Friday, 15 December 2017

"patients with CFS/ME do not exhibit insufficient concentrations of circulating total 25(OH)D"

The title heading this post comes from the findings reported by Kate Earl and colleagues [1] (open-access available here), where '25(OH)D' refers to calcifediol, a compound typically used to estimate how much vitamin D is present in the body and CFS/ME refers to Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

After assaying some 92 people with CFS/ME and an almost equal number of 'age-matched healthy controls' (HCs) for plasma total 25(OH)D and individual vitamin D metabolites - "25(OH)D2 and 25(OH)D3" - researchers concluded that vitamin D deficiency was not rife in their cohort. Indeed we are told that: "total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively)." The authors were also able to report that vitamin D supplementation by the CFS/ME group seemed to be a primary reason for their findings.

There are a few important strengths to the Earl results that are worth mentioning. Not least that vitamin D metabolites were measured by mass spectrometric methods similar to other independent research occasions (see here for example). Mass spectrometry seems to have quite a few advantages over other methods of vitamin D analysis; now labelled as a gold-standard technique. Added to their use of a deuterated standard ("hexadeuterated (OH)D3") and one has some degree of confidence in the analytical results; albeit, as the authors acknowledge: "that only the main marker of vitamin D status, that is, 25(OH)D, was measured" and how "there is a need to assess all of the vitamin D metabolites" of which there are quite a few [2].

At first glance, the Earl findings seem pretty unremarkable. Supplementation with vitamin D, as everyone is being encouraged to do these days (see here), means higher levels of circulating vitamin D. I would be surprised if they didn't. This is also not the first time that vitamin D levels in relation to CFS/ME have been talked about in the peer-reviewed domain either (see here) albeit not always with the same results but again with that caveat about supplementation in mind.

Given however that a measure of fatigue - "the Chalder Fatigue Questionnaire" - was also included for all participants in the Earl study, and how nothing very much seemed to be present when looking at any connection between fatigue scores and vitamin D status, this provides a possible clue that vitamin D is probably not a big player specifically in relation to the presentation of fatigue in most cases of CFS/ME. Such a questionnaire does not rule out other potential associations (e.g. post-exertional malaise, PEM) nor that other, potential comorbidity appearing alongside CFS/ME might not have a stronger vitamin D link (see here for example). But for now, it adds to the literature (see here) casting doubt on any direct role for vitamin D in relation to CFS/ME.

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[1] Earl KE. et al. Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. BMJ Open. 2017 Nov 8;7(11):e015296.

[2] Abu Kassim NS. et al. Simultaneous determination of 12 vitamin D compounds in human serum using online sample preparation and liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2017 Dec 6. pii: S0021-9673(17)31772-7.

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Thursday, 14 December 2017

The inter-pregnancy interval and risk of offspring autism yet again

I'm gonna try and keep this post quite brief starting with the observation that: "ASD [autism spectrum disorder] was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth."

So said the findings reported by Laura Schieve and colleagues [1] adding to quite a consistent research theme (see here and see here and see here). Based on "data from the Study to Explore Early Development [SEED]" initiative, with "rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history" researchers were quite confident in their observations. SEED, I might add, is developing quite a good peer-reviewed autism research reputation (see here).

Implications? Well, based on the current collected peer-reviewed research literature in this area it appears that there may be a specific time frame when it comes to potentially modifying the risk of offspring autism. Please don't take this as gospel but an interpregnancy interval (IPI) of somewhere between 12-18 and 60-72 months 'seems' to be emerging as an 'optimal' period based on the collected data currently to hand. I say this bearing in mind that multiple factors associated with pregnancy and birth *seem* to be associated with offspring outcomes (indeed, Schieve and colleagues have examined others too). This probably also includes what happens after birth (see here for example) and factors like parental age at conception/birth too (see here).

