Do we have the proper guard rails for first-in-man clinical trials?

Consider drug efficacy before first-in-human trials

“On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.

Ethical review boards must focus on clinical promise as well as safety to hold the first tests of drugs in humans to a higher standard.

Image credit Richard Wilkinson.

The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.”…

… continue reading Consider drug efficacy before first-in-human trials, by Jonathan Kimmelman and Carole Federico, Nature, 30 January 2017.

Let’s Reduce the Number of People that get Breast Cancer by Decreasing the Environmental Risk

Endocrine Disrupting Chemicals (EDCs) and Breast Cancer

It is possible to reduce the number of people that get Breast Cancer in the first place.

The following video explains Breast Cancer UK position and the science behind it.

More Information

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome

A national survey of DES daughters and unexposed controls

2017 Study Abstract

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure.

Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey.

Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer.

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls, US National Library of Medicine National Institutes of Health, Archives of women’s mental health, NCBI PubMed PMID: 28064340, 2017 Jan 7.

Image credit Alessandra.

Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women.

Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

More DES DiEthylStilbestrol Resources

Doctors need to solicit input from patients too

“I don’t think listening is enough” says Suzanne Gordon

Suzanne Gordon on soliciting input not just listening, The BMJ Blog, 26 Jan, 17.

Image credit @bmj_latest.

Want to be a better physician or nurse leader? Enhance patient safety? Effectively lead teams? One of the current consultant prescriptions is the recommendation that leaders spend more time listening than talking. Whether in the larger management literature or in the articles and books that specifically target healthcare, listening is portrayed as a key to leadership.

I am all for listening. Of course people have to listen to each other rather than silence, ignore, dismiss, or denigrate one another. When it comes to the implementation of genuine teamwork and patient safety within the hierarchical environment of health care, I don’t think listening is enough. As Amy Edmondson has written in her book Teaming, “Research shows that hierarchy, by its very nature, dramatically reduces speaking up by those lower in the pecking order. We are hard-wired, then socialized, to be acutely sensitive to power, and to work to avoid being seen as deficient in any way by those in power.”

Whether it’s nurses dealing with doctors, junior doctors dealing with senior ones, or patients dealing with the “team” that is supposed to be centered around their needs, subtle or overt manifestations of power hierarchy all too often defeat admonitions that people should speak up. To remedy this requires more than active listening, it requires actively soliciting input from those on the team, particularly those lower on the totem poll—which includes not only staff but patients.

Frontline staff are often reluctant to speak up, tell higher ups when something is wrong, or warn them about a potential catastrophe or even just an everyday glitch. They are equally hesitant to cross-monitor members of the team and help maintain situational awareness by providing new, and not always welcome, information. As for offering their ideas for innovation and quality improvements, they may feel no one is interested or will listen. To counter these entrenched beliefs and perceptions—which are often based on past experience—requires a leadership commitment to aggressively solicit input rather than waiting for staff—whether professional or non-professional—to tell leaders something they need to know.

Soliciting input—and then actively welcoming it—can do a lot to help people see that it is safe to admit error, provide a needed warning or heads up, convey new information and update their colleagues and co-workers about the latest developments or changes in a situation. Asking people—and this must include patients—what they think, what they’re worried about, if they agree with, or understand a plan of care, and then respectfully responding to the need for clarification or further information gives people permission to speak up. This is critical when working with professionals or other healthcare workers and even more so when dealing with anxious, frightened, and vulnerable patients. In an environment in which people may be reluctant to speak up because they have not traditionally felt that it was psychologically safe to do so, soliciting input as a kind of “standing order” builds the foundation upon which effective listening is built.

In healthcare, which has staunchly resisted systematic teaming training, anecdotal evidence and research data document that leaders who do this are the exception not the rule. Which is why the skill of soliciting has to be both preached and practiced.

Consider a few examples.

A physician wants to discharge a patient to his home with a complex regimen of IV medication that the patient’s wife will have to administer at home. The patient’s nurse, and social worker, not the physician, have a great deal of information about the wife’s ability to deal with her husband’s medication regimen. The physician does not, however, solicit input from either nurse or social worker about the wisdom of his plan. Instead he simply orders nurse and social worker to prepare for the discharge. As a result, the patient’s wife becomes extremely upset, which generates a day long conflict in which the physician becomes increasingly frustrated as the nurses and social worker hint at, rather than clearly discuss, the problem and remedy—a delay of one or two days in the discharge.

Imagine what would have happened if the physician had gone to the social worker, and the nurse—as well as the patient’s wife—and solicited their input by asking if they thought his plan was reasonable? The result would have been the same—a delayed discharge—but the destructive conflict would have been avoided and all would have felt they were members of an effective team.

