy included a combination of key words 'quality of life' and 'breast cancer' or 'breast carcinoma' in titles. A total of 971 citations were identified and after exclusion of duplicates, the abstracts of 606 citations were reviewed. Of these, meetings abstracts, editorials, brief commentaries, letters, errata and dissertation abstracts and papers that appeared online and were indexed ahead of publication were also excluded. The remaining 477 papers were examined. The major findings are summarized and presented under several headings: instruments used, validation studies, measurement issues, surgical treatment, systemic therapies, quality of life as predictor of survival, psychological distress, supportive care, symptoms and sexual functioning.
Results
Instruments-Several valid instruments were used to measure quality of life in breast cancer patients. The European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer specific complementary measure (EORTC QLQ-BR23) and the Functional Assessment Chronic Illness Therapy General questionnaire (FACIT-G) and its breast cancer module (FACIT-B) were found to be the most common and well developed instruments to measure quality of life in breast cancer patients. Surgery-different surgical procedures led to relatively similar results in terms of quality of life assessments, although mastectomy patients compared to conserving surgery patients usually reported a lower body image and sexual functioning. Systemic therapies-almost all studies indicated that breast cancer patients receiving chemotherapy might experience several side-effects and symptoms that negatively affect their quality of life. Adjuvant hormonal therapies also were found to have similar negative impact on quality of life, although in general they were associated with improved survival. Quality of life as predictor of survival-similar to known medical factors, quality of life data in metastatic breast cancer patients was found to be prognostic and predictive of survival time. Psychological distress-anxiety and depression were found to be common among breast cancer patients even years after the disease diagnosis and treatment. Psychological factors also were found to predict subsequent quality of life or even overall survival in breast cancer patients. Supportive care-clinical treatments to control emesis, or interventions such as counseling, providing social support and exercise could improve quality of life. Symptoms-Pain, fatigue, arm morbidity and postmenopausal symptoms were among the most common symptoms reported by breast cancer patients. As recommended, recognition and management of these symptoms is an important issue since such symptoms impair health-related quality of life. Sexual functioning-breast cancer patients especially younger patients suffer from poor sexual functioning that negatively affect quality of life.
Conclusion
There was quite an extensive body of the literature on quality of life in breast cancer patients. These papers have made a considerable contribution to improving breast cancer care, although their exact benefit was hard to define. However, quality of life data provided scientific evidence for clinical decision-making and conveyed helpful information concerning breast cancer patients' experiences during the course of the disease diagnosis, treatment, disease-free survival time, and recurrences; otherwise finding patient-centered solutions for evidence-based selection of optimal treatments, psychosocial interventions, patient-physician communications, allocation of resources, and indicating research priorities were impossible. It seems that more qualitative research is needed for a better understanding of the topic. In addition, issues related to the disease, its treatment side effects and symptoms, and sexual functioning should receive more attention when studying quality of life in breast cancer patients.
doi:10.1186/1756-9966-27-32
PMCID: PMC2543010  PMID: 18759983
13.  Ghost Authorship in Industry-Initiated Randomised Trials 
PLoS Medicine  2007;4(1):e19.
Background
Ghost authorship, the failure to name, as an author, an individual who has made substantial contributions to an article, may result in lack of accountability. The prevalence and nature of ghost authorship in industry-initiated randomised trials is not known.
Methods and Findings
We conducted a cohort study comparing protocols and corresponding publications for industry-initiated trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg in 1994–1995. We defined ghost authorship as present if individuals who wrote the trial protocol, performed the statistical analyses, or wrote the manuscript, were not listed as authors of the publication, or as members of a study group or writing committee, or in an acknowledgment. We identified 44 industry-initiated trials. We did not find any trial protocol or publication that stated explicitly that the clinical study report or the manuscript was to be written or was written by the clinical investigators, and none of the protocols stated that clinical investigators were to be involved with data analysis. We found evidence of ghost authorship for 33 trials (75%; 95% confidence interval 60%–87%). The prevalence of ghost authorship was increased to 91% (40 of 44 articles; 95% confidence interval 78%–98%) when we included cases where a person qualifying for authorship was acknowledged rather than appearing as an author. In 31 trials, the ghost authors we identified were statisticians. It is likely that we have overlooked some ghost authors, as we had very limited information to identify the possible omission of other individuals who would have qualified as authors.
Conclusions
Ghost authorship in industry-initiated trials is very common. Its prevalence could be considerably reduced, and transparency improved, if existing guidelines were followed, and if protocols were publicly available.
Of 44 industry-initiated trials, there was evidence of ghost authorship in 33, increasing to 40 when a person qualifying for authorship was acknowledged rather than appearing as an author.
Editors' Summary
Background.
Original scientific findings are usually published in the form of a “paper”, whether it is actually distributed on paper, or circulated via the internet, as this one is. Papers are normally prepared by a group of researchers who did the research and are then listed at the top of the article. These authors therefore take responsibility for the integrity of the results and interpretation of them. However, many people are worried that sometimes the author list on the paper does not tell the true story of who was involved. In particular, for clinical research, case histories and previous research has suggested that “ghost authorship” is commonplace. Ghost authors are people who were involved in some way in the research study, or writing the paper, but who have been left off the final author list. This might happen because the study “looks” more credible if the true authors (for example, company employees or freelance medical writers) are not revealed. This practice might hide competing interests that readers should be aware of, and has therefore been condemned by academics, groups of editors, and some pharmaceutical companies.
Why Was This Study Done?
This group of researchers wanted to get an idea of how often ghost authorship happened in medical research done by companies. Previous studies looking into this used surveys, whereby the researchers would write to one author on each of a group of papers to ask whether anyone else had been involved in the work but who was not listed on the paper. These sorts of studies typically underestimate the rate of ghost authorship, because the main author might not want to admit what had been going on. However, the researchers here managed to get access to trial protocols (documents setting out the plans for future research studies), which gave them a way to investigate ghost authorship.
What Did the Researchers Do and Find?
In order to investigate the frequency and type of ghost authorship, these researchers identified every trial which was approved between 1994 and 1995 by the ethics committees of Copenhagen and Frederiksberg in Denmark. Then they winnowed this group down to include only the trials that were sponsored by industry (pharmaceutical companies and others), and only those trials that were finished and published. The protocols for each trial were obtained from the ethics committees and the researchers then matched up each protocol with its corresponding paper. Then, they compared names which appeared in the protocol against names appearing on the eventual paper, either on the author list or acknowledged elsewhere in the paper as being involved. The researchers ended up studying 44 trials. For 31 of these (75% of them) they found some evidence of ghost authorship, in that people were identified as having written the protocol or who had been involved in doing statistical analyses or writing the manuscript, but did not end up listed in the manuscript. If the definition of authorship was made narrower, and “ghost authorship” included people qualifying for authorship who were mentioned in the acknowledgements but not the author list, the researchers' estimate went up to 91%, that is 40 of the 44 trials. For most of the trials with missing authors, the ghost was a statistician (the person who analyzes the trial data).
What Do These Findings Mean?
In this study, the researchers found that ghost authorship was very common in papers published in medical journals (this study covered a broad range of peer-reviewed journals in many medical disciplines). The method used in this paper seems more reliable than using surveys to work out how often ghost authorship happens. The researchers aimed to define authorship using the policies set out by a group called the International Committee of Medical Journal Editors (ICMJE), and the findings here suggest that the ICMJE's standards for authorship are very often ignored. This means that people who read the published paper cannot always accurately judge or trust the information presented within it, and competing interests may be hidden. The researchers here suggest that protocols should be made publicly available so that everyone can see what trials are planned and who is involved in conducting them. The findings also suggest that journals should not only list the authors of each paper but describe what each author has done, so that the published information accurately reflects what has been carried out.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040019.
