The Cochrane Collaboration: Medicine’s Best-Kept Secret

By Alan Cassels, Foreward by Sir Iain Chalmers, 2015

The-Cochrane-Collaboration book cover omage
To celebrate its 20th anniversary, writer and professional medical skeptic Alan Cassels was selected to draw back the curtains on the Cochrane Collaboration. His extensive interviews of Cochranites allowed him to document their achievements, resulting in a book that its leadership ultimately refused to publish.

” In the complex, ever-evolving realm of modern medicine, how can you even begin to understand what’s hocus-pocus and what really works? Best-selling author and researcher Alan Cassels answers with a single word: Cochrane.

Though largely unknown to the public, the Cochrane Collaboration is made up of more than 30,000 medical researchers and consumer representatives from more than 100 countries – unbiased experts and investigators who parse the science of modern health care and delve deep into the evidence (or lack thereof) to determine what works and what doesn’t.

In this frank, factual and entertaining volume, Cassels draws from more than 160 interviews to shed light on this international cadre of medical truth-seekers whose rigorous work helps prevent medical misjudgement, reduce unnecessary suffering, preserve lives and circumvent the squandering of billions of dollars. “

More books from Alan Cassels

DES and the identification problem

DES plaintiffs face many problems, both legal and practical

Proposals to “further strengthen product liability laws as a substitute for direct government intervention“‘ were studied in this 1983 study.

AKRON LAW REVIEW, Vol. 16:3, by BARRY S. ROBERTS and CHARLES F. RoYSTER. full PDF Winter, 1983.

Diethylstilbestrol (DES), a synthetic estrogen, was developed in 19371 and was widely prescribed in the 1940’s, 1950’s and 1960’s for pregnant women to prevent miscarriages.

The drug has caused a number of maladies to daughters who were exposed in utero to the drug, the most serious of which is clear cell adenocarcinoma, a rare form of vaginal cancer.

The Food and Drug Administration (FDA) withdrew its approval of DES as a miscarriage preventative in 1971, and since then the focus has shifted to products liability actions filed against the drug manufacturers. The plaintiffs have been largely unsuccessful in these actions, although some innovative judicial theories have recently been advanced in allowing recovery.

This article will examine the history of this drug, how it was used and regulated as well as the subsequent legal turmoil and the proffered resolutions to the quandary. The impact of these theories and of proposals to “further strengthen product liability laws as a substitute for direct government intervention“‘ will also be studied.

More DES DiEthylStilbestrol Resources

Tackling Antimicrobial Resistance

How healthcare professionals, and those working in local authorities, can bring down levels of antibiotic prescribing

The pressure on healthcare professionals to prescribe antibiotics is great. But we need to conserve antibiotics and use them appropriately or we risk losing the power of these medicines.

  1. The scale of the problem
  2. Why we need to act now
  3. Antibiotic prescribing in England
  4. How we can put down on inappropriate prescribing
  5. We all have a role to play

Sources and more information

Pesticides in dairy products linked to Parkinson’s disease

Pesticide Found in Milk Decades Ago May Be Associated with Signs of Parkinson’s

image of cow-grazing
A pesticide used prior to the early 1980s and found in milk at that time may be associated with signs of Parkinson’s disease in the brain, according to a study published in the December 9, 2015, online issue of Neurology®, the medical journal of the American Academy of Neurology. Cows Grazing.

2015 Study Abstract

Objective
To examine the relationship between midlife milk intake and Parkinson disease (PD) incidence through associations with substantia nigra (SN) neuron density and organochlorine pesticide exposure in decedent brains from the Honolulu-Asia Aging Study.

Methods
Milk intake data were collected from 1965 to 1968 in 449 men aged 45–68 years with postmortem examinations from 1992 to 2004. Neuron density (count/mm2) was measured in quadrants from a transverse section of the SN. Additional measures included brain residues of heptachlor epoxide, an organochlorine pesticide found at excessively high levels in the milk supply in Hawaii in the early 1980s.