Or consider the dilemma relayed to me by several attending physicians on a neo-natal ICU at a major teaching hospital. The NICU attendings said they constantly tell their residents to call them with any problems they have on the weekend or at night. Because many residents are afraid they’ll get a bad mark if they express confusion or ask for help, they don’t get a lot of calls even though many residents have lots of questions. What’s the solution? Soliciting input. As my colleague neo-natalogist John Chou recommends, attendings can pick up the phone, call the unit, page the resident and then say, “hey, I know we have this very sick patient. We haven’t talked in a while, and I just wanted to know if you had any questions or concerns I can help with?”

When soliciting input is accompanied by a genuine offer of help—rather than appears in the guise of quizzing or passing judgment—Chou says, he always learns about critical details that can impact the course of a tiny patient’s life.

Finally, I can say as a patient, that when a physician asks me what I think about the treatment he or she is about to recommend (something I have occasionally experienced), wonders if I will have any problems with it, or follows up with a call asking me how things are going, my trust in that caregiver and willingness to follow the recommended treatment increases exponentially.

It’s pretty simple, when you ask you might hear something that is actually worth listening to.

Suzanne Gordon is a healthcare journalist and co-editor of  The Culture and Politics of Healthcare Work Series at Cornell University Press. Her latest book is Collaborative Caring: Stories and Reflections on Teamwork in Healthcare, which she co-edited and she is co-author of Beyond the Checklist: What Else Healthcare Can Learn from Aviation Teamwork and Safety. Most importantly she is a patient.

Link between early menstruation and early menopause

Starting periods at a young age is linked to early menopause

Women are more likely to go through menopause early if they started menstruating before their 12th birthday.

This is the conclusion of the largest study of its kind, involving 50,000 postmenopausal women in the UK, Australia, Japan and Scandinavia.

2017 Study Abstract

STUDY QUESTION
Are parity and the timing of menarche associated with premature and early natural menopause?

SUMMARY ANSWER
Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP

WHAT IS KNOWN ALREADY
Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power.

Early menarche, nulliparity and the risk for premature and early natural menopause, Oxford University Press, doi.org/10.1093/humrep/dew350, 25 January 2017.

Image credit Texas.713.

STUDY DESIGN, SIZE, DURATION
This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE).

PARTICIPANTS/MATERIALS, SETTING, METHODS
Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation.

MAIN RESULTS AND THE ROLE OF CHANCE
The median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children.

LIMITATIONS, REASONS FOR CAUTION
Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias.

WIDER IMPLICATIONS OF THE FINDINGS
Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause.

STUDY FUNDING/COMPETING INTEREST(S)
InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

High body mass index during pregnancy not associated with a long term risk of obesity in offspring

High Pregnancy BMI Not Linked to Offspring BMI

This new study looked at whether increased body mass index (BMI) in mothers while pregnant was causally associated with excess weight in offspring during childhood and adolescence. It also examined whether this effect was over and above the expected contribution of genes to being overweight.

2017 Study Abstract

Background

It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.

Methods and Findings

Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study, PLOS one, dx.doi.org/10.1371/journal.pmed.1002221, January 24, 2017.

Image credit remon rijper.

We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample).

In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21–0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome.

A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21–0.30) at age 7 and 0.03 SD (95% CI -0.26–0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC.

When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19–0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11–0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.

Conclusions

Our findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.

162 chemical substances shortlisted by the European Chemicals Agency for possible regulatory action

Image credit ECHA, shows what EU action has been taken since previous screenings of substances

Helsinki, 12 January 2017 – The European Chemicals Agency (ECHA) has selected 162 substances from REACH registrations for further scrutiny by the Member State competent authorities in its annual IT screening exercise. The competent authorities will carry out a manual examination of the dossiers they prioritise to decide whether regulatory action is needed.

The selection is based on an automated IT screening focusing on substances with potential carcinogenic, mutagenic or toxic to reproduction (CMR), persistent, bioaccumulative and toxic (PBT), endocrine-disrupting, sensitising or specific target organ toxicity following repeated exposure (STOT RE) properties.

Potential substances with these hazardous properties were then further prioritised based on uses that are likely to lead to exposure to humans or release to the environment. The Member State competent authorities will select substances from the shortlist for their manual examination.

If your company has registered one of substances now shortlisted, you will receive a letter from ECHA informing of the potential examination of your registration(s). We encourage you to update your dossiers to address any shortcomings as soon as possible. Up-to-date information will help the Member State authorities better assess whether the concern indicated by the screening is confirmed, and whether regulatory action is still needed.

You are also invited to a webinar taking place on 14 February. In this webinar, you will get more details about the screening process. You will also have the opportunity to ask questions from ECHA’s staff.

