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Autism research and other musings

Paul Whiteley
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  • November 18, 2016
  • 05:40 AM

Acute psychosis and urinary tract infection (again)

by Paul Whiteley in Questioning Answers

Consider this short blog post an extension of some previous discussions (see here and see here) on a rather peculiar 'association' between urinary tract infections (UTIs) and psychosis. UTIs basically refer to an infection in any part of the urinary system (kidneys, bladder, etc) typically treated with antibiotics. Psychosis is a state that causes a person to perceive or interpret things around them in an atypical way, usually accompanied by delusions or hallucinations. For a while now research has been connecting these two conditions.The paper by Chelsea Carson and colleagues [1] further adds to the peer-reviewed literature in this area with the observation of: "an association between UTIs and children and adolescents with acute non-affective psychosis." Based on a "retrospective chart review of 227 subjects ages 10–18 who were hospitalized between 2005 and 2014 for an acute episode of DSM-IV non-affective psychosis" compared with those presenting with depression with and without psychotic features, researchers noted that a UTI was not an uncommon diagnosis (20%). Bearing in mind the lack of any asymptomatic control group, authors concluded that screening for [comorbid] UTI in those presenting with acute psychosis might be warranted.I can't disagree with these findings and conclusions. Combined with other work [2] looking at "an association between an increased prevalence of UTI and acute psychotic relapse" in those diagnosed with schizophrenia, the idea that infection or immunological response to infection might have behavioural as well as physiological outcomes gathers strength from such findings. We still don't know all the hows-and-whys of such an association outside of the idea that inflammatory mechanisms may be at work (see here) but further investigations are most definitely implied.----------[1] Carson CM. et al. Urinary tract infections in children and adolescents with acute psychosis. Schizophrenia Research. 2016. Nov 10.[2] Miller BJ. et al. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry. 2013 Mar;74(3):271-7.----------Carson, C., Phillip, N., & Miller, B. (2016). Urinary tract infections in children and adolescents with acute psychosis Schizophrenia Research DOI: 10.1016/j.schres.2016.11.004... Read more »

  • November 17, 2016
  • 03:57 AM

Caring for the carer: what the science suggests

by Paul Whiteley in Questioning Answers

Papers such as the one published by Nikko Da Paz & Jan Wallander [1] I think represent one of the most important areas of autism research and practice when it comes to the practical translation of science to real-life. Tackling a very important topic - caring for the carers - the authors provide a "narrative review" of the peer-reviewed science literature looking at how "treatments that directly target parents' psychological well-being" in the context of autism are doing so far.Personally, I don't like the use of the word 'treatment' in this context because it implies that caring for the carers is akin to tackling some sort of disease. It's not. It also 'medicalises' the experience of caring for/raising children on the autism spectrum which I don't think anyone really wants to do. I might suggest that 'intervention' could be a better word to use.Da Paz and Wallander reported on "a total of 13 studies, seven randomized controlled trials (RCTs) and six pre-post test designs" that looked at various interventions pertinent to improving parent stress and reducing instances of depression and anxiety. They report: "Interventions that appeared promising included: Stress Management and Relaxation Techniques, Expressive Writing, Mindfulness-Based Stress Reduction, and Acceptance and Commitment Therapy" with some important caveats. Not least that if English is not your language of choice and/or you are not aged between 39-42 years old, the evidence base is rather sparse when it comes to what might be useful or not for managing your psychological health. In light of other research [2] there is quite a bit more to do in this area.Accepting that the publishing journal - Clinical Psychology Review - gives a rather large hint as to why the listed 'psychological' interventions were focused upon, I might also add a few comments about how other science and practice might also aid parents raising children on the autism spectrum. I've for example, covered the topic of respite care and parent stress before on this blog (see here) and how depending on your definition of respite, there is perhaps some value in either the utilisation of short break facilities or the use of domiciliary care/support where available. As per my previous discussion of this area, there is a rather large stumbling block to any talk about respite care insofar as in these austere times in which we live, some of the first social services that seem to suffer when budgets need to be reduced are respite services.I'm also minded to bring in the idea that outside of psychological techniques potentially impacting on parenting stress and any adverse outcomes, one might also look at more physical interventions too. So, for example, exercise is something that could be a rather useful intervention to look at given the pretty strong research links being forged between body and mind. The thing about exercise is that (a) depending on what regime you choose costs can range from free to expensive, and (b) there are a whole host of other factors potentially tied into a chosen sport, based on the choice of solitary sports vs. group sports for example and other factors. That various health agencies are already shifting when it comes to notions of potentially 'prescribing exercise' for something like depression and anxiety (see here for example) reflects how valuable moving a little more might be to lots of groups.I would champion the idea that quite a few more resources need to be put into caring for the carers when it specifically comes to parenting and autism. This is not about further 'blaming autism' for parenting stress or adverse outcomes but rather acknowledging that parenting whether in the context of autism or not, is a sometimes difficult task. And nobody benefits if parents/carers are just left to fend for themselves without the appropriate help and support...----------[1] Da Paz NS. & Wallander JL. Interventions that target improvements in mental health for parents of children with autism spectrum disorders: A narrative review. Clin Psychol Rev. 2016 Oct 27;51:1-14.[2] Zuckerman KE. et al. Pediatrician identification of Latino children at risk for autism spectrum disorder. Pediatrics. 2013 Sep;132(3):445-53.----------Da Paz NS, & Wallander JL (2016). Interventions that target improvements in mental health for parents of children with autism spectrum disorders: A narrative review. Clinical psychology review, 51, 1-14 PMID: 27816800... Read more »

  • November 16, 2016
  • 03:58 AM


by Paul Whiteley in Questioning Answers

With all rights reserved for Keith Geraghty and his publication in the Journal of Health Psychology [1] (open-access) I want to reproduce his abstract relevant to the PACE trial commenting on the ups-and-downs of this study looking at the use of CBT (cognitive behaviour therapy) and GET (graded exercise therapy) for chronic fatigue syndrome (CFS) (also known as myalgic encephalomyelitis, ME):"Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request."For those familiar with PACE [2] and the 'angry sea' saga following its publication (see here for some of that saga), this paper represents one of the the first 'peer-reviewed' discussions that makes reference to the reanalysis of 'trial improvers' vs. that included in the original PACE trial publication (see here). Indeed, combined with other (as yet unpublished in the peer-reviewed domain) re-analyses (see here), there seem to be some pretty stark differences noted between the different 'versions' in terms of the effectiveness of different arms of the intervention tested during the PACE trial. Even before these latest re-analyses, some agencies were already adjusting the strength of their recommendations when it came to CBT and/or GET for CFS/ME (see here). Does this mean other organisations might follow suit?The other issue central to the Geraghty discussions is that of 'enforced data release' and data transparency. This has been a focal point when it comes to PACE (including that with reference to other papers on the trial) and perhaps something that has significantly added to the sometimes bitter discussions about the trial. As Geraghty notes: "The PACE-Trial stands out as a showcase example of why data transparency is needed in contemporary science. Patients suffering from health conditions like CFS, and independent scientists, should have the right to see the evidence behind the claims of any scientific study, especially if this evidence is used to direct health policy or promote certain treatments – as was the case for the PACE-Trial." In light of how PACE has been contributory to public policy, and indeed was part funded by agencies such as "the UK Department for Work and Pensions", I don't think many people would argue against suitable data transparency in this case.I say nothing more at this point in time but will no doubt be returning to this topic as the peer-reviewed literature allows (which should be quite soon). If there are however, some lessons that can already be learned from PACE-gate (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community rather than labelling elements of them 'vexatious' or worse) one would hope that they would be applied to future research projects related to CFS/ME (see here) as well as their anticipated long-term follow-up [3]...Music: The King and what wise men (might) say (easily recognisable to any Black Cats fan).----------[1] Geraghty KJ. 'PACE-Gate': When clinical trial evidence meets open data access. J Health Psychol. 2016 Nov 1. pii: 1359105316675213.[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.[3] Nijhof SL. et al. Internet-based therapy for adolescents with chronic fatigue syndrome: long-term follow-up. Pediatrics. 2013 Jun;131(6):e1788-95.----------Geraghty KJ (2016). 'PACE-Gate': When clinical trial evidence meets open data access. Journal of health psychology PMID: 27807258... Read more »