Possible mechanisms of effect? Yet again, it is more than likely that multiple factors are going to be influencing risk (or not) of offspring autism. I am drawn to the idea that a depletion of micronutrients associated with pregnancy might be an area for further investigation in relation to the IPI effect on offspring autism risk. This set in the context that pregnancy places some significant physical and biological demands on a mother's body; demands probably not immediately resolved as soon as baby enters the big, wide world. As to which micronutrients might be the more important to replenish, well, take yer pick (see here and see here for examples). Bearing, that is, in mind that no medical or clinical advice is given or intended...

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[1] Schieve LA. et al. Autism spectrum disorder and birth spacing: Findings from the study to explore early development (SEED). Autism Research. 2017. Nov 22.

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Wednesday, 13 December 2017

"A Blood Based Diagnostic Test for Coeliac Disease" (minus dietary gluten?)

The findings reported by Vikas Sarna and colleagues [1] have the potential to excite. Excite because, as the authors note: "A diagnosis of celiac disease based on serologic and histologic evidence and duodenal histology requires patients to be on gluten-containing diets" but a "growing number of individuals adhering to a gluten-free diet (GFD) without exclusion of celiac disease complicates its detection." A diagnostic test therefore, that could confirm/reject a diagnosis of coeliac disease (CD) without someone having to have gluten in their diet for some weeks, might be a rather exciting prospect.

Having previously posted their study aims and objectives on the ClinicalTrials.gov website (see here), authors tested the idea that "multimerized HLA bound to different gliadin-peptides (tetramer) and with the help of a flow-cytometer identify (along with other relevant T-cell-markers) gluten specific T-cells."

If all that sounds a little 'science-y' the long-and-short of it is the suggestion that the specific gene variants linked to CD - HLA-DQ2 and HLA-DQ8 variants - produce molecules -  HLA-DQ8 and HLA-DQ2 molecules - that bind to 'super-charged' gluten peptides to form a more complex molecule (tetramer) that has some rather important effects on components of the immune system, specifically on CD4+ T cells. Looking for such 'gluten specific T-cells' could be done by adding HLA-DQ-gluten tetramers to blood samples from patients with suspected/diagnosed CD. I think...

Anyhow, examining blood samples from a range of people - "62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten-sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]" - researchers put their test to the test. Most samples were analysed blind: "except for samples from subjects with celiac disease on a gluten-containing diet" and results were compared.

"An HLA-DQ-gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD." The sensitivity and specificity figures reported by Sarna are pretty good when authors managed to 'optimise' their results based on the values obtained. Indeed: "The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI, 1.00-1.00]) and 90% specificity (95% CI, 0.83-0.98) vs controls." Even a couple of the control participants - 'presumed healthy individuals' - were actually found to have unrecognised CD.

More science needs to be done before this potential diagnostic test is rolled out further and potentially across many, many groups. Larger participant numbers and a greater diversity of participants in terms of ethnicity, sex/gender and age need to included for study. I'm also wondering whether those with other autoimmune conditions/diagnoses could also be included in future research plans too, on the basis that birds of an autoimmune feather tend to flock together (see here and see here).

Things do seem to be getting rather interesting when it comes to CD these days. Alongside this rather exciting work, there is also the prospect of preparations that degrade gluten peptides also coming into the mainstream (see here) and how nutrients like vitamin D might also show some potentially important gastrointestinal effects [2] (see here also) pertinent to CD and beyond. No, it's not quite the end of the 'lifelong gluten-free diet' (yet!), but science is seemingly moving just a little bit closer...

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[1] Sarna VK. et al. HLA-DQ-Gluten Tetramer Blood Test Accurately Identifies Patients With and Without Celiac Disease in Absence of Gluten Consumption. Gastroenterology. 2017 Nov 13. pii: S0016-5085(17)36352-7.

[2] Scricciolo A. et al. Vitamin D3 Versus Gliadin: A Battle to the Last Tight Junction. Dig Dis Sci. 2017 Nov 20.

