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  • September 22, 2016
  • 09:27 AM
  • 296 views

Will tardigrades get humanity into space?

by gdw in FictionalFieldwork

The mighty water bear Tardigrades, aka water bears, are tiny animals that can be found just about everywhere on earth, with a slight preference for the moisture in moss. They happily amble along on their four pairs of legs and slurp up plant cells, algae, and even smaller invertebrates that can’t get away fast enough […]... Read more »

Boothby TC, Tenlen JR, Smith FW, Wang JR, Patanella KA, Nishimura EO, Tintori SC, Li Q, Jones CD, Yandell M.... (2015) Evidence for extensive horizontal gene transfer from the draft genome of a tardigrade. Proceedings of the National Academy of Sciences of the United States of America, 112(52), 15976-81. PMID: 26598659  

Koutsovoulos G, Kumar S, Laetsch DR, Stevens L, Daub J, Conlon C, Maroon H, Thomas F, Aboobaker AA, & Blaxter M. (2016) No evidence for extensive horizontal gene transfer in the genome of the tardigrade Hypsibius dujardini. Proceedings of the National Academy of Sciences of the United States of America, 113(18), 5053-8. PMID: 27035985  

Hashimoto T, Horikawa DD, Saito Y, Kuwahara H, Kozuka-Hata H, Shin-I T, Minakuchi Y, Ohishi K, Motoyama A, Aizu T.... (2016) Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein. Nature communications, 12808. PMID: 27649274  

  • September 22, 2016
  • 03:14 AM
  • 277 views

"Paediatricians are seeing more children with developmental-behavioural conditions"

by Paul Whiteley in Questioning Answers

The findings reported by Harriet Hiscock and colleagues [1] are brought to the blogging table today, specifically that suggestion that paediatricians, at least in Australia, might be encountering an increased number of "developmental/behavioural conditions" as part of their workload.Looking at the clinical experiences of some 180 paediatricians who took part in the study in late 2013 and comparing them with data from 2008, researchers probed a number of practices relating to "(i) conditions seen; (ii) consultation duration; (iii) imaging and pathology ordered; and (iv) prescribing." The details associated with seeing an increasing number of children "with developmental-behavioural conditions" included: "More paediatricians reported diagnoses of autism spectrum disorder... attention-deficit/hyperactivity disorder... and intellectual disability... in first consultations."Whilst being slightly careful that 'seeing more children with developmental-behavioural conditions' is not necessarily equated with there 'being' more children with such issues, I'm inclined to suggest that such data is important. Quite a few times in the British media at least, stories have emerged about long waiting times for developmental assessments (see here for one example) and how an already stretched National Health Service (NHS) is seemingly struggling in some parts, to cope with the number of referrals coming through (see here).As part of a wider peer-reviewed and 'other' evidence base suggesting that (a) the estimated prevalence rates for autism have increased (see here) and (b) there may be a 'real' increase in 'rates of behaviour' associated with an autism spectrum disorder (ASD) (see here) I am becoming more and more convinced that old arguments about 'better awareness' or 'diagnostic switching' are becoming less relevant to the debate about the increasing numbers of cases of autism (see here for example).I don't doubt that as a society we are far more aware of autism than we ever were (we've even started 'screening for it' during early infancy here in Blighty) and where decades ago someone for example, might have been diagnosed with a learning disability even though they presented with autistic features so things are a little different nowadays. But the sorts of stresses and strains being placed on developmental screening and diagnostic services (particularly paediatric services) in comparison to times gone by are seemingly not comparable anymore. Even taking into account population increases and changes to the organisation of screening and diagnostic services, talk of a growing tide of children being diagnosed, or waiting to be assessed, as being on the autism spectrum is something that really should be prompting a lot more urgency and action. I might also add that arguments about better clinical awareness - did they really miss all those children? - really do a disservice to those who have been skillfully diagnosing autism for many years. Value our experts!And alongside the talk about children being diagnosed, adult services too are also under a lot more pressure these days...----------[1] Hiscock H. et al. Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. J Paediatr Child Health. 2016 Sep 4.----------Hiscock H, Danchin MH, Efron D, Gulenc A, Hearps S, Freed GL, Perera P, & Wake M (2016). Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. Journal of paediatrics and child health PMID: 27594610... Read more »

  • September 21, 2016
  • 12:35 PM
  • 259 views

Protect kids from toxic secondhand smoke, experts urge

by Dr. Jekyll in Lunatic Laboratories

It's advice most smokers with children probably take lightly, but they shouldn't. Parents and policy advocates should take a "zero tolerance" approach to exposing children to secondhand cigarette smoke, which can be responsible for lifelong cardiovascular consequences in addition to respiratory and other health issues.

... Read more »