  • November 15, 2016
  • 03:56 AM

Autism, ESSENCE and the question of reassessment

by Paul Whiteley in Questioning Answers

I talked about ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations - only yesterday (see here) and here I am covering the topic again on this blog. There is good reason however that this concept appears once more, as I draw your attention to the paper by Anne-Katrin Kantzer and colleagues [1] and the specific observation that: "Co-existence with other conditions was the rule" when it comes to the diagnosis of autism.OK, it's nothing new to say that the label of autism rarely appears in some sort of diagnostic vacuum (see here). Indeed, if there is anything that has been learned about autism over the years it is that aside from the incredible heterogeneity present across the spectrum in terms of clinical presentation, many grand theories 'about autism' have been scuppered as a consequence of their assumptions on autism being some sort of stand-alone label. A case in point: theory of mind (ToM); that even some of the major proponents of this theory have come to realise [2] has seen a "a widening of interest to other clinical groups." Indeed it has (see here for example), indeed it has. And other grand theories appear also to be following suit [3]...The Kantzer paper - including some notable names on the authorship list - set out to examine the diagnostic outcomes of some 96 children "initially assessed for suspected ASD [autism spectrum disorder] at an average age of 2.9 years" who were followed up some two years later. There is an important word included in the Kantzer study: prospectively; as opposed to retrospectively, meaning that participants were assessed and followed in real-time (rather than solely relying on the examination of previous historical records). Various behavioural and psychometric measures were employed by the authors as part of a "broad neurodevelopmental examination... by a multi-professional team" and some rather interesting details emerged.So: "In a cohort of young children who screened positive for autism spectrum symptoms, 93% of all with an Autism spectrum disorder (ASD) at time1 (T1) had ASD two years later." What this tell us is that in the most part, the diagnosis of autism/ASD over 2 years in young children is fairly stable. Other data has highlighted similar things. But then the question: what about the ~7% where an ASD diagnosis perhaps wasn't as stable? I've covered this topic a few times on this blog (see here and see here), where for whatever reason, the diagnosis of autism is not necessarily a lifelong label for everyone. The still controversial idea that around 9% of those originally diagnosed with autism might 'lose' their diagnosis (see here) and indeed any/many 'broader autism features' (see here) could be pertinent here accepting that in the Kantzer data we are told: "The children who did not meet criteria for ASD at T2 had symptoms of or met criteria for other neurodevelopmental/neuropsychiatric disorders in combination with marked autistic traits." I might also draw your attention to other work from members of the Kantzer group that indicated that even into adulthood, diagnoses along the autism spectrum might similarly not always be 'lifelong' for whatever reason(s) (see here).Next: "The vast majority of children with ASD also had other neurodevelopmental symptoms or diagnoses." This kinda reiterates the notion of ESSENCE, as details such as: "Hyperactivity was observed in 42% of children with ASD at T2, and Intellectual Developmental Disorder in 30%" provide some diagnostic flesh on the bones of what ESSENCE might look like in clinical terms. Indeed, although the topic of continued debate [4] insofar as how one screens for something like attention-deficit hyperactivity disorder (ADHD) in autism, the overlap between the conditions is likely to be significant (see here).Finally: "The risk of “over-diagnosis” of ESSENCE/ASD problems by screening for ASD at 2.5 years appears to be minimal." Accepting that important changes to the way that autism is diagnosed by at least one schedule is likely to produce some important differences in who fulfils criteria (see here), the authors seem to be fairly confident that early diagnosis might actually be (a) possible and (b) pretty accurate. The stress is most definitely on 'early diagnosis' save any charges of further health inequalities facing those on the autism spectrum.I titled this post  'Autism, ESSENCE and the question of reassessment' because I do also want to pass some brief comment about the value of reassessment picked up by the authors: "Reassessments covering the whole range of these conditions are necessary for an optimized intervention—adapted to the individual child’s needs." This is going to take quite a huge shift in thinking and practice insofar as ensuring that a diagnostic assessment for autism does not just include an ADOS or something related but rather includes a wider spread of behavioural and psychometric instruments pertinent to various other labels/features. I can see there being objections to this line of thought; not least that in these austere times we live in when waiting times for an initial assessment can already be quite long (see here) and money and resources are stretched thin on the ground for autism, screening for a range of potential additional issues is likely to further burden limited resources. The idea also that not hitting diagnostic thresholds for autism at one point does not rule out a child hitting them at a later time point is also something likely to impact on screening and assessment services. I suppose it all depends on whether policy-makers and purse-string holders value detail or value cost-saving?Either way, the Kantzer paper once again highlights that a diagnosis of autism rarely exists in a diagnostic vacuum.Music to close (it's been a while) and an 80's blast from the past: Billy Ocean - Get Outta My Dreams, Get Into My Car (although please, do not get into a car with someone you don't know, no matter how well they serenade you).----------[1] Kantzer A-K. et al. Young children who screen positive for autism: Stability, change and “comorbidity” over two years. Research in Developmental Disabilities. 2016. Nov 3.[2] Happé F. & Conway JR. Recent progress in understanding skills and impairments in social cognition. Curr Opin Pediatr. 2016 Dec;28(6):736-742.[3] Dajani DR. et al. Heterogeneity of executive functions among comorbid neurodevelopmental disorders. Sci Rep. 2016 Nov 9;6:36566.[4] Yerys BE. et al. Evaluation of the... Read more »

  • November 14, 2016
  • 04:13 AM

ESSENCE meets connective tissue disorders?

by Paul Whiteley in Questioning Answers

ESSENCE referred to in the title of this post concerns 'Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations', a concept championed by the ever-intrepid Prof. Christopher Gillberg and colleagues. Combined with some rather important discussions about the research validity of the concept of a singular 'autism' (see here) [part of the ESSENCE issues described] I'm drawn to quite a few of the proposals put forward by this research group it has to be said.It is with ESSENCE in mind, that I'm rather interested in the paper by Carolina Baeza-Velasco and colleagues [1] and the observation that following a review of the pertinent research literature, there is some support for a possible connection between ESSENCE issues and another favourite topic on this blog: Joint Hypermobility Syndrome (JHS) and the spectrum of connective tissue disorders (see here for example). JHS and connective tissue disorders refer to a group of conditions where various connective tissues are 'weaker' than they should typically be, with various knock-on effects and symptoms."The clinical picture of EDS-HT/JHS [EDS = Ehlers-Danlos syndrome] is poorly known by the medical community, as is the presence of "ESSENCE" (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) problems in affected children" was the starting point for this review paper of the various research literature on this topic. Authors searched, surveyed and concluded that: "Children with EDS-HT/JHS present ESSENCE problems that often coexist and tend to be recognized before the HDCT [hereditary disorder of the connective tissue]." Further: "Awareness of these interconnected clinical problems might help improve early referral, diagnosis and treatment of EDS-HT/JHS."In a previous blog post on the issue of 'joint hypermobility, gait and autism' (see here), discussions turned to how there may be some important 'intersection' going on with regards to the presentation of motor and gait issues in autism and connective tissues disorders present in some people. I don't want to make sweeping generalisations nor move too far away from the current thinking linking specific brain functions and motor issues [2] but there is some sound logic in how neurodevelopmental issues might go hand-in-hand with connective tissue disorders. If for example, we turn to some of the other manifestations of something like JHS - functional bowel issues such as constipation and/or irritable bowel syndrome (IBS) - there are other potential overlapping features that might also prove to be just as important (see here).There is a need for quite a bit more research in this area before any grand, sweeping generalisations are made. That and the idea that yet another level of screening might be implied for those with ESSENCE issues or conversely, those diagnosed with connective tissue disorders...Music to close: The JCB song. For the next time you're stuck behind one....----------[1] Baeza-Velasco C. et al. A connective tissue disorder may underlie ESSENCE problems in childhood. Res Dev Disabil. 2016 Oct 29. pii: S0891-4222(16)30240-2.[2] Gillberg C. et al. Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. The Scientific World Journal. 2013;2013:710570.----------Baeza-Velasco C, Grahame R, & Bravo JF (2016). A connective tissue disorder may underlie ESSENCE problems in childhood. Research in developmental disabilities PMID: 27802895... Read more »

Baeza-Velasco C, Grahame R, & Bravo JF. (2016) A connective tissue disorder may underlie ESSENCE problems in childhood. Research in developmental disabilities. PMID: 27802895  

  • November 12, 2016
  • 05:17 AM

Bifidobacterium longum 1714 attenuates stress?

