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1.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
2.  Creating a Three-Parent Child: An Educational Paradigm for the Responsible Conduct of Research 
The field of assisted reproduction is renowned for its remarkable advances and constant pushing forward of research boundaries in an effort to offer innovative and effective methods for enhancing fertility. Accompanying these advances, however, are physiological, psychological, and bioethical consequences that must be considered. These concomitant advances and consequences make assisted reproduction an excellent educational paradigm for inculcating responsible conduct in both research and clinical practice. Ultimately, responsible conduct rests on the ethical researcher and clinician. Here, we present the as-yet unapproved, contentious assisted reproductive technology of mitochondrial replacement transfer (MRT) as an ideal educational platform to foster the responsible conduct of research by advancing dialogue among multi-disciplinary scholars, researchers, and students. Using a likely future case, we present the basic science, legal, and ethical considerations, and the pedagogical principles and strategies for using MRT as an effective educational paradigm. Society will benefit when the ethical issues inherent in creating children with three genetic parents as well as germline interference are discussed across multiple academic levels that include researchers, legal experts, bioethicists, and government-appointed commissions. Furthermore, undergraduate and graduate students should be included because they will likely determine the ethical fates of these biotechnologies. While emerging assisted reproduction technologies such as MRT are highly complex and will take years to be readily available for patients in need, now is the time to consider their scientific, legal, ethical, and cultural/religious implications for ensuring the responsible conduct of research.
doi:10.1128/jmbe.v15i2.873
PMCID: PMC4278475  PMID: 25574276
3.  Article processing charges, funding, and open access publishing at Journal of Experimental & Clinical Assisted Reproduction 
Journal of Experimental & Clinical Assisted Reproduction is an Open Access, online, electronic journal published by BioMed Central with full contents available to the scientific and medical community free of charge to all readers. Authors maintain the copyright to their own work, a policy facilitating dissemination of data to the widest possible audience without requiring permission from the publisher. This Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single £330 article processing charge (APC), due at the time of manuscript acceptance for publication. Payment of the APC is not a condition for formal peer review and does not apply to articles rejected after review. Additionally, this fee is waived for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Considering ordinary publication fees related to page charges and reprints, the APC at Journal of Experimental & Clinical Assisted Reproduction is comparable to costs associated with publishing in some traditional print journals, and is less expensive than many. Implementation of the APC within this Open Access framework is envisioned as a modern research-friendly policy that supports networking among investigators, brings new research into reach rapidly, and empowers authors with greater control over their own scholarly publications.
doi:10.1186/1743-1050-2-1
PMCID: PMC546227  PMID: 15649322
4.  Tracking Official Development Assistance for Reproductive Health in Conflict-Affected Countries 
PLoS Medicine  2009;6(6):e1000090.
Preeti Patel and colleagues report inequity in the disbursement of official development assistance for reproductive health between countries affected by conflict and those unaffected.
Background
Reproductive health needs are particularly acute in countries affected by armed conflict. Reliable information on aid investment for reproductive health in these countries is essential for improving the efficiency and effectiveness of aid. The purpose of this study was to analyse official development assistance (ODA) for reproductive health activities in conflict-affected countries from 2003 to 2006.
Methods and Findings
The Creditor Reporting System and the Financial Tracking System databases were the chosen data sources for the study. ODA disbursement for reproductive health activities to 18 conflict-affected countries was analysed for 2003, 2004, 2005, and 2006. An average of US$20.8 billion in total ODA was disbursed annually to the 18 conflict-affected countries between 2003 and 2006, of which US$509.3 million (2.4%) was allocated to reproductive health. This represents an annual average of US$1.30 disbursed per capita in the 18 sampled countries for reproductive health activities. Non-conflict-affected least-developed countries received 53.3% more ODA for reproductive health activities than conflict-affected least-developed countries, despite the latter generally having greater reproductive health needs. ODA disbursed for HIV/AIDS prevention and treatment increased by 119.4% from 2003 to 2006. The ODA disbursed for other direct reproductive health activities declined by 35.9% over the same period.
Conclusions
This study provides evidence of inequity in disbursement of reproductive health ODA between conflict-affected countries and non-conflict-affected countries, and between different reproductive health activities. These findings and the study's recommendations seek to support initiatives to make aid financing more responsive to need in the context of armed conflict.
Editors' Summary
Background
Reproductive health concerns the bodily functions and systems that are involved in conceiving and bearing offspring. A reproductively healthy person is able to have a responsible, satisfying and safe sex life and to reproduce if and when they chose to do so. More specifically, to ensure their reproductive health, both men and women need access to safe and effective birth control methods, they need to know how to avoid sexually transmitted diseases (including HIV/AIDS), and they need access to treatment should they become infected. Women also need access to appropriate health-care services to safeguard their own health and their offspring's health during pregnancy and childbirth. Reproductive health is essential for the wellbeing of individuals and families and for the social and economic development of nations. Consequently, some of the official development assistance (ODA) given to developing countries by wealthier nations and by international agencies is being used to improve reproductive health. Indeed, several of the Millennium Development Goals (internationally agreed targets designed to eradicate global poverty by 2015) are directly related to reproductive health, including the improvement of maternal health and the control of HIV/AIDS.
Why Was This Study Done?
Many developing countries, such as Afghanistan, the Democratic Republic of Congo, Iraq, and Sudan, are experiencing violent conflicts. Such conflicts tend to slow down the development of low-income countries, and can also cause harm to reproductive health by damaging the health-service infrastructure and by increasing exposure to sexual violence. Although conflict-affected low-income countries rely heavily on international and humanitarian aid for basic health-care provision, there is little reliable information about how much of this aid is invested in reproductive health in such countries. This information is needed to ensure that development aid is used effectively. In this study, therefore, the researchers analyze the amount of ODA disbursed (the amount of official development money paid to recipient countries) for reproductive health activities in conflict-affected countries between 2003 and 2006.
What Did the Researchers Do and Find?
The researchers identified eighteen countries (mostly “least-developed” countries as defined by the Organisation for Economic Co-operation and Development; OEDC) that had been at war at sometime during the study period. They obtained information on ODA disbursements for reproductive health activities mainly from the Creditor Reporting System (CRS) database, which is maintained by the OECD, but also from the Financial Tracking System (FTS) database, which is maintained by the United Nations Office for the Coordination of Humanitarian Affairs. An average of US$20.8 billion in ODA was disbursed annually to the 18 conflict-affected countries between 2003 and 2006. Only US$509.3 million (2.4%) of this was allocated to reproductive health. Put another way, each person living in these conflict-affected countries received US$1.30 per year for their reproductive health needs. By contrast, people in non-conflict-affected least-developed countries each received 50% more ODA for reproductive health activities, even though these countries often had better reproductive health indicators than the conflict-affected countries. The researchers also found that nearly half of ODA disbursed for reproductive health was used for HIV/AIDS-related activities. This portion of ODA increased slightly during the study period in the conflict-affected countries whereas ODA disbursed for other reproductive health activities fell by a third.
