Anxiety levels in kids with autism meta-analysed

The results of the meta-analysis published by Francisca van Steensel & Emma Heeman [1] (open-access) on the topic of anxiety levels in children diagnosed with an autism spectrum disorder (ASD) should not really be a surprise to anyone.

Concluding a few things based on the analysis of the peer-reviewed literature in this area - 83 articles on the topic - the main points were that "anxiety levels of youth with ASD are much higher compared to typically developing children" and further that "as IQ increases, so does the difference in anxiety levels between ASD and typically developing children" (age also showing a similar relationship to that of IQ). The authors suggest that quite a bit more investigation is required on this topic not least in areas such as managing/treating anxiety issues in the context of autism, distinguishing anxious signs and symptoms from the traits of autism and importantly noting "the impact of anxiety for the daily functioning—not only for the children themselves, but also for the family." I might add that at least one of these authors has some research form when it comes to looking at the complicated relationship between autism and anxiety (see here).

I've covered anxiety and autism on this blog more times that I can remember (see here and see here for examples). I hope I'm not too forward in saying that various types of anxiety disorder do appear to be over-represented when it comes to a diagnosis of autism and that anxiety can sometimes (day-to-day) be more disabling to a person that the presentation of their autism.

What's missing from the van Steensel / Heeman analysis? Well I might suggest two things. First, a realisation that in these days of 'autism rarely appearing in a diagnostic vacuum' (see here) some of the other comorbidity over-represented in relation to autism might also be important to the presentation of anxiety. I'm thinking specifically about the quite nebulous term 'depression' as being one prime example (see here) but there may be others too (see here). Second, and also potentially related to the first point is the idea that somatic features might also be an important part of a relationship between anxiety and autism. I've just mentioned about depression and anxiety perhaps not being unstrange diagnostic bedfellows, well, things like gastrointestinal (GI) issues can be part of that relationship too (see here for example).  We can argue all day about whether anxiety is a cause or effect of physiological issues (with and without autism in mind) but there is a growing evidence base to suggest that psychology and the somatic are not necessarily totally independent systems.

As to the question of treating/managing anxiety when it occurs with autism, the authors mention about the potential usefulness of something like cognitive behavioural therapy (CBT) as one avenue (see here). One could also entertain the use of more pharmacotherapeutic strategies too; bearing in mind the need for good medicines management and a focus on minimising any side-effects. I'd also draw your attention to another avenue gaining some research traction: exercise (see here). Acknowledging that participation in physical activity can sometimes be a bit of an issue when it comes to autism (see here for example), there is no reason to suggest that what might work for the population at large in terms of 'exercise for anxiety' should not be equally applicable to presented anxiety in the context of the autism spectrum. Indeed, added to other potentially positive outcomes associated with exercise use with autism in mind (see here) , I'd very much like to see a lot more research conducted on this potentially important area.

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[1] van Steensel FJA. & Heeman EJ. Anxiety Levels in Children with Autism Spectrum Disorder: A Meta-Analysis. J Child & Family Studies. 2017; 26: 1753.

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'Vulnerability' to radicalisation and autism or autistic traits: tread carefully

I was more than a little hesitant to post this entry given the sensitivity of the material it covers. I opted to publish this post because peer-reviewed science is peer-reviewed science...

In a recent piece for The Conversation, Dr Clare Allely asked a very difficult but potentially important question: "Are autistic people at greater risk of being radicalised?"

Based on her own research [1] and in light of several high profile cases where an autism diagnosis has been mentioned in the same breath as various terrorist-related offences, some with a potential radicalisation element to them (see here and see here) it is indeed timely that such a question is posed.

This is a sensitive area. Yes, I very much appreciate that people commit crimes, not their diagnostic labels (see here) and sweeping generalisations are not required, but "it is crucial to consider how the diagnosis of autism may have presented as a contextual vulnerability" when it comes to such issues.

There are various sensitivities to consider before it comes to even examining any possible link between vulnerability to radicalisation and autism or autistic traits. One needs only look at the effects of years and years of sweeping generalisations about schizophrenia and 'dangerousness' for example (see here) to see how stigma can build up quickly and how damaging it can be on a personal and societal level. Science and clinical practice need to tread very carefully indeed, whilst also not shying away from any uncomfortable results.

The Allely piece for the The Conversation touches however on several important points pertinent to the idea that 'vulnerability' to radicalisation may be perhaps elevated in relation to a diagnosis of autism for various reasons. I've stressed the word 'vulnerability' for several reasons...

First off, use of the word 'vulnerable' - "unable to take care of him or herself, or unable to protect him or herself against significant harm or exploitation" - in the context of autism is, I think, under-used. I don't say that in any 'pity me' fashion but rather that many people on the autism spectrum are/should be classed as 'vulnerable' despite any [typically sweeping] notions about being 'high' or 'low' functioning or other description of their positioning on the autism spectrum. There are several other examples of this vulnerability in action in the peer-reviewed literature [2] and indeed, autistic commentators have themselves noted various other scenarios (see here) specifically where enhanced victim risk of coercion and bullying is part and parcel of such vulnerability. With such vulnerability comes inevitable heightened risks for all manner of potential adverse outcomes.

Dr Allely also talks about how: "Searching for a “need to matter” or social connection and support for someone who is alienated or without friends may also present as risk factors" when it comes to enhanced risk for radicalisation. I think again, this may be something of an important point when it comes to parts of the autism spectrum. The idea for example, that those on the autism spectrum do not want (or need) friends is an unfortunate side-effect of years and years of further sweeping generalisations when it comes to trying to define the spectrum. The whole 'lacking in empathy' thing (myth?) has, I think, played a big part in perpetuating the idea that difficulties in forming relationships with peers for example, has sometimes been misinterpreted as not wanting relationships with others. Obviously one has to guard against making counter sweeping generalisations that everyone with autism wants lots and lots of friends around them all of the time, but what seems to be true is that autistic people do in the most part want significant others around them at certain points and want the benefits that friendships and belonging bring under their own terms. The vacuum created by not belonging to a social circle or not having that 'need to matter' to others is something faced by at least some on the autism spectrum and could therefore be considered a risk factor for vulnerability to issues like radicalisation especially when others with an ulterior motive come forward with a seemingly welcoming face and message. Indeed, one might also see evidence of this when one talks about hacking or cyber-terrorism in the context of a diagnosis of autism...

