1601 Developments in hearing screening in South Africa

The last summary of 2015 dealt with the important matter of vision screening in children, particularly in deprived communities, but one cannot consider screening for visual impairment without also giving thought to screening for hearing deficits.  In South Africa the recently-released White Paper on NHI (National Health Insurance) which is focused on universal health care for all South Africans, makes a case for prioritisation of Primary Health Care (PHC). One of the cornerstones of PHC is the further development of the Integrated School Health Programme (ISHP).  In 2013/14 70 mobile clinics visited schools in the (mostly rural/peri-urban) districts assigned to pilot NHI and assessed ~880 000 learners. Almost 44 000 (21%) were referred for eye care and some 14 000 (7%) were referred for hearing problems.  This gives some idea of the potential burden, not only for those screening but also for the secondary level caregivers who are required to perform definitive tests.  Hearing loss is a significant global healthcare problem because of its widespread prevalence and long-term consequences for affected individuals and for society.  The WHO estimates that there are >32 million children suffering from disabling hearing loss, most of which do not have access to early detection services.  Consequences include impaired speech, language and cognitive skills and associated reductions in literacy, academic, social and economic development.  The shortage of healthcare professionals in sub-Saharan Africa (estimated at <1 audiologist per million people) and the expense of audiometric equipment are important barriers that must be overcome if one is to make inroads into this underserved area of child health.  A number of South Africans have made significant contributions in the development of technology that would allow non-specialist caregivers to carry out high volume screenings, even in deprived areas. Arguably the most exciting contribution has been that of Swanepoel and colleagues from the University of Pretoria who have not only developed hearScreen, a trademarked and validated smartphone screening application, but have also linked the phone (cost ~$85) to relatively inexpensive headphones (~$35).  A calibration step confirmed the accuracy and reliability of the set up at 1, 2 and 4kHz with intensities of 20, 30 and 40dB, irrespective of phone battery power (tested at <10%, 50% and >90%). The system also takes ambient noise levels into consideration. Field trials involving 162 school children aged between 5.6 and 7.7 years were carried out by audiology students, comparing the smartphone system to conventional audiometry.  Results showed agreement in 97.8% of cases. Referral for definitive testing was recommended in 4.3% of cases assessed by the smartphone vs. 3.7% in those assessed by conventional screening.  Average smartphone screening duration was only 60.9 seconds.  Follow-up results were not available at the time of publication so sensitivity and specificity could not be reported, but the results are nonetheless extremely exciting, offering the possibility of an affordable solution to large-scale screening of children in poorly-resourced environments.

Read more:

Int J Audiol 2014; 53: 841-9

National Health Insurance for South Africa www.gov.za/documents/national-health-insurance-10-dec-2015-0000

Int J Pediatr Otorhinolaryngol 2014; 78: 290-5   

1602 Aorta-Vena cava (A:VC) ratio as a measure of dehydration in children

Nobody will question the importance of diarrhoeal disease in developing countries and the resultant burden on health systems. Statistics indicate that each year there are 1.7 billion episodes worldwide resulting in 124 million outpatient visits, 9 million hospitalisations and >700 000 deaths.  At a facility/point-of-care level it is important to differentiate between mild-moderate and severe dehydration as the former will likely respond to oral rehydration while the latter requires intravenous fluids.  Parenteral rehydration is also not without risks, so again one would not wish to unnecessarily expose infants and children who do not require this form of treatment.  Percentage dehydration is typically assessed on clinical grounds at the time of presentation, but without knowledge of the weights before and after the onset of diarrhea the assessment of dehydration may not always be accurate.  Several studies have used the inferior vena cava diameter as a predictor of volume status in children and reported good area-under-the-curve (AUC) values of >0.7, sensitivities of >85%, and specificities of ~60%. However these studies had small sample sizes and included older children, adolescents and even young adults.  To study the value of this modality in a high-volume, resource-poor setting staffed by general practice nurses, researchers from Bangladesh and the USA prospectively enrolled 850 children with acute diarrhoea as part of the DHAKA (Dehydration: Assessing Kids Accurately) project.  The first step was to familiarize, train and assess competence in the nurses’ use of ultrasound.  The eligible children were weighed and managed according to standard rehydration protocols, and percentage dehydration was confirmed by calculating the difference between weight on presentation and stable weight after rehydration (which was reached at a median time of 14 hours).  Median percent dehydration on entry was severe (>9%) in 11%, while 44% were classified as not dehydrated (calculated % difference between entry and stable weight <3%). The remainder were classified as ‘some dehydration’ (3-9%).  While almost all the nurses correctly identified the aorta, in 11% of cases other structures were identified as the IVC (e.g splenic or portal vein).  For 750 cases in which all data were available there was a relationship between A:VC ratio and percentage dehydration, with each 1-point increase in the ratio predicting a 1.1% increase in percentage dehydration.  However the AUC result was poor (0.60) as were sensitivity and specificity at 67% and 49% respectively.  The results of this study contradict the previous studies, and in line with a systematic review from 2015 conclude that the modality is not accurate enough to be used as an independent assessment tool for severe dehydration in resource-poor settings. Results might be different if ultrasound assessments are done by specialists, but this would not be consistent with the primary care model in such settings.

Read more:

PLoS One doi:10.1371/journal.pone.0146859

J Pediatr 2015 166: 908-16

Adv Emerg Nurs J2014 36: 271-8   

1603 Stunting and obesity

A couple of recent studies have highlighted the finding that obesity is becoming a problem in stunted children, most likely as a result of ‘nutrition transition.’ Historically stunting has been a characteristic of undernutrition which, if sustained, has an ongoing effect on linear growth. Early correction of nutritional deficits (i.e. within the first 1000 days of life ‘window’) has the potential to restore the growth trajectory, but if socio-economic and nutritional advances only occur beyond that window there is evidence of weight being enhanced to a greater degree than height.   In an Indonesian study of ~7500 children aged between 2 and 5 years that was carried out over four time periods (1993, 1997, 2000, 2007) there was a progressive decrease in stunting (from 50.1 to 35.7%) and an increase in overweight/obesity from 10.8-17.4%. At each time point those who were stunted were more likely to be overweight/obese than children of age-appropriate height (OR 1.35 – 2.28; p<0.05). These findings are similar to those recently reported in a secondary analysis of a South African survey carried out in 2005 on 519 children aged between 3 and 10 years.  The prevalence of overweight was 8.3% and 3.7% were obese. More children from Gauteng were obese (14.1%) vs those from Mpumalanga (6.3%), but stunting rates were similar between the provinces at ~17%. In the obese group 68.4% were stunted while in the normal and underweight groups only 13.6% were stunted.  Both stunting and obesity have long-term consequences, the former potentially affecting adult height, academic achievement, earning potential and birthweight of offspring, while the adverse effects of obesity in adults are known and are a subject of current debate around the world.  It is clear that reversal of stunting is desirable, but the two studies cited above suggest that there is more to it than simply supplementing calories. The ‘nutrition transition’ argument aligns with current efforts focused on the ‘upwardly mobile’ to limit children’s exposure to first-world evils of sugar-containing drinks, fast foods and carbohydrate-rich diets, and the articles conclude that the solution is a public health one i.e. there is an emphasis on health policies and interventions that educate the public about breast-feeding and make ‘high-micronutrient-content’ complementary foods available. The real question is whether this is simply a matter of feeding ‘appropriate nutrients’ that enhance linear growth rather than fat accumulation, or is there more to it such as ‘programming’ or conditioning that actually reduces the stunted child’s ability to gain height?  While catch-up of linear growth is often regarded as possible if addressed beyond 2-3 years of age, Leroy et al argue that studies that have shown this have incorrectly used HAZ scores (z-scores for height for age vs. the cross-sectional population mean) rather than the HAD score (height for age difference using expected height from international standards). When HAD scores are used no such catch up occurs. If there is indeed a pathophysiological constraint on linear growth after the first 1000days of life it is not surprising that late nutritional support and supplementation result in weight rather than height gain.

Read more:

S Afr Med J 2016; 106: 65-9

Medscape  May 21, 2015

BMC Pediatrics 2015; 15: 145

1604 Sildenafil to reduce the risk of foetal distress

Whereas summary 1602 advocated against the use of ultrasound measurement of the aorta:vena cava ratio to estimate severity of dehydration, other non-invasive measurements of foetal blood flow by ultrasound and Doppler have been shown to be predictive of intrapartum foetal compromise during labour, or to reliably exclude those not at risk.  The indices used are the cerebro-umbilical ratio (C-U ratio) and umbilical venous flow. The C-U ratio measures the ratio of the pulsatility indices of the middle cerebral and umbilical arteries, and in a study of 400 women and their offspring showed that the C-U ratios were significantly lower in those who subsequently required emergency caesarean sections (C/S) than in the group delivering by normal vaginal delivery.  A ratio below the 10^th percentile was associated with a 6-fold greater risk of C/S than if the ratio was at or above the 10^th percentile, and a ratio above the 90^th centile was protective against foetal compromise. In another study involving 589 subjects, umbilical venous flow rates were significantly lower in fetuses that were delivered by emergency C/S for presumed foetal compromise (Relative Risk 2.83: CI 1.16-6.91). These studies were carried out in healthy women in whom foetal growth had been normal, and the objective was to identify predictors of foetal compromise during labour where no previous risk factors had been identified.  Any paediatrician who has been involved in medicolegal cases involving cerebral palsied children will know that the essence of the debate goes around what should or should not have been done by the attending staff in order to avoid or prevent cerebral hypoxia, hypoxic ischaemic encephalopathy and subsequent CP.  The research addressed here focuses exactly on such fetuses and children, making the point that in many pregnancies placental function is sufficient to allow growth, but may not be adequate to withstand the demands of labour, during which uterine contractions may be associated with a 60% decline in uterine blood flow.  The C-U ratio evidence strongly suggests that among appropriately-grown fetuses there are some with evidence of cerebral redistribution similar to that seen in growth restricted fetuses. There is also evidence that such redistribution is an adaptive response to sub-optimal placental function and occurs prior to obvious deterioration in growth velocity. To protect fetuses with sub-clinical risk for compromise during labour, researchers from Australia are preparing for the “Reducing the risk of fetal distress with sildenafil study” (RIDSTRESS) in which women planning vaginal delivery with appropriately-grown singleton pregnancies at 37+ weeks will have foetal ultrasound and Doppler studies and will be given sildenafil or placebo.  The drug has been used safely in pregnant women with pulmonary hypertension and in management of pre-eclampsia, and ex vivo and animal studies have demonstrated that sildenafil (a phosphodiesterase 5 inhibitor) improves uteroplacental blood flow through its vasodilatory effects on uterine and umbilical arteries. The primary objective is to determine whether the drug reduces the rate of emergency C/S for foetal compromise.  While the results may ultimately be extremely exciting, one has to wonder how they would affect clinical care since routine vascular studies in uncomplicated deliveries are unlikely, as would be the routine administration of sildenafil to all women expecting a normal birth.

Read more:

J Transl Med 2016; 14:15

Am J Obstet Gynecol 2013; 208: 124.e1-6

BJOG 2011; 118: 624-8     

1605 Toxicity of short- course oral corticosteroids in children

Both the relative safety of corticosteroids and clinical experience over several decades have led to a level of comfort when the decision is made to administer the drug.  Admittedly clinicians have concerns when prescribing high-dose, long-term steroids, but such concerns reduced when standard or low doses are used for short periods, and when inhaled formulations are used rather than oral, but how comfortable should one be in the case of short-term oral administration?  In a recent report, adverse drug reactions (ADRs) after a short-course of oral steroids were found in 565 subjects in a systematic review and meta-analysis of 38 studies involving 3200 children between 1-month and 18 years of age. More than one adverse reaction occurred in many cases so that the final number of ADRs was in fact 850.  A short course was defined as one administered for ≤14 days, and the reasons for treatment included asthma, bronchiolitis, croup, acute renal failure, allergic rhinitis, dengue fever, infantile spasms, nephrotic syndrome, acute leukaemia, idiopathic thrombocytopaenic purpura and systemic lupus erythematosus.  The most frequent ADR was vomiting (in 5.4%), which was more common with prednisolone than with dexamethasone and was the commonest reason for withdrawal of the medication. Presumably such vomiting is a local gastrointestinal response to the drug, in which case one should add other GIT ADRs such as nausea (in 1.9% of cases) and abdominal pain (in 1.3%). However one cannot add the three percentages for an incidence of 8.6% because some of these ADRs coexisted.  Disturbances in behaviour were second to vomiting (4.7%) and included anxiety, hyperactivity and aggressive behaviour, all of which were more common with higher than with lower doses of prednisolone.  Sleep disturbances were next at 4.3%, and if as above one regards this ADR as a behavioural effect, the incidence climbs towards 9%.  While infection occurred in only 0.9% it was regarded as the most important side effect with 3 children contracting varicella zoster infection. One of these died and two were admitted to ICU.  In those studies that measured blood pressure there was an elevation in 39%, while where hypothalamic-pituitary axis suppression was measured it was found in 81%, and where followed up, returned to normal in 10-12 days after cessation. So overall, perhaps not too much to worry about ,but certainly worthy of consideration and awareness when one is presented with a situation that warrants the treatment.