Read the Perspective by Liz Wager, which discusses these findings in more depth
The International Committee of Medical Journal Editors (ICMJE) is a group of general medical journal editors who have produced general guidelines for biomedical manuscripts; their definition of authorship is also described
The Committee on Publication Ethics is a forum for editors of peer-reviewed journals to discuss issues related to the integrity of the scientific record; the Web site lists anonymized problems and the committee's advice, not just regarding authorship, but other types of problems as well
Good Publication Practice for Pharmaceutical Companies outlines common standards for publication of industry-sponsored medical research, and some pharmaceutical companies have agreed to these
doi:10.1371/journal.pmed.0040019
PMCID: PMC1769411  PMID: 17227134
14.  Uncovering Treatment Burden as a Key Concept for Stroke Care: A Systematic Review of Qualitative Research 
PLoS Medicine  2013;10(6):e1001473.
In a systematic review of qualitative research, Katie Gallacher and colleagues examine the evidence related to treatment burden after stroke from the patient perspective.
Please see later in the article for the Editors' Summary
Background
Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.
Methods and Findings
The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.
Conclusions
Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems.
Systematic Review Registration
International Prospective Register of Systematic Reviews CRD42011001123
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the blood supply of the brain is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs that thin the blood, reduce blood pressure and reduce cholesterol (major risk factors for stroke) alongside behavioral counseling can reduce the risk of a second stroke.
Why Was This Study Done?
Treatment for, and rehabilitation from, stroke is a lengthy process that requires considerable personal investment from the patient. The term “treatment burden” describes the self-care practices that patients with stroke and other chronic diseases must perform to follow the complicated management strategies that have been developed for these conditions. Unfortunately, treatment burden can overwhelm patients. They may be unable to cope with the multiple demands placed on them by health-care providers and systems for their self-care, a situation that leads to poor adherence to therapies and poor outcomes. For example, patients may find it hard to complete all the exercises designed to help them regain full movement of their limbs after a stroke. Treatment burden has been poorly examined in relation to stroke. Here, the researchers identify and describe the treatment burden in stroke by undertaking a systematic review (a study that uses predefined criteria to identify all the literature on a given topic) of qualitative studies on the patient experience of stroke management. Qualitative studies collect non-quantitative data so, for example, a qualitative study on stroke treatment might ask people how the treatment made them feel whereas a quantitative study might compare clinical outcomes between those receiving and not receiving the treatment.
What Did the Researchers Do and Find?
The researchers identified 69 qualitative studies dealing with the experiences of stroke management of adult patients and analyzed the data in these papers using framework synthesis—an approach that divides data into thematic categories. Specifically, the researchers used a coding framework informed by normalization process theory, a sociological theory of the implementation, embedding and integration of tasks and practices; embedding is the process of making tasks and practices a routine part of everyday life and integration refers to sustaining these embedded practices. The researchers identified four main areas of treatment burden for stroke: making sense of stroke management and planning care; interacting with others, including health care professionals, family and other patients with stroke; enacting management strategies (including enduring institutional admissions, managing stroke in the community, reintegrating into society and adjusting to life after stroke); and reflecting on management to make decisions about self-care. Moreover, they identified problems in all these areas, including inadequate provision of information, poor communication with health-care providers, and unsatisfactory inpatient care.
What Do These Findings Mean?
These findings show that stroke management is extremely demanding for patients and is influenced by both the micro and macro organization of health services. At the micro organizational level, fragmented care and poor communication between patients and clinicians and between health-care providers can mean patients are ill equipped to organize their care and develop coping strategies, which makes adherence to management strategies less likely. At the macro organizational level, it can be hard for patients to obtain the practical and financial help they need to manage their stroke in the community. Overall, these findings suggest that care provision for stroke needs to be transformed so that the needs of patients rather than the needs of health-care systems are prioritized. Further work is required, however, to understand how the patient experience of treatment burden is affected by the clinical characteristics of stroke, by disability level, and by other co-existing diseases. By undertaking such work, it should be possible to generate a patient-reported outcome measure of treatment burden that, if used by policy makers and health-care providers, has the potential to improve the quality of stroke care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001473.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
Wikipedia provides information on the burden of treatment and on the normalization process theory (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001473
PMCID: PMC3692487  PMID: 23824703
15.  The Relationship of Previous Training and Experience of Journal Peer Reviewers to Subsequent Review Quality 
PLoS Medicine  2007;4(1):e40.
Background
Peer review is considered crucial to the selection and publication of quality science, but very little is known about the previous experiences and training that might identify high-quality peer reviewers. The reviewer selection processes of most journals, and thus the qualifications of their reviewers, are ill defined. More objective selection of peer reviewers might improve the journal peer review process and thus the quality of published science.
Methods and Findings
306 experienced reviewers (71% of all those associated with a specialty journal) completed a survey of past training and experiences postulated to improve peer review skills. Reviewers performed 2,856 reviews of 1,484 separate manuscripts during a four-year study period, all prospectively rated on a standardized quality scale by editors. Multivariable analysis revealed that most variables, including academic rank, formal training in critical appraisal or statistics, or status as principal investigator of a grant, failed to predict performance of higher-quality reviews. The only significant predictors of quality were working in a university-operated hospital versus other teaching environment and relative youth (under ten years of experience after finishing training). Being on an editorial board and doing formal grant (study section) review were each predictors for only one of our two comparisons. However, the predictive power of all variables was weak.
Conclusions
Our study confirms that there are no easily identifiable types of formal training or experience that predict reviewer performance. Skill in scientific peer review may be as ill defined and hard to impart as is “common sense.” Without a better understanding of those skills, it seems unlikely journals and editors will be successful in systematically improving their selection of reviewers. This inability to predict performance makes it imperative that all but the smallest journals implement routine review ratings systems to routinely monitor the quality of their reviews (and thus the quality of the science they publish).
A survey of experienced reviewers, asked about training they had received in peer review, found there are no easily identifiable types of formal training and experience that predict reviewer performance.
Editors' Summary
Background.
When medical researchers have concluded their research and written it up, the next step is to get it published as an article in a journal, so that the findings can be circulated widely. These published findings help determine subsequent research and clinical use. The editors of reputable journals, including PLoS Medicine, have to decide whether the articles sent to them are of good quality and accurate and whether they will be of interest to the readers of their journal. To do this they need to obtain specialist advice, so they contact experts in the topic of the research article and ask them to write reports. This is the process of scientific peer review, and the experts who write such reports are known as “peer reviewers.” Although the editors make the final decision, the advice and criticism of these peer reviewers to the editors is essential in making decisions on publication, and usually in requiring authors to make changes to their manuscript. The contribution that peer reviewers have made to the article by the time it is finally published may, therefore, be quite considerable.
Although peer review is accepted as a key part of the process for the publishing of medical research, many people have argued that there are flaws in the system. For example, there may be an element of luck involved; one author might find their paper being reviewed by a reviewer who is biased against the approach they have adopted or who is a very critical person by nature, and another author may have the good fortune to have their work considered by someone who is much more favorably disposed toward their work. Some reviewers are more knowledgeable and thorough in their work than others. The editors of medical journals try to take in account such biases and quality factors in their choice of peer reviewers or when assessing the reviews. Some journals have run training courses for experts who review for them regularly to try to make the standard of peer review as high as possible.