What Do These Findings Mean?
Although these findings do not take into account money provided to conflict-affected developing countries for reproductive health activities by large philanthropic organizations, they nevertheless reveal an inequality between conflict-affected and non-conflict affected countries in terms of the development money provided for reproductive health. This is a worrying finding given that reproductive health tends to suffer in countries affected by war and poor reproductive health can slow down development. The findings of this study also suggest that funding for non-HIV reproductive health activities is declining in conflict-affected countries. Importantly, they also highlight additional research that is needed to ensure that donors of development aid can be more responsive in future to the reproductive health needs of conflict-affected countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000090.
This study is further discussed in a PLoS Medicine Perspective by Paul Spiegel and colleagues
The World Health organization provides information about reproductive health, including information on its 2004 global strategy for reproductive health (in several languages)
The US Centers for Disease Control and Prevention also provides information on reproductive health (in English and Spanish)
Wikipedia has a page on reproductive health (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages
The United Nations provides information on the Millennium Development Goals
The Organisation for Economic Cooperation and Development provides information on ODA through its Creditor Reporting System database; the United Nations Office for the Coordination of Humanitarian Affairs provides similar information for other donors through its Financial Tracking System database
The Reproductive Health Response in Conflict Consortium promotes access to reproductive health programs in emergencies and advocates for policies that support reproductive health of persons affected by armed conflict
doi:10.1371/journal.pmed.1000090
PMCID: PMC2682761  PMID: 19513098
5.  Factors Affecting Journal Quality Indicator in Scopus (SCImago Journal Rank) in Obstetrics and Gynecology Journals: a Longitudinal Study (1999-2013) 
Acta Informatica Medica  2014;22(6):385-388.
Introduction:
Awareness of the latest scientific research and publishing articles in top journals is one of the major concerns of health researchers. In this study, we first introduced top journals of obstetrics and gynecology field based on their Impact Factor (IF), Eigenfactor Score (ES) and SCImago Journal Rank (SJR) indicator indexed in Scopus databases and then the scientometric features of longitudinal changes of SJR in this field were presented.
Method and material:
In our analytical and bibiliometric study, we included all the journals of obstetrics and gynecology field which were indexed by Scopus from 1999 to 2013. The scientometric features in Scopus were derived from SCImago Institute and IF and ES were obtained from Journal Citation Report through the Institute for Scientific Information. Generalized Estimating Equation was used to assess the scientometric features affecting SJR.
Result:
From 256 journals reviewed, 54.2% and 41.8% were indexed in the Pubmed and the Web of Sciences, respectively. Human Reproduction Update based on the IF (5.924±2.542) and SJR (2.682±1.185), and American Journal of obstetrics and gynecology based on the ES (0.05685±0.00633) obtained the first rank among the other journals. Time, Index in Pubmed, H_index, Citable per Document, Cites per Document, and IF affected changes of SJR in the period of study.
Discussion:
Our study showed a significant association between SJR and scientometric features in obstetrics and gynecology journals. According to this relationship, SJR may be an appropriate index for assessing journal quality.
doi:10.5455/aim.2014.22.385-388
PMCID: PMC4315645  PMID: 25684846
Journal quality; obstetrics and gynecology; Impact Factor; Eigenfactor Score; SCImago Journal Rank
6.  Assisted Reproductive Technology after the Birth of Louise Brown 
Background
Public interest in Assisted Reproductive Technology (ART) has remained high since the birth of the world’s first in vitro fertilization baby, Louise Brown, in the United Kingdom. ART allows scientists to manipulate the fertilization process in order to bypass some pathological obstacles such as blocked fallopian tubes and non-functioning ovaries in the females, and blocked vas deferens and low sperm count in the males. The purpose was to provide a historical outline and identify the researches that most contributed to ART.
Methods
A review of published experimental and clinical studies of assisted reproduction carried out at the University of Bristol library website (MetaLib®). A cross-search of seven different medical databases (AMED-Allied and Complementary Medicine Database, BIOSIS Previews on Web of Knowledge, Cochrane Library, Embase, and the Medline on Web of Knowledge, OvidSP and PubMed) was completed by using the key words to explore the major milestones and progress in the development and implementation of ART.
Results
A speedy advancement in the development of different assisted reproductive techniques makes infertility problem more treatable than it ever had been.
Conclusion
Although no other field in the medicine has integrated new knowledge into the daily practice more quickly than ART yet, there is a need for social research to counterbalance the dominance of biomedical one, in particular the people’s actual experiences and expectations of ART.
PMCID: PMC3799275  PMID: 24163793
Assisted reproductive technology; History; Infertility management; Louise Brown; Milestones; Timelines
7.  Empirical research in bioethical journals. A quantitative analysis 
Journal of Medical Ethics  2006;32(4):240-245.
Objectives
The objective of this research is to analyse the evolution and nature of published empirical research in the fields of medical ethics and bioethics.
Design
Retrospective quantitative study of nine peer reviewed journals in the field of bioethics and medical ethics (Bioethics, Cambridge Quarterly of Healthcare Ethics, Hastings Center Report, Journal of Clinical Ethics, Journal of Medical Ethics, Kennedy Institute of Ethics Journal, Nursing Ethics, Christian Bioethics, andTheoretical Medicine and Bioethics).
Results
In total, 4029 articles published between 1990 and 2003 were retrieved from the journals studied. Over this period, 435 (10.8%) studies used an empirical design. The highest percentage of empirical research articles appeared in Nursing Ethics (n = 145, 39.5%), followed by the Journal of Medical Ethics (n = 128, 16.8%) and the Journal of Clinical Ethics (n = 93, 15.4%). These three journals account for 84.1% of all empirical research in bioethics published in this period. The results of the χ2 test for two independent samples for the entire dataset indicate that the period 1997–2003 presented a higher number of empirical studies (n = 309) than did the period 1990–1996 (n = 126). This increase is statistically significant (χ2 = 49.0264, p<.0001). Most empirical studies employed a quantitative paradigm (64.6%, n = 281). The main topic of research was prolongation of life and euthanasia (n = 68).
Conclusions
We conclude that the proportion of empirical research in the nine journals increased steadily from 5.4% in 1990 to 15.4% in 2003. It is likely that the importance of empirical methods in medical ethics and bioethics will continue to increase.
doi:10.1136/jme.2004.011478
PMCID: PMC2565792  PMID: 16574880
empirical ethics; retrospective quantitative study; empirical methods in bioethics
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.  In memoriam: Celso-Ramon Garcia, M.D. (1922–2004), reproductive medicine visionary 
This article traces the career of Celso-Ramon Garcia (1922–2004), noted physician, educator, and internationally renowned pioneer in the field of reproductive endocrinology. His work helped to formulate oral contraceptives used by millions of women throughout the world. Garcia's research collaborators included Gregory Pincus and John Rock, who together finalized the landmark clinical data needed to secure initial FDA approval for "the pill" in 1960. In addition to Garcia's monumental work in contraceptive endocrinology, his scholarly interests encompassed physiology of the menopause, minimally invasive reproductive surgery, as well as psychological aspects of infertility. Closely identified with the University of Pennsylvania, Garcia was instrumental in establishing the first formal clinical program in reproductive biology and influenced countless young scientists whose training he supervised and mentored. His distinguished career was emblematic of the best of the medical profession, characterized by compassion, intellect, and a sincere desire to help others. Our manuscript outlines Garcia's wide range of interests, acknowledges his superior fund of knowledge, and honors his humanitarian spirit – all of which contributed to an impressive legacy of medical discoveries. The impact of Prof. Garcia's work will continue to be felt for many years.
doi:10.1186/1743-1050-2-2
PMCID: PMC548289  PMID: 15673473
10.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
Objective
An application was received to review the evidence on the ‘The Da Vinci Surgical System’ for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of ‘The Da Vinci Surgical System’ include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers.