Results
Neuron density was lowest in nonsmoking decedents who consumed high amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d vs intake that was less (95% confidence interval 22.7%–55.7%, p < 0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in 9 of 10 brains as compared to 63.4% (26/41) for those who consumed no milk (p = 0.017). For those who were ever smokers, an association between milk intake and neuron density was absent.

Conclusions
Milk intake is associated with SN neuron loss in decedent brains unaffected by PD. Whether contamination of milk with organochlorine pesticides has a role in SN neurodegeneration warrants further study.

Sources and more information
  • Midlife milk consumption and substantia nigra neuron density at death, AAN,
    doi.org/10.1212/WNL.0000000000002254, December 9, 2015.
  • Pesticide Found in Milk Decades Ago May Be Associated with Signs of Parkinson’s,
    American Academy of Neurology (AAN), December 09, 2015.

Female fertility prognosis and diethylstilbestrol – high-risk pregnancies and successful childbearing

Adapted psychological and medical care can lead to successful childbearing

Las-manos-del-destino
In spite of their difficult past reproductive history 4 young DES-women conceived successfully with adapted psychological and medical care in 1998 in France. Las manos del destino.

1998 Study Abstract

Diethylstilbestrol (DES) exposure in utero in females is a cause of clear-cell adenocarcinoma of the cervix and of several anatomical and functional disorders of the genital tract. DES exposure must be evoked whenever counselling women for reproductive disorders.

In France around 80,000 women have had in utero DES exposure. The cases of 4 young women who consulted our Reproduction Center for reproductive disorders illustrate the usual difficulties faced by these patients.

In spite of their difficult past reproductive history (uterine malformations, repeated miscarriages, ectopic pregnancies) and low fertility rate, all four women conceived successfully, either after spontaneous or induced ovulation. We stress the need for adapted psychological and medical care which can lead to successful childbearing in the vast majority of these high-risk patients.

Sources and more information
  • Female fertility prognosis and diethylstilbestrol. Personal data and review of the literature, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PMID: 9648005, 1998 Apr.
More DES DiEthylStilbestrol Resources

Are we one giant step closer to the end of antibiotics?

Bacteria Resistant to ALL Drugs Shows up in Denmark

superbug image
Bacteria resistant to ALL antibiotics have arrived in Europe, and experts fear it could be the start of a global epidemic of untreatable infections.

Agricultural use of antibiotics is by far the greatest threat to us, promoting drug resistance on a grander scale than hospital use. We must get all countries to agree to eliminate colistin and carbapenem antibiotics, in particular, from animal use. They are our last ditch antibiotics at a time when there is little drug development. This, and limiting some types of food imports, will slow the tide of this latest superbug threatening us. Its arrival is inevitable though, given global travel and trade. We’ll just need to keep our finger in the dike for now while hoping that the government will restrict the importation of foods likely to be carriers of this gene, greatly reduce or bar the use of critical antibiotics in agriculture, and will allocate new resources to the development of treatments for these resistant organisms.

  • Continue reading New Superbug Resistant To All Antibiotics Linked To Imported Meat, forbes, DEC 10, 2015.
  • Statement by Antibiotic Resistance Action Center on spread of dangerous superbug gene from China to Denmark, publichealth, December 3, 2015.

Methodology for EU EDC screening

Impact assessment on criteria to identify endocrine disruptors – technical meeting on the Joint Research Center methodology

European Commission Joint Research Center presents chemical screening methodology for the impact assessment on criteria to identify endocrine disruptors

A technical meeting on the JRC methodology for evidence screening of chemicals developed in the context of the Impact Assessment on criteria to identify Endocrine Disruptors took place on 6 November 2015 in Brussels.