Why Was This Study Done?
It is hard for journal editors to know who will make a good peer reviewer, and there is no proven system for choosing them. The authors of this study wanted to identify the previous experiences and training that make up the background of good peer reviewers and compare them with the quality of the reviews provided. This would help journal editors select good people for the task in future, and as a result will affect the quality of science they publish for readers, including other researchers.
What Did the Researchers Do and Find?
The authors contacted all the regular reviewers from one specialist journal (Annals of Emergency Medicine). A total of 306 of these experienced reviewers (71% of all those associated with the journal) completed a survey of past training and experiences that might be expected to improve peer review skills. These reviewers had done 2,856 reviews of 1,484 separate manuscripts during a four-year study period, and during this time the quality of the reviews had been rated by the journal's editors. Surprisingly, most variables, including academic rank, formal training in critical appraisal or statistics, or status as principal investigator of a grant, failed to predict performance of higher-quality reviews. The only significant predictors of quality were working in a university-operated hospital versus other teaching environment and relative youth (under ten years of experience after finishing training), and even these were only weak predictors.
What Do These Findings Mean?
This study suggest that there are no easily identifiable types of formal training or experience that predict peer reviewer performance, although it is clear that some reviewers (and reviews) are better than others. The authors suggest that it is essential therefore that journals routinely monitor the quality of reviews submitted to them to ensure they are getting good advice (a practice that is not universal).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040040
• WAME is an association of editors from many countries who seek to foster international cooperation among editors of peer-reviewed medical journals
• The Fifth International Congress on Peer Review and Biomedical Publication is one of a series of conferences on peer review
• The PLoS Medicine guidelines for reviewers outline what we look for in a review
• The Council of Science Editors promotes ethical scientific publishing practices
• An editorial also published in this issue of PLoS Medicine discusses the peer review process further
doi:10.1371/journal.pmed.0040040
PMCID: PMC1796627  PMID: 17411314
16.  Facilitating the Recruitment of Minority Ethnic People into Research: Qualitative Case Study of South Asians and Asthma 
PLoS Medicine  2009;6(10):e1000148.
Aziz Sheikh and colleagues report on a qualitative study in the US and the UK to investigate ways to bolster recruitment of South Asians into asthma studies, including making inclusion of diverse populations mandatory.
Background
There is international interest in enhancing recruitment of minority ethnic people into research, particularly in disease areas with substantial ethnic inequalities. A recent systematic review and meta-analysis found that UK South Asians are at three times increased risk of hospitalisation for asthma when compared to white Europeans. US asthma trials are far more likely to report enrolling minority ethnic people into studies than those conducted in Europe. We investigated approaches to bolster recruitment of South Asians into UK asthma studies through qualitative research with US and UK researchers, and UK community leaders.
Methods and Findings
Interviews were conducted with 36 researchers (19 UK and 17 US) from diverse disciplinary backgrounds and ten community leaders from a range of ethnic, religious, and linguistic backgrounds, followed by self-completion questionnaires. Interviews were digitally recorded, translated where necessary, and transcribed. The Framework approach was used for analysis. Barriers to ethnic minority participation revolved around five key themes: (i) researchers' own attitudes, which ranged from empathy to antipathy to (in a minority of cases) misgivings about the scientific importance of the question under study; (ii) stereotypes and prejudices about the difficulties in engaging with minority ethnic populations; (iii) the logistical challenges posed by language, cultural differences, and research costs set against the need to demonstrate value for money; (iv) the unique contexts of the two countries; and (v) poorly developed understanding amongst some minority ethnic leaders of what research entails and aims to achieve. US researchers were considerably more positive than their UK counterparts about the importance and logistics of including ethnic minorities, which appeared to a large extent to reflect the longer-term impact of the National Institutes of Health's requirement to include minority ethnic people.
Conclusions
Most researchers and community leaders view the broadening of participation in research as important and are reasonably optimistic about the feasibility of recruiting South Asians into asthma studies provided that the barriers can be overcome. Suggested strategies for improving recruitment in the UK included a considerably improved support structure to provide academics with essential contextual information (e.g., languages of particular importance and contact with local gatekeepers), and the need to ensure that care is taken to engage with the minority ethnic communities in ways that are both culturally appropriate and sustainable; ensuring reciprocal benefits was seen as one key way of avoiding gatekeeper fatigue. Although voluntary measures to encourage researchers may have some impact, greater impact might be achieved if UK funding bodies followed the lead of the US National Institutes of Health requiring recruitment of ethnic minorities. Such a move is, however, likely in the short- to medium-term, to prove unpopular with many UK academics because of the added “hassle” factor in engaging with more diverse populations than many have hitherto been accustomed to.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In an ideal world, everyone would have the same access to health care and the same health outcomes (responses to health interventions). However, health inequalities—gaps in health care and in health between different parts of the population—exist in many countries. In particular, people belonging to ethnic minorities in the UK, the US, and elsewhere have poorer health outcomes for several conditions than people belonging to the ethnic majority (ethnicity is defined by social characteristics such as cultural tradition or national origin). For example, in the UK, people whose ancestors came from the Indian subcontinent (also known as South Asians and comprising in the main of people of Indian, Pakistani, and Bangladeshi origin) are three times as likely to be admitted to hospital for asthma as white Europeans. The reasons underpinning ethnic health inequalities are complex. Some inequalities may reflect intrinsic differences between groups of people—some ethnic minorities may inherit genes that alter their susceptibility to a specific disease. Other ethnic health inequalities may arise because of differences in socioeconomic status or because different cultural traditions affect the uptake of health care services.
Why Was This Study Done?
Minority ethnic groups are often under-represented in health research, which could limit the generalizability of research findings. That is, an asthma treatment that works well in a trial where all the participants are white Europeans might not be suitable for South Asians. Clinicians might nevertheless use the treatment in all their patients irrespective of their ethnicity and thus inadvertently increase ethnic health inequality. So, how can ethnic minorities be encouraged to enroll into research studies? In this qualitative study, the investigators try to answer this question by talking to US and UK asthma researchers and UK community leaders about how they feel about enrolling ethnic minorities into research studies. The investigators chose to compare the feelings of US and UK asthma researchers because minority ethnic people are more likely to enroll into US asthma studies than into UK studies, possibly because the US National Institute of Health's (NIH) Revitalization Act 1993 mandates that all NIH-funded clinical research must include people from ethnic minority groups; there is no similar mandatory policy in the UK.
What Did the Researchers Do and Find?
The investigators interviewed 16 UK and 17 US asthma researchers and three UK social researchers with experience of working with ethnic minorities. They also interviewed ten community leaders from diverse ethnic, religious and linguistic backgrounds. They then analyzed the interviews using the “Framework” approach, an analytical method in which qualitative data are classified and organized according to key themes and then interpreted. By comparing the data from the UK and US researchers, the investigators identified several barriers to ethnic minority participation in health research including: the attitudes of researchers towards the scientific importance of recruiting ethnic minority people into health research studies; prejudices about the difficulties of including ethnic minorities in health research; and the logistical challenges posed by language and cultural differences. In general, the US researchers were more positive than their UK counterparts about the importance and logistics of including ethnic minorities in health research. Finally, the investigators found that some community leaders had a poor understanding of what research entails and about its aims.
What Do These Findings Mean?