The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men’s health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision.
Clinical Need
Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen.
Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer.
Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium.
The Da Vinci Surgical System
The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon’s console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon’s hands at the surgeon’s console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of “wristed” instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon’s console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback.
Research Questions
For endometrial and cervical cancers,
1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
For prostate cancer,
3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
Research Methods
Literature Search
Search Strategy
A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles (January 1, 2000-May 12, 2010)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)
Study design and methods must be clearly described
Health technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies
Exclusion Criteria
Duplicate publications (with the more recent publication on the same study population included)
Non-English papers
Animal or in-vitro studies
Case reports or case series without a referent or comparison group
Studies on long-term survival which may be affected by treatment
Studies that do not examine the cancers (e.g. advanced disease) or outcomes of interest
Outcomes of Interest
For endometrial and cervical cancers,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Number of complications*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of conversions to laparotomy*
Number of lymph nodes recovered
For prostate cancer,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Amount of morphine use/pain*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of transfusions*
- Duration of catheterization
- Number of complications*
- Number of anastomotic strictures*
Number of lymph nodes recovered
Oncologic factors
- Proportion of positive surgical margins
Long-term outcomes
- Urinary continence
- Erectile function
Summary of Findings
Robotic use for gynecologic oncology compared to:
Laparotomy: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.
The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.
More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.
Laparoscopy: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for length of hospitalizations and blood loss is low.
Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.
Robotic use for urologic oncology, specifically prostate cancer, compared to:
Retropubic surgery: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.
Surgeon skill had an impact on cancer control and functional outcomes.
The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. There is some suggestion that robotic surgery is safe with respect to less post-operative pain management required compared to retropubic surgery, however improved study design and measurement of complications need to be further addressed.
Clinical significance of significant findings for length of hospitalizations is low.
Laparoscopy: benefits of robotic surgery in terms of less blood loss and fewer individuals requiring transfusions likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for blood loss is low.
The potential link between less blood loss, improved visualization and improved functional outcomes is an important consideration for use of robotics.
All studies included were observational in nature and therefore the results must be interpreted cautiously.
Economic Analysis
The objective of this project was to assess the economic impact of robotic-assisted laparoscopy (RAL) for endometrial, cervical, and prostate cancers in the province of Ontario.
A budget impact analysis was undertaken to report direct costs associated with open surgery (OS), endoscopic laparoscopy (EL) and robotic-assisted laparoscopy (RAL) based on clinical literature review outcomes, to report a budget impact in the province based on volumes and costs from administrative data sets, and to project a future impact of RAL in Ontario. A cost-effectiveness analysis was not conducted because of the low quality evidence from the clinical literature review.
Hospital costs were obtained from the Ontario Case Costing Initiative (OCCI) for the appropriate Canadian Classification of Health Intervention (CCI) codes restricted to selective ICD-10 diagnostic codes after consultation with experts in the field. Physician fees were obtained from the Ontario Schedule of Benefits (OSB) after consultation with experts in the field. Fees were costed based on operation times reported in the clinical literature for the procedures being investigated. Volumes of procedures were obtained from the Ministry of Health and Long-Term Care (MOHLTC) administrative databases.
Direct costs associated with RAL, EL and OS included professional fees, hospital costs (including disposable instruments), radiotherapy costs associated with positive surgical margins in prostate cancer and conversion to OS in gynecological cancer. The total cost per case was higher for RAL than EL and OS for both gynecological and prostate cancers. There is also an acquisition cost associated with RAL. After conversation with the only supplier in Canada, hospitals are looking to spend an initial 3.6M to acquire the robotic surgical system
Previous volumes of OS and EL procedures were used to project volumes into Years 1-3 using a linear mathematical expression. Burden of OS and EL hysterectomies and prostatectomies was calculated by multiplying the number of cases for that year by the cost/case of the procedure.
The number of procedures is expected to increase in the next three years based on historical data. RAL is expected to capture this market by 65% after consultation with experts. If it’s assumed that RAL will capture the current market in Ontario by 65%, the net impact is expected to be by Year 3, 3.1M for hysterectomy and 6.7M for prostatectomy procedures respectively in the province.
RAL has diffused in the province with four surgical systems in place in Ontario, two in Toronto and two in London. RAL is a more expensive technology on a per case basis due to more expensive robot specific instrumentation and physician labour reflected by increased OR time reported in the clinical literature. There is also an upfront cost to acquire the machine and maintenance contract. RAL is expected to capture the market at 65% with project net impacts by Year 3 of 3.1M and 6.7M for hysterectomy and prostatectomy respectively.
PMCID: PMC3382308  PMID: 23074405
11.  Approaches to improve the diagnosis and management of infertility 
Human Reproduction Update  2009;15(4):391-408.
BACKGROUND
Recent advances in our understanding of the causes of infertility and of assisted reproductive technology (ART) have led to the development of complex diagnostic tools, prognostic models and treatment options. The Third Evian Annual Reproduction (EVAR) Workshop Meeting was held on 26–27 April 2008 to evaluate evidence supporting current approaches to the diagnosis and management of infertility and to identify areas for future research efforts.
METHODS
Specialist reproductive medicine clinicians and scientists delivered presentations based on published literature and ongoing research on patient work-up, ovarian stimulation and embryo quality assessment during ART. This report is based on the expert presentations and subsequent group discussions and was supplemented with publications from literature searches and the authors' knowledge.
RESULTS
It was agreed that single embryo transfer (SET) should be used with increasing frequency in cycles of ART. Continued improvements in cryopreservation techniques, which improve pregnancy rates using supernumerary frozen embryos, are expected to augment the global uptake of SET. Adaptation and personalization of fertility therapy may help to optimize efficacy and safety outcomes for individual patients. Prognostic modelling and personalized management strategies based on individual patient characteristics may prove to represent real progress towards improved treatment. However, at present, there is limited good-quality evidence to support the use of these individualized approaches.