by Paul Whiteley in Questioning Answers

It's been quite a week hasn't it? Indeed for quite a few people it's been a stressful few days so perhaps timely that I'm talking about the 'attenuation of stress' in today's post.Despite the relatively small sample size included in the paper by by AP Allen and colleagues [1] there is something rather tantalising about their results suggesting that in healthy volunteers "consumption of B. longum [Bifidobacterium longum 1714] 1714 is associated with reduced stress and improved memory."Tantalising because as well as further directing research attention towards the important relationship that is the gut-brain axis (see here for another example) the findings provide initial support for the concept of "psychobiotics—live microorganisms with a potential mental health benefit" set within a human (not mouse) context.The Allen paper (who incidentally is on Twitter) is open-access and has previously provided signs that it was to be published (see here). Here are a few choice details:Take 22 (male) volunteers aged between 18 and 40 years of age who fitted various inclusion/exclusion criteria including no "self-report habitually taking any probiotic products" and ask them to take B. longum 1714 for 4 weeks after giving them a placebo preparation containing just maltodextrin and magnesium stearate and no probiotic for 4 weeks. Deliver various physical, psychometric and self-report questionnaires/tests at various intervals covering things like the "Socially evaluated cold pressor procedure" (SECPT) and other measures and see how things pan out according to placebo/psychobiotic use and after "a 2-week post-probiotic follow-up."Results: well, as per the opening paragraph of this post, there did seem to be some effects to be had potentially associated with B. longum administration. So, when it came to that 'put your hand in cold water' test (SECPT), participants as a group lasted slightly longer in the cold water than on previous testing occasions. When researchers looked at salivary cortisol levels (a measure of psychological stress) following this acute stress test, they observed some potentially important differences between the initial (baseline) test, the period covering placebo use and the period covering the psychobiotic use. This accompanied some differences in reported state anxiety. Such acute stress findings were also complemented by some subtle but potentially important differences in self-reported daily stress levels (lower) following the period of psychobiotic use (something that "returned to a higher level during the 2-week follow-up period"). The authors also report on some findings associated with testing cognition across the various phases of the study but I'm gonna stay focused on the stress part of things for now before anyone moves towards describing B. longum 1714 as some sort of nootropic of choice just yet.Of course there is still much to do in this area before anyone gets too carried away with things (how about a few more blinded RCTs pitting placebo against psychobiotic?) but the results are interesting. You could argue that there may have been some influence of practice effects associated with some of the results given the short timescales but I'm gonna take the findings at face-value. More so when when set in the context of other microbial preparations also potentially dealing with certain types of stress under experimental conditions (see here for example).Mode of action? Well, the authors mention the 'vagus nerve' as potentially being important given the suggestion of a connection between the trillions of wee beasties that populate our gut (the gut microbiota) and brain function(s). The specifics however are yet to be decided upon; and it is also worth noting that as part of the probiotic formulation called VSL#3, B. longum 1714 might have some important 'bowel' effects as per other findings (see here) onwards to behaviour(s) and labels (see here). I'm also intrigued by the finding that post-probiotic there was a suggestion of a waning of some of the previously reported effects implying that far from probiotics being accepted and 'assimilated' into our collected gut microbiota, there may be mechanisms at work tied to going back to the status quo."Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects." Wise words before anyone makes a run on B. longum 1714 or any related preparations but this is an interesting piece of research. Given also the so-far relatively good safety profile of various probiotics, there is an important argument for experimentally testing such stress relief and/or cognition-aiding properties under a wide range of contexts.To close, we lost another one in 2016. There must be a helluva party going on upstairs...----------[1] Allen AP. et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational Psychiatry. 2016; 6: e939.----------Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, Murphy E, Cryan JF, Dinan TG, & Clarke G (2016). Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational psychiatry, 6 (11) PMID: 27801892... Read more »

  • November 11, 2016
  • 04:04 AM

"While you're here, I just want to talk about your weight"

by Paul Whiteley in Questioning Answers

The important Doctor-Patient relationshipIn a slight departure from the typical material discussed on this blog, I want to briefly direct readers to the paper by (Prof) Paul Aveyard and colleagues [1] and results suggesting that: "A behaviourally-informed, very brief, physician-delivered opportunistic intervention is acceptable to patients and an effective way to reduce population mean weight."The title of this post comes from some of the media coverage of the Aveyard study summarising how general practitioners (GPs) in particular, might be ideally placed to bring up the topic of 'weight issues' when seeing some of their patients for other health matters.Minus any charges of plagiarism, I'd like to particularly draw readers attention to the example given in the Aveyard paper of a 'typical physician intervention'. So:"Physician: While you're here, I just wanted to talk about your weight. You know the best way to lose weight is to go to [Slimming World or Rosemary Conley] and that's available free on the NHS?Patient: Oh?Physician: Yes, and I can refer you now if you are willing to give that a try?Patient: Yes, ok.Physician: Ok, what you need to do is take this envelope back outside to the person who weighed you and they will book you into the weight loss course now.Patient: Ok.Physician: Good, but I'd like to see how you're getting on, so come and see me again in 4 weeks, please. Ok?Patient: Ok, see you then."In these days of the 10-minute consultation combined with something of an 'epidemic' of obesity and overweightedness I like the idea that a 30-second chat from an authority figure like a GP with a patient can potentially transform lives, even if only a proportion of the intended market. Despite the fact that only 40% of those offered weight reduction classes actually attended, there are some pretty decent statistics included in the paper to suggest that for this group, weight change was better than for those who weren't offered any additional support ("mean weight change at 12 months was 2·43 kg with the support intervention and 1·04 kg with the advice intervention, giving an adjusted difference of 1·43 kg"). And with decreasing weight, so the risk of various other health complaints also decreases accepting the old/new adage of 'not out-running a bad diet' [2].In these days of the soundbite and 140-characters or less, it makes me wonder what other health promotion advice might be amenable to a very brief chat from someone like a GP?To close, lest we forget...----------[1] Aveyard P. et al. Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial. Lancet. 2016. Oct 24.[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015 Aug;49(15):967-8.----------Aveyard, P., Lewis, A., Tearne, S., Hood, K., Christian-Brown, A., Adab, P., Begh, R., Jolly, K., Daley, A., Farley, A., Lycett, D., Nickless, A., Yu, L., Retat, L., Webber, L., Pimpin, L., & Jebb, S. (2016). Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial The Lancet DOI: 10.1016/S0140-6736(16)31893-1... Read more »

Aveyard, P., Lewis, A., Tearne, S., Hood, K., Christian-Brown, A., Adab, P., Begh, R., Jolly, K., Daley, A., Farley, A.... (2016) Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial. The Lancet. DOI: 10.1016/S0140-6736(16)31893-1  

  • November 10, 2016
  • 04:09 AM

Atopy increases vulnerability to affective and anxiety issues?

by Paul Whiteley in Questioning Answers

In a year of impossible things...I was rather interested to read the recent paper by Renee Goodwin and colleagues [1] observing that: "Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy."Atopy, referring to a predisposition to developing allergic diseases such as eczema, asthma and/or hayfever, is something on the 'up' in research terms when it comes to aspects of psychiatry and/or developmental outcomes (see here for example). Goodwin et al set about further testing the possibility of a link based on data "drawn from the Raine Study (N = 2868) [a favourite initiative on this blog], a population-based birth cohort study in Western Australia."Looking at signs of atopy - "using parent report and objective biological confirmation (sera IgE)" - at ages 1-5 years and "the range of internalizing and externalizing mental health problems at ages 5-17 years" authors reported on some interesting patterns/correlations in relation to affective and anxiety problems potentially being linked. Authors also described how their results held strong even "after adjusting for a range of potential confounders."Whilst there are always going to be issues associated with studies linking one or two variables across various years, the Goodwin paper represents yet another example of how further research resources need to be ploughed into the area of immune function and behaviour. Yes, I appreciate that we are entering the era of immunopsychiatry (if I can call it that) and that there is some good science emerging in this area (see here) but questions about the [various] hows and whys still need answering [2].----------[1] Goodwin RD. et al. Childhood atopy and mental health: a prospective, longitudinal investigation. Psychol Med. 2016 Oct 20:1-9.[2] Hatfield SJ. et al. What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes. Clin Exp Dermatol. 2016 Nov 2.----------Goodwin RD, Robinson M, Sly PD, & Holt PG (2016). Childhood atopy and mental health: a prospective, longitudinal investigation. Psychological medicine, 1-9 PMID: 27762174... Read more »

  • November 9, 2016
  • 05:16 AM

A 'frank' presentation of autism?