"Autistic special interests such as fantasy, obsessiveness (extreme compulsiveness), the need for routine/predictability and social/communication difficulties can all increase the vulnerability of an person with ASD [autism spectrum disorder] to going down the pathway to terrorism." I'm not in total agreement with everything said in that sentence but some of it could ring true. As difficult as this may be to face, forensic examination of cases where autism has been cited alongside terrorist activities has noted obsessions in particular, to be a potentially important variable. As a case in point: "The court heard Smith had been interested in making bombs since the age of 10 and said it was "something to do when he was bored"". A long interest in 'making bombs' at any age is not something typical; let alone when starting such an interest as a 10-year old. The source of such interests is likely to be complex but, with all the media attention paid these days to terrorism and talk of the objects of terrorism and the like easily found on the internet and other media, it's not difficult to find a context for why someone might become utterly engrossed and/or obsessed with such material for years and years.

What's missing from the Allely article? Well, I'd like to see quite a few more resources dedicated to the idea that comorbidity around a diagnosis of autism might also play an important role in both risk of radicalisation and any onward decisions to actually implement acts of terrorism. Again, minus sweeping generalisations or passing the buck from one label to another, quite a few diagnostic labels with a psychiatric element to them do seem to be over-represented when it comes to autism (see here) and services are not necessarily suited to picking them up or managing them for everyone (see here). This applies particularly to those conditions characterised by an altered sense of reality (see here) - I assume, a potentially important point for some when it comes to for example, transitioning from ideas to acts.

Another issue that ties in with some factors already mentioned is the idea that "everyday young people in social transition, on the margins of society, or amidst a crisis of identity" may be over-represented among some parts of radicalised terrorism. Minus any psychobabble, it wouldn't be difficult to fit some on the autism spectrum into some of those categories on the basis for example, of being marginalised or being 'amidst a crisis of identity'. Obviously one could argue that such issues are not autism-specific; quite a few young (and old) people probably feel disenfranchised particularly in today's modern society and hence a diagnosis of autism per se is not the defining variable. But again, we come back to that issue of vulnerability...

Reiterating that any talk about a link between autism and vulnerability to radicalisation in the context of terrorism is fraught with difficulties and risks, there is a need for further scientific investigation into this area. Radicalisation is a complicated process (see here); the risk of which is not something that can be just laid at the door of labels like autism or autistic traits. One needs to be mindful not to stigmatise whole swathes of the population on the basis of a few, very high-profile cases. Yes, people want quick and easy answers to the questions of 'how and why' but I doubt there are any simple or universal answers to issues such as radicalisation and further.

The fact however, that the Allely article was published at all highlights how this issue is starting to come into the public consciousness. If indeed some of the facets of autism or the issues created by a diagnosis of autism are found to be a variable in some cases of radicalisation and beyond, resources aplenty need to be poured into what can be done to educate against and mitigate any excess risk both inside and outside the context of a diagnosis of autism or autistic traits. All this however needs to be done carefully minus further stigmatisation and any scaremongering (that includes sensationalised newspaper headlines) but always realising that science should not being afraid to try and find answers to difficult questions in as many different quarters as are required.

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[1] Faccini L. & Allely CS. Rare instances of individuals with autism supporting or engaging in terrorism. Journal of Intellectual Disabilities and Offending Behaviour. 2017; 8: 70-82.

[2] Brown-Lavoie SM. et al. Sexual knowledge and victimization in adults with autism spectrum disorders. J Autism Dev Disord. 2014 Sep;44(9):2185-96.

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On your marks, GETSET...

I don't doubt that the article published by Lucy Clark and colleagues [1] (open-access) on the topic of testing "the efficacy and safety of graded exercise delivered as guided self-help" in the context of chronic fatigue syndrome (CFS) is going to divide opinion. I say that on the basis that graded exercise therapy (GET) as part of a suite of interventions linked into the PACE trial for example, has taken up masses of column inches in the lay and science media over the years and seems set to do so for some time to come.

I'm going to try and talk about the Clark paper as context-free as I can, bearing in mind that science does not exist in some sort of vacuum detached from real-life. I say that on the basis that this is supposed to be a science-related blog and whilst being very much aware of the discussion/politics around the potential rights-and-wrongs of various components of the PACE trial, I don't want them to necessarily spill over to this piece of new science.

So, GETSET - graded exercise therapy guided self-help trial - was the name of trial [2] and the design was such that "an open-label, pragmatic randomised controlled trial done at two UK National Health Service (NHS) secondary-care clinics for chronic fatigue syndrome in central London and Kent" was employed. Over 200 participants diagnosed with CFS - "who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome" - were included for study; half of which were allocated to receive 'specialist medical care' (SMC) with the other half receiving SMC with "additional guided graded exercise self-help (GES)." The trial lasted for 8-12 weeks and the primary outcomes were "fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale)" delivered at baseline and 12 weeks and relying on self-report. We are also told that "Participants were also followed up at 12 months after randomisation, and these results will be published in a separate paper."

Results: as per some further commentary on the study [3] by someone not totally unknown to some of the authors on the Clark paper, the use of SMC + GES did seem to show some effects on self-reported fatigue scores insofar as correlating with "significantly lower mean fatigue score... and higher self-reported physical function score... than did patients managed with specialist medical care alone." They also reported that: "participants in the GES groups had better outcomes than did participants in the control group for work and social adjustment scores, depression, and anxiety, but not for general physical symptoms." Importantly however, it is noted that (a) "physiotherapists reported that 43 participants (42%) adhered to GES completely or very well, 31 (30%) moderately well, and 30 (29%) slightly or not at all" and (b) only about 20% of those receiving GES "noted improvements (“much” or “very much better”) in overall health" and even less (15%) in relation to the symptoms of CFS. This was not a study demonstrating total and universally successful outcomes.