CONCLUSIONS
Greater quality control and standardization of clinical and laboratory evaluations are required to optimize ART practices and improve individual patient outcomes. Well-designed, good-quality studies are required to drive improvements to the diagnosis and management of ART processes.
doi:10.1093/humupd/dmp012
PMCID: PMC2691653  PMID: 19380415
infertility work-up; in vitro fertilization; ovarian response; predictive factors; single embryo transfer
12.  The biology of infertility: research advances and clinical challenges 
Nature medicine  2008;14(11):1197-1213.
Reproduction is required for the survival of all mammalian species, and thousands of essential ‘sex’ genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.
doi:10.1038/nm.f.1895
PMCID: PMC3786590  PMID: 18989307
13.  A Cross-Sectional Study of the Psychosexual Impact of Cancer-Related Infertility in Women: Third-Party Reproductive Assistance 
Introduction
This study empirically assessed emotional and sexual functioning, reproductive concerns, and quality of life (QOL) of cancer-related infertile women in comparison to those without a cancer history and explored awareness of third-party reproduction options in cancer survivors.
Methods
One hundred twenty-two cancer survivors (Gynecologic and Bone Marrow/Stem Cell Transplant) with cancer-related infertility and 50 non-cancer infertile women completed a self-report survey assessing: reproductive concerns(RCS), mood(CES-D), distress(IES), sexual function(FSFI), menopause(SCL), QOL(SF-12), relationships(ADAS), and exploratory (reproductive options) items.
Results
Cancer survivors exhibited greater sexual dysfunction and lower physical QOL than non-cancer infertile women (P<0.001). No significant group differences were identified for mood (CES-D), mental health QOL (SF-12), reproductive concerns (RCS), and relationship satisfaction (ADAS). All groups scored in the FSFI range of sexual dysfunction, and with RCS scores above published means. Multivariate comparisons showed comparable depression and distress levels for all groups, but cancer survivors had poorer physical QOL [F(5,146)=4.22, P<0.01]. A significant effect was also found for knowledge of third-party reproductive options on depression and distress levels [F(3,97)=4.62, P<0.01]. Adjusted means demonstrated higher depression and distress scores for women with perceived unmet informational needs.
Conclusions
Overall, loss of fertility was an emotionally challenging experience for women regardless of its cause. Cancer survivors were found to have lower scores of physical QOL and sexual function than non-cancer infertile women. Unmet informational needs about reproductive options appeared to be associated with negative mood and increased distress in cancer survivors.
Implications for Cancer Survivors
Targeted interventions to increase knowledge about reproductive options could be of great assistance to women pursuing parenthood in cancer survivorship. Additionally, intervention studies to improve sexual functioning and QOL in women with cancer-related infertility should be a priority of future research.
doi:10.1007/s11764-010-0121-2
PMCID: PMC3701949  PMID: 20373042
cancer; infertility; survivorship; quality of life; third-party parenting
14.  Ethics reporting practices in clinical research publications: A review of four Indian journals 
Background:
Manuscript authors of scientific journals are expected to report if their studies were conducted according to international and national ethical guidelines and inform readers regarding ethics approval and informed consent obtained from participants and/or their legally acceptable representative/s. In the present study we assessed the reporting practices of ethics approval and informed consent (assent in case of pediatric studies) in four Indian journals.
Materials and Methods:
Original research articles published over a period of 4 years (2009-2012) in four major national clinical journals, viz. Journal of Association of Physicians of India (JAPI), Indian Journal of Surgery (IJS), Journal of Obstetrics and Gynecology of India (JOGI), and Indian Journal of Orthopedics (IJO) were reviewed with regard to documentation of ethics approval and written informed consent and assent in case of pediatric participants.
Results:
We reviewed 673 research articles and found that, overall ethical approval was mentioned in 163 (24.2%) and informed consent or assent was mentioned in 179 (26.5%) articles in all four journals. Individually we found, in JAPI of the 174 manuscripts reviewed, 74 (42.5%) reported having obtained approval from the ethics committee and 68 (39.1%) reported taking written informed consent from participants. In IJS of 123 manuscripts, 18 (14.6%) reported ethics committee approval and 20 (16.2%) reported informed consent from participants. In JOGI of 152 manuscripts, 21 (13.8%) reported ethics committee approval while 49 (32.2%) reported informed consent from participants. In IJO, of 224 manuscripts, 50 (22.3%) reported ethics committee approval and 42 (18.7%) reported obtaining informed consent.
Conclusion:
Majority of the publications did not provide information regarding compliance to ethical guidelines in spite of the availability of various guidelines. Thus, there is a need for awareness and training on bioethics for authors, reviewers, and editors of biomedical journals.
doi:10.4103/2229-3485.134316
PMCID: PMC4073550  PMID: 24987584
Ethical approval; ethics committee; informed consent
15.  Misrepresentation of Randomized Controlled Trials in Press Releases and News Coverage: A Cohort Study 
PLoS Medicine  2012;9(9):e1001308.
A study conducted by Amélie Yavchitz and colleagues examines the factors associated with “spin” (specific reporting strategies, intentional or unintentional, that emphasize the beneficial effect of treatments) in press releases of clinical trials.
Background
Previous studies indicate that in published reports, trial results can be distorted by the use of “spin” (specific reporting strategies, intentional or unintentional, emphasizing the beneficial effect of the experimental treatment). We aimed to (1) evaluate the presence of “spin” in press releases and associated media coverage; and (2) evaluate whether findings of randomized controlled trials (RCTs) based on press releases and media coverage are misinterpreted.
Methods and Findings
We systematically searched for all press releases indexed in the EurekAlert! database between December 2009 and March 2010. Of the 498 press releases retrieved and screened, we included press releases for all two-arm, parallel-group RCTs (n = 70). We obtained a copy of the scientific article to which the press release related and we systematically searched for related news items using Lexis Nexis.
“Spin,” defined as specific reporting strategies (intentional or unintentional) emphasizing the beneficial effect of the experimental treatment, was identified in 28 (40%) scientific article abstract conclusions and in 33 (47%) press releases. From bivariate and multivariable analysis assessing the journal type, funding source, sample size, type of treatment (drug or other), results of the primary outcomes (all nonstatistically significant versus other), author of the press release, and the presence of “spin” in the abstract conclusion, the only factor associated, with “spin” in the press release was “spin” in the article abstract conclusions (relative risk [RR] 5.6, [95% CI 2.8–11.1], p<0.001). Findings of RCTs based on press releases were overestimated for 19 (27%) reports. News items were identified for 41 RCTs; 21 (51%) were reported with “spin,” mainly the same type of “spin” as those identified in the press release and article abstract conclusion. Findings of RCTs based on the news item was overestimated for ten (24%) reports.
Conclusion
“Spin” was identified in about half of press releases and media coverage. In multivariable analysis, the main factor associated with “spin” in press releases was the presence of “spin” in the article abstract conclusion.