  • September 21, 2016
  • 11:46 AM
  • 273 views

Brain Imaging: UK Biobank Epidemiology Study

by William Yates, M.D. in Brain Posts

I wanted to alert Brain Posts readers to a very important ongoing study out of the United Kingdom.The UK Biobank prospective epidemiological study is a study designed to identify imaging markers for a wide variety of diseases. Additionally, a goal of the study is to better understand disease mechanisms.Here is what is being collected on 100,000 healthy participants who will be tracked over decades:Brain structural and functional imaging (fMRI)Brain diffusion tensor imaging (DTI)Neuropsychological testing, i.e. cognitionBody and cardiac imagingGeneticsLifestyle informationBiomarker phenotypingHealth recordsThis ambitious study reminds me of the Framingham study in the U.S. that helped identify a group of risk factors for cardiac and vascular disease.Some early results from the UK Biobank study of early 5,000 subjects has been published in Nature Neuroscience.The manuscript shows that the UK Biobank will be a powerful resource in replicating other studies. They reported a initial attempt to replicate an Austrian Stroke Prevention study (ASPS) finding. The UK Biobank data analysis demonstrated changes in brain gray matter on T2* imaging linked to older age, smoking and increased BMI. This finding is felt to demonstrate increased brain iron accumulation with aging and degeneration.The UK Biobank data results were "highly concordant with the ASPS".I highly recommend reviewing this early manuscript in the UK Biobank Epidemiological Study.  Readers can access the free full-text manuscript by clicking on the PMID link in the citation below. It features a review of the methodology of the study. Numerous important research findings will emerge from this study in the years and decades to come.The Brits are to be congratulated on such an important and costly effort.Image of brain is an iPad screen shot from the iPad app 3D Brain.Follow me on Twitter WRY999Miller KL, Alfaro-Almagro F, Bangerter NK, Thomas DL, Yacoub E, Xu J, Bartsch AJ, Jbabdi S, Sotiropoulos SN, Andersson JL, Griffanti L, Douaud G, Okell TW, Weale P, Dragonu I, Garratt S, Hudson S, Collins R, Jenkinson M, Matthews PM, & Smith SM (2016). Multimodal population brain imaging in the UK Biobank prospective epidemiological study. Nature neuroscience PMID: 27643430... Read more »

Miller KL, Alfaro-Almagro F, Bangerter NK, Thomas DL, Yacoub E, Xu J, Bartsch AJ, Jbabdi S, Sotiropoulos SN, Andersson JL.... (2016) Multimodal population brain imaging in the UK Biobank prospective epidemiological study. Nature neuroscience. PMID: 27643430  

  • September 21, 2016
  • 04:30 AM
  • 297 views

Limb Symmetry Indices…It May Not Be as Accurate as We Thought

by Kyle Harris in Sports Medicine Research (SMR): In the Lab & In the Field

Take Home Message: Limb symmetry indices may not be sufficient to identify strength and performance deficits, particularly in patients who have a history of bilateral anterior cruciate ligament (ACL) reconstruction.... Read more »

  • September 21, 2016
  • 02:41 AM
  • 267 views

Respite care and parent stress with autism in mind

by Paul Whiteley in Questioning Answers

"While most studies found that respite care was associated with lower stress, several found that respite care was associated with higher stress."That sentence is perhaps the most important finding recorded in the 'integrative review' published by Kim Whitmore [1] looking at "the relationship between respite care and stress among caregivers of children with ASD [autism spectrum disorder]."Covering a "final sample of 11 primary research reports" the author provides yet another example of how sweeping generalisations in relation to autism really do no-one no good and how "tailoring respite care services to the unique family needs" is most definitely the way forward.This is important stuff [2]. I've previously talked about how - again, minus any sweeping generalisations - parental stress in relation to raising a child with autism is one of the more pressing issues when it comes to the health and wellbeing of carers (see here). A steady flow of firsthand accounts also substantiate this finding even in some instances talking about "trauma-related symptomatology" [3]. Respite as one tool in the arsenal to care for the carers is something important; not least because of how such stress can sometimes severely impact on parental quality of life (see here) and potentially onward parent-child (and other) relationships. In amongst all the discussions about autism - how we view it and the implications for the person diagnosed - the effect of a diagnosis on parents/carers can sometimes get a little lost in all the noise.What's more to say on this topic? Well, I think it is perhaps important to bring in the paper by Southby [4] who brought up an interesting point about how: "Residential respite appears to be the default conceptualization of 'respite' for carers, service users and stakeholders." It's not, and as per the organisation that I'm linked to, something like domiciliary support (otherwise known as home care) can sometimes provide a viable alternative to residential respite/placement. The knowledge that a person does not have to leave the family home, for example, can in some instances have a more positive impact on carer stress, and indeed, most probably will be less cost- and resource-intensive too. I don't also doubt that when it comes to stress for the person diagnosed with autism (an important consideration), for some the familiarity of the home environment is something not to be tinkered with by thoughts of residential respite. But again as per the idea of 'tailoring' resources to individual needs, for some families [5], residential respite every now-and-again should not be discounted.Finally, it's all well and good talking about the benefits of respite and tailoring respite to meet individual needs, but the cold, hard reality of providing respite in these austere times should not also be forgotten. Indeed, as social purse strings are tightened alongside criteria for eligibility for such services, the factors associated with use and non-use of such services present some difficult choices [6] and are only likely to become even more narrow in future...----------[1] Whitmore KE. Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. J Pediatr Nurs. 2016 Aug 31. pii: S0882-5963(16)30150-6.[2] Dyches TT. et al. Respite Care for Single Mothers of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2016 Mar;46(3):812-24.[3] Stewart M. et al. Through a trauma-based lens: A qualitative analysis of the experience of parenting a child with an autism spectrum disorder. Journal of Intellectual and Developmental Disability. 2016. Sep 16.[4] Southby K. Barriers to non-residential respite care for adults with moderate to complex needs: A UK perspective. J Intellect Disabil. 2016 Jul 20. pii: 1744629516658577.[5] Harper A. et al. Respite care, marital quality, and stress in parents of children with autism spectrum disorders. J Autism Dev Disord. 2013 Nov;43(11):2604-16.[6] Preece D. & Jordan R. Short breaks services for children with autistic spectrum disorders: factors associated with service use and non-use. J Autism Dev Disord. 2007 Feb;37(2):374-85.----------Whitmore KE (2016). Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. Journal of pediatric nursing PMID: 27592275... Read more »

  • September 20, 2016
  • 04:31 PM
  • 313 views

Potentially harmful chemicals widespread in household dust

by Dr. Jekyll in Lunatic Laboratories

Household dust exposes people to a wide range of toxic chemicals from everyday products, according to a new study. A multi-institutional team conducted a first-of-a-kind meta-analysis, compiling data from dust samples collected throughout the United States to identify the top ten toxic chemicals commonly found in dust.

