Tag Archives: Children

A Drug Treatment for Autism

Autism affects 1-2% of children. These children may have problems with social interaction, adhere to strict routines, have repetitive behaviours, restricted interests, poor self-care, and/or heightened sensory experiences. A very wide array of genetic mutations and environmental exposures interact to produce the phenotype. It is a neurological disease and one theory, the “cell danger hypothesis”, holds that certain neurological pathways are prone to become over-activated and respond as though they were under ‘threat’. Purines released from mitochondria leech through the cell membrane where they play a role in activating microglia and affecting synaptic remodelling – a topic covered in other News Blogs.[1][2] A drug called suramin inhibits the action of purines such as ATP. It is used in high doses to control trypanosomiasis (sleeping sickness). It is toxic at high dose, but might it be effective at a lower dose for autism? A very small, double-blind trial has been carried out in which five matched pairs of autistic children were randomised to a single intravenous dose of suramin or saline.[3] Metabolic pathways were affected as expected, and the treatment was associated with improvement on a standard score two days after the infusion. It is early days, but it is just possible that we are entering a period where autism will be added to the growing list of neuro/psychiatric disorders that can be mitigated by pharmacological therapy based on an improved understanding of molecular pathogenesis.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain. NIHR CLAHRC West Midlands News Blog. 13 January 2017.
  2. Lilford RJ. A Fascinating Account of the Opening up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. Naviaux RK, Curtis B, Li K, et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann Clin Transl Neurol. 2017.

Nodding Syndrome: Autoimmune Reaction to the Parasitic Worms That Cause River Blindness?

We have described the above enigmatic disorder of young children in East Africa before; a degenerative brain disease characterised by repetitive nodding movement, an inability to swallow, and eventually global brain failure.[1] Authors of a recent study hypothesised that the disease may be caused by an autoimmune response to the river blindness parasite.[2] They detected auto-antibodies to the parasite more often in cases than age-matched controls from the same village. The antibody attacks various cell markers in the mouse brain among neural networks that are affected in nodding syndrome. But only about half the patients with nodding syndrome exhibited the antibodies. The authors speculate that a number of yet to be identified antibodies may also be involved. I wonder why the disease does not map onto the geography of river blindness, which appears to be much broader than that of nodding syndrome.

So, here is my hypothesis. Remember, a few News Blogs ago,[3] I articulated a ‘three hits hypothesis’ as the cause of many diseases. One example was cytomegalovirus infection, which in the presence of the malaria parasite, and along with genetic predisposition, leads to Burkitt’s lymphoma. So I suspect that exposure to river blindness may be a sensitising event, and propose a search for a further exposure that is more specific to the ‘nodding syndrome belt’ extending from South Sudan, through Uganda to North Tanzania (see Figure).

Map of African countries showing where River Blindness is endemic and where outbreaks of Nodding Disease have occurred.

Data on River Blindness taken from the World Health Organization.

— Richard Lilford, CLAHRC WM Director

References:

  1. Chilton PJ. A Mysterious Disease with Unknown Cause. NIHR CLAHRC West Midlands News Blog. 27 June 2014.
  2. Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med. 2017; 9.
  3. Lilford RJ. Three Hits Hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.

Childhood Decline in Physical Activity

Previously we have seen evidence from a cohort of children and adolescents in Norfolk that the decline in physical activity among modern young people takes place after childhood and during adolescence.[1] However in the majority of studies, including that which we looked at, the estimates of activity are largely based on reports. Now comes a new paper from Farooq and colleagues using objective measurements based on an accelerometer.[2] This new study shows that the previous conclusion was probably wrong. The study shows that there is a decline in moderate to vigorous physical activity throughout childhood and adolescence. A further interesting finding is that this study, based on objective measurements of activity, did not replicate the prevailing view that energy expenditure declines more rapidly in girls than in boys. This paper has considerable implications for policy. I would like to thank Professor Jeremy Dale for bringing this important paper to my attention.

— Richard Lilford, CLAHRC WM Director

References:

  1. Corder K, van Sluijs EMF, Ekelund U, Jones AP, Griffin SJ. Change in children’s physical activity over 12 months; longitudinal results from the SPEEDY study. Pediatrics. 2010; 126(4): e926-35.
  2. Farooq MA, Parkinson KN, Adamson AJ, et al. Timing of the decline in physical activity in childhood and adolescence: Gateshead Millennium Cohort Study. Br J Sports Med. 2017.

Crying Infants – the Epidemiology of ‘Colic’

The period following childbirth is stressful for parents and uncontrollable crying is an important cause of this stress. Wolke and colleagues [1] have consolidated the results of studies across the world in a meta-analysis and show that:

  1. Crying peaks at around six weeks of age, and then declines sharply over the next three months.
  2. Bottle or mixed-fed babies cry less than those that are purely breastfed.
  3. Crying is much more common in some countries (Canada and UK) than others (Denmark and Japan), and this is a robust finding (i.e. replicated across many studies). I don’t suppose that this is the result of lower breastfeeding rates in Denmark and Japan than in Canada or the UK?