Outside of just those outcomes, the important issue of side-effects or adverse events potentially associated with intervention were also analysed: "non-serious adverse events were reported by 27 (28%) of 97 participants who received guided graded exercise self-help and by 23 (23%) of 102 patients who received specialist medical care only, with no significant differences between the two groups." A couple of participants also dropped out of the study who were using GES but generally intervention seemed to be "well-tolerated" according to the authors.

Limitations? Well, the authors do discuss a few; not least that 'self-report' was the main avenue for data collection. Likewise: "We did not measure any objective outcomes, such as actigraphy, which might have tested the validity of our self-rated measures of physical activity." That last point is quite a large study weakness throughout a lot of research looking at physical activity in many areas, particularly given the availability of some rather accurate and reliable equipment these days (see here). Indeed, the fact that the GES intervention was supervised by physiotherapists yet seemingly had no objective measures of anything physiotherapist-related is a little unusual. I might also add that whilst fatigue is a primary symptom of CFS, there are various other symptom manifestations (e.g. post-exertional malaise, PEM) that also require a lot more investigation in terms of effects from intervention; something particularly pertinent to any intervention that has an 'exertional' component to it. It's also important to note something else discussed by authors: "this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors." Perhaps something of an olive branch is meant by that statement, particularly in light of the issues noted with something like the biopsychosocial (BPS) model being [deleteriously] applied to CFS down the years (see here).

There is a need for further research in this area before anyone gets ahead of themselves with the Clark results as some media headlines seem to have. Other studies [4] combined with opinion from some patient organisations (see here) have highlighted potential issues following the use of GET, and in particular it's use as a 'blanket form of treatment' for CFS. Indeed, 'blanket forms of treatment' have in my mind, been a source of real pain and discomfort to many people suffering (yes, suffering) with CFS; something hopefully being addressed by other research talking about subgroups and phenotypes (see here) and expected changes to clinical guidance here in Blighty for example due quite soon.

As to the question of mechanism(s) pertinent to GET being applied to 'some' CFS, we're still left wanting. I could speculate about issues such as 'de-conditioning' that is bound to be part-and-parcel of CFS and how GET could be targeting this variable. But really, nobody knows everything there is to know about how something like GET might impact on physiology because no-one seems to have measured it in any great detail. Again, quite a few of the trials from the group(s) behind GETSET and PACE have tended to be quite 'light' on physiological measurements before and after intervention; something that perhaps needs to be addressed.

So, there you have it. Some potentially important results but also an area that requires any awful lot more study before any sweeping generalisations are made and made without patient involvement. I await also the follow-up results from this research team to see what happened in the longer term...

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[1] Clark LV. et al. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. Lancet. 2017. June 22.

[2] Clark LV. et al. Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study. JMIR Res Protoc. 2016 Jun 8;5(2):e70.

[3] Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. Lancet. 2017. June 22.

[4] Núñez M. et al. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9.

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MoBa does prenatal fever and autism risk

'MoBa does..' is fast becoming a common title on this blog (see here and see here). Referring to the Norwegian Mother and Child Cohort Study (MoBa), this initiative based on the examination of 100,000 pregnancies in Norway is yielding some useful observations for all-manner of different condition/labels.

When MoBa is applied to autism, a few names seem to quite consistently crop up - Mady Hornig and Ian 'virus hunter' Lipkin - as is the same for today's blogging material from Hornig and colleagues [1] (open-access). Their findings supporting "a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD [autism spectrum disorder]" make for interesting reading.

Authors set about determining whether maternal fever episodes during pregnancy might show some connection with risk of offspring autism. To do this they relied on questionnaire data from pregnant mums completed at specific times of their pregnancy pertinent to "fever, along with their timing, as well as the names of medications used for fever, and the timing of that medication use" as a function of a subsequent diagnosis of offspring autism or not. That 'medication use' side of things adds to a further stream of research suggesting that some medicines used as fever-reducers/eliminators (antipyretics) during pregnancy might also have some bearing on offspring behavioural/developmental outcomes (see here and see here for examples). Alongside such information, authors also took into account various potentially confounding variables that might have also affected offspring autism risk.

Results: based on data covering nearly 100,000 children, with nearly 600 subsequently being diagnosed with an ASD, researchers concluded that: "Prenatal fever was associated with increased ASD risk among offspring." Exposure to reported pregnancy fever at any time during pregnancy seemed to be more common in those children who were eventually diagnosed with ASD but notably during the second trimester of pregnancy. They also noted a possible dose-response effect from pregnancy fever exposure: "Risks increased markedly and dose dependently with fever frequency, with particularly strong effects after 12 weeks’ gestation." As to the use of antipyretics and any additional risk or mitigation of risk, I'm inclined to suggest that on this research occasion, there wasn't very much to see either way.

Added to the idea that infection exposure during the nine months that makes us might also affect the risk of subsequent offspring autism (see here), this latest data sit well with the idea that infection and/or response to infection during pregnancy might very well be able to influence offspring outcomes. Pregnancy is a time of reprogrammed maternal immune function (to stop mum's immune system attacking the developing foetus) so already science has a basis for looking at something like enhanced maternal immune activation (MIA) during pregnancy as being potentially pertinent to offspring outcomes particularly autism.

Of course one has to note that the strengths of the MoBa study - "a large, prospective, population-based birth cohort with exposure data collected in 4-week intervals and linkage to a patient registry for case ascertainment" - need to be balanced against the weakness, i.e. maternal self-report. The authors have however promised more detailed study in this area: "we are testing the possibility that risk is associated with specific infectious agents through sequence-based and serological assays of samples collected mid-pregnancy and at birth from cases and controls" so there may be more to add in future times [2] in addition to some already published inklings from authors (see here).

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[1] Hornig M. et al. Prenatal fever and autism risk. Molecular Psychiatry. 2017. June 13.

[2] Mahic M. et al. Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere. 2017. June 21.

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Ariel pesticide use and neurodevelopmental diagnoses patterns

"When compared with surrounding areas, the zip codes exposed to yearly aerial pyrethroid spraying had a higher prevalence of ASD/DD [autism spectrum disorder/childhood developmental delay]."