... Read more »

  • September 20, 2016
  • 03:11 AM
  • 290 views

First trimester maternal vitamin D status and offspring autism risk?

by Paul Whiteley in Questioning Answers

Vitamin D - the sunshine vitamin/hormone - is seemingly everywhere these days in research terms. At the time of writing this post we have news that vitamin D might cut the risk of severe asthma attacks if taken alongside prescribed asthma medication. The week before that it was the suggestion that vitamin D might be part of the explanation as to why childhood learning difficulties were more commonly found in children conceived during the winter months. Vitamin D is seemingly shouldering quite a bit of responsibility when it comes to health and wellbeing.Today I'm adding to that research responsibility by introducing the paper by Jianzhang Chen and colleagues [1] who suggested that: "Lower first trimester maternal serum levels of 25(OH) D were associated with increased risk of developing autism in offspring." 25(OH)D by the way, is calcifediol, and refers to the typical metabolite assayed for to provide a measure of ones vitamin D status.Chen and colleagues accessed archived maternal blood samples taken during the first trimester of pregnancy - "11–13 weeks gestational age" - for some "68 children diagnosed with ASD [autism spectrum disorder] and 68 sex and age matched typically-developing children." Not only was vitamin D status examined in those samples but various other potentially useful metabolites: "unmetabolized folic acid (FA), vitamin B12, homocysteine (HCY) and High Sensitivity C Reactive protein (CRP)" that may have some important autism-related links for some (see here and see here for example).Their report on this occasion focused on the vitamin D results and the finding that mums of children diagnosed with autism/ASD were as a group more likely to present with lower levels of 25(OH)D than control (not-autism) mums. Indeed, when it came to the percentages of who were and weren't vitamin D deficient, some 55% of mums with a child with autism fell into this category compared with less than 30% of control mums. I might add that vitamin D deficiency is typically only one 'banding' when it comes to looking at vitamin D status. With the caveats that this was a study of maternal vitamin D and autism offspring risk in China (so not necessarily translatable to other parts of the world; see discussions shortly) authors also observed a possible correlation between maternal vitamin D status and autism 'severity' in their cohort.Bearing in mind my recent discussions on the maternal body as 'an environment in autism science' (see here) and the potential pitfalls this presents, the data from Chen et al are interesting. Accepting also that I have a bit of a research 'thing' for vitamin D when it comes to autism on this blog (see here and see here for examples), this work seemingly fits in pretty well with the idea that nutritional factors at critical periods may indeed play a role in the development of at least some autism. Indeed, when one talks about season of conception as potentially being associated with offspring risk of behavioural or developmental issues [2], vitamin D levels look like an attractive research target. The next stage in this research process would be independent replication and perhaps, looking at other populations too.In fact, on the topic of other populations similarly studied with maternal vitamin D status and offspring autism or autistic traits in mind, the research path previously trodden might not be all one-way. Take for example research coming out of Australia [3] a few years back that observed little in the way of connection between maternal vitamin D levels and offspring development (see here). OK, they used the Autism Spectrum Quotient (AQ) as their behavioural diagnoser (something that might not be cutting the appropriate mustard in recent times) but all-in-all they found little in the way of any relationship in contrast to the Chen findings. The fact that the Raine study data used in the Australian paper also included quite a few more participants also offers a significant advantage to the smaller Chen study.But I don't think we can just discount the Chen results as they stand, as more and more vitamin D is thrust onto the [autism] research stage. Combined with the recent guidance from the Government here in Blighty suggesting that vitamin D supplementation perhaps needs to be a lot more widespread than it is (see here and see here) throughout the population as a whole, research opportunities aplenty present themselves in this area of growing importance...Oh, and that includes with regards to the genetics of vitamin D metabolism too (see here).To close, if you are easily offended by bad language, please stay away from this advert for a cookbook (probably not the language you're likely to hear on Bake Off whatever channel it's on).----------[1] Chen J. et al. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. Journal of Psychosomatic Research. 2016; 89: 98-101.[2] Zerbo O. et al. Month of conception and risk of autism. Epidemiology. 2011 Jul;22(4):469-75.[3] Whitehouse AJ. et al. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord. 2013 Jul;43(7):1495-504.----------Chen, J., Xin, K., Wei, J., Zhang, K., & Xiao, H. (2016). Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring Journal of Psychosomatic Research, 89, 98-101 DOI: 10.1016/j.jpsychores.2016.08.013... Read more »

  • September 19, 2016
  • 11:11 AM
  • 285 views

Preventing Depression Following Brain Injury

by William Yates, M.D. in Brain Posts

Depression is a common feature following traumatic brain injury (TBI). Post-TBI depression may be difficult to treat and evolve into a chronic depression syndrome.A recent published study demonstrates that prophylactic SSRI antidepressant treatment may reduce the incidence of depression following TBI.This study was conducted by investigators affiliated with Baylor College of Medicine and the Department of Psychiatry at the University of Iowa.Ninety four subjects were recruited to this randomized control trial.Active drug treatment was provided by the selective serotonin reuptake inhibitor sertraline. Subjects were dosed up to 100 mg per day of sertraline and followed for 24 weeks.The primary findings of the study included the following:Sertraline was well-tolerated with few adverse events in the study populationBy 24 weeks approximately 25% of control subjects met criteria for depression while only about 7% of sertraline subjects met criteria for depressionThe number of subjects needed to treat to prevent one person developing depression post-TBI was 5.9... Read more »