by Paul Whiteley in Questioning Answers

"Many individuals with ASD [autism spectrum disorder] have a distinctive behavioral presentation that is recognizable within moments, a phenomenon we call "frank" ASD." So said the paper by Ashley de Marchena & Judith Miller [1] who carried out an "empirical study of frank ASD" and by the looks of my Twitter feed when I initially posted about this study, there are quite a few varied opinions about the concept of 'frank' autism.Although 'frank autism' makes up a significant portion of the chatter about the de Marchena/Miller paper, the authors do provide an alternative description using the term "classic autism" and how "there is no unitary "classic" presentation, and classic autism does not seem to correspond to level of functioning." On that basis, they set about surveying just over 150 clinicians involved in the diagnostic assessment of autism/ASD using a "13-item questionnaire about frank ASD" and report results on just how many people in their cohort were familiar with this term, how widespread they thought it might be as well as how it might be comprised.Results: "Ninety-seven percentage of respondents were familiar with the phenomenon. Respondents estimated that 40% of the ASD population has a frank presentation." The sorts of behaviours respondents thought were most frequently associated with frank autism were things like eye contact issues, the "presence of motor mannerisms, and atypical gait or posture" and communicative styles. Surprisingly: "respondents reported detecting frank features rapidly, with the majority forming their impressions within the first ten minutes of interaction or observation." Ten minutes, eh?"We discuss these findings within the context of diagnostic decision-making and behavioral phenotyping of ASD" said the authors, as some important insights into clinical decisions about autism assessments are potentially revealed in this paper.In line with the comments received about this paper on social media, there are a few things to note. First and foremost is the idea that clinicians might be pretty good at spotting [some] autism fairly quickly. I don't think this should surprise anyone given that autism is diagnosed by behaviour (and developmental history) and whilst nothing beats a comprehensive assessment, experienced clinicians are always going to have 'hunches' or mental tick-boxes based on their previous experiences of diagnosing autism (or not). I might add that one needs only read some of the literature behind the development of the ICF core sets for autism (which are due out in the not-so-distant-future) to see such expertise in action (see here).But... experts whilst being experts aren't always correct as we've seen on other occasions when it comes to experts and autism screening/diagnosing (see here). There is also the suspicion that bias could be creeping into clinical decision-making too which could potentially affect diagnostic rates for specific groups for example (see here). Indeed, with all the changes being applied to some of the diagnostic criteria for autism as per the introduction of DSM-5, one wonders how such 'bias' is going to affect groupings such as the SCD 'catch-all' description (see here) for example?I would also be a little concerned that behaviours "absent from diagnostic criteria (e.g., atypical gait or posture)" are being potentially used to form clinical opinions/decisions. Yes, I appreciate that motor issues - potentially linked to gait and posture - are in the ascendancy again when it comes to autism (see here for example) but in light of known comorbidity accompanying autism such as dyspraxia for example [2] I think we have to be quite cautious about the mindset being applied here and how comorbidity is potentially being grouped into core autism. I might also add that the growing interesting in tic disorder(s) being 'over-represented' in autism is something else that could potentially be affected by such 'frank' thinking (see here).I'm a great believer in appropriate screening and detailed diagnostic assessment when it comes to autism on the basis of many variables, not least that autism rarely comes as a stand-alone diagnosis (see here) and that autistic traits are seemingly present across various other different labels too (see here and see here). Whilst it is not unexpected that those assessing and diagnosing day-after-day may build up a mental picture of what autism is (and isn't), there are cautions attached to the idea that clinical impressions are being formed seemingly so early during 'interaction or observation' and what this could mean for the heterogeneity of autism and the presentation of its important over-represented comorbidities.Music to close and something a little relaxed to ease your 2016 worries: Erik Satie - Gymnopédie No.1.----------[1] de Marchena A. & Miller J. "Frank" presentations as a novel research construct and element of diagnostic decision-making in autism spectrum disorder. Autism Res. 2016 Oct 21.[2] MacNeil LK. & Mostofsky SH. Specificity of dyspraxia in children with autism. Neuropsychology. 2012 Mar;26(2):165-71.----------de Marchena, A., & Miller, J. (2016). “Frank” presentations as a novel research construct and element of diagnostic decision-making in autism spectrum disorder Autism Research DOI: 10.1002/aur.1706... Read more »

  • November 8, 2016
  • 03:57 AM

"A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis"

by Paul Whiteley in Questioning Answers

Contrary to Murphy's Law - 'never repeat a successful experiment' - replication or reproducibility is a cornerstone of good science. Today, I'm blogging about a piece of research that aimed to do just that as per the findings reported by Stephen Walker and colleagues [1] (open-access).The title of this post has been borrowed from the title of the Walker paper to illustrate how moving on from the quite widely known 'fact' that functional gastrointestinal (GI) symptoms are over-represented when it comes to the label of autism (see here for example) so further research focus is required on more pathological bowel conditions potentially linked to autism too (see here). Yes, I know this potentially takes us into some uncomfortable territory but for those with autism suffering with various bowel issues (and I do mean suffering) this marks some important science for them and their families onward to the resolution of any further health inequalities.The latest Walker paper follows on from their original findings [2] which have been previously covered on this blog (see here) observing that: "ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease." ASDGI by the way, referred to their small grouping of "twenty five consecutive ASDGI cases (6 autism; 19 autism spectrum disorder) with histopathologic findings of ileitis, colitis, or both."This latest time around authors report on the extending of their 'initial findings' in "an additional case/control cohort." Further they "report a gene expression profile in peripheral blood that may reflect the presence of ASD-associated ileocolitis and provide a putative surrogate biomarker that, upon validation, would be of significant clinical relevance." Potentially, big words.The paper is open-access but here are a few choice details:Biopsy samples - "a specimen from each of seven anatomic locations (from the terminal ileum to rectum)" - and blood samples were provided by 21 participants (patients) diagnosed with an autism spectrum disorder (ASD). All presented with gastrointestinal (GI) symptoms and all had "a history of normal development for at least 12 months followed by developmental regression and onset of gastrointestinal symptoms." All also had "histologically-confirmed ileitis, colitis, or both in at least one of seven collected and archived colonic biopsies." A control group of 21 'typically-developing' children "without ASD who had gastrointestinal symptoms... but no identifiable histologic inflammation on any biopsies in either the ileum or colon" were also included for analysis.Part 1 of the study "compared whole genome gene expression profiles of inflamed ASD GI mucosal tissue (ASDIC+) to non-inflamed TD mucosal tissue (TDIC−) in biopsies from both the terminal ileum and colon." This is pretty much what was done by the authors during their first research voyage in this area. Part 2 was more novel insofar as blood gene expression profiles were compared between the groups. It's also important to note that: "blood was obtained from the same patients, and at the same time, as their respective mucosal tissue samples."Results: applying a statistical technique called Principal Component Analysis (PCA) looking at gene expression in those mucosal (bowel) samples, authors were again able to say that there were differences between inflamed and non-inflamed samples/groups. They also observed some potentially important differences in those blood samples too: "Nine of these DETs [gene transcripts that are differentially-expressed] were also differentially expressed in blood in our most recent cohort." You might ask what does this actually tell us about the autism+GI group? Well, nothing and something, insofar as it is not really being ethical to start taking bowel biopsies from children with autism without any indication to do so, which means that comparisons between non-GI and GI+ children with autism were not possible. The data do however suggest that a "putative peripheral marker could provide a proxy for gastrointestinal inflammation and also provide functional insights."Insofar as the details of what genes were being differentially expressed in ASDIC+ vs. TDIC- samples and how these overlapped with the previous study from the authors, there were some interesting candidates including "a key mitochondrial folate pathway gene, MTHFD2 (methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2, methenyltetrahydrofolate cyclohydrolase)" hinting at an effect beyond just immune function and inflammation/inflammatory signalling. Authors modelled various combinations of these genes expressed (or not) to try and come up with some preliminary Receiver Operating Characteristic (ROC) curve analysis. Regular readers of this blog will probably have heard me talk about ROC analyses before (see here for example) with regards to the search for potential classifiers or biomarker profiles associated with autism. Bearing in mind the small participant numbers included in this study and the final figures arrived at, I'd suggest that quite a bit more work is required before anyone takes the reported findings as gospel just yet. But they are interesting...So, there you have it. This is important work for two reasons: (i) more pathological bowel states can and do present alongside autism [3] (the diagnosis of autism is seemingly protective of very little as science is learning) and (ii) with the strong requirement for further investigations in this area, science is seemingly starting on a path to potentially identifying blood-based 'biomarkers' possibly useful in identifying those who might benefit from further screening for such bowel issues.Given the history and debate in the area of bowel disease accompanying some autism, I'm not expecting giant fanfares to greet these results nor any big rush to try and prove/disprove these latest findings. That is an unfortunate truth and in the end, it is the children/adults with autism and significant GI issues who lose out as a consequence. The fact that this and the previous work by the authors is peer-reviewed science and not just speculation however will I think eventually be important, as talk about medical comorbidity accompanying autism continues at a pace [4] (see here too) and further moves towards 'what can we do about such issues?' eventually start to come to the forefront.And just before I go, there may also be other research uses for biopsies as and when they have to be taken from children/adults under clinical investigation [5]...To close, I note there is an election across the Pond. With all the nastiness that has followed the campaign, surely there's an easier way to pick the Leader of the Free World...----------[1] Walker SJ. et al. A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. Sc... Read more »

  • November 7, 2016
  • 04:13 AM

8.6% of children with autism have epilepsy?