Editors' Summary
Background
The mass media play an important role in disseminating the results of medical research. Every day, news items in newspapers and magazines and on the television, radio, and internet provide the general public with information about the latest clinical studies. Such news items are written by journalists and are often based on information in “press releases.” These short communications, which are posted on online databases such as EurekAlert! and sent directly to journalists, are prepared by researchers or more often by the drug companies, funding bodies, or institutions supporting the clinical research and are designed to attract favorable media attention to newly published research results. Press releases provide journalists with the information they need to develop and publish a news story, including a link to the peer-reviewed journal (a scholarly periodical containing articles that have been judged by independent experts) in which the research results appear.
Why Was This Study Done?
In an ideal world, journal articles, press releases, and news stories would all accurately reflect the results of health research. Unfortunately, the findings of randomized controlled trials (RCTs—studies that compare the outcomes of patients randomly assigned to receive alternative interventions), which are the best way to evaluate new treatments, are sometimes distorted in peer-reviewed journals by the use of “spin”—reporting that emphasizes the beneficial effects of the experimental (new) treatment. For example, a journal article may interpret nonstatistically significant differences as showing the equivalence of two treatments although such results actually indicate a lack of evidence for the superiority of either treatment. “Spin” can distort the transposition of research into clinical practice and, when reproduced in the mass media, it can give patients unrealistic expectations about new treatments. It is important, therefore, to know where “spin” occurs and to understand the effects of that “spin”. In this study, the researchers evaluate the presence of “spin” in press releases and associated media coverage and analyze whether the interpretation of RCT results based on press releases and associated news items could lead to the misinterpretation of RCT results.
What Did the Researchers Do and Find?
The researchers identified 70 press releases indexed in EurekAlert! over a 4-month period that described two-arm, parallel-group RCTs. They used Lexis Nexis, a database of news reports from around the world, to identify associated news items for 41 of these press releases and then analyzed the press releases, news items, and abstracts of the scientific articles related to each press release for “spin”. Finally, they interpreted the results of the RCTs using each source of information independently. Nearly half the press releases and article abstract conclusions contained “spin” and, importantly, “spin” in the press releases was associated with “spin” in the article abstracts. The researchers overestimated the benefits of the experimental treatment from the press release as compared to the full-text peer-reviewed article for 27% of reports. Factors that were associated with this overestimation of treatment benefits included publication in a specialized journal and having “spin” in the press release. Of the news items related to press releases, half contained “spin”, usually of the same type as identified in the press release and article abstract. Finally, the researchers overestimated the benefit of the experimental treatment from the news item as compared to the full-text peer-reviewed article in 24% of cases.
What Do These Findings Mean?
These findings show that “spin” in press releases and news reports is related to the presence of “spin” in the abstract of peer-reviewed reports of RCTs and suggest that the interpretation of RCT results based solely on press releases or media coverage could distort the interpretation of research findings in a way that favors experimental treatments. This interpretation shift is probably related to the presence of “spin” in peer-reviewed article abstracts, press releases, and news items and may be partly responsible for a mismatch between the perceived and real beneficial effects of new treatments among the general public. Overall, these findings highlight the important role that journal reviewers and editors play in disseminating research findings. These individuals, the researchers conclude, have a responsibility to ensure that the conclusions reported in the abstracts of peer-reviewed articles are appropriate and do not over-interpret the results of clinical research.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001308.
The PLOS Hub for Clinical Trials, which collects PLOS journals relating to clinical trials, includes some other articles on “spin” in clinical trial reports
EurekAlert is an online free database for science press releases
The UK National Health Service Choices website includes Beyond the Headlines, a resource that provides an unbiased and evidence-based analysis of health stories that make the news for both the public and health professionals
The US-based organization HealthNewsReview, a project supported by the Foundation for Informed Medical Decision Making, also provides expert reviews of news stories
doi:10.1371/journal.pmed.1001308
PMCID: PMC3439420  PMID: 22984354
16.  Current status of assisted reproductive technology in Korea, 2009 
Obstetrics & Gynecology Science  2013;56(6):353-361.
Great advances have been made in the field of assisted reproductive technology (ART) since the first in vitro fertilization (IVF) baby was born in Korea in the year of 1985. However, it deserve to say that the invaluable data from fertility centers may serve as a useful source to find out which factors affect successful IVF outcome and to offer applicable information to infertile patients and fertility clinics. This article intended to report the status of ART in 2009 Korean Society of Obstetrics and Gynecology surveyed. The current survey was performed to assess the status and success rate of ART performed in Korea, between January 1 and December 31, 2009. Reporting forms had been sent out to IVF centers via e-mail, and collected by e-mail as well in 2012. With International Committee Monitoring Assisted Reproductive Technologies recommendation, intracytoplasmic sperm injection (ICSI) and non-ICSI cases have been categorized and also IVF-ET cases involving frozen embryo replacement have been surveyed separately. Seventy-four centers have reported the treatment cycles initiated in the year of 2009, and had performed a total of 27,947 cycles of ART treatments. Among a total of 27,947 treatment cycles, IVF and ICSI cases added up to 22,049 (78.9%), with 45.3% IVF without ICSI and 54.7% IVF with ICSI, respectively. Among the IVF and ICSI patients, patients confirmed to have achieved clinical pregnancy was 28.8% per cycle with oocyte retrieval, and 30.9% per cycle with embryo transfer. The most common number of embryos transferred in 2009 is three embryos (40.4%), followed by 2 embryos (28.4%) and a single embryo transferred (13.6%). Among IVF and ICSI cycles that resulted in multiple live births, twin pregnancy rate was 45.3% and triple pregnancy rate was 1.1%. A total of 191 cases of oocyte donation had been performed to result in 25.0% of live birth rate. Meanwhile, a total of 5,619 cases of frozen embryo replacement had been performed with 33.7% of clinical pregnancy rate per cycle with embryo transfer. When comparing with international registry data, clinical pregnancy rate per transfer from fresh IVF cycles including ICSI (34.1%,) was comparable to clinical pregnancy rate per transfer in European Society for Human Reproduction and Embryology report was 32.5% though lower than 45.0% for USA data. There was no remarkable difference in status of assisted reproductive technology in Korea between the current report and the data reported in 2008. The age of women trying to get pregnant was reconfirmed to be the most important factor that may have impact on success of ART treatment.
doi:10.5468/ogs.2013.56.6.353
PMCID: PMC3859020  PMID: 24396813
International Committee for Monitoring Assisted Reproductive Technologies; Korea; Reproductive techniques; Survey
17.  Fertility Preservation 
Mayo Clinic Proceedings  2011;86(1):45-49.