One does has to be a little careful in interpreting the results published by Steven Hicks and colleagues [1] (open-access available here) looking at "ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis" compared with control areas with "no state-approved aerial applications." Correlation after all, is not the same as causation. But I found the data from Hicks et al to be rather interesting and worthy of a blog entry in light of other, independent peer-reviewed data (see here).

So, looking at all children who were evaluated over a 5-year period at "one of six pediatric outpatient clinics" in New York state, researchers divided participants up depending on their zip code "into aerial-exposed and control zip codes" when it came to pyrethroid spraying. Said spraying was in relation to use of an insecticide "as a preventive tool against mosquitoes carrying eastern equine encephalitis (EEE) and West Nile virus (WNV)." The authors noted that: "The effects of this application on neurodevelopmental patterns in local children have not been investigated."

Pesticide exposure was estimated based on the amount used over a 3-year period in each zip code and reported as kilograms per square kilometre. Alongside looking at rates of "neurodevelopmental delay (ASD and DD)" as a function of zip code/exposure patterns, researchers also included various potentially modifying factors in their calculations: "regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates)."

When all was said and done, authors observed a significant relationship between ASD/DD and aerial pesticide exposure. They noted that: "Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD."

Authors caution that "this study is observational and does not establish a causal relationship between pyrethroid exposure and ASD/DD" but also note that there needs to be a lot more experimental study done on how aerial spraying is conducted and any possible effects on the population down below. And before you say anything, yes, I know that aerial spraying is being done for a perfectly valid reason. But that's not to say it should be just given a free pass in terms of either effectiveness or safety...

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[1] Hicks SD. et al. Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application. Front Pediatr. 2017 May 24;5:116.

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Autism awareness among the young is actually quite good

The message of 'increasing awareness of autism' is still a strong one in modern times despite the label of autism officially entering medical texts some 80+ years ago. We have a World Autism Awareness Week and a World Autism Awareness Day and lots more in-between to raise awareness of autism and what the label [differentially] means to many, many people.

The findings reported by Karola Dillenburger and colleagues [1] seem to suggest that, particularly among children and young adults, the autism awareness message is getting through as they observed: "Children and young people have good levels of awareness and knowledge about autism and reported positive attitudes towards peers with autism." Even further: "A higher than expected number of children and young people self-reported being on the autism spectrum."

Based on analysis of "two large-scale surveys: the Kids Life and Times survey for 11-year olds and the Young Life and Times survey for 16-year olds" yielding some 3300 children and young adults, researchers posed various questions including those pertinent to autism awareness. The results suggested that some 80% of teenagers had some knowledge about autism compared with about 50% of younger children. Most participants held positive attitudes towards autism including recognition that bullying is an issue that some on the autism spectrum are particularly at risk of. Further: "Self-reported prevalence of autism was 3.1% for teenagers and 2.7% for the younger children." That last point was based on the study population being based in Northern Ireland (which interestingly, has recently reported a rather large upswing in the number of formally-diagnosed cases of autism too).

These are rather positive results insofar as the recognition of autism and indeed, how common it is in modern times. It is perhaps not unexpected that some of these authors have some research form in this area [2]. The authors frame the result in terms of boding well for "peer-mediated support strategies for inclusive education" but I think they go much further than that. Assuming that awareness covers the entire spectrum of autism (see here) and not just a part/branch of it, I'd like to think these findings go some way to supporting efforts to 'make autism more visible' and onward, ensuring that the wants and needs of those on the spectrum are more readily expressed and addressed. Media and culture probably has a lot to do with such findings (see here for example) but the fact that many classrooms and schools do now cater for students on the autism spectrum no doubt played an important role in these findings.

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[1] Dillenburger K. et al. Autism awareness in children and young people: surveys of two populations. J Intellect Disabil Res. 2017 Jun 7.

[2] Dillenburger K. et al. Creating an Inclusive Society… How Close are We in Relation to Autism Spectrum Disorder? A General Population Survey. J Appl Res Intellect Disabil. 2015 Jul;28(4):330-40.

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How helpful is a 'geek index'?

A quote to begin: "male offspring of older fathers had higher ‘geek index’ scores, a composite measure of high IQ, strong focus on the subject of interest and social aloofness."

So said the findings published by Magdelena Janecka and colleagues [1] (open-access) who set out to determine whether "having an older father is associated with certain beneficial traits" in offspring. Their use of the term 'geek index' (GI) was derived from a "composite measure of non-verbal intelligence, restrictive interests and reduced need to fit in with the peer group" based on data derived from the TEDS (Twin Early Development Study) initiative (something that has cropped up before on this blog). As one might imagine, use of the term 'geek index' in a science article was always likely to make some media headlines (see here for example).

In terms of study design and numbers, this was a biggie with study participants in the thousands. The geek index was derived from scores "of (i) non-verbal intelligence, (ii) restrictive and repetitive behaviours (RRBs) and (iii) social aloofness." Further: "Scores on the Raven’s Standard Progressive Matrices test were used to obtain (i). Childhood Autism Spectrum Test (CAST) scores were used to obtain both (ii) and (iii)." Various statistical 'transformations' were conducted on said scores to give that geek index sum and, not forgetting the parental age bit, paternal age was also thrown into the statistical mix.

As per the opening sentence, those children born to older fathers (but not older mothers) seemed to more frequently present with a higher geek index. This association persisted after controlling for various potentially confounding variables: "maternal age, sex, zygosity and SES [socio-economic status]." Researchers further observed that: "GI was positively linked with future academic attainment—including the key predictors of future SES—suggesting a phenotypic advantage in the offspring of older fathers."

These are interesting results and notwithstanding some study limitations i.e. "It was not possible to determine whether the advantageous effects of GI extend beyond secondary education, and correlate with future SES" require further independent investigation. Offspring being born to older fathers has generally been associated with various less-than-positive outcomes so this article kinda paints a more positive picture for children and families. Indeed, one of the commentators talking about these findings suggests that "perhaps we are destined for future society of geniuses that are going to help us solve all the world's problems." One would hope so.