These findings reveal a large gap between US and UK researchers in terms of policy, attitudes, practices, and experiences in relation to including ethnic minorities in asthma research. However, they also suggest that most UK researchers and community leaders believe that it is both important and feasible to increase the participation of South Asians in asthma studies. Although some of these findings may have been affected by the study participants sometimes feeling obliged to give “politically correct” answers, these findings are likely to be generalizable to other diseases and to other parts of Europe. Given their findings, the researchers warn that a voluntary code of practice that encourages the recruitment of ethnic minority people into health research studies is unlikely to be successful. Instead, they suggest, the best way to increase the representation of ethnic minority people in health research in the UK might be to follow the US lead and introduce a policy that requires their inclusion in such research.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000148.
Families USA, a US nonprofit organization that campaigns for high-quality, affordable health care for all Americans, has information about many aspects of minority health in the US, including an interactive game about minority health issues
The US Agency for Healthcare Research and Quality has a section on minority health
The UK Department of Health provides information on health inequalities and a recent report on the experiences of patients in Black and minority ethnic groups
The UK Parliamentary Office of Science and Technology also has a short article on ethnicity and health
Information on the NIH Revitalization Act 1993 is available
NHS Evidences Ethnicity and Health has a variety of policy, clinical, and research resources on ethnicity and health
doi:10.1371/journal.pmed.1000148
PMCID: PMC2752116  PMID: 19823568
17.  Towards evidence‐based medicine for paediatricians 
To give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence‐based” answers to common questions that are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format that has been successfully developed by Kevin Mackway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, although they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor to search the grey, unpublished literature. What Archimedes offers is practical, best evidence‐based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching2 and obtaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best quality evidence to answer the question (http://www.cebm.net). A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as the number needed to treat), books by Sackett4 and Moyer5 may help. To pull the information together, a commentary is provided, but to make it all much more accessible, a box provides the clinical bottom lines.
Electronics‐only topics that have been published on the BestBets site (www.bestbets.org) and may be of interest to paediatricians include the following.
Can steroids be used to reduce post tonsillectomy pain?
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the instructions for authors at www.archdischild.com. Three topics are covered in this issue of the journal:
Is teething the cause of minor ailments?
Should steroid creams be used in cases of labial fusion?
Does erythromycin cause pyloric stenosis?
References
1 Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health. Issue 1. London: BMJ Books, 2000.
2 Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3 Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4 Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
5 Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health. Issue 1. London: BMJ Books, 2000.
Can: doing, using and replicating evidence‐based child health
The practice of evidence‐based child health is said to be the five‐step way of asking questions, acquiring information, appraising the evidence, applying the results and assessing our performance.
If the truth be known, for the vast majority of the time, most of us perform our clinical practice replicating what we have done previously. Most of the time this is based on the combination of excellent education, skilled interpretation of clinical findings, and good discussions with children and families. We hope that the education we rely on was (and remains) based on the best available scientific evidence. If it is, we are practising a form of “micro‐evidence‐based healthcare (EBHC)” (doing just step 4).
Sometimes, we question our knowledge (or more uncomfortably, someone does this for us), and will head off to top up our understanding of an area. This “using” mode, if we use well‐appraised resources to supply our thirst for information, will also promote the practice of evidence‐based care. This midi‐EBHC asks us to go through steps 1, 2 and 4.
Occasionally, we also actually need to go through the entire process of getting “down and dirty” with the primary research and appraising it to influence our practice. Maxi‐EBHC is considerably more demanding in time, but largely more satisfying intellectually.
If we reframe the practice of EBHC as using the family and child values, the best evidence, and our clinical expertise, then we can do it by micro‐methods, midi‐methods or maxi‐methods, and choose the most appropriate approach for the situation we confront.
Acknowledgement
I thank Dr Sharon Straus, Director of the Center for Evidence‐based Medicine, University of Toronto, Toronto, Ontario, Canada.
doi:10.1136/adc.2006.110080
PMCID: PMC2083440
18.  Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles 
PLoS Medicine  2011;8(3):e1000425.
Adriane Fugh-Berman and colleagues analyzed a selection of published opinion pieces on hormone therapy and show that there may be a connection between receiving industry funding for speaking, consulting, or research and the tone of such opinion pieces.
Background
Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.
Methods and Findings
We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.
Conclusion
There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past three decades, menopausal hormones have been heavily promoted for preventing disease in women. However, the Women's Health Initiative (WHI) study—which enrolled more than 26,000 women in the US and which was published in 2004—found that estrogen-progestin and estrogen-only formulations (often prescribed to women around the age of menopause) increased the risk of stroke, deep vein thrombosis, dementia, and incontinence. Furthermore, this study found that the estrogen-progestin therapy increased rates of breast cancer. In fact, the estrogen-progestin arm of the WHI study was stopped in 2002 due to harmful findings, and the estrogen-only arm was stopped in 2004, also because of harmful findings. In addition, the study also found that neither therapy reduced cardiovascular risk or markedly benefited health-related quality of life measures.
Despite these results, two years after the results of WHI study were published, a survey of over 700 practicing gynecologists—the specialists who prescribe the majority of menopausal hormone therapies—in the US found that almost half did not find the findings of the WHI study convincing and that 48% disagreed with the decision to stop the trial early. Furthermore, follow-up surveys found similar results.
Why Was This Study Done?
It is unclear why gynecologists and other physicians continue to prescribe menopausal hormone therapies despite the results of the WHI. Some academics argue that published industry-funded reviews and commentaries may be designed to convey specific, but subtle, marketing messages and several academic analyses have used internal industry documents disclosed in litigation cases. So this study was conducted to investigate whether hormone therapy–promoting tone could be identified in narrative review articles and if so, whether these articles were more likely to have been authored by people who had accepted funding from hormone manufacturers.
What Did the Researchers Do and Find?
The researchers conducted a comprehensive literature search that identified 340 relevant articles published between July 2002 and June 2006—the four years following the cessation of the estrogen-progestin arm of the women's health initiative study. Ten authors had published four to six articles, 47 authored two or three articles, and 371 authored one article each. The researchers focused on authors who had published four or more articles in the four-year period under study and, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. After individually analyzing a batch of articles, the readers met to provide their initial assessments, to discuss them, and to reach consensus on tone and scientific accuracy. Then after the papers were evaluated, each author was identified and the researchers searched for authors' potential financial conflicts of interest, defined as publicly disclosed information that the authors had received payment for research, speaking, or consulting on behalf of a manufacturer of menopausal hormone therapy.
Common themes in the 50 articles included arguments that clinical trial results should not guide treatment for individuals and suggestions that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Furthermore, of the ten authors studied, eight were found to have received payment for research, speaking or consulting on behalf of menopause hormone manufacturers, and 30 of 32 articles evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest. Articles promoting the use of menopausal hormone therapy were more than twice as likely to have been written by authors with conflicts of interest as by authors without conflicts of interest. Furthermore, Three authors who were identified as having financial conflicts of interest were authors on articles where sections of their previously published articles were repeated word-for-word without citation.
What Do These Findings Mean?
The findings of this study suggest that there may be a link between receiving industry funding for speaking, consulting, or research and the publication of apparently promotional opinion pieces on menopausal hormone therapy. Furthermore, such publications may encourage physicians to continue prescribing these therapies to women of menopausal age. Therefore, physicians and other health care providers should interpret the content of review articles with caution. In addition, medical journals should follow the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts, which require that all authors submit signed statements of their participation in authorship and full disclosure of any conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000425.