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Tuesday, 12 December 2017

Low birth weight and autism: rise of the population attributable risk

RIP Cheggers.
"LBW [low birth weightaccounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population."

Those were the observations made by Sandie Ha and colleagues [1] and with it, another example of the use of the population attributable risk/fraction in the context of autism (see here for another occasion). Published in 2014 but only recently appearing on PubMed, Ha et al report results based on data from the 2011 (US) National Survey of Children’s Health, (NSCH) - a "random-digit-dial phone survey conducted between February 2011 and June 2012" - where data on birth weight and receipt or not of a diagnosis of "attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), behavior and conduct disorder (BCD) and learning disability (LD)" were available. As an aside, I've talked about the other studies arising from the NSCH program before on this blog (see here and see here for examples).

Including data pertinent to around 81,000 children aged between 2 and 17 years of age, researchers reported that around 9% of the cohort were "born with a LBW as reported by their parent" in response to the question: "What was [sampling child’s] birth weight?" There were some interesting correlates alongside those responses regarding LBW status: "children who were female, non-Hispanic black, had single mothers, had less educated mothers, were poorer, lacked insurance, were exposed to in-home smoking, or born prematurely were more likely to have LBW compared to those with normal BW."

Insofar as 'neurobehavioural disorders' (ND) also asked about: "The weighted prevalence of parent-reported ND among children ages 2 to 17 was approximately 9.9% for ADHD, 2.3% for ASD, 4.1% for BCD, and 10.6% for LD." Yes, this was a telephone-based survey where "both exposure and outcome are based on parental reporting, and thus the information may not represent actual diagnoses" but with the size of the participant numbers included, these prevalence/frequency figures still make for important reading.

Then to the main event - the population-attributable risk percentage (PAR%) and the finding headlining this post: "LBW [low birth weight] accounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population." The authors caution that "maternal age at delivery, gestational age, and pregnancy complications could be important confounders" and were not taken into account in their analyses and could be "potential reasons for LBW" alongside undetected "congenital anomalies or genetic disorders." Caution is required.

It's not new news that birth weight might impact on something like autism risk (see here and see here). One also has to bear in mind that something like LBW may not necessarily appear in isolation to other pregnancy or birth events (see here) so a wider research agenda perhaps needs to be followed. But the size of the PAR% talked about by Ha and colleagues is not easily ignored. Taking into account that LBW for some may very well have some 'genetic' influences, one is left asking whether those more 'social' variables linked to LBW might be to some degree 'influenced' with a corresponding effect on neurodevelopmental 'consequences' reported. I say this in the context that poverty as a variable, has already been linked to some diagnoses included in the Ha study (see here)...

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[1] Ha SU. et al. Population attributable risks of neurobehavioral disorders due to low birth weight in US children. Adv Pediatr Res. 2014;1. pii: 2.

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Monday, 11 December 2017

On hormonal contraception and suicide risk

I'll freely admit that the material covered in the paper by Charlotte Wessel Skovlund and colleagues [1] suggesting that: "Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide" is (a) slightly outside of the typical remit of this blog and (b) not something that I'm particularly qualified to talk about. I was however minded to discuss this paper in the context that previous work from this research group has *linked* hormonal contraception use with depression [2] (see here for some of the media on this past paper) and in the more general context of blogging occasions where depression and risk of suicide have been discussed here (see here).

Similar to their last research outing where hormonal contraception - 'birth control methods that act on the endocrine system' - was analysed, some of those rather important Scandinavian population registries were the source study material. Denmark was the country of choice and "a nationwide prospective cohort study of all women in Denmark who had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15 and who turned 15 during the study period, which extended from 1996 through 2013." You'll note the words 'no psychiatric diagnoses, antidepressant use' were included, illustrating how researchers were already mindful of the role that depression has in such extreme behaviour(s). Researchers collected information "about use of hormonal contraception" and also suicide attempts and completions. This, based on resources such as the Danish National Prescription Register, illustrating once again the long Scandinavian tradition of "creating nationwide administrative and health registries" [3].