As per the title of this post, I would however question how useful/helpful the term 'geek index' is when it comes to outcomes and implications. Yes, I know there is such a thing as 'geek chic' these days, but let's not forget that the word 'geek' has it's primary origins as a term of ridicule in many languages. To quote one definition: "the word typically connotes an expert or enthusiast or a person obsessed with a hobby or intellectual pursuit, with a general pejorative meaning of a "peculiar person, especially one who is perceived to be overly intellectual, unfashionable, or socially awkward."" I'm not so sure that every child (youngster or teenager) would be particularly happy to be labelled as scoring high on a geek index. Surely something a little more scientific could replace such a term?

Going also back to those study caveats provided by the authors, I might also raise the idea that just because someone shows an intellectual advantage when it comes to something like STEM (science, technology, engineering and mathematics) subjects does not necessarily mean that their future is going to be a rosy one in terms of employment, income or other markers of SES. “If you look at who does well in life right now, it’s geeks” is one of the quotes attributed to the first author of the paper; and with it as massive a sweeping generalisation as you will ever see.

If we for example, assume that strengths in STEM might be over-represented when it comes to the autism spectrum (see here) we should be seeing lots and lots of people either diagnosed with autism or possessing significant autistic traits thriving in such roles and in life in general. The reality however is that skills pertinent to STEM often do not appear in a vacuum (see here) as I would put forward the suggestion that future research might also consider the possibility of a relationship between the geek index (or other term) and the presentation of something like anxiety or depression and how that might also impact on later adult outcomes for example. The additional idea that social aloofness also makes up part of the geek index is something else that needs quite a lot more work on as part of any 'advantage' arguments being put forward...

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[1] Janecka M. et al. Advantageous developmental outcomes of advancing paternal age. Translational Psychiatry. 2017. 7; e1156.

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Autism, learning disability and diagnostic substitution

The findings reported by Cynthia Nevison and Mark Blaxhill [1] represent the source blogging material today. Their quite detailed analysis of individual state data based on the "United States Individuals with Disabilities Education Act" (IDEA) is front and centre and what it might mean for the argument that the quite phenomenal rise in diagnoses of autism or autism spectrum disorder (ASD) is due wholly or in part, to a switch from the diagnosis of intellectual (learning) disability to autism.

Based on examining IDEA data for each of the 50 states of the United States covering various years, various years of birth and various ages, authors concluded that sweeping generalisations about widespread diagnostic switching/substitution were not necessarily borne out in such State level data analysis. They did find that: "Nationwide ID [intellectual disability] prevalence declined steeply over the last two decades, but the decline was driven mainly by ~15 states accounting for only one-fourth of the U.S. school population." Further, when assigning specific statistical conditions to states based on things like the decrease in ID being comparable to the increase in autism diagnoses or the increase in autism diagnoses being substantially greater than the decrease in ID diagnoses, authors reported a complex picture generally pertinent to the idea that "ID prevalence stayed relatively constant while ASD prevalence rose sharply."

This is not the first time that some of these authors have used IDEA data to put forward a view that the increase in cases of autism is real and not just an artifact of changing diagnostic criteria for example (see here). Indeed, both authors have an interest in this area [2] and dedicated some peer-reviewed science time to it. Personally, I find this kind of detailed scrutiny to be refreshing in these days of sweeping generalisations and soundbites about many facets of autism. Indeed, as time goes on and the numbers of those being diagnosed with autism creep ever higher worldwide (see here), older arguments about diagnostic substitution have seemingly become less and less convincing. No, diagnosticians weren't that bad at diagnosing autism X number of years ago...

Having said that, I do still think there is a place for diagnostic substitution when it comes to explaining *some* of the increase in cases being diagnosed. Data such as that from King & Bearman [3] estimating that about a quarter of the increase in cases of autism in places such as California might be due to diagnostic switching from ID cannot simply be forgotten or brushed under the scientific carpet. I should also mention that autism can very well exist in the presence of ID too (see here); even more so in specific populations (see here).

I know that old battle lines about a real vs. artificial increase in cases of autism still persist in many circles and I understand some of the reasons why each side believe what they believe. What is however not in dispute, is the fact that there are quite massive numbers of people (children and adults) being diagnosed as on the autism spectrum year-on-year worldwide (with additional many unable to access timely and appropriate diagnostic services) and resources aplenty are required to identify their specific needs and provide accordingly. No easy task in these continuing days of austerity, cuts and the like...

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[1] Nevison CD. & Blaxill M. Diagnostic Substitution for Intellectual Disability: A Flawed Explanation for the Rise in Autism. J Autism Dev Disord. 2017 Jun 6.

[2] Blaxill MF. What's going on? The question of time trends in autism. Public Health Rep. 2004 Nov-Dec;119(6):536-51.

[3] King M. & Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009 Oct;38(5):1224-34.

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Schizophrenia and CRP meta-analysed again

"Our study provides evidence that higher CRP [C-reactive protein] levels are associated with increased risk of SZ [schizophrenia], especially for young adult patients less than 30 years."

So said the results of the 'updated' meta-analysis by Zhichao Wang and colleagues [1] (open-access available here) surveying the peer-reviewed literature on this topic "from inception to November 1, 2016." The 'updated' bit to their discussion refers to the fact that this is not the first time that CRP - a molecule associated with inflammation or inflammatory processes - and schizophrenia have received the meta-analysis treatment (see here for example).

So, "18 studies representing 1963 patients with SZ and 3683 non-SZ controls" were identified and as per the opening sentence to this post, "blood CRP levels were moderately increased in people with SZ... irrespective of study region, sample size of included studies, patient mean age, age of SZ onset and patient body mass index."

The authors do mention the idea that elevated levels of CRP in cases of schizophrenia fits in with the idea that immune function might be doing so much more than just fighting off infection and the like (see here). Indeed, they talk about: "The rationale that plasma CRP levels were increased significantly in studies with participants’age less than 30 years probably lies in that in the early stages of SZ, a particularly large number of inflammatory substances will be secreted, such as blood CRP and interleukin-10, which are very likely to be related to the development of SZ" with the requirement for further investigations. They also talk about how "high peripheral levels of CRP could increase the permeability of the blood–brain barrier through the adjustment of the function of tight junctions, which contributed to the increase in some pro-inflammatory cytokines, such as CRP to enter the central nervous system." This is an idea that has found favour in other quarters too [2].