  • September 19, 2016
  • 02:59 AM
  • 298 views

Constipation in schizophrenia

by Paul Whiteley in Questioning Answers

"Constipation and dyspepsia are disturbing gastrointestinal symptoms that are often ignored in research on physical comorbidities of schizophrenia."Go on."The prevalence of constipation was 31.3%, and of dyspepsia 23.6%."So said the findings reported by Tomi Virtanen and colleagues [1] who assessed "dyspepsia and constipation in a sample of outpatients with schizophrenia spectrum psychoses." Alongside the general practitioner assessment of such functional bowel complaints, researchers also "assessed the possible contribution of several sociodemographic, lifestyle, and clinical variables" including gender/sex and medication use.As per the sentence above, functional bowel issues such as constipation and dyspepsia might not be unstrange bedfellows alongside a diagnosis of schizophrenia spectrum disorders. There were however some important potential 'correlates' associated with such bowel issues, not least that certain types of medication might exert some effect(s). So for example: "Clozapine use markedly increases the risk of constipation and may lead to life-threatening complications." Even something like the (not-so) humble medicine called paracetamol might also show some relationship to bowel symptoms according to the Virtanen data.Glancing through the other peer-reviewed literature on the topic of bowel issue prevalence and schizophrenia, I was struck by how little there seems to be at present. Yes, there are various papers talking about the comorbidity of certain bowel diseases and schizophrenia [2] but when it comes to the question of 'how prevalent are functional bowel disorders (i.e. constipation, diarrhoea, etc) in cases of schizophrenia?' there appears to be something of a bit of a research gap. This is perhaps a more important topic than many might realise given the suggestion that 'the gut might matter' when it comes to at least some schizophrenia [3]. Yet another example of the gut-brain axis at work eh?The very important effect that something like medication might have on the presentation of bowel issues in schizophrenia is not to be sniffed at either. When words like: "Constipation associated with antipsychotic treatment is frequent in patients with schizophrenia. It can be severe when early detection fails." one really would think that a lot more would be done to further quantify such risk and importantly, start providing viable options to reduce any risk from such potentially severe functional bowel effects. On this matter, and minus any charges of me providing clinical and/or medical advice (I'm not), I might draw your attention to the data suggesting that the use of probiotics in cases of schizophrenia with bowel issues [4] (see here for further discussion) might be something to look further at. More so if one assumes that such something like constipation might be more readily described in terms of irritable bowel syndrome (IBS) for some, and the growing moves towards using probiotics as an intervention aid with that label in mind (see here). Dietary advice could also be something that could be utilised a lot more assuming that a diagnosis of schizophrenia (spectrum disorder) might confer some enhanced risk for a poor diet and nutrition [5].Who knows, treating such bowel issues as and when they present might also have some interesting knock-on effects for other areas of functioning too...----------[1] Virtanen T. et al. Dyspepsia and constipation in patients with schizophrenia spectrum disorders. Nord J Psychiatry. 2016 Aug 26:1-7.[2] Mäkikyrö T. et al. Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health. 1998 Jul;112(4):221-8.[3] Severance EG. et al. Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep. 2015 May;17(5):27.[4] Dickerson FB. et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1). pii: PCC.13m01579.[5] Teasdale SB. et al. A nutrition intervention is effective in improving dietary components linked to cardiometabolic risk in youth with first-episode psychosis. Br J Nutr. 2016 Jun;115(11):1987-93.----------Virtanen T, Eskelinen S, Sailas E, & Suvisaari J (2016). Dyspepsia and constipation in patients with schizophrenia spectrum disorders. Nordic journal of psychiatry, 1-7 PMID: 27564411... Read more »

  • September 18, 2016
  • 03:01 PM
  • 284 views

The new findings heart repair research

by Dr. Jekyll in Lunatic Laboratories

Scientists trying to find ways to regenerate a damaged heart have shed more light on the molecular mechanisms that could one day make this a reality. Whilst other organs such as the liver can regenerate, the heart muscle has very little ability to do so after suffering damage, such as a heart attack.
In the womb the body is able to produce heart muscle cells but soon after birth it effectively stops producing them.... Read more »

  • September 17, 2016
  • 08:27 AM
  • 283 views

Comorbidities surrounding paediatric chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME)

by Paul Whiteley in Questioning Answers

"This large nationwide registry linkage study confirms that the clinical picture in CFS/ME [chronic fatigue syndrome / myalgic encephalomyelitis] is complex."That sentence, taken from the paper by Inger Bakken and colleagues [1] (open-access available here), is perhaps the under-statement of the year as authors sought to "describe comorbidities diagnosed in primary care in children diagnosed with CFS/ME in specialist health care" and "describe the timing of the diagnoses from primary care in relation to the timing of the CFS/ME diagnosis."I grow tired of saying this but yet again, one of those very useful Scandinavian population registries was the starting point for the study - this time based in Norway - as some 1600 children diagnosed with CFS/ME were identified. Their data were compared against nearly 5000 children diagnosed with type 1 diabetes (T1DM) and a little over 1.3 million control - general child population - children. You could say that this was an adequately powered study.A couple of important points were identified from the analysis of patient records. First: "Among children with CFS/ME, the most frequently observed primary care diagnosis was “weakness / general tiredness”." This is probably not unexpected given the nature of CFS/ME. Despite such weakness/general tiredness being initially identified in the vast majority of those with CFS/ME, sleep disturbances were also found more commonly among this group compared to other participants. Rather interestingly, asthma was also reported to be more common in the CFS/ME group than either of the control groups potentially reinforcing a role for atopy in the course/onset of at least some CFS/ME [2].Next: "we found higher frequencies of depression and anxiety in the CFS/ME group." This is an important point that one has to be slightly careful with in terms of the introduction of psychological/psychiatric elements to a diagnosis of CFS/ME. I'll come back to this shortly.Next: "Elevated frequencies of all diagnoses related to infection were observed in the CFS/ME group. In particular, infectious mononucleosis was far more frequent in this group (17.2 %) than in the control groups (T1DM: 3.7 %, general child population: 2.9 %). Influenza, acute tonsillitis, “strep throat”, and pneumonia were also more frequent in the CFS/ME group." Minus any sweeping generalisations, the suggestion that an infection illness might be part and parcel of at least some cases of CFS/ME is potentially borne out by this data. Infectious mononucleosis a.k.a glandular fever as a 'trigger' for CFS/ME is not unknown to the research [3] and other literature for example.Finally: "The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %." Whilst everyone would love to see a timely diagnosis of CFS/ME made, particularly when it comes to children, this data kinda suggest that diagnosis in Norway can still a long and drawn out process. Yes, I understand that many of the numerous diagnostic criteria used to diagnose CFS/ME rely on symptoms being present for an extended period of time but this does little to aid the child and their family and the important effects of such symptoms on things like schooling and other important facets of childhood.The Bakken findings provide an important research snapshot of CFS/ME in children. The themes of (i) infection being potentially important to quite a few cases and (ii) the quite long time lag between primary care (i.e. General Practitioner, GP) diagnosis of weakness / general tiredness and specialist diagnosis of CFS/ME are important ones that research and practice can/should perhaps learn some lessons from.Insofar as the observation of depression and/or anxiety being more frequently present in cases of CFS/ME, the authors make reference to the paper by Winger and colleagues [3] (see this post for more information). Winger et al reported that depressive symptoms in their group did not seemingly link/explain the reduction of health-related quality of life scores they reported for their cohort of adolescents with CFS. Taken together with the Bakken results, the implication is that whilst more commonly reported in CFS/ME, depression (and anxiety) issues are important to cases. They cannot however at this point be described as anything more than comorbid. I say this because, unfortunately, there are still opinions out there that might see depression, anxiety and other psychiatric manifestations as 'causative' of CFS/ME rather than, as I see it, being a symptom stemming from the effects of CFS/ME. If you are bed-bound, not able to go to school, not able to socialise properly and not able to do all the things your peers are doing, it is highly likely that your psychology will eventually be affected to some degree."The long time spans observed from the first diagnosis of weakness / general tiredness in primary care to a specialist health care diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal." I also struggle to disagree with that sentence.----------[1] Bakken IJ. et al. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128.[2] Yang TY. et al. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211.[3] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13:96.----------Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, & Håberg SE (2016). Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC family practice, 17 (1) PMID: 27590471... Read more »