Read more:

Arch Dis Child 2016; doi:10.1136/archdischild-2015-309522

Clin Endocrinol (Oxf) 2015; 82: 648-56

Pediatr Dermatol 2008; 25: 484-6

1606 Musculoskeletal abnormalities in congenital diaphragmatic hernia (CDH) survivors

Summary 1506 discusses CDH and oesophageal atresia ± fistula in the context of surgical approach i.e.  conventional vs. endoscopic ‘minimally-invasive’ surgery (MIS).  Pros and cons of the procedures are discussed and one of the stated pro’s of MIS is a better cosmetic result including less in the way of chest deformities and scoliosis.  A recent article from Japan reviews the musculoskeletal outcomes after 1.3 to 7.6 years for 159 survivors of CDH surgery carried out in 9 high-volume centres. Survival rate after surgery was high at 79.8%, and features of treatment included open surgery in all, gentle ventilation/‘permissive hypercarbia,’ nitric oxide administration in 66%, extracorporeal membrane oxygenation in 5.7%, and patch repair in 35.4%. Just over 80% were diagnosed antenatally.  The objective of the research was to identify predictors of three different types of musculoskeletal deformity: scoliosis, pectus excavatum and chest deformity. Predictors of interest included factors such as size of defect, liver herniation and position of the stomach, and also Apgar scores, best oxygenation index after 24 hours, duration of mechanical ventilation and dependence on oxygen at discharge. Scoliosis (after exclusion of cases with congenital scoliosis) was observed in 12.6%, pectus excavatum in 11.9% and chest asymmetry in 7.5%, with scoliosis sometimes occurring in combination with one of the others.  Whereas the authors found factors such as reduction in oxygenation index within 24 hours of birth to be predictive of scoliosis, and low Apgar scores at 5 minutes to predict pectus excavatum, and suggest that each musculoskeletal abnormality has its own specific predictors, it is far more likely that the various metabolic and respiratory ‘predictors’ are related to severity of the condition at birth and that the severity at birth influences the longer-term outcome. In the longer term it is the physical and mechanical factors such as relatively small size of the thorax on the affected size, excessive tension associated with large repairs, imbalanced lung development, increased work of breathing and development of postoperative emphysema on the affected side that will influence the deformities. The study confirms previous work on musculoskeletal residua, some of which has extended into adulthood and shown a need for surgical intervention for the deformities.

Read more:

Pediatr Int 2016; doi:10.1111/ped.12922

Pediatr Surg Int 2011; 27: 1343-9

J Pediatr Int 2010;45: 155-60   

1607 Importance of zinc in very low birthweight (VLBW) infants

It has been established that zinc is a key element for growth and development.  It is one of the most abundant trace elements in humans and is necessary for activity of proteins such as enzymes, membrane proteins, gene-regulators and hormone receptors.  The zinc interacts with the proteins in various ways, promoting enzymatic processes, maintaining quaternary structure stability and/or by enhancing interactions with other molecules.   Insufficient zinc during embryogenesis may impact on organ development, and maternal zinc restriction during pregnancy may influence foetal growth.  Preterm neonates are at particular risk as a consequence of low body stores due to reduced time for placental transfer, increased endogenous losses and marginal intake.  An Italian review of literature covering the role of zinc in early life identified 81 relevant studies, and results showed that preservation of zinc balance is important for avoidance of pre- and postnatal consequences.  Typical signs of zinc deficiency in newborns include dermatitis and growth impairment, but zinc status in the first few weeks of life may influence the occurrence of other pathological conditions. On the growth issue one needs to ensure that enteral and parenteral nutritional sources contain adequate zinc.  While the role of zinc has been studied in the context of intestinal function and also dysfunction, the clinical effects of zinc on the neonatal intestine remain relatively unexplored despite several experimental models and clinical evidence suggesting a role for zinc in the pathogenesis of necrotizing enterocolitis (NEC).  Zinc modulates the expression of cytokines and their receptors in models of colitis, has trophic effects on the mucosa, and modulates intestinal permeability. Importantly, zinc deficiency appears to worsen asphyxial damage due to reduced antioxidant activity. Limited available data suggest that in a randomized controlled study, zinc supplementation to ~100 VLBW neonates significantly reduced morbidity, NEC and mortality vs. the controls.  Neurologically, zinc regulates the expression of neurotrophic factors that reduce insult-induced apoptosis and promote neuronal regeneration. VLBW infants are at risk of hypoxic brain damage and severity of the damage may be influenced by activity of zinc-dependent metallothioneins and through the possible role of zinc in modulation of cerebral vascular tone. In the neonatal lung zinc may be important in the context of bronchopulmonary dysplasia through its role in reduction of oxidative damage, remodeling action of metalloproteinases, promotion of epithelial development and protection against infection, however clinical studies are again lacking in this area.