Armed with such data, one might envisage that further studies on the possibility of controlling CRP and other related compounds (see here) *could* represent one route to eventually treating at least some types of schizophrenia...

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[1] Wang Z. et al. Association between C-reactive protein and risk of schizophrenia: An updated meta-analysis. Oncotarget. 2017 May 18.

[2] Najjar S. et al. Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry. 2017 May 23;8:83.

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Oral vitamin D and the inflammatory effects of sunburn

In something of a departure from the typical content of this blog, I want to briefly introduce the paper by Jeffrey Scott and colleagues [1] and specifically the findings that: "Compared to placebo, participants receiving vitamin D3 (200,000 IU) demonstrated reduced expression of pro-inflammatory mediators TNF-α... and iNOS... in skin biopsy specimens 48 hours after experimental sunburn."

Based on a small number of participants who either received a high dose of vitamin D - "vitamin D3 (cholecalciferol)" - or a placebo one hour after experimental sunburn, authors describe how there seemed to be some merit in supplementing with vitamin D (oral dosage form) to help mitigate some of the more damaging, inflammatory effects of sunburn based on their observations. They further noted: "increased skin expression of the anti-inflammatory mediator arginase-1, and a sustained reduction in skin redness, correlating with significant expression of genes related to skin barrier repair" in their supplemented group.

It is perhaps timely that this research is discussed today given the current heatwave that has settled over most of Blighty. If like me, you are sometimes prone to the odd bout of sunburn (8 hours at Flamingo Land has quite a lot to answer for!) such findings could eventually prove to be quite useful. Obviously there is the strong advice not to get sunburn in the first place but added to the various creams and lotions to soothe the skin after sunburn, the possibility that vitamin D supplementation might also come in handy is worthwhile experimentally investigating further. The fact that vitamin D is produced in the skin (albeit in a quite complicated series of biological processes) suggests that Mother Nature knew what she was doing when it came to skin exposure to (excess) sunlight.

On one last point - that related to "the immunotherapeutic properties of vitamin D" - I'd also like to think that other areas of science and medicine could benefit from further research in this area. I've discussed research before on this blog talking about how vitamin D supplementation might be important to certain labels under certain conditions with an immune system/inflammatory component attached to them (see here). Assuming that what goes on in the skin under inflammatory conditions following sunburn is not necessarily a hundred million miles away from what happens to other parts of the body under similar inflammatory conditions, there is perhaps quite a bit we can learn from the sunshine vitamin/hormone and it's multi-faceted effects...

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[1] Scott JF. et al. Oral vitamin D rapidly attenuates inflammation from sunburn: an interventional study. J Invest Dermatol. 2017 May 30. pii: S0022-202X(17)31558-0.

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The ADOS-2, autism and "complex psychiatric conditions"

The findings reported by Brenna Maddox and colleagues [1] caught my eye recently and the specific finding that: "The ADOS-2 accurately identified all adults with ASD [autism spectrum disorder]; however, it also had a high rate of false positives among adults with psychosis."

ADOS-2 as in the Autism Diagnostic Observation Schedule mark 2, represents one of the premier gold-standard observational instruments for the assessment of autism or ASD. I've talked about ADOS quite a bit on this blog including the various efforts to further 'reduce down' this schedule and it's counterpart, the Autism Diagnostic Interview (ADI) to speed up the diagnostic/assessment process for example (see here).

Drawing on data derived from "adults in community mental health centers (n = 75)" where ADOS-2 was delivered, researchers observed something of a recurrent theme in screening/assessment circles in that the instruments used to look for autistic traits might not necessarily just be picking up exclusively autistic traits (see here for another example). That and/or the idea that the presentation of autistic traits might not be just confined to autism; important in these days of realisation that autism rarely exists in some sort of diagnostic vacuum (see here).

There is an interesting note added to the Maddox paper insofar as their findings serving "as a reminder that social communication difficulties measured by the ADOS-2 are not specific to ASD, particularly in clinically complex settings." This is not necessarily a new finding [2] but does further stress the 'interconnections' between autism and other labels/diagnoses (see here) as once again, the important observations made by people such as Mildred Creak and colleagues [3] are forgotten/brushed under the carpet at our peril.

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[1] Maddox BB. et al. The Accuracy of the ADOS-2 in Identifying Autism among Adults with Complex Psychiatric Conditions. J Autism Dev Disorder. 2017. June 6.

[2] Morrison KE. et al. Distinct profiles of social skill in adults with autism spectrum disorder and schizophrenia. Autism Res. 2017 May;10(5):878-887.

[3] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.

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Vitamin D deficiency is rife in an in-patient psychiatric unit for young people

"Adolescents within tier 4 adolescent mental health services may be at higher risk of vitamin D deficiency and so assessment of vitamin D levels should be considered as part of a standard physical health review for this group of young people."

So said the results reported by Neil Stewart & Simon Lewis [1] (open-access) who surveyed blood test results of patients admitted to a tier 4 psychiatric unit for vitamin D levels. Such a study was conducted on the basis that "it is plausible that vitamin D and/or vitamin D deficiency have a role in the pathogenesis of mental illness." Yes, indeed I might agree (see here and see here for examples).

Authors identified some 27 individuals who were tested for vitamin D deficiency between 2012 and 2014 from a population of 56. Over 80% (22/27) had vitamin D levels falling into the deficient or severely deficient range, and none of them had vitamin D levels reaching the bottom end of the typical range (75–250 nmol/L). A few other points are worthwhile noting: "In individuals from BME [black and minority ethnic] groups, who were potentially at higher risk of vitamin D deficiency due to increased skin pigmentation, 52.9% (9/17) were tested for vitamin D levels and 100% were deficient or severely deficient."

I was rather happy to see that authors have very much stuck to their findings minus too much speculation about their meaning. They, for example, suggest that all patients entering their particular service should "be considered at high risk of vitamin D deficiency" for whatever reason(s). They emphasise that vitamin D testing should be part and parcel of the routine physical examination normally provided to patients. They even talk about correcting any deficiency/insufficiency whilst monitoring vitamin D levels for any adverse effects or toxicity. In short, treat the physical health of their patients/service users despite the focus of their service being psychiatric. Lessons I'm sure that could be applied to many different labels/diagnoses with a behavioural or psychiatric element to them.