  • September 16, 2016
  • 10:16 AM
  • 326 views

The Brain in Super Agers

by William Yates, M.D. in Brain Posts

My Twitter post on a recently published study of brain structure in a group of high performing older adults received quite a bit of attention (see below).Felicia Sun and colleagues at Massachusetts General Hospital and Harvard Medical School selected an interesting research design.A group of elderly subjects between the ages of 60 and 80 years were identified as showing "superaging". This was defined as scoring like young adults on two neuropsychological tests: The Long Delay Free Recall measure of the California Verbal Learning Test and part B of the Trail Making Test.They then imaged the brain structure and function of the super agers using MRI. The results were compared to two groups: elderly adults without superior cognitive performance and younger adults with age-typical neuropsychological performance.A key finding from their study was that super agers had brain hippocampal volumes greater than typical older adults and this measure was comparable to young adults.Super agers also had greater brain volumes than typical older adults in the following regions:Anterior temporal cortexMedial frontal cortexAnterior midcingulate cortexThe authors noted in the discussion section:"We found support for our hypothesis regarding the structural integrity of the default mode and salience networks, with superagers showing much less atrophy than typical older adults in key nodes of these networks, which we refer to as the "superageing signature".The authors also note their longitudinal study was not able to identify the factors that may play a key role in super agers. Candidate factors include genetic factors, exercise, diet and social activity levels. These factors are likely to be studied in future research.Readers with more interest in this study can access the free full-text manuscript by clicking the citation link below.Figure of hippocampus is an iPad screen shot from the app 3D Brain.Follow me on Twitter @WRY999"Study suggests how 'super aging' older adults retain youthful memory abilities" #neuroscience #feedly https://t.co/DdlXUGbRRp— W.R.Yates, M.D.✍ (@WRY999) September 14, 2016 Sun FW, Stepanovic MR, Andreano J, Barrett LF, Touroutoglou A, & Dickerson BC (2016). Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging. The Journal of neuroscience : the official journal of the Society for Neuroscience, 36 (37), 9659-9668 PMID: 27629716... Read more »

Sun FW, Stepanovic MR, Andreano J, Barrett LF, Touroutoglou A, & Dickerson BC. (2016) Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging. The Journal of neuroscience : the official journal of the Society for Neuroscience, 36(37), 9659-9668. PMID: 27629716  

  • September 16, 2016
  • 05:01 AM
  • 278 views

Air travel and diving possibly increase risk of pneumothorax in BHD patients

by Joana Guedes in BHD Research Blog

Birt–Hogg–Dubé syndrome is caused by germline mutations in the FLCN gene and characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax (SP) and renal cancer. Because sudden changes in air pressure can increase the chances of developing a collapsed lung, a concern many BHD patients have is whether it is safe to air travel and scuba dive, or whether this increases the chances of a pneumothorax. In a new study, Johannesma et al. (2016) evaluate the incidence of SP in patients with BHD during or shortly after air travel and diving. The study was conducted by sending a survey to a cohort of BHD patients. The authors assessed SP episodes occurring within 1 month after air travel or diving and concluded that exposure to changes in air pressure associated with flying and diving may increase the risk of developing pneumothorax.... Read more »

Johannesma, P., van de Beek, I., van der Wel, J., Paul, M., Houweling, A., Jonker, M., van Waesberghe, J., Reinhard, R., Starink, T., van Moorselaar, R.... (2016) Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt–Hogg–Dubé syndrome. SpringerPlus, 5(1). DOI: 10.1186/s40064-016-3009-4  

  • September 16, 2016
  • 04:24 AM
  • 319 views

Anxiety disorders and mortality risk: implications for autism?