The US National Heart, Lung, and Blood Institute has more information on the Womens Health Initiative
The US National Institutes of Health provide more information about the effects of menopausal hormone replacement therapy
The Office of Women's Health, U.S. Department of Health and Human Services provides information on menopausal hormone therapy
The International Committee of Medical Journal Editors Uniform Requirements for Manuscripts presents Uniform Requirements for Manuscripts published in biomedical journals
The National Womens Health Network, a consumer advocacy group that takes no industry money, has factsheets and articles about menopausal hormone therapy
PharmedOut, a Georgetown University Medical Center project, has many resources on pharmaceutical marketing practices
doi:10.1371/journal.pmed.1000425
PMCID: PMC3058057  PMID: 21423581
19.  Guidelines, Editors, Pharma And The Biological Paradigm Shift 
Mens Sana Monographs  2007;5(1):27-30.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.
There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.
Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.
A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.
Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.
Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials
The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.
Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.
There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left.
Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.
An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.
We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.
The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.
Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.
Why does pharma adopt questionable tactics? The reasons are essentially two:
What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.
Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.
The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.
What is necessary for industry captains and long-term players is to realise:
Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.
In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.
doi:10.4103/0973-1229.32176
PMCID: PMC3192391  PMID: 22058616
Academia; Pharmaceutical Industry; Clinical Practice Guidelines; Best Practice Guidelines; Academic Medical Centers; Medical Associations; Research Journals; Clinical Research; Public Welfare; Pharma Image; Corporate Welfare; Biological Psychiatry; Law Suits Against Industry
20.  Adherence to HAART: A Systematic Review of Developed and Developing Nation Patient-Reported Barriers and Facilitators 
PLoS Medicine  2006;3(11):e438.
Background
Adherence to highly active antiretroviral therapy (HAART) medication is the greatest patient-enabled predictor of treatment success and mortality for those who have access to drugs. We systematically reviewed the literature to determine patient-reported barriers and facilitators to adhering to antiretroviral therapy.
Methods and Findings
We examined both developed and developing nations. We searched the following databases: AMED (inception to June 2005), Campbell Collaboration (inception to June 2005), CinAhl (inception to June 2005), Cochrane Library (inception to June 2005), Embase (inception to June 2005), ERIC (inception to June 2005), MedLine (inception to June 2005), and NHS EED (inception to June 2005). We retrieved studies conducted in both developed and developing nation settings that examined barriers and facilitators addressing adherence. Both qualitative and quantitative studies were included. We independently, in duplicate, extracted data reported in qualitative studies addressing adherence. We then examined all quantitative studies addressing barriers and facilitators noted from the qualitative studies. In order to place the findings of the qualitative studies in a generalizable context, we meta-analyzed the surveys to determine a best estimate of the overall prevalence of issues. We included 37 qualitative studies and 47 studies using a quantitative methodology (surveys). Seventy-two studies (35 qualitative) were conducted in developed nations, while the remaining 12 (two qualitative) were conducted in developing nations. Important barriers reported in both economic settings included fear of disclosure, concomitant substance abuse, forgetfulness, suspicions of treatment, regimens that are too complicated, number of pills required, decreased quality of life, work and family responsibilities, falling asleep, and access to medication. Important facilitators reported by patients in developed nation settings included having a sense of self-worth, seeing positive effects of antiretrovirals, accepting their seropositivity, understanding the need for strict adherence, making use of reminder tools, and having a simple regimen. Among 37 separate meta-analyses examining the generalizability of these findings, we found large heterogeneity.
Conclusions
We found that important barriers to adherence are consistent across multiple settings and countries. Research is urgently needed to determine patient-important factors for adherence in developing world settings. Clinicians should use this information to engage in open discussion with patients to promote adherence and identify barriers and facilitators within their own populations.
An analysis of qualitative and quantitative studies found consistent barriers to adherence to HIV therapy across multiple settings and countries, ranging from access to medication to problems with complicated regimens.
Editors' Summary
Background.
The World Health Organization has estimated that in 2005, about 38 million people worldwide were living with HIV/AIDS; the mortality caused by HIV/AIDS is very high. Antiretroviral drugs are effective at controlling the disease and extending life span. However, it is important for people to stick to the drug regimens exactly in order to keep levels of HIV low, prevent it from becoming resistant to drugs, and stop the illness from progressing. However, many people find it very difficult to take antiretroviral drugs precisely as they should. There is already some evidence from research studies on the reasons why this is the case. There are two different research approaches taken by these studies: “qualitative” methods, which try to find out about attitudes and behaviors using focus groups, interviews, or other techniques; and “quantitative” methods, which try to find out about peoples' opinions and experience using surveys with set questions for the participants to answer, and then count the different responses.
Why Was This Study Done?
The investigators wanted to put together all of the available evidence from published research studies (called doing a “systematic review”) on which factors affected people's adherence to antiretroviral drugs. They wanted to do a systematic review because it is thought to be a very rigorous way of appraising all the available evidence (although there is considerable debate about the value of using such a method to analyze the results of qualitative research).
What Did the Researchers Do and Find?
The study team searched biomedical literature databases as well as conference abstracts and research registries using a defined set of search queries. They screened all the scientific papers they found; those reporting results of original research into factors affecting antiretroviral adherence were then analyzed in more detail. 84 relevant studies were identified, of which 37 used “qualitative” methods (focus groups, interviews, open-ended questioning) and 47 used “quantitative” methods (surveys). Most of these studies had been carried out in the developed world. Then, the researchers extracted the factors affecting adherence from the original studies, which could be either “positive” factors (helping adherence) or “negative” ones (making adherence more difficult). They classified the factors into four key themes: “patient related” (e.g., seeing positive results, fear of disclosure, being depressed); “beliefs about medication” (e.g., faith in how well the drugs worked, side effects); “daily schedules” (e.g., using reminder tools, disruptions to routine); and “interpersonal relationships” (e.g., trusting relations with health-care provider; social isolation).
  Many barriers to adherence were common to both developed and developing settings. Some factors were unique to the studies conducted in the developing world, such as financial constraints and problems with traveling to get access to treatment. Fear of disclosure was an important barrier identified in many of the studies.
What Do These Findings Mean?
The researchers combined the results of many different studies and identified factors that help or obstruct adherence to antiretroviral treatment. By identifying influences common to the different settings, greater weight can be placed on the factors that were identified. Only 12 of the studies included in this research were from the developing world, where the majority of HIV/AIDS patients live; hence more work is needed to examine and address the factors influencing antiretroviral adherence in these parts of the world. This study provides researchers and health policy makers with a starting point for changes that might help to ensure greater adherence to antiretroviral treatment.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030438.
Medline Plus information on AIDS medicines (Medline Plus is a service of the US National Library of Medicine and the National Institutes of Health)
Joint United Nations Programme on HIV/AIDS has information about the state of the HIV/AIDS epidemic worldwide
The World Health Organization has an HIV/AIDS program site providing comprehensive information on the HIV/AIDS epidemic worldwide
The World Health Organization pages on antiretroviral therapy
doi:10.1371/journal.pmed.0030438
PMCID: PMC1637123  PMID: 17121449
21.  How Evidence-Based Are the Recommendations in Evidence-Based Guidelines? 
PLoS Medicine  2007;4(8):e250.
Background
Treatment recommendations for the same condition from different guideline bodies often disagree, even when the same randomized controlled trial (RCT) evidence is cited. Guideline appraisal tools focus on methodology and quality of reporting, but not on the nature of the supporting evidence. This study was done to evaluate the quality of the evidence (based on consideration of its internal validity, clinical relevance, and applicability) underlying therapy recommendations in evidence-based clinical practice guidelines.