What the study does not show is how crying varies within families or by birth order. Nor does there seem to be an effective remedy for the problem. Pilgrim was right, it is not easy being a human, not at the beginning, not in the middle, and certainly not at the end.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Wolke D, Bilgin A, Samara M. Systematic Review and Meta-Analysis: Fussing and Crying Durations and Prevalence of Colic in Infants. J Pediatr. 2017.

 

Computer Interpretation of Foetal Heart Rates Does Not Help Distinguishing Babies That Need a Caesarean from Those That Do Not

In an earlier life I was involved in obtaining treatment costs for a pilot trial of computerised foetal heart monitoring versus standard foetal heart monitoring (CTG). The full trial, funded by NIHR, has now been published in the Lancet,[1] featuring Sara Kenyon from our CLAHRC WM theme 1. With over 46,000 participants the trial found no difference in a composite measure of foetal outcome or intervention rates. Perinatal mortality was only 3 per 10,000 women across both arms and the incidence of hypoxic encephalopathy was less than 1 per 1,000. Of course, the possibility of an educational effect from the computer decision support (‘contamination’) may have reduced the observed effect, but this could only be tested by a cluster trial. However, such a design would create its own set of problems, such as loss of precision and bias through interaction between method used and baseline risk across interventions and control sites. Also, the control group was not care as usual, but the visual display IT system shorn of its decision support (artificial intelligence) module.[2] Some support for the idea that control condition affected care in a positive direction, making any marginal effect of decision support hard to detect, comes from the low event rate across both study arms. Meanwhile, the lower than expected baseline event rates mean that any improvement in outcome will be hard to detect in future studies. So here is another topic that, like vitamin D given routinely to elderly people,[3] now sits below the “horizon of science” – the combination of low event rates and low plausible effect sizes mean that we can move on from this subject – at least in a high-income context. If you want to use the computerised method, and its costs are immaterial, then there is no reason not to; economics aside there appear to be no trade-offs here, since both benefits and harms were null.

— Richard Lilford, CLAHRC WM Director

References:

  1. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet. 2017.
  2. Keith R. The INFANT study – a flawed design foreseen. Lancet. 2017.
  3. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.

Worm Wars Continued

We have discussed results of deworming before and argued that it is important to treat at cluster level because of rapid re-infection from reservoirs in soil. A recent important meta-analysis compares deworming targeted at children versus a community-wide intervention.[1] It finds that community-wide approaches are more effective than treatment targeted at children for roundworms (Ascaris) and hookworms (Ancylostoma), but not whipworms (Trichuris). This finding is consistent with the much greater efficiency of the medicine in the former two worm types. The relative effect was greater in roundworms (odds ratio >16) than the more dangerous hookworms (OR >4), consistent with the shorter life-span of hookworm eggs than of roundworm eggs. These are important findings, but there is a worry that resistance may emerge with mass treatment. It would be interesting to see whether any studies have been done in slum populations specifically.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Clarke NE, Clements ACA, Doi SA, et al. Differential effect of mass deworming and targeted deworming for soil-transmitted helminth control in children: a systematic review and meta-analysis. Lancet. 2017; 389: 287-97.

Keeping a Child Back at School

We have often talked about Hattie’s work on evidence-based education.[1-4] Now we turn to retention (pages 97-99) – the act of keeping a child back and having them repeat a year of school on the grounds of poor performance.[5] Numerous papers, including a meta-analysis of 20 studies,[6] have shown retention to be associated with negative effects for the retained student. In subsequent years they have lower scores for a whole range of subjects: language, arts, reading, mathematics, work-study skills, and social studies, as well as social and emotional adjustment and behaviour, self-concept, and attitude to school. So a picture is starting to emerge – remember streaming is also unhelpful.[7] So any act that demeans a child or destroys her self-confidence is bad, while bright children are not held back by having less bright peers in the classroom. See also our News Blog on the Michelle Obama effect.[8]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Evidence-based Education. NIHR CLAHRC West Midlands News Blog. 24 February 2017.
  2. Lilford RJ. The School, the Teacher of the Pupil – Which is Most Important? NIHR CLAHRC West Midlands News Blog. 28 October 2016.
  3. Lilford RJ. Ask Not to Whether, But Why, Before the Bell Tolls. NIHR CLAHRC West Midlands News Blog. 29 July 2016.
  4. Lilford RJ. Education Update. NIHR CLAHRC West Midlands News Blog. 2 September 2016.
  5. Hattie J. Visible Learning: A Synthesis of Over 800 Meta-Analyses Relating to Achievement. Oxon, UK: Routledge, 2009.
  6. Jimerson SR. Meta-analysis of Grade Retention Research: Implications for Practice in the 21st Century. School Psychol Rev. 2001; 30(3): 420-37.
  7. Lilford RJ. Evidence-Based Education (or How Wrong the CLAHRC WM Director Was). NIHR CLAHRC West Midlands News Blog. 15 July 2016.
  8. Lilford RJ. More on Education. NIHR CLAHRC West Midlands News Blog. 16 September 2016.