Results: "Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI=1.85–2.10) for suicide attempt and 3.08 (95% CI=1.34–7.08) for suicide." I should put that in some context in terms of hundreds of thousands of women - "nearly half a million women" - who were tracked over the course of the study, and how nearly 7000 first suicide attempts were recorded and 71 [completed] suicides registered. The numbers were comparatively small; bearing in mind that behind each figure is a person, a life and a family.

Taking into account the tenet 'correlation is not the same as causation' and indeed, appreciating how complex and individual suicidal thoughts and behaviour can be, these are potentially important data minus any scaremongering. Certainly these are findings worthy of quite a lot more study, particularly in light of the large population included for study mimicking the authors' previous chosen study design, alongside the prospective nature of their investigation.

Mechanisms of effect? I don't think anyone is quite there yet with regards to definitive hows-and-whys. I note that others have talked about a possible *correlation* between elevations in progesterone and suicide attempts [4] but such observations need to be treated cautiously at this point, again reiterating how complex and individual the processes leading someone to suicidal thoughts and behaviours are. Skovlund and colleagues did talk about suicide risk potentially differing according to different contraceptive formulations used: "Risk estimates for suicide attempt were 1.91... for oral combined products, 2.29... for oral progestin-only products, 2.58... for vaginal ring, and 3.28... for patch" potentially suggesting that specific products might have differing risk profiles. This is something else that could perhaps help isolate any pertinent mechanisms.

Questions remain, not least: Are there particular groups of women, based on genetics or other biology, that may be at increased risk of depression and/or suicide when taking such contraception? The answer: we don't yet know. Bearing in mind that in this, and their other work on hormonal contraception and depression, age seemed to be an important variable as per the observation: "Adolescent women experienced the highest relative risk" thus representing a good place to start. And on the topic of adolescent women perhaps having an elevated risk, I might also draw your attention to the findings reported by Jean Twenge and colleagues [5] who discussed another potentially important variable to consider: "Since 2010, adolescents spent more time on social media and electronic devices, activities positively correlated with depressive symptoms and suicide-related outcomes." I wonder if this is something that perhaps needs to be controlled for in future studies?

To close, there's always someone to talk to (see here) if needs be, and please, talk to your medical professional (not Dr Google) if you're at all concerned by these latest findings.

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[1] Skovlund CW. et al. Association of Hormonal Contraception With Suicide Attempts and Suicides. Am J Psychiatry. 2017 Nov 17:appiajp201717060616.

[2] Skovlund CW. et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162.

[3] Pottegård A. et al. Data Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017 Jun 1;46(3):798-798f.

[4] Mousavi SG. et al. Recurrent suicide attempt and female hormones. Advanced Biomedical Research. 2014;3:201. doi:10.4103/2277-9175.142046

[5] Twenge J. et al. Increases in Depressive Symptoms, Suicide-Related Outcomes, and Suicide Rates Among U.S. Adolescents After 2010 and Links to Increased New Media Screen Time. Clinical Psychological Science. 2017. Nov 14.

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Sunday, 10 December 2017

From limp to scurvy in the context of autism

"A panel of nutritional markers was sent, and a presumptive diagnosis of scurvy was made."

So said the case report detailed by Adam Yan and colleagues [1] as, yet again (see here and see here), the topic of scurvy in the context of autism appears in the peer-reviewed science literature. Scurvy, a condition affecting various tissues of the body, comes about as a result of a lack of adequate vitamin C in the diet. It's thought of as a rare disease nowadays, following on from some 'limey' historical observations (see here).

I say that scurvy is a rare disease, but as per the other blogging occasions when it's received attention, for those diagnosed on the autism spectrum it's not as rare as it should be. Indeed, even Yan et al note that "scurvy is increasingly identified in children with ASD [autism spectrum disorder] and developmental delay who consume restrictive diets, often lacking in fruits and vegetables." Their case report highlights how clinicians need to be observant...