Methods and Findings
A cross-sectional analysis of cardiovascular risk management recommendations was performed for three different conditions (diabetes mellitus, dyslipidemia, and hypertension) from three pan-national guideline panels (from the United States, Canada, and Europe). Of the 338 treatment recommendations in these nine guidelines, 231 (68%) cited RCT evidence but only 105 (45%) of these RCT-based recommendations were based on high-quality evidence. RCT-based evidence was downgraded most often because of reservations about the applicability of the RCT to the populations specified in the guideline recommendation (64/126 cases, 51%) or because the RCT reported surrogate outcomes (59/126 cases, 47%).
Conclusions
The results of internally valid RCTs may not be applicable to the populations, interventions, or outcomes specified in a guideline recommendation and therefore should not always be assumed to provide high-quality evidence for therapy recommendations.
From an analysis of cardiovascular risk-management recommendations in guidelines produced by pan-national panels, McAlister and colleagues concluded that fewer than half were based on high-quality evidence.
Editors' Summary
Background.
Until recently, doctors largely relied on their own experience to choose the best treatment for their patients. Faced with a patient with high blood pressure (hypertension), for example, the doctor had to decide whether to recommend lifestyle changes or to prescribe drugs to reduce the blood pressure. If he or she chose the latter, he or she then had to decide which drug to prescribe, set a target blood pressure, and decide how long to wait before changing the prescription if this target was not reached. But, over the past decade, numerous clinical practice guidelines have been produced by governmental bodies and medical associations to help doctors make treatment decisions like these. For each guideline, experts have searched the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluated the quality of that evidence, and then made recommendations based on the best evidence available.
Why Was This Study Done?
The recommendations made in different clinical practice guidelines vary, in part because they are based on evidence of varying quality. To help clinicians decide which recommendations to follow, some guidelines indicate the strength of their recommendations by grading them, based on the methods used to collect the underlying evidence. Thus, a randomized clinical trial (RCT)—one in which patients are randomly allocated to different treatments without the patient or clinician knowing the allocation—provides higher-quality evidence than a nonrandomized trial. Similarly, internally valid trials—in which the differences between patient groups are solely due to their different treatments and not to other aspects of the trial—provide high-quality evidence. However, grading schemes rarely consider the size of studies and whether they have focused on clinical or so-called “surrogate” measures. (For example, an RCT of a treatment to reduce heart or circulation [“cardiovascular”] problems caused by high blood pressure might have death rate as a clinical measure; a surrogate endpoint would be blood pressure reduction.) Most guidelines also do not consider how generalizable (applicable) the results of a trial are to the populations, interventions, and outcomes specified in the guideline recommendation. In this study, the researchers have investigated the quality of the evidence underlying recommendations for cardiovascular risk management in nine evidence-based clinical practice guides using these additional criteria.
What Did the Researchers Do and Find?
The researchers extracted the recommendations for managing cardiovascular risk from the current US, Canadian, and European guidelines for the management of diabetes, abnormal blood lipid levels (dyslipidemia), and hypertension. They graded the quality of evidence for each recommendation using the Canadian Hypertension Education Program (CHEP) grading scheme, which considers the type of study, its internal validity, its clinical relevance, and how generally applicable the evidence is considered to be. Of 338 evidence-based recommendations, two-thirds were based on evidence collected in internally valid RCTs, but only half of these RCT-based recommendations were based on high-quality evidence. The evidence underlying 64 of the guideline recommendations failed to achieve a high CHEP grade because the RCT data were collected in a population of people with different characteristics to those covered by the guideline. For example, a recommendation to use spironolactone to reduce blood pressure in people with hypertension was based on an RCT in which the participants initially had congestive heart failure with normal blood pressure. Another 59 recommendations were downgraded because they were based on evidence from RCTs that had not focused on clinical measures of effectiveness.
What Do These Findings Mean?
These findings indicate that although most of the recommendations for cardiovascular risk management therapies in the selected guidelines were based on evidence collected in internally valid RCTs, less than one-third were based on high-quality evidence applicable to the populations, treatments, and outcomes specified in guideline recommendations. A limitation of this study is that it analyzed a subset of recommendations in only a few guidelines. Nevertheless, the findings serve to warn clinicians that evidence-based guidelines are not necessarily based on high-quality evidence. In addition, they emphasize the need to make the evidence base underlying guideline recommendations more transparent by using an extended grading system like the CHEP scheme. If this were done, the researchers suggest, it would help clinicians apply guideline recommendations appropriately to their individual patients.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040250.
• Wikipedia contains pages on evidence-based medicine and on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
• The National Guideline Clearinghouse provides information on US national guidelines
• The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
• Information is available on the Canadian Hypertension Education Program (CHEP) (in French and English)
• See information on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, an organization that has developed an grading scheme similar to the CHEP scheme (in English, Spanish, French, German, and Italian)
doi:10.1371/journal.pmed.0040250
PMCID: PMC1939859  PMID: 17683197
22.  The Role of HIV-Related Stigma in Utilization of Skilled Childbirth Services in Rural Kenya: A Prospective Mixed-Methods Study 
PLoS Medicine  2012;9(8):e1001295.
Janet Turan and colleagues examined the role of the perception of women in rural Kenya of HIV-related stigma during pregnancy on their subsequent utilization of maternity services.
Background
Childbirth with a skilled attendant is crucial for preventing maternal mortality and is an important opportunity for prevention of mother-to-child transmission of HIV. The Maternity in Migori and AIDS Stigma Study (MAMAS Study) is a prospective mixed-methods investigation conducted in a high HIV prevalence area in rural Kenya, in which we examined the role of women's perceptions of HIV-related stigma during pregnancy in their subsequent utilization of maternity services.
Methods and Findings
From 2007–2009, 1,777 pregnant women with unknown HIV status completed an interviewer-administered questionnaire assessing their perceptions of HIV-related stigma before being offered HIV testing during their first antenatal care visit. After the visit, a sub-sample of women was selected for follow-up (all women who tested HIV-positive or were not tested for HIV, and a random sample of HIV-negative women, n = 598); 411 (69%) were located and completed another questionnaire postpartum. Additional qualitative in-depth interviews with community health workers, childbearing women, and family members (n = 48) aided our interpretation of the quantitative findings and highlighted ways in which HIV-related stigma may influence birth decisions. Qualitative data revealed that health facility birth is commonly viewed as most appropriate for women with pregnancy complications, such as HIV. Thus, women delivering at health facilities face the risk of being labeled as HIV-positive in the community. Our quantitative data revealed that women with higher perceptions of HIV-related stigma (specifically those who held negative attitudes about persons living with HIV) at baseline were subsequently less likely to deliver in a health facility with a skilled attendant, even after adjusting for other known predictors of health facility delivery (adjusted odds ratio = 0.44, 95% CI 0.22–0.88).
Conclusions
Our findings point to the urgent need for interventions to reduce HIV-related stigma, not only for improving quality of life among persons living with HIV, but also for better health outcomes among all childbearing women and their families.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Every year, nearly 350,000 women die from pregnancy- or childbirth-related complications. Almost all these “maternal” deaths occur in developing countries. In sub-Saharan Africa, for example, the maternal mortality ratio (the number of maternal deaths per 100,000 live births) is 500 whereas in industrialized countries it is only 12. Most maternal deaths are caused by hemorrhage (severe bleeding after childbirth), post-delivery infections, obstructed (difficult) labor, and blood pressure disorders during pregnancy. All these conditions can be prevented if women have access to adequate reproductive health services and if trained health care workers are present during delivery. Notably, in sub-Saharan Africa, infection with HIV (the virus that causes AIDS) is an increasingly important contributor to maternal mortality. HIV infection causes maternal mortality directly by increasing the occurrence of pregnancy complications and indirectly by increasing the susceptibility of pregnant women to malaria, tuberculosis, and other “opportunistic” infections—HIV-positive individuals are highly susceptible to other infections because HIV destroys the immune system.