Read more:

Nutrients 2015; 7: 10427-10446

Autoimmun Rev 2015; 14: 277-85

Am J Clin Nutr 2013; 98: 1468-74

1608 Is the low carbohydrate high fat (LCHF) diet appropriate for infants and children?

The saying that ‘the jury is still out on this one’ can literally be applied to this question as the Health Professions Council of South Africa continues its investigation into Professor Tim Noakes’ advice to a mother on social media that “the key is to wean the infant onto a LCHF diet”. Not entirely surprising, the response on the part of many professional dieticians was to question the dogma of “the key.”  In fact one might question the total strategy employed in the propagation and dissemination of the Noakes/Banting diet, whether for adults or for children. Granted there was never any suggestion that this was a Noakes invention, and in fact he was simply basing his recommendations on studies of other scientists and on the often questionable link between high fat intake and pathological circulating lipid levels. His enthusiasm appears to have related to personal experience and eagerness to share with victims of incipient or established metabolic syndrome. But perhaps there was a place for more in the way of scientific and collegial discourse before exposure in the media and the publication of recipe books for adults and children.  On the other hand, even with a scientific approach to promotion of a low carbohydrate diet, a recent report from Sweden shows that many doctors, nurses and dieticians were wary of the option. In fact only 47% of >250 participants recommended the low carbohydrate diet following dissemination of an evidence-based national guideline advocating low carbohydrate diets as an option for obesity treatment even in the absence of diabetes.  The most commonly reported concern was that the long-term effects are unknown. Some of the reluctance probably also comes from the evidence that while the low carbohydrate diet achieves more weight loss in the short term than a low fat diet, over the longer term it makes little difference whether an individual who is adherent and committed to weight loss is on a low carbohydrate, low fat, high protein, low glycaemic index or Mediterranean diet. The Noakes/Banting diet that is being punted in South Africa is in the ketogenic range of <10% of energy from carbohydrates.  In this regard Noakes has co-authored a number of research papers that contribute to the literature promoting a LCHF diet for athletes. But while potentially beneficial to burn fat rather than carbohydrate during exercise, is the ketogenic diet good for normal infants and young children? The literature that is available on the latter topic is obviously biased towards subjects in whom the diet has been prescribed for therapeutic reasons e.g. intractable epilepsy. This introduces confounding variables, but where growth has been measured it is often/usually below the norm, although possibly as a result of inadequate attention to total caloric and/or protein intake.

Read more:

BMC Nutrition 2016 doi 10.1186/s40795-015-0042-6

Dev Med Child Neurol 2014; 56: 898-904

J Child Neurol 2014; 29: 1496-1501         

1609 Consequences of foetal exposure to valproate and its derivatives

During December of 2015, drug manufacturers in collaboration with the Medicines Control Council issued a notice advising against the use of valproate or its derivatives in female children, female adolescents, pregnant women and women of childbearing potential for any indication other than epilepsy not effectively controlled by other medicines with less risk of toxicity. If continued use is necessary it should be at the lowest possible dose.  In considering such notices to the medical profession it is always interesting to review the literature and examine the delay between the publication of data citing adverse events, and the formal emergence of warnings against drug use. In the case of valproate, reports of congenital abnormalities appeared in the 1980’s but from a broader Cochrane review from 2014 and a recent review in the Lancet Neurology journal, it appears that the analysable evidence covering congenital abnormalities and psychoneurodevelopment has emerged over the past decade. Notably, the South African authorities were not far behind European agencies and the European Academy of Neurology in publishing the alert and recommendations. Valproate is a powerful neuroactive drug with a number of actions including potentiation of GABA transmission , reduced release of beta-hydroxybutyric acid, inhibition of NMDA-receptor-mediated excitatory transmission, blockade of sodium and calcium channels, and modulation of serotonergic and dopaminergic neurotransmission.  These diverse actions explain both its anti-seizure effects and use in other situations such as mood disorders and migraine. On the other hand its many actions are likely to account for its wide diversity of adverse effects.  While the drug alert advocates against use in female children and adolescents and this might be interpreted as valproate having a future effect on reproductive outcome, there does not appear to be evidence for an effect on maternal genes, so the warning appears to relate more to avoiding the drug and long-term dependence by resorting to alternative treatment wherever possible.  Specific problems that have been linked to valproate include spina bifida, craniosynostosis, cleft palate, hypospadias, atrial septal defect and polydactyly, with a risk that is 2-7 times greater than with other antiepileptic drugs The risk increases with higher dosages and if there is a history of congenital malformation in a previous child.  There are also significant risks of lower IQ (by ~10 points) and poorer cognitive outcomes (again dose-dependent). Risks of autism spectrum disorders and attention deficit hyperactivity disorder have also been reported.

Read more:

Lancet Neurol 2016; 15: 210-18

Neurotoxicol Teratol 2016; 54: 5-14

Cochrane Database Systematic Rev 2014 CD010236          

1610 Adverse outcomes after assisted reproduction (AR)

It has been known for some time that assisted reproduction (AR), whether by standard in vitro fertilization (IVF) or intractytoplasmic sperm injection (ICSI) is associated with an increased risk of congenital abnormalities. These include hypospadias, septal defects, cleft lip ± cleft palate and gastrointestinal atresias.  Abnormalities of imprinting associated with syndromes (Beckwith-Wiedermann, Angelman and maternal hypomethylation syndrome) are also seen, specifically after ICSI. Overall risk appears to be twice that of normally-fertile couples.  To that risk it appears that one should now add risks of leukaemia, Hodgkin’s lymphoma, and a requirement for early intervention programmes for offspring of AR pregnancies.  While some researchers have found increased risks of leukaemia, central nervous system (CNS) tumours, hepatoblastomas, retinoblastomas, and neuroblastomas  (some of which could be related to imprinting syndromes), many studies fail to detect an association between AR and childhood cancer risk. In a study based on the Medical Birth Registry of Norway which contains individual information (including AR) on all children born between 1984 and 2011, cancer data were obtained and cross-correlated with the Cancer Registry of Norway. Follow-up started at date of birth and ended on the date of the first cancer diagnosis, death, emigration or end date of the study. A Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of overall cancer risk between children conceived by AR and those not. The study cohort comprised 1 628 658 children, of which 25 782 were conceived by ART. Of the total 4554 cancers, 51 occurred in ART-conceived children. Risk of overall cancer was not significantly elevated (HR 1.21; 95% CI 0.90–1.63). However, increased risk of leukaemia was observed for children conceived by AR compared with those who were not (HR 1.67; 95% CI 1.02–2.73). Elevated risk of Hodgkin's lymphoma was also found for AR-conceived children (HR 3.63; 95% CI 1.12–11.72), although this was based on small numbers. While the association appears to be strong, what is not clear is whether abnormalities are related to the ‘mechanics’ of AR or to the underlying cause/s of the sub-fertility/infertility.  In another study the prevalence of Early Intervention (EI) enrolment in Massachusetts compared singleton children conceived via AR with children born to mothers with indicators of subfertility but no AR (Subfertile), and children born to mothers who had no indicators of subfertility and conceived naturally (Fertile). The odds of EI enrolment were 27% higher among the AR group (odds ratio 1.27; 95% confidence interval (CI): 1.19 ̶ 1.36) and 20% higher among the Subfertile group (odds ratio 1.20; 95% CI: 1.12 ̶ 1.29) compared with the Fertile group, even if the rate of preterm birth was held constant.  As stated for the haematological abnormalities, what is not clear is the extent to which AR is responsible vs. the basis of the parental sub- or infertility. While doubled or even trebled, the overall risk of an adverse foetal/neonatal outcome after AR remains quite small, from the data somewhat below 10%.  Nevertheless doctors and other health professionals who discuss AR as a solution to fertility issues must ensure that patients are aware of current research and are able to make fully-informed decisions regarding the risks to which they might be exposing their offspring. 