More on Brain Health in Young Children and Effect on Life Course

Brain health in early childhood is a recurring theme of your News Blog. Peter Chilton referred me to an interesting article in Nature Human Behaviour published at the end of last year.[1] This study was based on a prospective study of children in the South Island of New Zealand. The investigators wanted to determine the prognosis for the 20% of the population with the worst brain health indicators at age three. These indicators include single parent family; low socioeconomic group; poor self-control; and low IQ. Outcome variables covered a range of important economically burdensome outcomes, such as obesity, cigarette smoking, and crime. These variables were harvested from various databases where health and crime statistics are recorded. A 20% ‘segment’ of this young population could be defined which predicted 80% of crime, and similar high rates on other outcomes. This 20:80 ratio, called the Pareto ratio, is often encountered in social science – for example, wealth distributes itself roughly in this proportion across many societies (about 20% of people control 80% of wealth). The authors say that their study shows plenty of ‘headroom’ for preventive interventions. That is to say, society could achieve massive gains if health and social outcomes among the highest risk segment could be improved to average levels. We have discussed interventions, such as early childhood education, before.[2-4] Many studies show statistically significant and economically worthwhile results for such interventions, but the gains come nowhere near the theoretical headroom defined here. Likely this is because brain health at age three is only partly the result of remediable factors.

— Richard Lilford, CLAHRC WM Director

References:

  1. Caspi A, Houts RM, Belsky DW, Harrington H, Hogan S, Ramrakha S, Poulton R, Moffitt TE. Childhood forecasting of a small segment of the population with large economic burden. Nature Hum Behav. 2016; 1: 0005.
  2. Lilford RJ. Pregnancy before age 16 – dropping quite rapidly from a peak in 1997. NIHR CLAHRC West Midlands News Blog. February 10, 2017.
  3. Lilford RJ. If you want to reduce partner violence or teenage pregnancy, then teach algebra and history? NIHR CLAHRC West Midlands News Blog. December 9, 2016.
  4. Lilford RJ. Evidence-based education (or how wrong the CLAHRC WM Director was). NIHR CLAHRC West Midlands News Blog. July 15, 2016.

Hidden Disadvantage to Caesarean Section

Some modern health care may end up changing the genetics of the human race. For example, the CLAHRC WM Director established a genetic basis for male infertility,[1] and sure enough, children born following injection of sperm into the mother’s egg have an increased risk of infertility.[2] What about Caesarean section? Childbirth is a struggle because, compared to all other animals (primates included), the baby’s head is big relative to the size of the mother’s pelvis. Evolution allows this to continue under an equilibrium where the distribution of pelvic sizes is maintained at a level where the beneficial effects of big brain/head balances the risk of catastrophic birth from a pelvis below the threshold where risk rises rapidly. Caesarean section skews natural selection and pelvic sizes according to this elegant mathematical model.[3] But are pelvic sizes indeed becoming smaller?

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford R, Jones AM, Bishop DT, Thornton J, Mueller R. Case-control study of whether subfertility in men is familial. BMJ. 1994; 309: 570.
  2. Belva F, Bonduelle M, Roelants M, et al. Semen quality of young adult ICSI offspring: the first results. Hum Reprod. 2016; 31(12): 2811-20.
  3. Mitteroecker P, Huttegger SM, Fischer B, Pavlicev M. Cliff-edge model of obstetric selection in humans. P Natl Acad Sci USA. 2016.

Early Introduction of Allergenic Foods for Breastfeeding Infants and Risk of Allergy

This is an important question for us all – is the early introduction of allergenic (allergy causing) foods, such as peanuts and egg, associated with higher risk of allergy? The short answer is no.[1] In fact the risk of clinical allergy is lower when peanut and egg is introduced early (at three months) than when introduced later (at six months). It was non-significantly lower by Intention-to-Treat, but significantly lower (p<0.003) in the per protocol analysis (2.4% vs. 7.3%). ‘Compliance’ was poor; less than half of cases in the early introduction group adhered to protocol. The non-adherers had similar rates of allergy to the control (normal practice/delayed introduction) group. There appeared to be a ‘dose’ response with higher intake of allergenic foods associated with greater reductions in the incidence of allergy. Biological testing for allergy gave even stronger protective results for early introduction than did the clinical data reported above. The results are consistent with previous observational and experimental studies. Taken in the round, the results are compelling, shifting probability densities sharply in favour of effectiveness. The World Health Organization recommends exclusive breast feeding to six months of age. Time for change in guidelines in high-income countries?

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Perkin MR, Logan K, Tseng A, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. New Engl J Med. 2016; 374: 1733-43.