Going back to the idea that vitamin D deficiency might play a role in various conditions/states outside of those linked to bone health, the authors add to other voices suggesting that more investigation is needed to confirm/refute links between vitamin D status and behavioural or psychiatric issues. They note: "If an association between depression and vitamin D deficiency were to be confirmed through future study, vitamin D supplementation could potentially be a cost-effective treatment adjunct with minimal adverse effects." Again, I can't argue with the logic.

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[1] Stewart NF. & Lewis SN. Vitamin D deficiency in adolescents in a tier 4 psychiatric unit. BJPsych Bull. 2017 Jun;41(3):133-136.

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Food neophobia and autistic traits (or at least AQ defined autistic traits)

I was rather interested in the findings reported by Lorenzo Stafford and colleagues [1] suggesting "a positive association between food neophobia and the magnitude of autistic traits." Food neophobia is a fear of eating new or unfamiliar foods, and is something that most parents will have encountered at some point in their child/children's lives. With autism in mind, this type of issue is seemingly not uncommon in amongst various other food-related symptoms that can also be present.

Looking at the "broader aspects of autistic traits" and specifically whether a non-autistic (not diagnosed with autism) population showed any connection between their scores on the Autism Spectrum Quotient (AQ) and their scores on the Food Neophobia Scale (FNS), authors set about their study. They also examined whether olfactory sensitivity - "an olfactory threshold test for a food related odour" - might also show an effect in any relationship.

As per the opening paragraph to this entry, authors reported something of a relationship between AQ scores and FNS scores. Importantly, olfactory sensitivity did not seem to link in with AQ scores, suggesting that the link with food neophobia was not necessarily because of enhanced food odour perception for example. At least in this cohort.

This is potentially important work. Bearing in mind the quite small participant group (N=50), the reliance on "student participants" (not always the most representative of groups) as a non-clinical group and the assumption that AQ is actually measuring just the traits of autism (see here), the findings carry some interest. If there is indeed a connection between autistic traits and food neophobia, one could quite sensibly ask whether intervention(s) to ameliorate or reduce certain autistic traits might have some important knock-on effects for aspects of problematic food-related behaviours in relation to autism. Y'know, similar to the idea offered by other independent studies suggesting for example, that anxiety in the context of autism might be influenced by core traits (such as RRBs [restricted and repetitive behaviours]) and the implications thereof. Further investigations are implied.

And for those who might not fully understand just what food-related issues can mean in the context of autism...

Music to close: Harder, Better, Faster, Stronger.

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[1] Stafford KD. et al. Autistic traits associated with food neophobia but not olfactory sensitivity. Appetite. 2017. June 3.

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On baby teeth, metals and autism

So: "using novel biomarkers of early life exposure, we observed differences in uptake of multiple toxic and essential elements over the second and third trimesters and early postnatal periods in MZ [monozygotic] and DZ [dizygotic] twins discordant for ASD [autism spectrum disorder]."

That was the conclusion reached in the paper by Manish Arora and colleagues [1] (open-access). Using baby teeth as a sort of 'biologic hard drive' according to the accompanying press release (see here), researchers observed some interesting differences across twin groups with or without a diagnosis of ASD according to various pre- and post-natal periods. In particular they noted that: "In ASD cases, higher lead levels were observed over the prenatal period and first 5 months postnatally" and: "Zinc levels were lower in cases during the third trimester."

This paper has already received quite a lot of media attention (see here for example). Thankfully, many of the media outlets have focused on some of the quite important details when it comes to the study; namely that the total number of participants was quite small overall, despite being drawn from a larger research initiative: the Roots of Autism and ADHD Twin Study in Sweden (RATSS).

I am however very interested in both the methods employed during the Arora study and the results obtained. Baby teeth as a focus of autism research? I've speculated on that before (see here). The use of "Laser ablation-inductively coupled plasma mass spectrometry" is also rather good to see; being a method of choice for the determination of metals in various samples (ICP mass spectrometry) coupled to the use of laser ablation to free up the dentine surface of baby teeth for said analysis.

The results talking about levels of lead (Pb) and zinc (Zn) are also not entirely novel in relation to the autism spectrum. On this blog I've talked before about other, independent research observing a possible relationship between lead exposure and autistic traits (see here) on the basis that lead is a known neurotoxin and seemingly serves no physiological function in the body. Zinc, typically reductions in zinc levels, are also not entirely unknown to the autism spectrum either (see here); where zinc is required for quite a few important biological reactions/processes [2].

What's missing from the Arora study? Well, without trying to 'rock the boat' or anything, the focus on lead, zinc and manganese is a little limited given that other types of metals have also been discussed in the context of autism (see here). Yes, I know to mention mercury in the same sentence as autism is high on the 'hot potato' scale but peer-reviewed science is peer-reviewed science (see here). I might also have liked to see how tooth levels of those metals also correlated with blood levels of metals in the context that exposure might not be the only issue when talking about atypical metal levels and autism (see here).

Still, this is a good initial effort and should hopefully pave the way for further investigations into how metal exposure and/or inadequacies can very much impact on behaviour and development.

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[1] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.

[2] Frassinetti S. et al. The role of zinc in life: a review. J Environ Pathol Toxicol Oncol. 2006;25(3):597-610.

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Arora M, Reichenberg A, Willfors C, Austin C, Gennings C, Berggren S, Lichtenstein P, Anckarsäter H, Tammimies K, & Bölte S (2017). Fetal and postnatal metal dysregulation in autism. Nature communications, 8 PMID: 28569757

Autism and phenylketonuria: a double syndrome

I want to briefly talk about the letter to the editor from Esra Demirci [1] (open-access) today and a continuation of some rather important research/clinical chatter about the inborn error of metabolism called phenylketonuria (PKU) intersecting with cases of autism (see here).