Read more:

Pediatrics. 2016;137(3):e20152061 and   2016;137(3):e20152007

J Hum Reprod Sci 2012; 5: 244-7

Obstet Gynecol Surv. 2012;67: 566–583

1611 Point-of-care (POC) lactate measurement guides management of septic shock in paediatrics

The value of blood lactate as a predictor of mortality and morbidity in children with sepsis has been established for at least two decades. In a study of children admitted to a paediatric ICU for ‘sepsis syndrome’ or septic shock it was shown that no measures of perfusion at the time of admission discriminated between survival and death, whereas arterial lactate of ≤3 mmol/l at 12 hours had a positive predictive value for survival of 84%.  A more-recent study showed that survivors had mean admission lactate levels of 3.0mmol/l vs. 6.6mmol/l for non-survivors.  Further studies have also shown a relationship between non-survival and admission lactate of >3mmol/l, and a 100% correlation between death in ICU and admission lactate >13mmol/l. Persistently-raised lactate >3 mmol/l (>2 mmol/l in one study) has also been found to be a good predictor of mortality. Whereas lactate was previously considered to be a metabolic waste product of anaerobic metabolism and lone marker of tissue hypoperfusion, it is now regarded as a metabolic fuel reflecting the body’s response to stress.  What has recently added to the literature is an article highlighting a) difficulties in diagnosing sepsis and septic shock in children because they don’t manifest the classical signs shown in adults, and b) the value of handheld POC devices in measuring lactate levels in resource-poor settings.  POC devices have been shown to be accurate, relatively inexpensive to buy and supply with strips, and quick to administer (4 minutes vs. 65 minutes for laboratory estimation in one study).  These advantages permit early and appropriate treatment with fluids and inotropic support if required.  This may reduce mortality as indicated in a study showing that early lactate assessment had a 24% reduction in mortality in the study group vs. a routinely-screened group.  As a LMIC (low-middle-income country) and particularly with a current national focus on improving primary care and emergency services, South Africa would likely do well to consider adding POC lactate estimations to the assessment of infants and children in whom one is considering a diagnosis of sepsis or septic shock.

Read more:

Arch Dis Child 2016, 101: 297-8

Arch Dis Child Educ Pract Ed 2014; 99: 17-22

Intensive Care Med 1997; 23: 684-92

1612 Is H pylori achieving status as a significant super bug?

Beginning some three decades ago, H pylori has been found to be the organism responsible for gastritis, peptic ulcer disease, gastric carcinoma and mucosal-associated lymphoid tissue (MALT) lymphoma. The discovery revolutionised the treatment of acid-related ulcer disease, doing away with palliation using antacids and milk, and abolishing destructive surgery. Suddenly there was the prospect of cure through treatment of the organism with various combinations of antibiotics and inhibitors of gastric acid secretion.  The importance of the discovery was rewarded by the award of the Nobel prize to Barry Marshall and Robin Warren in 2005.  Once the world was aware of the existence and importance of H pylori it was found to be the most common infection worldwide, affecting some 50% of the world’s population.  In developing countries 30-50% of children and 90% of adults are infected and H pylori infection is regarded as a significant public health issue. Despite the high infection rates, <1% develop gastric carcinoma and MALT lymphoma and only 8-10% develop ulcers. In fact many of the remainder of infected individuals remain asymptomatic for life.  On the other hand, this is a unique organism, not only able to withstand the extreme acidity of the stomach but also, through transformation/conjugation, able to pick up exogenous DNA and produce remarkably diverse ‘offspring’ through its genomic plasticity. Not surprisingly, these characteristics also imbue the organism with the capacity to reinfect individuals who have been treated, and to develop resistance to antibiotics.  The challenge is now to defeat the organism in its efforts to gain lifelong ‘gastric residency’.  At this time we not only have first line treatment regimens but also second and third line interventions. The combination of amoxicillin, clarithromycin and a proton pump inhibitor (PPI) is probably the most-prescribed regimen worldwide provided that clarithromycin resistance is <15%. With higher resistance rates metronidazole, tetracycline or bismuth salicylate is recommended.  One may also use higher dosages of the PPI. Second line therapy includes the combination of the latter four agents (metronidazole, tetracycline, bismuth salicylate and a PPI) to which one may add a flouroquinolone.  However resistance to the latter is also emerging and levofloxacin- or moxifloxacin-based therapy may be introduced. Higher dosages used in second line treatment may result in side effects and the need to progress to the next level. This level involves greater use of antimicrobial susceptibility tests and possible use of rifabutin which is usually used to treat tuberculosis. As previously stated, a major problem is that no matter how effective one’s eradication strategy might be, the problem of reinfection remains, possibly with a different and/or more-resistant strain.  While some work has been done in the use of probiotics to increase the efficacy of antibiotics, experts in the field are of the opinion that the answer to the problems of widespread H pylori infection and related morbidity (and mortality) lies in the development of a vaccine, also not an easy task given the diversity of the organism and options of antibody development against whole extracts, flagellar antigens, adhesion antigens or urease.  In this regard, in a randomised and controlled study of a vaccine involving almost 4500 children between 6 and 15 years of age, Zeng et al reported infection in 14 children in the study group vs 70 among controls, an efficacy rate of 71.8%.  no doubt much more about vaccines to prevent infection will be forthcoming.