Why Was This Study Done?
Although skilled delivery attendants reduce maternal mortality, there are many barriers to their use in developing countries including cost and the need to travel long distances to health facilities. Fears and experiences of HIV-related stigma and discrimination (prejudice, negative attitudes, abuse, and maltreatment directed at people living with HIV) may also be a barrier to the use of skilled childbirth service. Maternity services are prime locations for HIV testing and for the provision of interventions for the prevention of mother-to-child transmission (PMTCT) of HIV, so pregnant women know that they will have to “deal with” the issue of HIV when visiting these services. In this prospective mixed-methods study, the researchers examine the role of pregnant women's perceptions of HIV-related stigma in their subsequent use of maternity services in Nyanza Province, Kenya, a region where 16% women aged 15–49 are HIV-positive and where only 44.2% of mothers give birth in a health facility. A mixed-methods study combines qualitative data—how people feel about an issue—with quantitative data—numerical data about outcomes.
What Did the Researchers Do and Find?
In the Maternity in Migori and AIDS Stigma (MAMAS) study, pregnant women with unknown HIV status living in rural regions of Nyanza Province answered questions about their perceptions of HIV-related stigma before being offered HIV testing during their first antenatal clinic visit. After delivery, the researchers asked the women who tested HIV positive or were not tested for HIV and a sample of HIV-negative women where they had delivered their baby. They also gathered qualitative information about barriers to maternity and HIV service use by interviewing childbearing women, family members, and community health workers. The qualitative data indicate that labor in a health facility is commonly viewed as being most appropriate for women with pregnancy complications such as HIV infection. Thus, women delivering at health facilities risk being labeled as HIV positive, a label that the community associates with promiscuity. The quantitative data indicate that women with more negative attitudes about HIV-positive people (higher perceptions of HIV-related stigma) at baseline were about half as likely to deliver in a health facility with a skilled attendant as women with more positive attitudes about people living with HIV.
What Do These Findings Mean?
These findings suggest that HIV-related stigma is associated with the low rate of delivery by skilled attendants in rural areas of Nyanza Province and possibly in other rural regions of sub-Saharan Africa. Community mobilization efforts aimed at increasing the use of PMTCT services may be partly responsible for the strong perception that delivery in a health facility is most appropriate for women with HIV and other pregnancy complications and may have inadvertently strengthened the perception that women who give birth in such facilities are likely to be HIV positive. The researchers suggest, therefore, that health messages should stress that delivery in a health facility is recommended for all women, not just HIV-positive women or those with pregnancy complications, and that interventions should be introduced to reduce HIV-related stigma. This combined strategy has the potential to increase the use of maternity services by all women and the use of HIV and PMTCT services, thereby reducing some of the most pressing health problems facing women and their children in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001295.
The United Nations Children's Fund (UNICEF) provides information on maternal mortality, including the WHO/UNICEF/UNFPA/World Bank 2008 country estimates of maternal mortality; a UNICEF special report tells the stories of seven mothers living with HIV in Lesotho
The World Health Organization provides information on maternal health, including information about Millennium Development Goal 5, which aims to reduce maternal mortality (in several languages); the Millennium Development Goals, which were agreed by world leaders in 2000, are designed to eradicate extreme poverty worldwide by 2015
Immpact is a global research initiative for the evaluation of safe motherhood intervention strategies
Maternal Death: The Avoidable Crisis is a briefing paper published by the independent humanitarian medical aid organization Médecins Sans Frontières (MSF) in March 2012
Information is available from Avert, an international AIDS charity on all aspects of HIV/AIDS, including information on women, HIV and AIDS, on HIV and pregnancy, on HIV and AIDS stigma and discrimination, and on HIV in Kenya (in English and Spanish); Avert also has personal stories from women living with HIV
The Stigma Action Network (SAN) is a collaborative endeavor that aims to comprehensively coordinate efforts to develop and expand program, research, and advocacy strategies for reducing HIV stigma worldwide, including mobilizing stakeholders, delivering program and policy solutions, and maximizing investments in HIV programs and services globally
The People Living with Stigma Index aims to address stigma relating to HIV and advocate on key barriers and issues perpetuating stigma; it has recently published Piecing it together for women and girls, the gender dimensions of HIV-related stigma
The Health Policy Project http://www.healthpolicyproject.com has prepared a review of the academic and programmatic literature on stigma and discrimination as barriers to achievement of global goals for maternal health and the elimination of new child HIV infections (see under Resources)
More information on the MAMAS study is available from the UCSF Center for AIDS Prevention Studies
doi:10.1371/journal.pmed.1001295
PMCID: PMC3424253  PMID: 22927800
23.  Systematic review: Effects, design choices, and context of pay-for-performance in health care 
Background
Pay-for-performance (P4P) is one of the primary tools used to support healthcare delivery reform. Substantial heterogeneity exists in the development and implementation of P4P in health care and its effects. This paper summarizes evidence, obtained from studies published between January 1990 and July 2009, concerning P4P effects, as well as evidence on the impact of design choices and contextual mediators on these effects. Effect domains include clinical effectiveness, access and equity, coordination and continuity, patient-centeredness, and cost-effectiveness.
Methods
The systematic review made use of electronic database searching, reference screening, forward citation tracking and expert consultation. The following databases were searched: Cochrane Library, EconLit, Embase, Medline, PsychINFO, and Web of Science. Studies that evaluate P4P effects in primary care or acute hospital care medicine were included. Papers concerning other target groups or settings, having no empirical evaluation design or not complying with the P4P definition were excluded. According to study design nine validated quality appraisal tools and reporting statements were applied. Data were extracted and summarized into evidence tables independently by two reviewers.
Results
One hundred twenty-eight evaluation studies provide a large body of evidence -to be interpreted with caution- concerning the effects of P4P on clinical effectiveness and equity of care. However, less evidence on the impact on coordination, continuity, patient-centeredness and cost-effectiveness was found. P4P effects can be judged to be encouraging or disappointing, depending on the primary mission of the P4P program: supporting minimal quality standards and/or boosting quality improvement. Moreover, the effects of P4P interventions varied according to design choices and characteristics of the context in which it was introduced.
Future P4P programs should (1) select and define P4P targets on the basis of baseline room for improvement, (2) make use of process and (intermediary) outcome indicators as target measures, (3) involve stakeholders and communicate information about the programs thoroughly and directly, (4) implement a uniform P4P design across payers, (5) focus on both quality improvement and achievement, and (6) distribute incentives to the individual and/or team level.
Conclusions
P4P programs result in the full spectrum of possible effects for specific targets, from absent or negligible to strongly beneficial. Based on the evidence the review has provided further indications on how effect findings are likely to relate to P4P design choices and context. The provided best practice hypotheses should be tested in future research.
doi:10.1186/1472-6963-10-247
PMCID: PMC2936378  PMID: 20731816
24.  Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature 
PLoS Medicine  2011;8(5):e1000434.
A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.