If the Member States or ECHA take actions on your substance, this information will be published on the Agency’s website, for example, in the list of substances potentially subject to compliance checks, the Registry of Intentions (RoI), the draft Community rolling action plan for substance evaluation, and the the Public Activities Coordination Tool (PACT). You can check the status of your substance through the Search for chemicals available on ECHA’s homepage.

ECHA does not make the list of shortlisted substances public as it is purely based on automated selection by IT and manual verification is needed to confirm a potential concern.

Background

ECHA and the Member State competent authorities conduct IT and manual screening annually as part of the common screening approach. The aim is to identify substances that pose a risk for human health or the environment and take them forward to the most appropriate REACH and CLP processes to ensure their safe use. The common screening approach is part of the SVHC Roadmap to 2020 implementation plan.

The previous three rounds of IT screening have identified altogether 893 substances for further scrutiny. Of those, Member States have examined 581 substances. 78 % required follow-up activities with some substances having more than one outcome. See the feature image above for more information.

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Air Pollution – What Can I Do?

Air quality – What’s the point of warnings?

Nick Hopkinson: Air quality – what’s the point of warnings? The BMJ Blog, 8 Dec, 16.

Image credit mattbuck.

The Thames is wreathed in smog – the Mayor of London, Sadiq Khan, issues an air quality alert and announces a new system of air quality warnings. There will be road-side dot matrix message signs on the busiest main roads into London, with instructions to switch engines off when stationary to reduce emissions. Air quality messages will be displayed on countdown signs at bus stops and river pier signs across the city as well as electronic update signs in the entrances of all 270 London Underground stations. Down the line from the studio the breakfast TV interviewer asks “what’s the point of the warnings, what can anyone do?” We have no choice but to breathe the air that’s there, so on the face of it this is not an unreasonable question. In fact there are three important constituencies these warnings are addressed to.

The first target is politicians and the political process – externalities, uncounted costs, are a cause of market failure. It is vital to raise the political cost of ignoring air quality. The Government is in breach of air quality regulations, with the British Lung Foundation reporting that 3,000 schools have been identified across the UK in areas of illegally high pollution. A public aware of air pollution and the harm it is causing to them and their children is an important step towards action to address the problem. Politicians respond to public pressure. Make an appointment. Talk to your MP about it.

The second target is people as polluters. Pausing on the way to the interview that morning I counted 100 consecutive cars crossing Lambeth Bridge – 84 were occupied by a single driver only. Some may feel they have no alternative, but for many there is a choice to use public transport or walk or cycle. You’re not stuck in the traffic, you are the traffic.

The third target is the vulnerable. People with lung disease and other long term conditions can take some steps to reduce their exposure. At the worst times, staying indoors and avoiding strenuous exercise may be necessary. Avoiding busy roads is sensible. Approaches to map pollution hot spots, such as the Cleanspace app, may help with this. Pollution increases the risk of exacerbations in people with COPD and asthma. They should be prompted to watch out for any increase in symptoms and to make sure that they know what to do if they develop a flare up – check their self-management plan or rescue pack.

Air pollution causes about 40,000 deaths per year in the UK according to a recent report from the Royal College of Physicians. WHO figures show that, worldwide, ambient air pollution contributes to 5.4% of all deaths. Reducing air pollution and the harms it causes is a personal and political issue – an informed public is a vital first step.

Nicholas S Hopkinson,
Reader in respiratory medicine at Imperial College, London.

Potentially Harmful Flame Retardants Chemicals found on All Young Children studied in New York City homes

Prevalence of historical and replacement brominated flame retardant chemicals in homes

Researchers at the Columbia Center for Children’s Environmental Health (CCCEH) within the Mailman School of Public Health report evidence of potentially harmful flame retardants on the hands and in the homes of 100 percent of a sample of New York City mothers and toddlers.

2017 Study Abstract

Background
Until their phase-out between 2005 and 2013, polybrominated diphenyl ethers (PBDEs) were added to household products including furniture, rugs, and electronics to meet flammability standards. Replacement brominated flame retardant (BFR) chemicals, including 2-ethylhexyl-2,3,4,5- tetrabromobenzoate (TBB) and bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH), which are components of the Firemaster 550® commercial mixture, are now being used to meet some flammability standards in furniture. The objective of this analysis was to evaluate the extent to which mothers and their children living in New York City are exposed to PBDEs, TBB, and TBPH.

Prevalence of historical and replacement brominated flame retardant chemicals in New York City homes, science direct, dx.doi.org/10.1016/j.emcon.2017.01.001, 20 January 2017.

Image credit abbybatchelder.