Read more:

World J Gastroenterol 2016; 22: 3150-7

Lancet 2015; 386: 1457-64

Saudi J Gastroenterol 2009; 15: 201-7 

1613 Antenatal dexamethasone before delivery by elective caesarean section (c/s)

On reading the title of this particular summary one should perhaps ask whether this is about finding a solution to a clinical problem or about compounding what is already regarded as a problem.  Certainly there is literature confirming that the incidence of respiratory distress is higher in neonates delivered by elective c/s than by vaginal delivery (e.g. 36/1000 vs 5.3/1000), with explanations for the excess ranging from surfactant deficiency due to preterm birth to lack of exposure to hormones, and excess lung fluid and transient tachypnoea because the lungs are not subjected to constriction during passage through the birth canal.  Experience within neonatal units is that while such infants are more mature and significantly larger than the usual population of premature infants with respiratory distress, the latter factors do not protect term infants or prevent complications such as pneumothorax if assisted ventilation is necessary. In fact the bigger babies are often worse off because of their greater ability to ‘fight’ the ventilator.  So, if one wants to avoid the problems and protect the infants, is the answer to provide antenatal steroids as is done when women present with preterm labour and there is a need to enhance and advance surfactant production?  A recent article from Egypt makes a case for antenatal dexamethasone administration based on a randomized and controlled study of steroids vs saline in two groups of women, each with 645 participants. Duration of pregnancy ranged from 38-44 weeks in both groups, while maternal ages were similar at ~29 years of age and median parity was 2. The commonest reason for elective c/s in both groups was previous c/s (in ~91% of cases). More control infants were admitted to the high care and neonatal intensive care units (6.7% vs 3.1% to high care and 3.9% vs 1.6% to NICU) with the study neonates being protected against transient tachypnoea to a greater extent than against respiratory distress syndrome.  However at issue here is not how best to prevent respiratory morbidity when babies are delivered by elective c/s, but why obstetricians and mothers are selecting dates for delivery prior to gestation of 39 weeks or onset of labour, both of which have been shown to reduce the risk of neonatal respiratory distress.  There is much evidence that South Africa’s private sector c/s rate is extremely high, in excess of 60%. The overwhelming majority of these are elective deliveries, performed at times that are convenient for doctor, patient and hospital. As such, one should perhaps be cautious about research offering a failsafe or ‘bailout’ options such as antenatal steroids rather than promoting strategies that extend the pregnancy until such time as it is safe or at least safer to perform the c/s. Can nature have got it so wrong that man should intervene surgically and now medically in a majority of apparently normal pregnancies?

Read more:

Eur J Obstet Gynecol Reprod Biol 2016; 199: 88-91

Acta Obstet Gynecol Scand 2007; 86: 389-94

BMJ 2005; 331: 662-4

1614 Brain connectivity network (BCN) charts for tracking attention span and identifying ADHD

Milestones are an important part of paediatrics whether used to assess gestational age, track neurodevelopment, monitor eruption of primary teeth or follow anthropometric indices. Some tools are in graphic form (e.g. growth charts) while others are presented as tables with indications of what should be achieved at given time points.  To this list one may now add normal development of BCNs.  With the advent of resting-state functional neuroimaging it is now possible to develop a charting tool and apply it to maturing functional relationships in the brain which are organized into several intrinsic connectivity networks (ICNs), each associated with distinct neurocognitive functions.  Relationships within and between these ICNs demonstrate clear trajectories of change from childhood to young adulthood. This has allowed researchers to plot normal as well as abnormal development of the capacity for sustained attention (i.e. maintenance of task-directed focus for extended periods of time) in the belief that network growth charting methods may be particularly useful in the diagnosis and assessment of attention deficit hyperactivity disorder (ADHD).  Underpinning this are network models that propose that sustained attention functioning requires engagement of task-positive networks (TPNs) that include the frontoparietal network (FPN) and dorsal and ventral attention networks (DAN and VAN), and also suppression of the default mode network (DMN) which is an ICN that is implicated in introspective attention and mind wandering. ADHD patients show disrupted organization within the DMN and inadequate suppression of this network by TPNs.   In normal subjects, functional connectivity patterns within the DMN and between DMN and TPNs exhibit massive maturation from childhood to young adulthood.  Armed with this knowledge researchers from the University of Michigan carried out neuroimaging on 1000 subjects between the ages of 8 and 22 years during the Penn Continuous Performance Test which consists of 180 trials/stimuli that require sustained attention.  Complete data were available for 519 subjects, 25 of whom were diagnosed with ADHD.  ‘Developmental’ charts (referred to as growth charts by the authors) were developed from the neuroimages for 15 ‘connectomic components,’ 5 of which showed evidence of vigorous maturation over time and together with one other component accounted for almost one-quarter of the variance in age-corrected task accuracy. Any downward deviation from the normative maturational trajectory (i.e. underexpression relative to age) predicted worse outcome.  Such deviations were in general indicative of attention impairment, and for 3 of the components’ maturational trajectories, deviation scores were significantly predictive of ADHD with odds ratios of between 1.7 and 2.0.   The authors write of the charts being used to identify/diagnose attention disorders, but given that ADHD is mostly diagnosable on history and appropriate examination and testing, one wonders whether a more useful application of this research would be in measuring response to treatment or the tracking of deviations over time to see whether patients track towards, parallel to or away from the mean.

Read more:

JAMA Psychiatry doi: 10.1001/jamapsychiatry.2016.0088

Neuroimage 2014; 86: 544-553

Brain Res 2009; 1273: 114-28

1615 Do diabetes camps ‘work’?

This is a question asked and answered in a systematic review of the literature that was carried out by a group of authors from Brazil, Belgium and America. In terms of the history, from the literature cited it appears that various countries established their camps during the 1950s, but in fact the first diabetes camp was in Michigan in 1925.  Since then diabetes camps have spread throughout the world. Published data show >400 camps worldwide (with 185 in the USA: 25,200 campers; and 15 in Canada: 1500 campers; and >30 000 campers in countries in Asia, South America, Europe, Oceania and Africa, the latter quoted as having 5 camps). However one must question the reliability of the published statistics because a quick internet search for South Africa alone brings up three websites with opportunities for diabetics (web.cdediabetes.co.za; www.youthwithdiabetes.com and www.diabetessa.org.za ). But to the question of whether the camps are effective? Most organisers regard camps as an opportunity for diabetes education, involving the sharing of feelings, ideas and knowledge with peers, the provision of emotional and social support, development of self-confidence and sense of belonging, and opportunity to put into practice learned content and new behaviours.  The final goal of all camps is along the lines of empowering individuals to become more independent, autonomous and capable of living full lives.  From the perspective of children and adolescents, camps allow them to participate in recreational activities and socialise with peers with diabetes. Over 90% campers appear to be interested in returning the following year, and almost 100% of parents regard such camps as a good experience for their child. Three points are relevant in terms of the latter comments: firstly it appears that most camps engage diabetics as counsellors; second, family involvement appears to enhance the value; and thirdly, inclusion of healthcare professional is advantageous for both campers and the professionals.  Knowledge about diabetes that is gained by campers (e.g. about self-testing, diet and insulin administration) appears to be retained, with greater gain shown by those who started with low scores, those who attend more than one camp, and where family sessions are part of the programme.  Overall it appears that physiological outcomes such as reduced levels of HbA1c also progress in much the same way as the knowledge variables. Mid- to long term outcomes also suggest benefits of camps in terms of HbA1c levels and ability to function normally, even with complications of diabetes.