Background
Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Methods and Findings
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
Conclusions
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Bipolar disorder (manic depression) is a serious, long-term mental illness that affects about 1% of adults at some time during their life. It usually develops in late adolescence or early adulthood and affects men and women from all backgrounds. People with bipolar disorder experience wild mood swings that interfere with daily life and damage relationships. During “manic” episodes, which can last several months if untreated, they may feel euphoric (“high”), energetic, or irritable. They may be full of ambitious plans, feel creative, and spend money recklessly. They can also have psychotic symptoms—they may see or hear things that are not there. During depressive episodes, affected individuals may feel helpless, worthless, and suicidal. Treatments for bipolar disorder include drugs to stabilize mood swings (for example, lithium and anticonvulsant medications), antidepressants to treat depressive episodes, and antipsychotic drugs to treat manic episodes. Psychotherapy can also help and patients can be taught to recognize the signs of approaching manic or depressive episodes and the triggers for these episodes.
Why Was This Study Done?
Treatment of bipolar disorder is divided into three phases: acute treatment lasting about 2 months to achieve remission, continuance treatment lasting from months 2 through 6 to prevent relapse, and long-term maintenance treatment to prevent recurrence. Second-generation (atypical) antipsychotics are widely used for acute treatment of manic episodes but are also used for maintenance treatment. For example, the atypical antipsychotic aripiprazole, which gained US approval for this indication in 2005, is now a popular choice among clinicians for treating bipolar disorder. But how much evidence is there to support aripiprazole's use in the maintenance treatment of bipolar disorder? Here, the researchers systematically search the published literature for double-blind randomized controlled trials of aripiprazole for this indication, critically analyze the quality of these trials, and undertake a citation search to investigate how the results of these trials have been disseminated in the scientific literature. In double-blind randomized controlled trials, patients are randomly assigned to receive a test drug or a control (generally, placebo), and the effects of these drugs compared; patients in the trial, and physicians administering treatments, would not know who is receiving the test drug or control until the trial is completed.
What Did the Researchers Do and Find?
The researchers' search for reports of double-blind randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder using predefined criteria identified only two publications, both describing a single trial—the Keck trial. Critical review of this trial identified four issues that limit its interpretation for supporting aripiprazole as a maintenance therapy: the trial was too short to demonstrate maintenance efficacy; all the trial participants had responded well to aripiprazole as an acute treatment so the generalizability of the trial's results was limited; the trial design meant that some of the apparent beneficial treatment results could have reflected the adverse effects of abrupt medication discontinuation in the control group; and the trial had a low completion rate. The researchers' citation search identified 80 publications that cited the Keck trial in discussions of the use of aripiprazole for maintenance treatment of bipolar disorder. Only a quarter of these papers presented any numerical data from the trial, only a third mentioned any of the reported adverse events, and only four papers mentioned the trial's limitations.
What Do These Findings Mean?
This evaluation of the evidence base supporting the use of aripiprazole for the maintenance treatment of bipolar disorder shows that the justification for this practice relies on the results of one published trial. Moreover, the methodology and reporting of this trial mean that its results cannot easily be generalized to inform the treatment of most patients with bipolar disorder. Worryingly, the researchers' citation search indicates that the Keck trial has been cited uncritically in the ensuing scientific literature. Although the unique features of bipolar disorder make it hard to undertake controlled studies of treatment options, the researchers express concern that “the publication and apparently uncritical acceptance of this trial may be diverting patients away from more effective treatments”.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000434.
The US National Institute of Mental Health has detailed information on bipolar disorder, including an Easy to Read booklet (in English and Spanish)
The UK National Health Service Choices website provides information on all aspects of bipolar disorder
The UK charity Mind has information on bipolar disorder and provides links to other useful organizations
MedlinePlus has links to further information on bipolar disorder (in English and Spanish)
doi:10.1371/journal.pmed.1000434
PMCID: PMC3086871  PMID: 21559324
25.  Association of Prenatal and Childhood Blood Lead Concentrations with Criminal Arrests in Early Adulthood 
PLoS Medicine  2008;5(5):e101.
Background
Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses.
Methods and Findings
Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead.
Conclusions
Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.
Kim Dietrich and colleagues find an association between developmental exposure to lead and adult criminal behavior.
Editors' Summary
Background.
Violent crime is an increasing problem in many countries, but why are some people more aggressive than others? Being male has been identified as a risk factor for violent criminal behavior in several studies, as have exposure to tobacco smoke before birth, having antisocial parents, and belonging to a poor family. Another potential risk factor for antisocial behavior as an adult is exposure to lead during childhood, although few studies have looked directly at whether childhood lead exposure is linked with criminal behavior in adulthood. Lead is a toxic metal that damages the nervous system when ingested or inhaled. It is present throughout the environment because of its widespread use in the past in paint, solder for water pipes, and gasoline. In 1978, 13.5 million US children had a blood lead level above 10 μg/dl, the current US Centers for Disease Control and Prevention blood lead level of concern (the average US blood lead level is 2 μg/dl). Lead paint and solder were banned in 1978 and 1986, respectively, by the US federal government; leaded gasoline was finally phased out in 1996. By 2002, only 310,000 US children had a blood lead level above 10 μg/dl. However, children exposed to lower levels of lead than this—through ingesting flakes or dust residues of old lead paint, for example—can have poor intellectual development and behavioral problems including aggression.
Why Was This Study Done?
Although some studies have suggested that childhood lead exposure is associated with later criminal behavior, these studies have often relied on indirect measurements of childhood lead exposure such as bone lead levels in young adults or a history of lead poisoning. Other studies that have measured childhood lead exposure directly have not followed their participants into adulthood. In this new study, the researchers investigate the association between actual measurements of prenatal and childhood blood lead concentrations and criminal arrests in early adulthood to get a clearer idea about whether early lead exposure is associated with subsequent violent behavior.
What Did the Researchers Do and Find?
Between 1979 and 1984, the researchers recruited pregnant women living in poor areas of Cincinnati, which had a high concentration of older, lead-contaminated housing, into the Cincinnati Lead Study. They measured the women's blood lead concentrations during pregnancy as an indication of their offspring's prenatal lead exposure and the children's blood lead levels regularly until they were six and half years old. They then obtained information from the local criminal justice records on how many times each of the 250 offspring had been arrested between becoming 18 years old and the end of October 2005. The researchers found that increased blood lead levels before birth and during early childhood were associated with higher rates of arrest for any reason and for violent crimes. For example, for every 5 μg/dl increase in blood lead levels at six years of age, the risk of being arrested for a violent crime as a young adult increased by almost 50% (the “relative risk” was 1.48).
What Do These Findings Mean?
These findings provide strong evidence that early lead exposure is a risk factor for criminal behavior, including violent crime, in adulthood. One possibility, which the authors were unable to assess in this study, is that lead exposure impairs intelligence, which in turn makes it more likely that a criminal offender will be caught (i.e., arrested). The authors discuss a number of limitations in their study—for example, they probably did not capture all criminal behavior (since most criminal behavior does not lead to arrest). Although both environmental lead levels and crime rates have dropped over the last 30 years in the US, the overall reduction was not uniform—inner-city children remain particularly vulnerable to lead exposure. The findings therefore suggest that a further reduction in childhood lead exposure might be an important and achievable way to reduce violent crime.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050101.
A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on childhood lead exposure and brain volume reduction in adulthood
Study researcher Kim Dietrich can be heard talking about “The Lethal Legacy of Lead”, a brief MP3 about lead exposure and violent crime
Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)
MedlinePlus provides a list of links to information on lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program
The UK Health Protection Agency also provides information about lead and its health hazards
doi:10.1371/journal.pmed.0050101
PMCID: PMC2689664  PMID: 18507497

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