by Paul Whiteley in Questioning Answers

"Epilepsy was reported to co-occur in 8.6 % of ASD [autism spectrum disorder] cases."That was the headline conclusion reported by Shiny Thomas and colleagues [1] as they drew on data from "the most recent U.S. National Survey of Children's Health, 2011-2012" to add to the extensive literature looking at how common epilepsy is when it comes to autism.Including some 1600 children/young adults diagnosed with autism - equivalent to a prevalence of 1.8% of the entire 85,000-strong cohort - researchers "examined parent-reported prevalence of co-occurring epilepsy" and eventually came up with that 8-9% figure. Further, they also observed that: "the co-occurrence of epilepsy was associated with increasing child age, female gender, intellectual disability, speech problems and lower socioeconomic status."This is important work. Epilepsy or seizure disorder is not something to be taken lightly under any circumstances; more so when applied to autism and the 'burden' of medical comorbidity that seems to be over-represented following a diagnosis (see here). The use of the U.S. National Survey of Children's Health (NSCH), 2011-2012 also has some significant strengths in terms of numbers of participants and has previously informed quite a few areas of autism research (see here for example).There is another important detail attached to the Thomas paper that is also worthy of comment in relation to how their prevalence figure compares with other independent studies in terms of epilepsy appearing comorbid to autism (readers should click on the 'Supplementary material' attachment shown here). Bearing in mind their data was derived from children "ages 2-17" and includes the term 'parent-reported' (as opposed to medical records reported) the 8.6% figure seems to be quite a conservative one. I say this on the basis that previous data from NSCH has observed slightly higher rates of epilepsy (see here) and other data sources have even talked about 1 in 5 children on the autism spectrum manifesting with a seizure or seizure disorder (see here). I of course realise that the word 'epilepsy' covers quite a bit of diagnostic ground and seizures/seizure disorder can present for a variety of reasons, but nonetheless I stand by the 8.6% comorbidity figure as perhaps being one of the lower values published in the peer-review domain.The additional observations that 'increasing age' and presence of intellectual (learning) disability might influence the presence of epilepsy in relation to autism are interesting but by no means novel findings. They do however offer something of a roadmap to monitoring those on the autism spectrum who may be at some enhanced risk of developing epilepsy and indeed, implementing the relevant strategies in a timely fashion to ensure that epilepsy is managed safely.Many questions still remain concerning the hows and whys of epilepsy intersecting with autism (and indeed, autism intersecting with epilepsy) including those related to more 'non-traditional' aspects (see here for example). What however is abundantly clear from the peer-reviewed and other literature in this area is that epilepsy is an important part of life for quite a few people on the autism spectrum and as many resources as possible should be pumped into looking at the relationship and offsetting / averting the potentially life-changing consequences that epilepsy can have on a person and their loved ones (see here).To close, when one mentions 'God Save the Queen' one should really specify which version one requires?----------[1] Thomas S. et al. Brief Report: Prevalence of Co-occurring Epilepsy and Autism Spectrum Disorder: The U.S. National Survey of Children's Health 2011-2012. J Autism Dev Disord. 2016 Oct 17.----------Thomas S, Hovinga ME, Rai D, & Lee BK (2016). Brief Report: Prevalence of Co-occurring Epilepsy and Autism Spectrum Disorder: The U.S. National Survey of Children's Health 2011-2012. Journal of autism and developmental disorders PMID: 27752862... Read more »

  • November 5, 2016
  • 05:20 AM

Sensory subtypes and anxiety and autism

by Paul Whiteley in Questioning Answers

"This is the first study to identify the existence of sensory subtypes among older children and adolescents with ASD [autism spectrum disorder] and explore their association with anxiety levels."Far be it from me to question the above quote provided in the paper by Mirko Uljarević and colleagues [1] but I'm inclined to suggest that there has already been some research published on the link between sensory issues and anxiety in the context of the autism spectrum before (see here and see here). Indeed, I do wonder whether the assertions put forward by Mazurek and colleagues [2] on how gastrointestinal (GI) issues (yes, they are over-represented) might be an important part of any sensory/anxiety mix in autism could be something that is further looked at by Uljarević in their cohort?Anyhow, the Uljarević paper is an interesting one given the idea that within the vast heterogeneity that is autism (or even the autisms) sensory issues as measured by "the short sensory profile" are notuniform in their presentation (a shocker, I know). The finding that anxiety scores, as measured by the Spence anxiety scales, were potentially a little different according to sensory subtype (sensory adaptive, sensory moderate, sensory severe) particularly when it came to the sensory adaptive grouping - "Children and adolescents from the adaptive subtype had significantly lower anxiety scores when compared with other two subtypes" - is important. The implication being that with various other variables not differing (chronological age, expressive language, or severity of autism diagnostic features) sensory issues might be one important driver of the presentation of anxiety when it comes to autism.As I've mentioned quite a few times on this blog, the topic of anxiety and autism is an important one (see here for example). There are a few different 'types' of anxiety (or anxiety diagnoses) that might be more applicable to autism alongside some discussion about how to measure anxiety when it comes to autism (see here). But the primary messages are: (i) anxiety is pretty rife in terms of accompanying a diagnosis of autism and (ii) the effects of anxiety can be absolutely, utterly disabling. Set in this light, if there are things that can be done to overcome anxiety over and above what might be traditionally offered (see here) by for example, 'affecting' those sensory issues, many people potentially stand to benefit.Next question: how does one go about 'intervening' when sensory issues are present alongside autism? Well, the science is still a little sparse here outside of the odd case report on something like bumetanide showing a potential effect [3] for example. I might draw your attention to some preliminary work on how visual sensory issues might be a target for other interventions (see here) but there is still some way to go in that area too and one needs to be mindful of how ophthalmologic disorder(s) may also contribute (see here). Going back to the Mazurek paper and the 'triad' of sensory issues, anxiety and bowel problems hinted at with at least some autism in mind, one could speculate that treating said bowel issues *might* have further positive effects on sensory and anxiety issues too. Indeed, in the more general context of how anxiety and another important label - depression - may well have a functional bowel issue link (see here), there is plenty of research fodder to draw on hinting at a 'gut-brain' link in some cases. No doubt there are other ways and means to tackle sensory issues as and when they impact on quality of life and by the sounds of other research [4] sensory issues in autism as described by the DSM-5 are going to be pretty widespread.To close, it's 'Remember, remember the 5th of November, gunpowder, treason and plot..' day here in the UK today. So here's V and his revolutionary chatter again and please, be careful this Bonfire night.----------[1] Uljarević M. et al. Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. Autism Res. 2016 Oct;9(10):1073-1078.[2] Mazurek MO. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76.[3] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014. pii: bcr2013202092[4] Green D. et al. Brief Report: DSM-5 Sensory Behaviours in Children With and Without an Autism Spectrum Disorder. J Autism Dev Disord. 2016 Nov;46(11):3597-3606.----------Uljarević M, Lane A, Kelly A, & Leekam S (2016). Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research, 9 (10), 1073-1078 PMID: 26765165... Read more »

Uljarević M, Lane A, Kelly A, & Leekam S. (2016) Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research, 9(10), 1073-1078. PMID: 26765165  

  • November 4, 2016
  • 05:03 AM

Hyperhomocysteinemia as a significant risk factor for autism?

by Paul Whiteley in Questioning Answers

The findings reported by Naushad Shaik Mohammad and colleagues [1] provide some blogging fodder today and the suggestion of a link between some of the genetics of the folate pathway and the finding of elevated levels of homocysteine with [some] autism in mind.OK, from the start, the genetics of folate metabolism mentioned in the context of autism typically means reference to the quite well replicated finding of issues with the gene methylenetetrahydrofolate reductase (MTHFR) (see here for some background). This gene (product) serves an important purpose in relation to the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate; the latter helping to convert the amino acid homocysteine to methionine. Outside of the importance of methionine to the process of DNA methylation (yep, some of that epigenetics stuff that you keep hearing about), there is quite a body of literature emerging to suggest that elevated levels of homocysteine might also have some important health effects.For quite a few years now, a specific genetic issue with MTHFR - MTHFR C677T - has been reported in quite a few people on the autism spectrum (see here). This allied to other independent research suggesting that the downstream effects of issues with MTHFR linked to elevations in levels of homocysteine may not also be an uncommon finding (see here). Shaik Mohammad et al therefore set about looking at the relationship between genetic issues with MTHFR and hyperhomocysteinemia in the context of autism.They did this by use of an "artificial neural network (ANN) model" where data initially from "138 autistic and 138 nonautistic children" on various genetic issues linked to folate metabolism (including MTHFR) were used as potential "predictors of autism risk." We are also told that: "Meta-analyses were carried out on 1361 ASD children and 6591 nonautistic children to explore the association of MTHFR C677T and homocysteine with the risk for ASD [autism spectrum disorder]."Results: well, the model wasn't exactly brilliant at predicting the risk of autism (63.8% accuracy). The authors call this a 'moderate' finding but I'd probably suggest that their results are yet another very good example of how heterogeneous the autism spectrum actually is. The idea of not using the term 'autism' as a research starting point in this context (see here) also receives support. Perhaps of greater importance were their findings linked to homocysteine and autism and how: "Hyperhomocysteinemia was observed in autistic children" to a greater extent that controls. They did also confirm that the MTHFR C677T genetic polymorphism was linked to 'inflating homocysteine levels' alongside another genetic issue called MTRR A66G (methionine synthase reductase). This is not an unusual finding in the context of what is already known about MTRR and homocysteine. The MTRR bit potentially linked to autism is however, something that this research group have previously suggested to 'reduce the risk' of autism [2].In terms of what these results mean in the context of autism, there are a few possibilities. First, screening. Knowing what we now seem to know about MTHFR and homocysteine in relation to quite a lot of people with autism, I would have thought it would be good practice to screen genetics/biochemistry. Minus any scaremongering or sweeping generalisations, the observation that hyperhomocysteinemia 'may' have links to cardiovascular disease and other adverse states for example, also perhaps implies screening save any further charges of health inequality when it comes to the label of autism. Next management. Far from being a 'nothing can be done about it' state, there is some good evidence that small adjustments to nutrition can potentially have positive effects on some of these parameters. With no medical or clinical advice given or intended, high levels of homocysteine seem in some cases, to be reactive to certain vitamin supplementation. The focus on vitamin B12 could also be set in the context of other recent studies of this vitamin (and its vitamers) with autism in mind (see here) (but I am careful not to link the two parameters just yet). And just recently there is news that there is a new way of assaying for vitamin B12 on the horizon which could also be useful. Finally, more research is indicated. As per my discussions not so long ago about another potentially important link to folate metabolism and autism (see here), there does appear to be quite a bit more to see when it comes to the folate cycle intersecting with homocysteine metabolism (and it's downstream effects). Yes, we can talk about whether folate is 'protective' or not when it comes to 'risk' of autism (see here and see here) but what this latest work suggests is that this area is complicated and potentially includes many genetic/epigenetic/biochemical variables that need to be taken into account.----------[1] Shaik Mohammad N. et al. Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatr Genet. 2016 Oct 17.[2] Mohammad NS. et al. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. 2009 Aug;19(4):171-6.----------Shaik Mohammad N, Sai Shruti P, Bharathi V, Krishna Prasad C, Hussain T, Alrokayan SA, Naik U, & Radha Rama Devi A (2016). Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatric ge... Read more »