Methods
We measured PBDEs, TBB, and TBPH using gas chromatography mass spectrometry in dust (n = 25) and handwipe (n = 11) samples collected between 2012 and 2013 from mothers and children living in New York City. We defined dust as enriched if the proportional distribution for a given BFR exceeded two-thirds of the total BFR content.

Results
We detected PBDEs and TBPH in 100% of dust and handwipe samples and TBB in 100% of dust samples and 95% of handwipe samples. Dust from approximately two-thirds of households was enriched for either PBDEs (n = 9) or for TBB + TBPH (n = 8). Overall, the median house dust concentration of TBB + TBPH (1318 ng/g dust) was higher than that of ΣPentaBDE (802 ng/g dust) and BDE-209 (1171 ng/g dust). Children generally had higher BFR handwipe concentrations compared to mothers (ΣPentaBDE: 73%, BDE-209: 64%, TBB + TBPH: 55%) and within households, BFR concentrations from paired maternal-child handwipes were highly correlated. Among mothers, we found a significant positive relation between house dust and handwipe BDE-209 and TBB + TBPH concentrations.

Conclusion
PBDEs, TBB and TBPH are ubiquitous in house dust and handwipes in a sample of mother-child pairs residing in New York City.

Is balancing risk the most important skill in clinical medicine?

What influences our perception of risk?

Jennifer McCaughan and Aisling E Courtney: Is balancing risk the most important skill in clinical medicine? The BMJ Blog, 24 Jan, 17.

Image credit abhishek047.

Every decision, both in life and in medicine, involves a balance of risk: the decision to go on holiday balances the risk of travelling to and staying in a foreign country against the benefit of a fortnight’s sunshine and relaxation; the decision to treat bacterial pneumonia balances the risk of anaphylaxis against the benefit of antibiotic therapy. Consciously and subconsciously, we make decisions for ourselves and our patients every day based on our perception of risk. Humans, however, are not good at accurately assessing risk. In 1990, research comparing people’s anxiety about nine different risks concluded that “there is no generally applicable dynamic relationship between perceived and actual risk”.

The answer is that we overestimate the risk of events that stimulate fear and emotion (such as terrorist attacks, child abduction and aeroplane crashes) while underestimating the risk associated with less emotive factors (such as obesity, smoking and car travel).

This is also true in medicine. Kidney transplantation is unarguably the optimal treatment for end stage kidney disease. The single modifiable factor which has the greatest impact on how long recipients survive with a kidney transplant is the length of time they spend on dialysis prior to transplantation.Some individuals develop antibodies to non-self HLA following pregnancy, blood transfusion, and transplantation resulting in a long waiting time for an organ offer as many donors have incompatible HLA types. This equates to a prolonged period on dialysis with the associated risk of death and becoming unfit for a kidney transplant. For these patients, HLA incompatible living donor transplantation may be an option; although the risk of rejection is higher, the long term survival outcomes are comparable to deceased donor transplantation and significantly better than remaining on dialysis.

Despite this, many centres are reluctant to accept kidneys associated with increased immunological risk for these patients. Why is this? Fear. Treating a patient with aggressive antibody mediated rejection following a kidney transplant can be a terrifying experience; there is the anxiety associated with the potential for loss of the transplant (for the donor, recipient, and transplant team), the distressing side effects of the intensive immunosuppressive treatment that is required and, for some, the major disincentive of immediate finger pointing and criticism when the short term risk fails to deliver.

On the other hand, when a patient deteriorates after many years on dialysis that may not stimulate the same emotive response or critical reception. However the reality remains that the median survival for a 40 year old patient commencing dialysis in the UK is approximately ten years and that transplantation may double or even triple that survival time. Objectively, the risk of transplanting highly sensitised patients after a short time on dialysis with a kidney associated with increased immunological risk has a favourable risk: benefit ratio. Subjectively, physicians fear the potential for rejection and graft loss so patients wait. And wait.

As clinicians, we need to have insight into our own biases in risk perception. Unpleasant and stressful cases in the past can distort our decision making in the present. This has the potential to result in suboptimal patient management. The ability to objectively balance the many aspects (surgical, anaesthetic, medical, immunological, psychological) of the risk associated with a treatment against that of avoiding the treatment is an essential skill for physicians. The capacity to do this effectively for each individual patient is the cornerstone of personalised medicine and an attribute of the exceptional clinician.

Jennifer McCaughan is a final year nephrology trainee in Northern Ireland. Her interest is in kidney transplantation and in higher immunological risk transplants in particular. She is currently undertaking a fellowship in renal transplantation and HLA in Toronto.

Aisling E Courtney is a consultant nephrologist, Belfast City Hospital.