Of the estimated 1.5 million men and women who were diagnosed as having cancer in 2010, approximately 10% are younger than 45 years. For these individuals, cancer treatment can be lifesaving but can permanently affect reproductive capacity. The American Society of Clinical Oncology has recommended that oncologists discuss the possibility of infertility with reproductive-age cancer patients and offer referral for fertility preservation consultation and therapy. Fertility preservation is an emerging field that offers treatment aimed at protecting future reproductive ability for individuals with cancer or other serious illnesses. Although fertility preservation strategies vary by patient age and sex, many allow patients to store gametes or reproductive tissues for potential future use to create offspring. As an emerging discipline, many questions remain about the role of fertility preservation. We performed a MEDLINE search from 1950 to June 2010 using the following MeSH terms: amenorrhea; antineoplastic agents; ovarian failure; premature; infertility, female; fertility preservation; infertility, male; adolescent and cancer; child and cancer; cryopreservation; and reproductive technologies, assisted. Studies considered for inclusion included those written in English and published before June 2010.
doi:10.4065/mcp.2010.0564
PMCID: PMC3012633  PMID: 21193655
18.  A small field for fertile science: the low visibility of reproductive science in high impact journals 
Purpose
Our success as a field and as individuals in reproductive science and medicine relies on our ability to produce high quality work that has broad visibility and impact. A common metric for assessing such success is the quantity of publications that are published in journals with high impact factors. It is unclear, however, how frequently work related to reproductive science and medicine actually appears in what are considered the highest impact journals.
Methods
To address this gap in knowledge, we first determined how the field of reproductive biology in general compared to other research areas in terms of composite journal impact factor. Second, using a targeted search approach in the PubMed database, we examined the relationship between a journal’s impact factor and the number of reproductive research articles published per journal issue.
Results
We found that compared to other major scientific disciplines, our field lacks journals with impact factors above 4. In addition, primary original research articles on reproduction—irrespective of male or female search terms—do not appear often in high impact journals. Instead, there is an increased percentage of secondary reproductive literature in high impact journals compared to topic-specific journals of lower impact.
Conclusions
There are likely several explanations for why reproductive science and medicine has low visibility, including the field’s small relative size, its lack of a specific disease and associated strong advocacy, and its surrounding social, ethical, and political unease. Nevertheless, there are concrete actions we can take to minimize the role of impact factor in our evaluation while simultaneously increasing influence through global awareness of the importance and need for reproductive research.
doi:10.1007/s10815-014-0205-4
PMCID: PMC4016373  PMID: 24652516
Reproduction; Impact factor; Male; Female; Gamete; Gonad; Ovary; Testis; Mammalian
19.  How international is bioethics? A quantitative retrospective study 
BMC Medical Ethics  2006;7:1.
Background
Studying the contribution of individual countries to leading journals in a specific discipline can highlight which countries have the most impact on that discipline and whether a geographic bias exists. This article aims to examine the international distribution of publications in the field of bioethics.
Methods
Retrospective quantitative study of nine peer reviewed journals in the field of bioethics and medical ethics (Bioethics, Cambridge Quarterly of Healthcare Ethics, Hastings Center Report, Journal of Clinical Ethics, Journal of Medical Ethics, Kennedy Institute of Ethics Journal, Nursing Ethics, Christian Bioethics, and Theoretical Medicine and Bioethics).
Results
In total, 4,029 articles published between 1990 and 2003 were retrieved from the nine bioethical journals under study. The United States (59.3%, n = 2390), the United Kingdom (13.5%, n = 544), Canada (4%, n = 160) and Australia (3.8%, n = 154) had the highest number of publications in terms of absolute number of publications. When normalized to population size, smaller affluent countries, such as New Zealand, Finland and Sweden were more productive than the United States. The number of studies originating from the USA was decreasing in the period between 1990 and 2003.
Conclusion
While a lot of peer reviewed journals in the field of bioethics profile themselves as international journals, they certainly do not live up to what one would expect from an "international" journal. The fact that English speaking countries, and to a larger extent American authors, dominate the international journals in the field of bioethics is a clear geographic bias towards the bioethical discussions that are going on in these journals.
doi:10.1186/1472-6939-7-1
PMCID: PMC1351197  PMID: 16412229
20.  State-mandated insurance coverage is associated with the approach to hydrosalpinges before IVF 
Reproductive biomedicine online  2014;29(1):131-135.
The aim of this study was to determine whether practice in states with infertility insurance mandates is associated with physician-reported practice patterns regarding hydrosalpinx management in assisted reproduction clinics. A cross-sectional, internet-based survey of 442 members of Society for Reproductive Endocrinology and Infertility or Society of Reproductive Surgeons was performed. Physicians practising in states without infertility insurance mandates were more likely to report performing diagnostic surgery after an inconclusive hysterosalpingogram than physicians practising in states with mandates (RR 1.2, 95% CI 1.1–1.3, P < 0.01). Additionally, respondents in states without mandates were more likely to report that, due to lack of infertility insurance coverage, they did not perform salpingectomy (SPX) or proximal tubal occlusion (PTO) before assisted reproduction treatment (RR 1.4, 95% CI 1.1–1.8, P = 0.01). Finally, respondents in states without mandates were less likely to report that the presence of assisted reproduction treatment coverage determined the urgency with which they pursued SPX or PTO before treatment (RR 0.7, 95% CI 0.5–1.0, NS). These results persisted after controlling for physician years in practice, age and clinic volume. In conclusion, self-reported physician practice interventions for hydrosalpinges before assisted reproduction treatment may be associated with state-mandated infertility insurance.
doi:10.1016/j.rbmo.2014.03.007
PMCID: PMC4114072  PMID: 24813751
assisted reproduction treatment; hydrosalpinx; insurance coverage; mandate; salpingectomy
21.  Reporting and Methods in Clinical Prediction Research: A Systematic Review 
PLoS Medicine  2012;9(5):e1001221.
Walter Bouwmeester and colleagues investigated the reporting and methods of prediction studies in 2008, in six high-impact general medical journals, and found that the majority of prediction studies do not follow current methodological recommendations.
Background
We investigated the reporting and methods of prediction studies, focusing on aims, designs, participant selection, outcomes, predictors, statistical power, statistical methods, and predictive performance measures.
Methods and Findings
We used a full hand search to identify all prediction studies published in 2008 in six high impact general medical journals. We developed a comprehensive item list to systematically score conduct and reporting of the studies, based on recent recommendations for prediction research. Two reviewers independently scored the studies. We retrieved 71 papers for full text review: 51 were predictor finding studies, 14 were prediction model development studies, three addressed an external validation of a previously developed model, and three reported on a model's impact on participant outcome. Study design was unclear in 15% of studies, and a prospective cohort was used in most studies (60%). Descriptions of the participants and definitions of predictor and outcome were generally good. Despite many recommendations against doing so, continuous predictors were often dichotomized (32% of studies). The number of events per predictor as a measure of statistical power could not be determined in 67% of the studies; of the remainder, 53% had fewer than the commonly recommended value of ten events per predictor. Methods for a priori selection of candidate predictors were described in most studies (68%). A substantial number of studies relied on a p-value cut-off of p<0.05 to select predictors in the multivariable analyses (29%). Predictive model performance measures, i.e., calibration and discrimination, were reported in 12% and 27% of studies, respectively.