The aim of this technical meeting was to present to Member States, Members of the European Parliament, countries from outside the EU and stakeholders the methodology developed by the JRC to estimate which chemicals may fall under the different options for criteria to identify endocrine disruptors as outlined in the roadmap. This methodology was developed in the framework of the impact assessment carried out by the European Commission on criteria to identify endocrine disruptors, in the context of the Plant Protection Products Regulation (EC) 1107/2009 and the Biocidal Products Regulation (EU) 528/2012.

Sources and more information
  • EU Public Health press release.
  • Selection of chemical substances to be screened in the context of the impact assessment on criteria to identify endocrine disruptors, EU PDF.
  • Watch it Full Screen on via SlideShare.
  • DES Daughter Network on SlideShare.

Compensation for DES-victims and the Dutch collective settlement

DES mothers who developed (or will develop) breast cancer should be compensated, taking into account the attributable risk

Compensation for diethylstilbestrol injury and Dutch DES-victims, an opinion.

Flora E van Leeuwenemail, Elisabeth JM van Erp, Theo JM Helmerhorst, Peter AM Heintz, April 2007.

As members of the Dutch Expert Committee on DES-related Health Effects, we respond to the Comment by Ellen ‘t Hoen and Graham Dukes on compensation for diethylstilbestrol injury.

Contrary to the opinion expressed by ‘t Hoen and Dukes, we, as well as the Dutch DES Centre, strongly believe that the recently agreed collective settlement of diethylstilbestrol claims in the Netherlands is unique and highly beneficial for Dutch diethylstilbestrol victims. Our opinion is based on the large number of diethylstilbestrol-related disorders covered and the fact that individual women do not have to start an expensive and emotionally difficult legal procedure with uncertain outcome, which could last several years. Individual women can now be compensated on the basis of medical evidence of diethylstilbestrol exposure and the presence of a diethylstilbestrol-related disorder covered by the settlement.

In close collaboration with the DES Centre, a careful procedure was followed before a settlement was proposed. The Expert Committee first reviewed published data on diethylstilbestrol-related health effects and decided for which disorders a causal association with diethylstilbestrol was established. We believe that no causal association has been established for breast cancer and early age at menopause in women whose mothers took diethylstilbestrol during pregnancy (“DES daughters”) because increased risks were reported in only one study. Subsequently, we determined the relative risk associated with diethylstilbestrol, on the basis of all available published data.

A unique aspect of the Dutch collective settlement is that it also allows compensation for diseases with a weak but established association with diethylstilbestrol. DES mothers (those who took diethylstilbestrol during pregnancy) have a 1·35-fold increased risk of breast cancer. This implies that the attributable risk is 26%—ie, among DES mothers with breast cancer, one in four cases can be attributed to diethylstilbestrol. Since there is no way to identify the one woman whose breast cancer was indeed caused by diethylstilbestrol, it was agreed that all (living) DES mothers who developed (or will develop) breast cancer should be compensated, taking into account the attributable risk.

The proposed collective settlement was widely publicised among those exposed to diethylstilbestrol, and, of more than 100 000 affected, the Amsterdam court received only four objections. The court validated the diethylstilbestrol agreement and ruled against the four defendants. We regret that this information was not included the Comment.

We declare that we have no conflict of interest. ”

Flora E van Leeuwen, Elisabeth J M van Erp, Theo J M Helmerhorst, Peter A M Heintz,
Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherland.

Sources (c) DES Centrum 2015,
DES Fonds 1e regelingcompensation for diethylstilbestrol injury.

More DES DiEthylStilbestrol Resources

Human Gene Editing important issues and need for appropriate regulatory oversight

Scientists urge caution on human gene editing

image of statue Human-Gene-Editing
The 2015 International Summit on Human Gene Editing concluded that it would be “irresponsible” to use a powerful tool for editing human genes until more is known about the consequences and ethics of passing genetic changes to future generations.

Abstract – 2015 International Summit Statement

Clinical Use: Germline.

Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.