Read more:

Diabetes Res Clin Pract 2016; 114: 15-22

Diabetes 1955; 4: 246

Acta Diabetol 2005; 42: 156-61      

1616 Update on otitis media with effusion (OME)

While debates might continue around aspects such as the use of antibiotics and/or grommets in the treatment of otitis media, and the impact of OME on long-term hearing loss and/or speech development, there is no question that OM is a common problem in paediatrics, affecting up to 80% of preschool children at some time.  As such, the condition continues as a focus for research, and was studied and recently reported by Iranian researchers. Since both acute OM and OME are now regarded as infectious diseases, the research compared nasopharyngeal bacteria and antibiotic resistance patterns in tissue obtained at the time of adenoidectomy from patients with and without OME.  All patients had intact tympanic membranes, so access to the middle ear was via the Eustachian tube.  Among the 72 patients studied (30 with OME), 46 had microbial infection (20/30 with OME vs. 26/42; p>0.05).  The most common bacteria were Strep viridans (in 53.3% with OME vs. 71.5% without), Staph aureus in 13.5% vs. 14.4%, H influenza in 6.6% vs. 4.7% and pneumococcus in 0% vs. 4.7%).  Bacterial sensitivity/resistance patterns were also similar.  While defined as the presence of effusion in the middle ear without signs and symptoms of inflammation, the pathogenesis of OME is not completely understood. Eustachian tube dysfunction, poor clearance of middle ear fluid, allergies and genetic predisposition have all been implicated, with increasing evidence of the role played by biofilms.  The authors of the Iranian study state as a limitation of their study the evaluation of bacteria only in planktonic (freely-suspended) and not biofilm form, while from the reverse aspect of negative cultures in OME fluid, other researchers comment that bacteria in OME exist as a biofilm which is “a state of very low metabolic activity, almost a suspended animation.”  Bacteria in this state are resistant to antibiotics but may still elicit an immune response, resulting in the production of the mucin-rich effusion.  Going back to the basics of what biofilms are, they were first observed in the 1940s on tooth surfaces, leading to studies that revealed surface-associated (as opposed to planktonic) micro-organisms that are phenotypically distinct with respect to gene transcription and growth rate.  They elicit specific mechanisms for initial attachment to a surface, development of a community structure and ecosystem, and detachment.  They are fairly ubiquitous, for example found in dental plaque, indwelling medical devices, industrial water piping and natural aquatic systems.  The general definition of a biofilm is an assemblage of microbial cells that is irreversibly associated with a surface, not removed by gentle rinsing, and enclosed in a matrix of primarily polysaccharide material, also known as EPS (extracellular polymeric substance).  All of which is interesting, but still begs the question of why some children develop OME while others do not.

Read more:

Eur Arch Otorhinolaryngol 2016; 273: 859-63

Emerg Inf Dis 2002; 8: 881-90

Clin Otolaryngol 2000; 25: 181-94

1617 Dilute apple juice better than oral rehydration solution (ORS) for mild gastroenteritis

The previous summary covered otitis media which is an extremely common condition. Even more common is childhood gastroenteritis with diarrhoeal disease and dehydration, accounting for up to 30% of infant and toddler deaths worldwide and ~8000 children under 5 dying each day.  Even in the developed United States, children under 5 have an average of 2 episodes of gastroenteritis per year, leading to 2-3 million consultations and 10% of all paediatric hospital admissions. Direct costs of out- and in-patient consultations are estimated at >$2bn per year, and as many as 300 US children die annually as a result of gastroenteritis and dehydration.  South Africa with its large rural and underserved populations is well aware of the ravages of gastroenteritis and dehydration, and clinical assessment of dehydration is taught to all categories of students and graduates, particularly those at the acute, primary care coalface.  The recognition of clinical signs such as depressed fontanelle, decreased tissue turgor and sunken eyes becomes second nature, with little critical attention given to the statistical relationships between positive signs and the presence or degree of dehydration.  In this regard it is worth reviewing a decade-old publication that systematically reviewed the precision and accuracy of symptoms, signs and basic laboratory tests for evaluating dehydration in infants and young children.  The following were evaluated: capillary refill time, skin turgor, tachy/hyperpnoea, sunken eyes, dry mucous membranes, cool extremities, weak pulse, absent tears, tachycardia, sunken fontanelle and overall appearance (e.g. lethargy).  Scoring systems using various combinations of these signs perform better than any one alone, and in general the greater the degree of dehydration, the greater the number of signs and the higher the scores. At lower levels of dehydration (~5%) the most useful individual signs are an abnormal capillary refill time, abnormal skin turgor and abnormal respiratory pattern.  Whereas there is little debate about when and how to treat severe dehydration at ≥10%, there is less clarity about treatment of gastroenteritis with mild dehydration.  In this regard a recent study from Canada randomized 647 children aged between 6 months and 5 years to treatment with half-strength commercial apple juice or commercial electrolyte maintenance solution. Eligible subjects had 3 or  more episodes of vomiting or diarrhoea over the preceding 24 hours, symptoms for less than 96 hours, weight ≥8 kg and minimal dehydration according to the 8-point Clinical Dehydration Scale and capillary refill time of <2 seconds.  Children treated with half-strength apple juice experienced treatment failure less often than controls (16.7% vs. 25%) and fewer children in the study group required intravenous rehydration in the subsequent 7 days (2.5% vs. 9.0%).  The benefit of apple juice over ORS was greatest in older children (>2 years), most likely related to palatability of the juice vs. the ORS.  The applicability of these results to the South African situation may be questioned i.e. would this be affordable? However since it is generally accepted that home-made ORS is potentially hazardous and one is therefore reliant on commercial products, the issue is perhaps whether one administers commercial ORS vs. diluted off-the-shelf fruit juice.