The subject of the Yan case report was a young boy diagnosed with autism who was described as non-verbal. He came to clinical attention following "a 2-week history of limp and oral mucosal bleeding." Unfortunately, his first contact with medical professionals resulted in less-than-revealing typical test results that meant he was discharged with "a referral to dentistry to address the oral mucosal changes." Things did not improve. He presented again to hospital, this time "with new onset of fevers for 1 week, ongoing limp that had progressed to complete refusal to weight bear, and persistent bleeding from his oral mucosa." This second time a few more investigations were ordered and a very (VERY) low level of vitamin C (ascorbic acid) was detected: "The low ascorbic acid level confirmed the diagnosis of scurvy with a concomitant diagnosis of anemia." Treatment in the form of vitamin C and an iron supplement (alongside a multivitamin) did the trick in terms of the limp/leg problem and bleeding gums.

What are the lessons from this case report? Well, yet again, the realisation that issues such as those related to feeding problems present quite widely in relation to autism (see here) and can very much impact on health is paramount. Indeed, it should really be part of standard medical care to monitor and keep monitoring children in particular, with a diagnosis of autism to ensure that their nutritional needs are being met in many areas (see here). If they're not, supplement (under appropriate medical guidance) and don't be afraid to do so, keeping in mind that each person/child is different (see here).

I'm also minded to mention that when medical and other allied healthcare practitioners are faced with a child/adult with autism that is non-verbal and presenting with 'symptoms', the onus really should be on medicine to turn investigator to find out 'hows-and-whys' rather than discharging with a 'we don't know' sentiment. I say this in the context that a diagnosis of autism is seemingly not protective against any other condition/label/disease occurring, and noting other, more catastrophic, examples where this has happened (see here). And minus any sweeping generalisations, a few correctly framed questions can sometimes be enlightening [2] for all-manner of different issues pertinent to autism...

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[1] Yan A. et al. Limp in a Child With Autism Spectrum Disorder. Global Pediatric Health. 2017. Nov 30.

[2] Cohen S. et al. Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Res. 2017 Dec 1.

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Saturday, 9 December 2017

Inflammatory bowel disease and autism (again)

"Children with ASD [autism spectrum disorder] were more likely to meet criteria for Crohn’s disease (CD) and Ulcerative colitis (UC) compared to controls."

So concluded Maunoo Lee and colleagues [1] following their "retrospective case-cohort study" of the US Military Health System database. Having previously published their findings as a conference abstract [2], authors gave their data the full peer-reviewed publication treatment covering nearly 300,000 people: ~48,000 children diagnosed with ASD and ~240,000 matched (not-autism) controls.

Alongside gathering data on the frequency of ICD-9 diagnostic codes for CD and UC - both defined as inflammatory bowel diseases (IBDs) - researchers also examined prescription data for treating/managing such bowel conditions. They observed differences in the prescription rate ratio (PRR) *potentially* reflective of either a more severe or more difficult to control form of IBD in children diagnosed with ASD. In short, and hopefully without making too many sweeping generalisations, IBDs are seemingly over-represented when it comes to a diagnosis of autism, and may be more likely to have an atypical pathological course.

Of course all of this is not new news. I've talked about other research that has reported similar things in relation to IBDs and autism (see here) alongside the 'now-not-questioned-so-much' data on the over-representation of functional bowel problems in relation to autism (see here). There's still a way to go in research and clinical terms to try and answer questions about how such bowel issues come about in relation to autism and whether one might consider some IBDs as being potentially 'novel' in relation to 'some' autism (see here). But the days of bowel problems in autism being some sort of fringe issue seem to well and truly gone, as perhaps 'suffering' as a result of such bowel issues can hopefully start to be addressed and other potential 'effects' (see here) investigated further minus hype, generalisation and/or fear...

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[1] Lee M. et al. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disorders. 2017. Nov 23.

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