Conclusions
The majority of prediction studies in high impact journals do not follow current methodological recommendations, limiting their reliability and applicability.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
There are often times in our lives when we would like to be able to predict the future. Is the stock market going to go up, for example, or will it rain tomorrow? Being able predict future health is also important, both to patients and to physicians, and there is an increasing body of published clinical “prediction research.” Diagnostic prediction research investigates the ability of variables or test results to predict the presence or absence of a specific diagnosis. So, for example, one recent study compared the ability of two imaging techniques to diagnose pulmonary embolism (a blood clot in the lungs). Prognostic prediction research investigates the ability of various markers to predict future outcomes such as the risk of a heart attack. Both types of prediction research can investigate the predictive properties of patient characteristics, single variables, tests, or markers, or combinations of variables, tests, or markers (multivariable studies). Both types of prediction research can include also studies that build multivariable prediction models to guide patient management (model development), or that test the performance of models (validation), or that quantify the effect of using a prediction model on patient and physician behaviors and outcomes (impact assessment).
Why Was This Study Done?
With the increase in prediction research, there is an increased interest in the methodology of this type of research because poorly done or poorly reported prediction research is likely to have limited reliability and applicability and will, therefore, be of little use in patient management. In this systematic review, the researchers investigate the reporting and methods of prediction studies by examining the aims, design, participant selection, definition and measurement of outcomes and candidate predictors, statistical power and analyses, and performance measures included in multivariable prediction research articles published in 2008 in several general medical journals. In a systematic review, researchers identify all the studies undertaken on a given topic using a predefined set of criteria and systematically analyze the reported methods and results of these studies.
What Did the Researchers Do and Find?
The researchers identified all the multivariable prediction studies meeting their predefined criteria that were published in 2008 in six high impact general medical journals by browsing through all the issues of the journals (a hand search). They then scored the methods and reporting of each study using a comprehensive item list based on recent recommendations for the conduct of prediction research (for example, the reporting recommendations for tumor marker prognostic studies—the REMARK guidelines). Of 71 retrieved studies, 51 were predictor finding studies, 14 were prediction model development studies, three externally validated an existing model, and three reported on a model's impact on participant outcome. Study design, participant selection, definitions of outcomes and predictors, and predictor selection were generally well reported, but other methodological and reporting aspects of the studies were suboptimal. For example, despite many recommendations, continuous predictors were often dichotomized. That is, rather than using the measured value of a variable in a prediction model (for example, blood pressure in a cardiovascular disease prediction model), measurements were frequently assigned to two broad categories. Similarly, many of the studies failed to adequately estimate the sample size needed to minimize bias in predictor effects, and few of the model development papers quantified and validated the proposed model's predictive performance.
What Do These Findings Mean?
These findings indicate that, in 2008, most of the prediction research published in high impact general medical journals failed to follow current guidelines for the conduct and reporting of clinical prediction studies. Because the studies examined here were published in high impact medical journals, they are likely to be representative of the higher quality studies published in 2008. However, reporting standards may have improved since 2008, and the conduct of prediction research may actually be better than this analysis suggests because the length restrictions that are often applied to journal articles may account for some of reporting omissions. Nevertheless, despite some encouraging findings, the researchers conclude that the poor reporting and poor methods they found in many published prediction studies is a cause for concern and is likely to limit the reliability and applicability of this type of clinical research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001221.
The EQUATOR Network is an international initiative that seeks to improve the reliability and value of medical research literature by promoting transparent and accurate reporting of research studies; its website includes information on a wide range of reporting guidelines including the REMARK recommendations (in English and Spanish)
A video of a presentation by Doug Altman, one of the researchers of this study, on improving the reporting standards of the medical evidence base, is available
The Cochrane Prognosis Methods Group provides additional information on the methodology of prognostic research
doi:10.1371/journal.pmed.1001221
PMCID: PMC3358324  PMID: 22629234
22.  Exposure to hazardous substances and male reproductive health: a research framework. 
Environmental Health Perspectives  2000;108(9):803-813.
The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving.
PMCID: PMC2556920  PMID: 11017884
23.  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
24.  National, Regional, and Global Trends in Infertility Prevalence Since 1990: A Systematic Analysis of 277 Health Surveys 
PLoS Medicine  2012;9(12):e1001356.
Gretchen Stevens and colleagues use information from demographic reproductive health surveys to estimate the global, regional, and country levels, patterns, and trends in infertility between 1990 and 2010.
Background
Global, regional, and national estimates of prevalence of and tends in infertility are needed to target prevention and treatment efforts. By applying a consistent algorithm to demographic and reproductive surveys available from developed and developing countries, we estimate infertility prevalence and trends, 1990 to 2010, by country and region.
Methods and Findings
We accessed and analyzed household survey data from 277 demographic and reproductive health surveys using a consistent algorithm to calculate infertility. We used a demographic infertility measure with live birth as the outcome and a 5-y exposure period based on union status, contraceptive use, and desire for a child. We corrected for biases arising from the use of incomplete information on past union status and contraceptive use. We used a Bayesian hierarchical model to estimate prevalence of and trends in infertility in 190 countries and territories. In 2010, among women 20–44 y of age who were exposed to the risk of pregnancy, 1.9% (95% uncertainty interval 1.7%, 2.2%) were unable to attain a live birth (primary infertility). Out of women who had had at least one live birth and were exposed to the risk of pregnancy, 10.5% (9.5%, 11.7%) were unable to have another child (secondary infertility). Infertility prevalence was highest in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Levels of infertility in 2010 were similar to those in 1990 in most world regions, apart from declines in primary and secondary infertility in Sub-Saharan Africa and primary infertility in South Asia (posterior probability [pp] ≥0.99). Although there were no statistically significant changes in the prevalence of infertility in most regions amongst women who were exposed to the risk of pregnancy, reduced child-seeking behavior resulted in a reduction of primary infertility among all women from 1.6% to 1.5% (pp = 0.90) and a reduction of secondary infertility among all women from 3.9% to 3.0% (pp>0.99) from 1990 to 2010. Due to population growth, however, the absolute number of couples affected by infertility increased from 42.0 million (39.6 million, 44.8 million) in 1990 to 48.5 million (45.0 million, 52.6 million) in 2010. Limitations of the study include gaps in survey data for some countries and the use of proxies to determine exposure to pregnancy.
Conclusions
We analyzed demographic and reproductive household survey data to reveal global patterns and trends in infertility. Independent from population growth and worldwide declines in the preferred number of children, we found little evidence of changes in infertility over two decades, apart from in the regions of Sub-Saharan Africa and South Asia. Further research is needed to identify the etiological causes of these patterns and trends.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Reproductive health is a priority global health area: the target for Millennium Development Goal 5B is to provide universal access to reproductive health by 2015. The indicators for monitoring progress in reaching this target are contraceptive prevalence rate, adolescent birth rate, antenatal care coverage, and the unmet need for family planning. Infertility, the inability to conceive after a prolonged period (the length of time varies in different definitions) of unprotected intercourse, is a critical but much neglected aspect of reproductive health. The inability to have children affects couples worldwide and causes emotional and psychological distress in both men and women. Many factors—including physiological, genetic, environmental, and social— contribute to infertility. According to the World Health Organization, infertility resulting from sexually transmitted diseases or reproductive tract infections is particularly problematic in Africa and Latin America.