Shaik Mohammad N, Sai Shruti P, Bharathi V, Krishna Prasad C, Hussain T, Alrokayan SA, Naik U, & Radha Rama Devi A. (2016) Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatric genetics. PMID: 27755291  

  • November 3, 2016
  • 05:10 AM

Antibiotic brain part 3

by Paul Whiteley in Questioning Answers

"This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood."So said the findings reported by Slykerman and colleagues [1] who relied on data from the Auckland Birthweight Collaborative Study (an initiative set up to determine whether "internationally recognized risk factors for small-for-gestational-age (SGA) term babies were applicable in New Zealand") to examine the suggestion that early life antibiotic use might be associated with a "detrimental effect on later neurocognitive outcomes."Relying on maternal report of antibiotic use among offspring "between 12 months and 3.5 years of age" researchers compared data with that derived from "Intelligence test scores and measures of behavioural difficulties" when children were 3.5, 7 and 11 years of age. They found that antibiotic use during the first 12 months of life was high in their cohort (70%) and that: "Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up." I've highlighted the 'relying on maternal report' bit because although parents are typically the experts on their own children (yes, they are), the reliance on parental report is not the same as reliance on objective medical or prescribing records for antibiotic use and important information on antibiotic type, dose and reason for such use that they typically contain. Indeed, I might also stress that correlating antibiotic use and developmental outcome whilst interesting should also be mindful of the myriad of other variables that might play a role, including the idea that 'behavioural difficulties' often don't present until later infancy for whatever reason. Be careful with single associations.But... I've labelled this post 'Antibiotic brain part 3' because I feel that the Slykerman findings are another important piece of evidence potentially pertinent to the idea that antibiotics may be pretty good at tackling bacterial infection but that also that they may have some quite potent effects on behaviour and development as well as physiology (see here for antibiotic brain part 1 and antibiotic brain part 2).What's the possible mode of action linking [early] antibiotic use and behaviour and development? Well, far be it from me to speculate too much but I'm minded to bring in the idea that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might play some role in any process. Minus hype [2] we're for example, already finding out how gut bacteria 'might' show some important behavioural connections (see here for example) and specifically how certain strains of bacteria might link to important states such as depression (see here and see here). It's not outside the realms of possibility that 'swallowing a grenade' (although not literally) designed to kill bacteria rather willy-nilly, might influencing either bacterial diversity in the gut or impact on specific strains that could be consider more rather than less beneficial.One more idea for science to perhaps consider relates to why antibiotics were given in the first place. If for example we assume that ear infection might be a common reason, could it not be that the actual symptoms over and above the [antibiotic] treatment might be the more important variable in relation to 'behavioural difficulties'? [3]There is much more to do in this area, but alongside the dangers of antibiotic resistance perhaps science might also be more open to the idea that antibiotics might do so much more than just impact on physiology?To close, for those in Blighty who might remember Hastings, 1066 and a certain Tapestry, things were a whole lot more complicated/gory that you might have expected...----------[1] Slykerman RF. et al. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr. 2016 Oct 4.[2] Bik EM. The Hoops, Hopes, and Hypes of Human Microbiome Research. Yale J Biol Med. 2016 Sep 30;89(3):363-373.[3] Niclasen J. et al. Associations between otitis media and child behavioural and learning difficulties: Results from a Danish cohort. Int J Pediatr Otorhinolaryngol. 2016 May;84:12-20.----------Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA (2016). Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992) PMID: 27701771... Read more »

Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA. (2016) Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992). PMID: 27701771  

  • November 2, 2016
  • 04:55 AM

ADHD (symptoms) and pain

by Paul Whiteley in Questioning Answers

If a primary goal of medicine is to relieve pain and suffering then the paper by Andrew Stickley and colleagues [1] might provide an important insight into how medicine might be missing some important groups when it comes to the experience of pain "assessed by the degree to which it interfered with work activity in the previous month."Drawing on data from the English 2007 Adult Psychiatric Morbidity Survey (APMS) (a resource that has cropped up on this blog before), authors set about examining "the association between ADHD [attention-deficit hyperactivity disorder] symptoms and pain in the general adult population" to ascertain any connection or not. Bearing in mind a 'screener' was employed when it came to ADHD symptoms (and the problems that other screeners have had when it comes to APMS (see here)) authors concluded that even after adjustment for "comorbid common mental disorders" those adults presenting with self-reported ADHD symptoms had "higher odds for experiencing pain."This is of course not the first time that pain has been suggested to be more frequent where ADHD symptoms or even ADHD is concerned. Fuller-Thomson and colleagues [2] reported that women diagnosed with ADHD were quite a bit more likely to report 'chronic pain' than not-ADHD controls alongside a spectrum of other adversities and issues. Even children / young adults with 'attention problems' have been reported to show a higher frequency of "chronic multisite pain" [3] thus potentially extending the relationship further through the age-groups.So what could be the reason(s) behind such an association? Well, outside of the large body of peer-reviewed evidence suggesting that the risk of injury is enhanced in relation to ADHD (see here) and what influence this might have, other work is potentially revealing. So, traumatic dental injuries and ADHD [4], the persistence of headaches and ADHD [5], the list goes on with regards to potential factors that could influence the presentation of pain. I might also draw your attention to the idea that the perception of pain may be 'altered' [6] when it comes to ADHD or the presentation of ADHD symptoms as demonstrated under experimental conditions. Indeed, this side of things might have some rather important implications for autism too (see here) given the 'over-representation' of ADHD in autism (see here). The idea also that use of something like methylphenidate, traditionally indicated for ADHD, might affect pain responses in ADHD is also worthy of greater research consideration [7].Finally, I'm also minded to suggest that rather than 'blaming it all on ADHD' pain accompanying ADHD or ADHD symptoms could also be due to other coexisting conditions. It's not for example, completely unknown for ADHD to coexist alongside conditions such as fibromyalgia for example [8] bearing in mind that fibromyalgia has a very definite connection to pain. I'm also wondering whether the quite strong link between ADHD and something like asthma (see here), might also be an additional source of pain either directly or indirectly too?The bottom line: yet another case of screening for / asking about other things when a psychiatric / behavioural diagnosis is given and treating / managing accordingly. Screen don't assume.----------[1] Stickley A. et al. ADHD symptoms and pain among adults in England. Psychiatry Res. 2016 Oct 3;246:326-331.[2] Fuller-Thomson E. et al. Attention-deficit/hyperactivity disorder casts a long shadow: findings from a population-based study of adult women with self-reported ADHD. Child Care Health Dev. 2016 Jul 20.[3] Skrove M. et al. Chronic multisite pain in adolescent girls and boys with emotional and behavioral problems: the Young-HUNT study. Eur Child Adolesc Psychiatry. 2015 May;24(5):503-15.[4] Sabuncuoglu O. & Irmak MY. The ADHD modeL for traumatic dental injuries: A critical review and update of the last 10 years. Dent Traumatol. 2016 Oct 17.[5] Parisi P. et al. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014 Mar;32:72-5.[6] Treister R. et al. Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD). Pain Pract. 2015 Jan;15(1):4-11.[7] Wolff N. et al. Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate. Child Adolesc Psychiatry Ment Health. 2016 Jul 22;10:24.[8] Derksen MT. et al. High frequency of adult attention deficit hyperactivity disorder among fibromyalgia patients in the Netherlands: should a systematic collaboration between rheumatologists and psychiatrists be sought? Clin Exp Rheumatol. 2015 Jan-Feb;33(1 Suppl 88):S141.----------Stickley A, Koyanagi A, Takahashi H, & Kamio Y (2016). ADHD symptoms and pain among adults in England. Psychiatry research, 246, 326-331 PMID: 27750114... Read more »