Germline editing poses many important issues, including:

  1. the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism);
  2. the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment;
  3. the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations;
  4. the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country;
  5. the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively;
  6. and the moral and ethical considerations in purposefully altering human evolution using this technology.

It would be irresponsible to proceed with any clinical use of germline editing unless and until

  1. the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives,
  2. and there is broad societal consensus about the appropriateness of the proposed application.

Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

Sources and More information

Endocrine-Disrupting Chemicals: 2nd Endocrine Society Scientific Statement

The Endocrine Society, Hormone Science to Health, 2015

EDC2 PDF image
In 2015, The Endocrine Society made a number of recommendations For and Beyond Research Over the Next 5 Years.

The past 5 years represent a leap forward in our understanding of EDC actions on endocrine health and disease. The scientific literature published during this period has provided much deeper insights into the underlying molecular and cellular mechanisms of action, the importance of critical developmental exposure periods, and stronger epidemiological studies in humans from around the world. Despite limitations due to differences in experimental design in cell and animal studies and the need for caution in inferring causality from epidemiological work in humans, most studies support links between exposure and adverse outcomes.

Recommendations for Research Over the Next 5 Years
– Mechanistic studies of EDC actions on nuclear hormone receptors need to be extended beyond ERs, AR, PR, GR, ThR, and PPARs to other nuclear hormone superfamily members and to membrane steroid hormone receptors.
– Investigate EDC effects on enzymes involved in steroidogenesis, hormone metabolism, and protein processing in humans and animal models.
– Consider tissue-specific effects of EDCs.
– Translate research from rodents into nonhuman primates, sheep, and other species; and take advantage of transgenic (especially humanized) animals, keeping in mind the need for a better understanding of hormones and early-life development in humans.
– Test additional critical periods beyond prenatal and early postnatal—eg, adolescence as an additional sensitive developmental window.
– Evaluate EDC outcomes at different life stages–not just adulthood.
– Design studies to consider sex and gender differences in response to EDCs.
– Perform longitudinal and multigenerational analyses in animals and humans.
– Evaluate and implement emerging and sensitive testing systems, including highthroughput systems, for hazard assessment, screening, and prioritization.
– In humans, consider genetic diversity and population differences in exposures and outcomes. This should include racial, ethnic, socioeconomic, and geographic variables.
– Expand research to emerging “EDCs of interest” and to mixtures of low-dose EDCs.
– The team science approach, including teams of basic, translational, and clinical scientists; epidemiologists; health care providers; and public health professionals, needs to be a priority for future research and funding.

Recommendations Beyond Research for the Next 5 Years
– Educate the public, the media, politicians, and governmental agencies about ways to keep EDCs out of food, water, and air and to protect developing children, in particular.
– Develop industrial partners such as “green chemists” and others who can create products that test and eliminate potential EDCs.
– Recognize that EDCs are an international problem and develop international collaborations.
– Cultivate the next generation of EDC researchers, green chemists, physicians, and public health experts with expertise in endocrine systems.
– Funding agencies need to go beyond the “one scientist, one project” and “one clinician, one patient” perspective to fund team science and healthcare.
– Funding agencies need to prioritize EDC research in the basic, clinical, and epidemiological realms, especially considering that the cost of research and prevention will result in substantial cost savings in treatment and mitigation.
– Emphasize the need for precaution and prevention.
– Determine how much evidence is enough, based on rigorous, peer-reviewed science—keeping in mind that absolute proof of harm, or proof of safety, is not possible.

Accepted: September 2, 2015 – First Published Online: November 6, 2015.

Sources and more information
  • Flickr album DES and EDCs Research.
  • EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, DOI: 10.1210/er.2015-1010, November 06, 2015.
  • Executive Summary to EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, DOI: 10.1210/er.2015-1093, September 28, 2015.
  • Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, NCBI PMCID: PMC2726844, doi: 10.1210/er.2009-0002, June 2009.