by Paul Whiteley in Questioning Answers

"Anxiety disorders significantly increased mortality risk. Comorbidity of anxiety disorders and depression played an important part in the increased mortality."So said the findings reported by Sandra Meier and colleagues [1] looking to assess any relationship between the presence of an anxiety disorder and mortality risk. Based on data from one of those oh-so-useful Scandinavian population registries (Denmark this time), researchers reported that: "The risk of death by natural and unnatural causes was significantly higher among individuals with anxiety disorders... compared with the general population." Death by unnatural causes was also linked in quite a few cases to "comorbid diagnoses of depression."Although making sombre reading, the data from Meier et al provide further evidence [2] that a psychiatric/behavioural diagnosis might have far-reaching implications when it comes to the risk of early mortality, be that based on natural causes or something rather more unnatural such as death by suicide or an enhanced risk of accidental death or death because of illness. This also follows a trend suggesting that severe mental illness also has social implications such as an increased risk of becoming a victim of crime too (see here). Quality of life, health-related or otherwise, is nearly always affected by such diagnoses.I introduced the 'implications for autism' bit to this post simply because (a) when it comes to comorbidity surrounding the diagnosis of autism, anxiety and depression (various types) pretty much come top with regards to psychiatric labels applied (see here and see here respectively) and (b) enhanced risk of early mortality is also an unfortunate feature when it comes to autism too (see here). Putting these findings together and well, I'm sure you can understand the need for quite a bit more study in this area and in particular, a reiteration of how utterly disabling anxiety and/or depression can be when it comes to autism.If and when possible roles for anxiety and/or depression are found to contribute to some of the excess risk of early mortality when it comes to autism, the bright side is that this could have implications for intervention and management and onwards a reduction in mortality risk. I might also introduce the findings reported by Butnoriene and colleagues [3] at this point, who suggested that sex differences might also be relevant to the type of risk factors associated with mortality. Discussions in this area should also probably include discussions on a related topic based on a particularly extreme path being selected by some on the autism spectrum (see here).Without trying to make connections where none might exist, I'm also inclined to suggest that outside of psychological and pharmacological interventions to tackle anxiety and/or depression comorbid to autism, one might also look to treating certain somatic correlates also potentially exerting an effect (see here). There is potentially lots to examine across such comorbidities as yet again, another very important line of study opens up that intersects with autism.Finally, dare I also add that other labels such as obsessive-compulsive disorder (OCD) that may also intersect with some autism (see here - yes, this is another Meier paper) might also increase the risk of early mortality when it comes to autism too [4]?----------[1] Meier SM. et al. Increased mortality among people with anxiety disorders: total population study. The British Journal of Psychiatry. 2016; 209: 216-221.[2] Pratt LA. et al. Excess mortality due to depression and anxiety in the United States: results from a nationally representative survey. Gen Hosp Psychiatry. 2016 Mar-Apr;39:39-45.[3] Butnoriene J. et al. Metabolic syndrome, major depression, generalized anxiety disorder, and ten-year all-cause and cardiovascular mortality in middle aged and elderly patients. Int J Cardiol. 2015;190:360-6.[4] Fernández de la Cruz L. et al. Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients. Mol Psychiatry. 2016 Jul 19.----------Meier SM, Mattheisen M, Mors O, Mortensen PB, Laursen TM, & Penninx BW (2016). Increased mortality among people with anxiety disorders: total population study. The British journal of psychiatry : the journal of mental science PMID: 27388572... Read more »

Meier SM, Mattheisen M, Mors O, Mortensen PB, Laursen TM, & Penninx BW. (2016) Increased mortality among people with anxiety disorders: total population study. The British journal of psychiatry : the journal of mental science. PMID: 27388572  

  • September 15, 2016
  • 04:25 AM
  • 300 views

Eicosapentaenoic acid (EPA)-predominant fatty acid supplements and the treatment of depression

by Paul Whiteley in Questioning Answers

"Further RCTs [randomised-controlled trials] should be conducted on study populations with diagnosed or clinically significant depression of adequate duration using EPA [eicosapentaenoic acid] -predominant omega-3 HUFA [highly unsaturated fatty acids] formulations."So went the conclusions of the review article published by Brian Hallahan and colleagues [1] who searched the peer-reviewed science literature for clinical trials "evaluating efficacy of omega-3 highly unsaturated fatty acids (HUFAs) in major depressive disorder." They found over 30 trials of omega-3 supplementation vs. placebo published between 1980 and 2014 that together included participant numbers in the thousands.They reported that among those diagnosed with depression, the type of fatty acid supplement used might matter: "eicosapentaenoic acid (EPA)-predominant formulations (>50% EPA) demonstrated clinical benefits compared with placebo." When it came to that other commonly discussed omega-3 fatty acid - docosahexaenoic acid (DHA) - the results were not so great for those diagnosed with depression in terms of changes to symptom presentation(s). Importantly too, the authors noted that: "EPA failed to prevent depressive symptoms among populations not diagnosed for depression."Interesting. More so when read alongside another recent review paper by Husted & Bouzinova [2] who similarly suggest that more targeted research is needed to "clarify an optimal dosage of EPA and DHA in [the] prevention of depression." They also described the idea that various processes particularly pertinent to the concept of inflammation (yes, depression and inflammation do seem to have some commonalities) might be a target for certain omega-3 fatty acids and onwards the presentation of depression. There may even be 'critical windows' where such supplementation might be more useful (see here) than others.What's the critical difference between EPA and DHA that could account for the Hallahan findings? Well, there are a few good articles on how not all omega-3 fatty acids are the same, but I found one that is pretty informative (see here). Chemically-speaking, there are differences in structure which might account for where and when these compounds might fit when it comes to various chemical reactions in the body. Going back to the whole inflammation thing, I understand that EPA might also have some important effects on an enzyme called delta-5-desaturase (D5D) but I'd guess this is not the only difference that might be important.I'll be keeping a watch out for developments in this area of study but for now, yet more evidence that food and nutrition might have some important influences on behaviour and psychiatry. Nutritional psychiatry is starting to come out from the clinical shadows perhaps...Music: The Fall and Eat Y'Self Fitter ('Up the stairs mister').----------[1] Hallahan B. et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British Journal of Psychiatry. 2016; 209: 192-201.[2] Husted KS. & Bouzinova EV. The importance of n-6/n-3 fatty acids ratio in the major depressive disorder. Medicina (Kaunas). 2016;52(3):139-47.----------Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, & Davis JM (2016). Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British journal of psychiatry : the journal of mental science PMID: 27103682... Read more »

Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, & Davis JM. (2016) Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British journal of psychiatry : the journal of mental science. PMID: 27103682  

  • September 14, 2016
  • 04:30 AM
  • 323 views

Stabilization Exercises or Manual Therapy for Low Back Pain

by Nicole Cattano in Sports Medicine Research (SMR): In the Lab & In the Field

Stabilization exercises are better than general exercises for people with chronic non-specific low back pain and possibly as effective as manual therapy.... Read more »

  • September 14, 2016
  • 04:26 AM
  • 281 views

Unexpected improvement in core autism symptoms following a probiotic?

by Paul Whiteley in Questioning Answers

The paper by Enzo Grossi and colleagues [1] (open-access) is definitely worthy of a post today and the suggestion that the "appropriate use of probiotics" might be something to consider for at least some diagnosed as being on the autism spectrum.Accepting that I'm slightly curious as to what would be considered 'inappropriate use of probiotics', the Grossi paper describes the clinical journey of a boy aged 12 diagnosed with an autism spectrum disorder (ASD) accompanied by learning (intellectual) disability who was concurrently diagnosed with coeliac disease (CD). The CD diagnosis was a slightly complicated affair given that whilst he presented with the relevant 'genetics' of CD (HLA genotypes) and "a slight elevation of transglutaminase antibodies" a gluten-free diet seemingly did very little in terms of clinical benefits and when it came to the "blood-specific tests for celiac disease" they were always negative. I'll come back to some of these points shortly but his chronic gastrointestinal (GI) symptoms that were first thought to be CD related were subsequently put down to irritable bowel syndrome (IBS).In light of the IBS diagnosis and given some pretty important research suggesting that specific probiotic formulations might have treatment-potential for some IBS (see here), a probiotic intervention was prescribed: VSL#3. What happened next is intriguing...After a few weeks of probiotic treatment, some 'apparent improvements' were noted in the boy's behavioural presentation. This led the authors to start looking more systematically at whether said improvements could be charted and possibly tied into his probiotic use. We are told that the various components of his behavioural plan that had been in place for some 6 years were continued without "any particular change." Use of the gold-standard assessment tool that is the ADOS - Autism Diagnostic Observation Schedule - was employed over a period of about a year-and-a-half to covering the period of probiotic use. Data for two ADOS assessments were available before the probiotic was installed and four assessments were carried out during and post-intervention. The results suggested that scores relevant to social affect (the DSM-5 term describing issues with social and communicative domains) changed over the intervention period in line with some of the observations made of this boy. Further: "This change was surprising since in our assessment records over several years, the patient status had remained steadily unchanged." It should also be noted that the GI symptoms, the initial target of probiotic use, also reduced "as expected."Yes, I know that this is a case report (and N=1) and given what we (think we) know about autism, such results can by no means be generalised to all autism. There could also be a million and one other variables potentially accounting for the results including something called puberty potentially playing a role (see here) given the age of the boy. One needs to be cautious.But... these are still potentially important results for quite a few different reasons. Going back to the description of CD being diagnosed and then un-diagnosed, regular readers might know about my interest in something called non-coeliac gluten sensitivity (NCGS) when it comes to something like autism (see here). The suggestion being that although a diagnosis of autism is not protective against a diagnosis of CD, the still emerging peer-reviewed data seems to suggest something slightly more gluten-fuzzy when it comes to at least some autism. That elevated levels of tissue transglutaminase are also not an uncommon finding in relation to [some] autism (see here) adds to the curiosity in this area.Bowel or GI issues occurring alongside autism? Well, I've said it before and I'll say it again: GI issues (both functional and pathological) are over-represented when  it comes to autism (see here). You can call it IBS or similar other bowel related label but the fact of the matter is that such issues are not uncommon and lots more resources need to be poured into looking at and importantly, treating such issues save any further health inequalities appearing alongside the label of autism. It makes good sense that if something like IBS is diagnosed, and the various meta-analyses suggest that probiotics might be one part of an intervention strategy for IBS, their use where IBS clusters with autism should be the same as when autism is not part of the equation. Simple as.The Grossi case report also highlights how gut and brain, with a healthy portion of gut microbiome, might show some important links for some on the autism spectrum [2]. This is by no means 'a new thing' (see here) and to some extent, justifies the various studies where gut bacteria for example, have been looked at in the context of autism (see here for example). That such a connection might also include issues with gut permeability (see here) is another important detail and is evidenced by the possibility that probiotics may also work on the gut membrane [3] as well as those trillions of wee beasties that call us home.In short, more research on the use of probiotics with autism is very much implied (and indeed is already in progress). Watch this space.To close, first we had Mr Pharmacist from The Fall. Now we have Oxymoronic from NOFX. Spot the difference...----------[1] Grossi E. et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Medical Case Reports. 2016; 4: 2050313X16666231.[2] Inoue R. et al. A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders. Biosci Biotechnol Biochem. 2016 Sep 1:1-9.[3] Mennigen R. et al. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol. 2009 May;296(5):G1140-9.----------... Read more »

  • September 13, 2016
  • 04:27 AM
  • 288 views

A 'characteristic chemical signature' to chronic fatigue syndrome?