The author describes a case report of a child who was diagnosed with an autism spectrum disorder (ASD) "after performing a clinical assessment that included the Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS)" and then subsequently diagnosed with PKU following some important metabolic investigations. They also highlight how instigation of a low phenylalanine diet - the treatment of choice for PKU - seemed to impact on the presentation of autism: "Eight months after the phenylalanine intake diet was initiated, he began to make eye contact, look when his name was said, and form two word sentences. His ABC scores fell from 57 to 46, and his CARS scores fell from 48 to 42."

The 'double syndrome' mentioned in the title of this post refers to the idea that there may be those on the autism spectrum who also have "an already described medical condition" and findings of autism and PKU comorbid fall into that category. I have to say that I'm a fan of this kind of thinking given the range of particularly metabolic conditions that do see to have 'an autistic element' to them (see here for another example). Screening is yet again implied (bearing in mind that PKU is already fairly routinely examined in all newborns in many countries). The idea, also yet again, that use of a low phenylalanine diet might also affect some of the signs and symptoms of autism in such cases remains a point for further investigation into hows and whys...

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[1] Demirci E. Autism Spectrum Disorder and Phenylketonuria: Dyzygotic Twins with Double Syndrome. Noro Psikiyatr Ars. 2017 Mar;54(1):92-93.

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Demirci E (2017). Autism Spectrum Disorder and Phenylketonuria: Dyzygotic Twins with Double Syndrome. Noro psikiyatri arsivi, 54 (1), 92-93 PMID: 28566968

ADHD and risk of injuries meta-analysed

I have already covered the growing peer-reviewed research base looking at the diagnosis of attention-deficit hyperactivity disorder (ADHD) and risk of injuries on this blog before (twice in fact, see here and see here).

The results of the systematic review and meta-analysis by Shahrokh Amiri and colleagues [1] (open-access hopefully available here) therefore come as little surprise: "Those with ADHD are nearly two times more likely to be injured" and necessitates only a brief blogging entry today.

Based on cumulative results - "35 studies were selected for quantitative analysis" - drawn from the peer-reviewed science literature between 2000 and 2014, something of a 'strong' association was determined between ADHD and risk of injuries.

The authors talk about how facets of ADHD might more readily predispose someone to a greater risk of injury as things like risk-taking behaviour(s) "a well-known predictor in road traffic injuries" provide an important connection, also complemented by other behaviours typically associated with ADHD. All-in-all the Amiri results again suggest that yet again, much more clinical inspection is required to (a) inform those diagnosed with ADHD about their enhanced risk, and (b) perhaps reduce the signs/symptoms and/or effects of ADHD so to modify any excess injury risk. Common sense it seems.

To close, Adam West sings...

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[1] Amiri S. et al. Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. J Inj Violence Res. 2017 Jun 1;9(2).

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Amiri S, Sadeghi-Bazargani H, Nazari S, Ranjbar F, & Abdi S (2017). Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. Journal of injury & violence research, 9 (2) PMID: 28554188

Cannabidiol for drug-resistant seizures in Dravet syndrome

"Cannabis drug cuts seizures in children with severe epilepsy in trial" went one of the headlines referencing the results published by Orrin Devinsky and colleagues [1]. Accompanied by an editorial talking about 'real data, at last' [2] on how a chemical component of cannabis - cannabidiol - might be rather useful for some forms of drug-resistant seizures in Dravet syndrome, there is quite a bit of enthusiasm about these latest findings added to other results from this authorship group (see here). The trial details for their latest results can also be found on the ClinicalTrials.gov website (see here).

Dravet syndrome is something that I had previously heard of in light of some connections being made with the presentation of autism or autistic features [3]. Indeed, in these days of the plural autisms (see here) and adherence to the old 'we don't know what causes autism' mantra (see here), there is still quite a bit more investigation needed on autism appearing alongside known genetic or metabolic conditions and what this might mean for prevalence estimates of autism for example.

Dravet syndrome (DS) - also called severe myoclonic epilepsy in infancy (SMEI) - is primarily characterised by a severe type of epilepsy present in early infancy that continues accompanied by a progressive decline of other developmental functions. Such a regression accompanying seizures has attracted some autism researchers' attention (see here) in view of the clinical profile of DS not being a million miles away from that seen in other instances of autistic regression (see here). This also bearing in mind that autism and epilepsy are also not unstrange bedfellows (see here).

In the latest study Devinsky et al set about testing the possible effectiveness of cannabidiol in cases of DS under the gold-standard - double-blind, placebo-controlled - conditions. Some 120 children and young adults diagnosed with DS were randomly allocated to receive "either cannabidiol oral solution [GWP42003-P] at a dose of 20 mg per kilogram of body weight per day or placebo" over a 14 week period. I should also mention that this was pharmaceutical grade cannabidiol. Researchers primarily focused on seizure frequency between the two groups but did also look at important issues such as the instances and types of adverse events (AEs).

As per the headlines, the results suggested that cannabidiol did seem to be quite effective at reducing the frequency of seizures in the treated group compared to controls. Over 40% of those in receipt of the active medication showed at least a 50% decrease in seizure frequency over the course of study. Perhaps a little worrying were the observations that around a quarter of those in receipt of the placebo also showed a similar pattern of reduction (and why this finding just escaped statistical significance for the group taking the active medicine). Results also showed a pattern of possible 'super-responders' to cannabidiol intervention: "The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo."

But then there were the AEs also identified. So: "Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group." This also is a bit of worry, particularly if cannabidiol is something that needs to be constantly taken to maintain any seizure-reducing effects.

On the whole these are interesting findings in need of greater research scrutiny. I will reiterate that this was a controlled study using pharmaceutical grade cannabidiol, so one has to be careful not to assume that either the findings or the intervention will be successful or available to the general population. This is a particularly important point in these days of talk about medicinal cannabis use and condition such as epilepsy (see here) for example.

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[1] Devinsky O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020.

[2] Berkovic SF. annabinoids for Epilepsy - Real Data, at Last. N Engl J Med. 2017 May 25;376(21):2075-2076.

[3] Li BM. et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav. 2011 Jul;21(3):291-5.

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Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, & Cannabidiol in Dravet Syndrome Study Group. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. The New England journal of medicine, 376 (21), 2011-2020 PMID: 28538134