Why Was This Study Done?
The researchers used a uniform measure of infertility that incorporated live birth as the outcome of interest (as this information is more commonly reported than pregnancies), a five-year “exposure period,” that is, a five-year period of being in an intimate relationship, not using contraceptives, and wanting a child (as the researchers calculated that this period was necessary to accommodate the time it takes to become pregnant and have a child, and to allow for incomplete information on frequency of unprotected intercourse). The researchers used a statistical model (Bayesian hierarchical model) to generate estimates for levels and trends of infertility in 190 countries over the time period 1990 to 2010 using information collected from national demographic and reproductive health surveys. The most data was available for South Asia and Sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers found that in 2010, 1.9% of women aged 20–44 years who wanted to have children were unable to have their first live birth (primary infertility), and 10.5% of women with a previous live birth were unable to have an additional live birth (secondary infertility). The researchers found that the levels of infertility were similar in 1990 and 2010, with only a slight overall decrease in primary infertility (0.1%, but with a more pronounced drop in Sub-Saharan Africa and South Asia) and a modest overall increase in secondary infertility (0.4%). Age affected infertility rates: the prevalence of primary infertility was higher among women aged 20–24 years than among older women. The age pattern was reversed and even more pronounced for secondary infertility. And primary infertility rates among women wanting children also varied by region, from 1.5% in Latin America and the Caribbean in 2010, to 2.6% in North Africa and the Middle East. With a few exceptions, global and country patterns of secondary infertility were similar to those of primary infertility.
What Do These Findings Mean?
These findings suggest that in 2010, an estimated 48.5 million couples worldwide were unable to have a child after five years. However, these findings also suggest that global levels of primary and secondary infertility hardly changed between 1990 and 2010. It is important to note that an infertility measure based on ability to become pregnant (rather than having a live birth—the outcome used in this study) may show different levels of infertility, and using an exposure period shorter than the five years used in this study would produce higher rates of infertility. However, because of the lack of widespread data collection on time to pregnancy, the methods used and results shown in this study provide useful insights into global, regional, and country patterns and trends in infertility.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001356.
The World Health Organization has information on reproductive health
Wikipedia defines infertility and gives some useful information (note that Wikipedia is a free online encyclopedia that anyone can edit)
Patient friendly information on infertility can be found at PubMed Health and NHS Choices
doi:10.1371/journal.pmed.1001356
PMCID: PMC3525527  PMID: 23271957
25.  Childhood Conditions Influence Adult Progesterone Levels 
PLoS Medicine  2007;4(5):e167.
Background
Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence.
Methods and Findings
To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19–39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227). Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R2 = 0.16). Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03) and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04).
Conclusions
This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults. Given the prolonged investment of human pregnancy and lactation, such plasticity (extending beyond any intrauterine programming) enables a more flexible and finely tuned adjustment to the potential constraints or opportunities of the later adult environment. This research is the first, to our knowledge, to demonstrate a postuterine developmental component to variation in reproductive steroid levels in women.
Alejandra Núñez-de la Mora and colleagues found that women of Bangladeshi origin who had spent their childhood in the UK had higher progesterone levels and matured earlier than those who had been children in Bangladesh.
Editors' Summary
Background.
Women's reproductive biology—which includes levels of sex hormones at different stages of the menstrual cycle—is known to vary greatly depending on the environment. This variation can be measured by looking at the levels of certain reproductive hormones in the saliva, for example, progesterone and estradiol. The levels of these hormones differ greatly from individual to individual. Women who live in environments where less food is available or infections are more common, or who do more physical work seem to have lower levels of these hormones compared to other women. Because these differences seem to persist over the long term, some researchers have suggested that various factors relating to an individual's environment early in life have a strong influence on later fertility. This theory is based on ideas drawn from evolutionary biology and ecology. Theoretically, a woman who limits her future fertility as a biological response to poor environments would eventually have greater evolutionary success than an individual who remains fertile in harsh conditions. Although the logical basis for this idea is attractive, there is not very much evidence that it is true.
Why Was This Study Done?
In this study, the researchers wanted to collect experimental evidence from human populations that would help them test the hypothesis outlined above. The study performed here made use of a “natural experiment” resulting from widespread migration of people from Bangladesh to the UK. 95% of these individuals come from one particular region of Bangladesh, Sylhet. People would experience extensive differences between the environments before and after migration, including economic factors, access to health services, exposure to infectious diseases, and so on. Therefore, a comparison of hormone levels between individuals who had migrated at different periods during their life might help to test the theory that early environmental factors affect later fertility.
What Did the Researchers Do and Find?
Five groups of women were selected and compared in this study. The groups included women who had grown up in Bangladesh but moved to the UK as adults; women who were born in Bangladesh but moved to the UK as children; women whose parents were from Bangladesh but who were born and raised in the UK; Bangladeshi women who were born and raised in Bangladesh; and finally a comparison group of women of European descent who were born and raised in the UK. Each woman in each of the five groups was asked to collect a sample of her own saliva each day for one menstrual cycle. The researchers tested the saliva samples to find out the levels of progesterone. The average progesterone level for the last 14 days of each woman's menstrual cycle (when progesterone levels are generally high) was then calculated and these values compared across the five groups. In particular, the researchers looked at the relationship between the age at which an individual arrived in the UK, the time spent in the UK, and the progesterone levels in saliva.
The researchers found statistically significant differences in progesterone levels between individuals who had migrated as children, second-generation migrants, and women of European descent, as compared to the levels for Bangladeshi women who had never migrated and women who migrated as adults. Progesterone levels for the first three groups were higher than those for the Bangladeshi women who had not migrated or who had migrated as adults. The age at which women migrated also seemed to be linked to their progesterone levels. Amongst women who migrated before the start of menstruation, those who migrated at a younger age had higher average progesterone levels. However, this relationship did not seem to hold true for women who had migrated after they started menstruating.
What Do These Findings Mean?
This study suggests that certain indicators of reproductive biology, such as progesterone levels, may be linked to environmental factors that an individual experiences early in life. The findings support the idea that harsh environments early in development are associated with lower fertility later in life. However, it is not clear from this study which precise environmental factors are involved; it is possible that exposure to infectious disease is important, but this possibility was not specifically tested in this research study. Finally, it is not certain whether the lower average progesterone levels of the particular groups studied would actually translate into lower fertility. It is possible that although certain individuals and groups had lower levels of this hormone, they may in fact have been as fertile as individuals with higher levels of the hormone.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040167.
Information from the US National Institutes of Health on fertility and infertility
Wikipedia entry on progesterone (Wikipedia is an internet encyclopedia anyone can edit)
Resources from the World Health Organization about sexual and reproductive health, including links to resources on family planning, infertility, and other related topics
World Health Organization country site for Bangladesh, providing key statistics and health resources
Moving Here: stories and experiences told of individuals' emigration to the UK
doi:10.1371/journal.pmed.0040167
PMCID: PMC1868040  PMID: 17503960

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