by Paul Whiteley in Questioning Answers

Today I'm (belatedly) talking about the paper by Robert Naviaux and colleagues [1] (open-access) and some further peer-reviewed discussion concerning the metabolomics of chronic fatigue syndrome (CFS). Suggesting that "targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology" when it comes to CFS, it is not surprising that this work has attracted some media interest (indeed, quite a lot of media interest).I don't want to regurgitate all the findings given that (a) they are numerous, and (b) the paper is open-access, but there are a few details worth noting.So:Some readers might recognise the names Robert and Jane Naviaux listed as authors on this current paper as one and the same team involved in all that suramin for [mouse] autism work (see here). Their previous focus on the application of metabolomics (specifically the use of mass spectrometry) following the use of suramin hints at the skills and expertise this group have in that field.Their research attention was turned to CFS with the aim to put further flesh on the idea that there may be some important biochemistry happening in cases of the condition.Eighty-four adults were included for study; 45 diagnosed with CFS by various criteria (yes, there are quite a few of them). They provided blood samples that were subject to analysis: "Targeted, broad-spectrum, chemometric analysis of 612 metabolites from 63 biochemical pathways was performed."Results: well, first various 'trigger' factors were linked to onset of CFS participants' symptoms. Biological triggers - "viral, bacterial, fungal/mold, and parasitic infections" - were most common but "no single infectious agent or other stressor was statistically more prevalent." There appear to be many [organic] roads to the development of CFS.'A characteristic chemical signature' is something that many media outlets have jumped on to based on these results. Indeed, with some very pretty Venn diagrams included, there did appear to be some chemical 'signatures' that defined CFS vs. not-CFS.  The sorts of compounds seemingly involved related to the: "Sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid and branch chain amino acid metabolites." I'm particularly interested in the amino acid chemistry detected and how it may overlap with other findings [2].The relevance of those chemical signatures in terms of biological processes were quite diverse but led authors to conclude that "the metabolic features of CFS are consistent with a hypometabolic state." Some media outlets have referred to this as a 'semi-hibernation like state' where metabolism is somehow slowed down. I'm not so sure this is the most accurate definition given that hibernation normally implies a time-limit to such a state. Unfortunately, for many, CFS does not magically stop come the biological Spring. There is also mention of how the findings might relate to other research in CFS including a role for mitochondrial function (see here) and NAD (see here).With some cautions attached to this line of work (see here), not least the quite small participant groups included for study and, I believe, the use of a single blood sample at one specific time point, this is interesting work. Added to a growing tide of research suggesting that if one looks, one might indeed find some biological issues associated with a diagnosis of CFS (see here for example), this is yet another stop in the journey towards understanding CFS is terms of biology not psychology. The next stop is of course independent replication."The study of larger cohorts from diverse geographical areas, and comparison with related medical disorders like depression and posttraumatic stress disorder, will be needed to validate the universality and specificity of these findings. The finding of an objective chemical signature in CFS helps to remove diagnostic uncertainty, will help clinicians monitor individualized responses to treatment, and will facilitate multicenter clinical trials." Big words that indeed require that independent replication, but the research future for CFS is already looking a little brighter as a result of the Naviaux findings.----------[1] Naviaux RK. et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Aug 29. pii: 201607571.[2] Georgiades E. et al. Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clin Sci (Lond). 2003 Aug;105(2):213-8.----------Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, & Gordon E (2016). Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America PMID: 27573827... Read more »

Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, & Gordon E. (2016) Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America. PMID: 27573827  

  • September 12, 2016
  • 12:36 PM
  • 294 views

Opioid Abuse: Treatment Guidelines

by William Yates, M.D. in Brain Posts

Molecular model of the drug buprenorphineThe U.S. Surgeon General recently sent a letter to all physicians about the danger of prescription opioids, particularly when used in combination with benzodiazepines (i.e. Valium, Xanax).  This combination greatly increases the risk of overdose death.Clinicians can successfully assist those with opioid use disorders. Marc Schuckit, M.D. recently published a nice summary review of entitled "Treatment of Opioid-Use Disorder" in the New England Journal of Medicine (see citation below).The review contains some nice tables including tables related to:Diagnostic criteria of opioid use disorderAn opiate withdrawal rating scaleOpioid free treatment aids in management of opioid withdrawalOpioid agonist aids in management of opioid withdrawalOpioid agonist use in long-term maintenanceOpioid withdrawal is generally non-life threatening, but extremely uncomfortable and a strong motivator for return to opioid use.Use of opioid agonists such as buprenorphine (pictured in molecular model above) is the best tolerated and least uncomfortable pathway to treatment of opioid withdrawal. However, it is restricted to prescription by a small group of physicians who have completed a special training program.This means many opioid users end up with less tolerated and more uncomfortable withdrawal episodes treated with drugs such as clonidine, diazepam or even over-the-counter drugs such as Imodium.The review notes that with high relapse rates, supervised opioid maintenance with prescribed opioids such as methadone or buprenorphine often are required for long-term abstinence. One barrier to using these types of interventions is availability and cost. Buprenorphine can be expensive and requires regular monitoring in a physicians office.With high costs and lack of access to supervised opioid management, opioid users commonly return to street heroin or prescription opioid pills (licit or illicit). Readers with more interest in this topic can access the free full-text manuscript by clicking on the DOI link in the citation below.Follow me on Twitter @WRY999Model of buprenorphine is from a Wikipedia Creative Commons File attributed to:Crystallographic data from J. Mazurek, M. Hoffmann, A. Fernandez Casares, P. D. Cox and M. D. Minardi (June 2014). "Buprenorphine". Acta Cryst. E70, o635. DOI:10.1107/S1600536814009672Schuckit, M. (2016). Treatment of Opioid-Use Disorders New England Journal of Medicine, 375 (4), 357-368 DOI: 10.1056/NEJMra1604339... Read more »

Schuckit, M. (2016) Treatment of Opioid-Use Disorders. New England Journal of Medicine, 375(4), 357-368. DOI: 10.1056/NEJMra1604339  

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