Stickley A, Koyanagi A, Takahashi H, & Kamio Y. (2016) ADHD symptoms and pain among adults in England. Psychiatry research, 326-331. PMID: 27750114  

  • November 1, 2016
  • 05:09 AM

On the "increasing evidence for an association between vitamin D insufficiency and depression"

by Paul Whiteley in Questioning Answers

The quote titling this brief post - "increasing evidence for an association between vitamin D insufficiency and depression" - comes from the review by Parker and colleagues [1] who seem to be no strangers to reviewing evidence on a possible link between the sunshine vitamin/hormone and depression [2].Affiliated to the Black Dog Institute in Oz ('black dog' being used as a metaphor for depression for quite a few years), the authors surveyed the quite voluminous peer-reviewed research literature on the topic of vitamin D and depression and concluded that there is 'adequate' evidence linking vitamin D levels and depression and also that: "Vitamin D supplementation/augmentation can be an effective treatment."With no medical or clinical advice given or intended, regular readers of this blog won't perhaps be too surprised by this latest review offering. I've covered the topic again and again and again on this blog and quite frankly it's getting to the point where I'm getting sick of hearing myself talk/type about it. That being said, there are still questions that need answering on this issue: (1) given that 'depression' is quite a nebulous term, are there specific 'types' of depression that vitamin D levels/supplementation seem to be more associated with? (2) what is/are the mode(s) of action? bearing in mind there may be some clues in other literature linked to the possible extra-skeletal actions of vitamin D and (3) how and where do the genetics of vitamin D metabolism fit into all this?I think it's also important to point out that depression is generally not something that just 'evaporates' when a vitamin D pill or any other pill is taken; more research needs to be done on the timing of supplementation and optimal dosage too as well as the potential use of vitamin D as an adjuvant to more traditional pharmacotherapy. There is a scheme of work to be followed but yet again, research on the possible link between vitamin D and depression continues at a pace.And as if to further prove the point [3]...----------[1] Parker GB. et al. Vitamin D and depression. J Affect Disord. 2016 Oct 11;208:56-61.[2] Parker G. & Brotchie H. 'D' for depression: any role for vitamin D? 'Food for Thought' II. Acta Psychiatr Scand. 2011 Oct;124(4):243-9[3] Shin YC. et al. The associations among vitamin D deficiency, C-reactive protein, and depressive symptoms. J Psychosom Res. 2016 Nov;90:98-104.----------Parker GB, Brotchie H, & Graham RK (2016). Vitamin D and depression. Journal of affective disorders, 208, 56-61 PMID: 27750060... Read more »

Parker GB, Brotchie H, & Graham RK. (2016) Vitamin D and depression. Journal of affective disorders, 56-61. PMID: 27750060  

  • October 31, 2016
  • 06:36 AM

HBOT and autism systematically reviewed again (and the same results?)

by Paul Whiteley in Questioning Answers

"To date, there is no evidence that hyperbaric oxygen therapy improves core symptoms and associated symptoms of ASD [autism spectrum disorder]."So said the results of the review by Xiong and colleagues [1] (open-access available here) completed under the auspices of the Cochrane Collaboration, leaders in the science and publication of systematic reviews (see here for another example).Looking at the collected peer-reviewed science on the topic of hyperbaric oxygen therapy (HBOT) for autism - where "the patient breathes near 100% oxygen intermittently while inside a hyperbaric chamber pressurized to greater than sea level pressure", authors looked to determine several factors. Whether "treatment with hyperbaric oxygen: 1. improves core symptoms of ASD, including social communication problems and stereotypical and repetitive behaviors; 2. improves noncore symptoms of ASD, such as challenging behaviors; 3. improves comorbid states, such as depression and anxiety; and 4. causes adverse effects."The results kinda mirrored what has already been previously described in the existing research review literature (see here), that based on one trial only [2] reaching their inclusion criteria, there is little evidence at the moment to say that HBOT is blanket indicated for autism.Obviously one has to be a little careful that 'absence of science' is not construed as 'absence of evidence'. Indeed, I'm a little annoyed that the authors start suggesting that HBOT "may not be appropriate" for further study with autism in mind in light of the lack of studies in this area based on "the absence of a persuasive theory of change from experimental and clinical studies, the unknown long-term safety of the treatment, and the financial and opportunity costs of not participating in other proven therapies." No, I'm not defending HBOT as an intervention for autism but I am defending the idea that research reviews based on one study should really be trying to clarify the science rather than block future research efforts. Indeed, I'm inclined to direct you to the paper by Rossignol and colleagues [3] potentially answering questions such as mode of action and how one might want to look at potential best-responders to this type of intervention (autisms people, autisms). That and what the Sampanthavivat study included in the Xiong review actually said about 'safety' during their trial: "interventions were safe and well tolerated with minimal side effect from middle ear barotraumas."To close, and in keeping with the date, a spooky song (and a rather spooky singer it has to be said...)----------[1] Xiong T. et al. Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2016 Oct 13;10:CD010922.[2] Sampanthavivat M. et al. Hyperbaric oxygen in the treatment of childhood autism: a randomised controlled trial. Diving Hyperb Med. 2012 Sep;42(3):128-33.[3] Rossignol DA et al. Hyperbaric oxygen treatment in autism spectrum disorders. Medical Gas Research. 2012; 2: 16.----------Xiong T, Chen H, Luo R, & Mu D (2016). Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 10 PMID: 27737490... Read more »

  • October 29, 2016
  • 05:08 AM

Living with severe autism: families share their experiences

by Paul Whiteley in Questioning Answers

Appreciating that the autism spectrum is truly a wide and heterogeneous one (or even several?), I'd like to direct your attention today to the findings reported by Jocelyn Bessette Gorlin and colleagues [1] on the topic of "the experiences of families living with a child with severe autism."In particular, I'd like to highlight the six areas that emerged from the "29 interviews with 22 participants from 11 families" related to family experiences and how, minus any sweeping generalisations, moves to tackle some of the issues raised in these areas might do quite a bit for the quality of life of everyone concerned.So, the six areas:(1) "families experienced autism as mysterious and complex because it is an invisible and unpredictable condition with diagnostic challenges." 'Mysterious' and 'complex' are words that have always followed the label of autism and as things stand at the moment, are unlikely to change in the coming years. Sure we know a little more about autism than we did a few years ago (i.e. the 'autisms', lots of comorbidity is potentially over-represented, etc) but in terms of longitudinal course and those important discussions (and actions!) about how to maximise quality of life 'for individuals' (the stress being on 'individuals'), concrete strategies are still few and far between. Diagnostic challenges? Well, certainly there are challenges to 'getting a diagnosis' in quite a few quarters still (see here for example) which is probably just as much down to money and resources as anything else. And just before you suggest that parents might not be sensitive to early issues potentially linked to autism, you're probably wrong (see here).(2) "families described severe autism behaviors that often caused self-injury, harm to others and damaged homes." This is the side of autism that people generally don't talk about as much as they should. Acknowledging that extremes like self-injurious behaviour (SIB) aren't exactly great dinner table conversation, such patterns of behaviour are often the ones that cause the most distress both to the person themselves and their family/loved ones around them. I don't think I can stress enough how vital it is that SIB is further (a) understood (in terms of potential meaning) and (b) acted upon, particularly where a person is at high risk of hurting themselves or others (see here for example). I might also add that important issues such as wandering (elopement) in relation to autism should also be given due consideration given its potential inclusion under the category of 'challenging behaviour'.(3) "profound communication deficits resulted in isolation between the family and child." I think this area is pretty self-explanatory. We can talk about the emerging role for assistive technologies as part of a package of interventions to aid this issue, but a lot more needs to be done in this area and indeed, is being done. And yes, this probably includes discussions around a re-framing of the communicative relationship between child/adult and family.(4) "families discussed the unrelenting stress from lack of sleep, managing the child's developmental delays, coordinating and financing services, and concern for the child's future." I'm a big fan of caring for the carer(s) when it comes to the quality of life for families touched by autism (see here for example). To mention words like 'parenting stress' when it comes to autism shouldn't be a taboo subject (see here) the same as it shouldn't be when talking about parenting in general. There may be many ways that professionals can intervene in this respect (see here). Insofar as parents/families looking to the future of their children/loved one and tackling the sentiments of 'why I can never die' (see here), well, this is where society also needs to step up both in terms of future planning and delivery of services appropriate, welcoming and responsive to the needs of individuals. And some parents do have to do it all themselves...(5) "families described consequences of isolation from friends, school, the public, and health providers." Although not everyone's experience, another uncomfortable issue associated with parenting a child with severe autism can be how isolating it is. It's little surprise that in the age of social media, this medium is being used to enable families to be/feel that little less isolated from the outside world. Aside from making more support agencies 'available' to families, there are a few other suggestions that might make things a little less isolating (see here).(6) "families portrayed their need for compassionate support and formed 'hybrid families' (nuclear, extended families and friends) to gain support." See point 5. I'd also argue that the formation of those 'hybrid families' perhaps overlap with those 'kingdoms of autism' talked about a few years back. Indeed, I get the impression that talk about families and kingdoms intersecting with how wide and heterogeneous the autism spectrum is, might be one reason why there are so many varied opinions about autism from all sorts of angles...These are all important points. Yes, I know that their relevance is going to be variably applicable to those (a) on the autism spectrum or (b) falling into that 'severe autism' bracket, but I don't doubt the lessons that could be learned would benefit quite a few people beyond the intended audience. As the authors note, their study results "could influence health care policies to improve the care for families caring for children with severe autism."Great words indeed, but how to put words into 'life-changing' practice? Well, for a start understand that the autism spectrum is indeed a wide and heterogeneous one...----------[1] Bessette Gorlin J. et al. Severe Childhood Autism: The Family Lived Experience. J Pediatr Nurs. 2016 Oct 6. pii: S0882-5963(16)30279-2.----------Bessette Gorlin J, McAlpine CP, Garwick A, & Wieling E (2016). Severe Childhood Autism: The Family Lived Experience. Journal of pediatric nursing PMID: 27720503... Read more »

Bessette Gorlin J, McAlpine CP, Garwick A, & Wieling E. (2016) Severe Childhood Autism: The Family Lived Experience. Journal of pediatric nursing. PMID: 27720503  

  • October 28, 2016
  • 06:15 AM

Lower autism rate under DSM-5 (yet again)

by Paul Whiteley in Questioning Answers

So: "Results indicate that individuals diagnosed with PDD [pervasive developmental disorder] by DSM-IV-TR criteria may not be diagnosed using DSM-5 criteria."That was the conclusion reached by Ferhat Yaylaci & Suha Miral [1] following their study of 150 children (3-15 years old) diagnosed with PDD "by DSM-IV-TR" whose symptoms/presentation were "reviewed through psychiatric assessment based on DSM-IV-TR and DSM-5 criteria." The percentage figure they arrived at (19.3%) indicated that about a fifth of participants might not reach diagnostic thresholds based on the DSM-5 criteria for autism spectrum disorder (ASD). PDD in DSM-IV by the way, refers to the autism spectrum.As per the title of this post, I'm not surprised by this data as previous independent studies have similarly shown a drop in numbers of those 'fitting' the revised diagnostic thresholds included in the latest version of the DSM (see here and see here and see here). Combined with data indicating that the new diagnostic category termed 'social (pragmatic) communication disorder (SCD)' in DSM-5 is likely to fill up rather quickly (see here) to accommodate those not reaching the ASD diagnostic thresholds, the question on everyone's lips is: what will it mean to be diagnosed with SCD in terms of function of the diagnosis, services offered and public perception?The short answer: we don't yet know.----------[1] Yaylaci F. & Miral S. A Comparison of DSM-IV-TR and DSM-5 Diagnostic Classifications in the Clinical Diagnosis of Autistic Spectrum Disorder. J Autism Dev Disorders. 2016. Oct 17.----------Yaylaci, F., & Miral, S. (2016). A Comparison of DSM-IV-TR and DSM-5 Diagnostic Classifications in the Clinical Diagnosis of Autistic Spectrum Disorder Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-016-2937-8... Read more »

  • October 27, 2016
  • 06:00 AM

Autism and inborn errors of metabolism

by Paul Whiteley in Questioning Answers

I'd like to think that the review article by Annik Simons and colleagues [1] (open-access) highlights some pretty strong evidence to suggest there being at least some connection between some autism and some of the collected inborn errors of metabolism. Indeed, when people generally talk about 'not knowing what causes autism' if we perhaps consider a more plural view of 'the autisms', there is a case to be made to say we might know what causes 'some' autism and some of it might lie in this area...Inborn errors of metabolism (IEM) cover a whole host of different conditions "in which there is an accumulation of toxic and/or complex compounds or energy problems within the cells due to enzymatic defects or other protein dysfunction." The absolutely magnificent work of people like Robert Guthrie who's name is synonymous with the neonatal heel prick test offered to newborns to screen for various IEMs and a jobbing physician called Ivar Asbjørn Følling who lent his name to a condition that was eventually called phenylketonuria (PKU), have proved to be some of the real successes of modern medicine.For quite a few years, peer-reviewed science has suggested some potentially important 'associations' between various behavioural and psychiatric labels manifesting in both treated and untreated IEMs (see here and see here for examples). Simons and colleagues decided to look through the collected research on this topic to provide "child and adolescent psychiatrists with an overview of metabolic disorders associated with child psychiatric symptoms, their main characteristics and recommendations for further investigations."So after boiling down the available peer-reviewed literature to some 71 articles (and in so doing making an important distinction between an inborn error of metabolism and the 'metabolic syndrome'!) authors summarise some of the key IEM associated with labels such as autism, attention deficit hyperactivity disorder (ADHD), learning disability, psychosis and eating disorders. Given that (a) the paper is open-access and (b) this blog tends to favour autism research, I'm gonna focus in on some of the details pertinent to the autism spectrum. I do however recognise that when it comes to the term 'over-represented comorbidity' in autism some of the other diagnostic labels covered by Simons et al might also come into the frame.Long quote coming up: "Known metabolic disorders in autism are phenylketonuria, disorders in purine metabolism (such as adenosine deaminase deficiency, adenylosuccinate lyase deficiency, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies), organic acidurias (such as propionic academia, 3-methylcrotonyl-CoA carboxylase deficiency and pyridoxine dependency), disorders of branched-chain amino acids creatine deficiency, biotinidase deficiency, cerebral folate deficiency, succinic semialdehyde dehydrogenase deficiency, Smith–Lemli–Opitz syndrome (SLOS), late infantile ceroid lipofuscinosis, histidinemia, Sanfilippo disease, glucose 6-phosphate dehydrogenase deficiency, urea cycle disorders, X-linked ichthyosis, and mitochondrial disorders." I've popped in a few links to other occasions where a specific IEM has been associated with autism and covered on this blog.Simons and colleagues also cover some of the important research findings where specific amino acids have been analysed and found in unusual levels in cases of autism as potentially being important too. This is relevant because disordered amino acid levels as noted in the case of phenylketonuria (PKU) and the aromatic amino acids phenylalanine (and tyrosine) can be an important finding in relation to some IEM. That they specifically focus on some of the research looking at homocysteine levels and autism is rather interesting (see here) and something that I am going to be discussing in future posts.What's more to say? Well, I think it is also important to highlight how Simons and colleagues talk about 'other signs and symptoms of the metabolic disease' [IEM] alongside the presentation of autism. This is important in the context that science is starting to more fully understand how a diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here) and quite a lot of different types of comorbidity seem to be 'over-represented'. I'd be inclined to suggest that this detail provides even stronger evidence for how IEM and at least some autism represent an important partnership.Finally, I refer back to one of the statements made by the authors on "recommendations for further investigations." They suggest that those presenting with: "A positive family history of metabolic disease... Symptoms or signs are triggered by food intake (esp high protein content foods), fever, fasting, surgery (catabolism)... Feeding difficulties, food refusal, failure to thrive, eating disorders combined with symptoms of myopathy or fatigue... Mental retardation and/or regression... Epilepsy, episodes of lethargy or confusion... Dysmorphic feature" should be considered for further investigations. Yes, some of the language is not what I would use and yes, that covers quite a bit of clinical ground but screening is the first part to ruling out such a potential organic correlate of some autism and may in some cases, yield potentially important insights (see here)...----------[1] Simons A. et al. Can psychiatric childhood disorders be due to inborn errors of metabolism? European Child & Adolescent Psychiatry. 2016. Sept 30.----------Simons A, Eyskens F, Glazemakers I, & van West D (2016). Can psychiatric childhood disorders be due to inborn errors of metabolism? European child & adolescent psychiatry PMID: 27695954... Read more »

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