Read more:

JAMA 2016; 315; 1966-74 and 2004; 291: 2746-54

Pediatrics 2008; 122: 545-9 and 1997; 100(5):E3

1618 Should the foetus exposed to alcohol be protected by law?

In a recent article Gardner from the Witwatersrand University’s Steve Biko Centre for Bioethics asks whether drinking during pregnancy should be criminalised in order to prevent fetal alcohol spectrum disorder (FASD). The term FASD is used as a collective, encompassing fetal alcohol syndrome (FAS) which is the most severe form, partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD).  Case reports in the late 1970s from the Cape drew attention to the problem in South Africa, with subsequent studies showing prevalence rates of FAS and PFAS in schoolchildren of around 7%. Recent studies in the Western Cape that include all forms of FASD show rates ranging from 10-20% in schoolchildren.  These are indeed scary statistics, suggesting that we are failing with generally accepted, ethically appropriate and potentially effective responses that assist women. Such responses include education; early identification and referral of women at risk for having an affected child; treatment and rehabilitation facilities catering for the needs of pregnant women; and access to contraception and abortion services. Interestingly, while paediatricians and geneticists were identifying the magnitude of the problem in South Africa, legal minds were also being applied to the question of protection of the foetus. Lupton, in an article some 20 years ago argued that South African law might permit a foetus, via a curator ad litem, to enforce its rights against its mother, thereby enjoying protection against alcohol abuse prior to its birth.  Over the years a number of states in the USA have introduced legislation that allows action to be taken against women who expose their unborn child to drugs or alcohol, but in general a number of views prevail.  These include one that states that the foetus is not a legal person until birth and therefore does not have rights of a person, and another that holds that the law should not accommodate an adversarial relationship between mother and foetus.  Superimpose on these views the important question of where one would draw the line? If drugs and alcohol have the potential to harm the foetus, then what about other potential hazards such as dietary fads or excessive exercise during pregnancy?  So on balance the criminalization of drinking during pregnancy is not an option.  But this does not mean the door is closed for ‘wrongful birth’ claims, for example against a healthcare provider if the mother argues after delivery that she would have chosen to abort the foetus had she been fully informed about the risks.

Read more:

S Afr J BL 2016; 9: 26-30

Wrongful pregnancy, birth and life: www.nortonrosefulbright.com/knowledge/publications/44118                         

 Med Law 1994; 13: 79-94           

1619 Medicolegal claims for wrongful pregnancy, birth or life

The previous summary on whether a foetus exposed to the deleterious effects of alcohol should be protected by the State also introduces important questions around rights of the foetus, mother, offspring i.e. ‘product of the pregnancy,’ and parents. Stakeholders on the other side of the debate include healthcare providers (counsellors, nurses, doctors, hospitals, and even ‘health care systems’). Wrongful pregnancy, wrongful birth and wrongful life are legal concepts with an abundance of literature around all three. Wrongful pregnancy would be argued for example where a man or woman who has supposedly undergone a procedure such as vasectomy or tubal ligation sues a doctor when he/she subsequently produces a child.  An example of wrongful birth was cited in the previous summary i.e. if the woman had been under the care of a counsellor, nurse or doctor during early pregnancy and the healthcare providers were aware of the potential for alcohol-induced foetal damage, following delivery of an affected child the mother could argue that if she’d been fully informed she would have chosen to terminate the pregnancy.  Such an approach would be consistent with the woman’s constitutional right of choice to terminate.  Wrongful life suits are not entertained in South Africa and seemingly not in other countries either. Such suits would typically be filed by the affected child. Courts are unwilling to deal with such cases because they do not wish to address the question of whether death is a better option than a disabled life. The argument is that this existential matter is best left to philosophers and theologians, but it is perhaps also a question of ‘degree’ e.g. as in multiple, disabling congenital abnormalities vs. achondroplastic dwarfism. Would a court be in a position to judge that the life of the achondroplastic plaintiff would be worse than death had s/he been aborted?  In fact such claims were fairly frequent in Israel until 2012, prior to which children could sue for wrongful birth until the age of 25. Using the argument that suing for wrongful life doesn’t only pose legal difficulties but ethical ones as well, the justices determined that such suits could in future only be filed by parents. 

Read more:

Wrongful pregnancy, birth and life: www.nortonrosefulbright.com/knowledge/publications/44118

Haaretz May 29 2012 birth defects

Med Law 1996; 15: 161-73

1620 Coronary artery dilatation in viral myocarditis

It is often debatable whether one should take too much notice of articles that include words such as “to our knowledge this is the first time this association has been reported” i.e. most likely one should await confirmation of results. Additional caution should be exercised when the results are based on small numbers and involve a 10-year review of historical data.  However when the report emanates from highly ranked universities and is published in a credible journal then one should at least bear the information in mind for possible future reference. The above comments come into consideration in a report on 14 cases of viral myocarditis in children in which definite coronary artery dilatation was found in 3 (z-scores ≥2.5) and “occult” dilatation was observed in another 6 (z-scores ≥2 on different days but ˂2.5).  KD was excluded in all patients, and while viral infection was not evident in all cases, there was definite myocarditis on clinical, electrocardiographic and biochemical grounds.  Of interest is that 8 of the children received intravenous immunoglobulin. The authors regard their apparently unique findings as reportable because of the possible overlap of coronary artery pathology in viral myocarditis and Kawasaki Disease (KD), particularly in small children in which the clinical picture of KD may be incomplete and one might make an incorrect diagnosis of KD and possibly embark on inappropriate treatment.  Mean age at presentation for the children studied was 1.67 ± 3.22 years, with 11 presenting with acute and 3 with sub-acute viral myocarditis.  The two conditions are not regarded as variants of the same disease process or spectrum e.g. at the level of the myocardium there are differences such as neutrophil infiltration predominating in KD whereas lymphocytes are dominant in viral myocarditis, and the cardiac prognosis for ‘coronary-involved’ KD (particularly untreated) is significant. Echocardiography was performed between 1 week and 1 year, and in some cases beyond. The coronary artery dilatation occurred within the first 8 days.  At last follow up at 12.5 ± 9.5 months the z-scores had returned to normal in all patients, which is prognostically more favourable than in KD with coronary artery involvement. So bottom line is less about being concerned that (viral) myocarditis and KD may have similar coronary artery outcomes and more about being aware that coronary artery dilatation may be seen with viral myocarditis and is not diagnostic of KD. 

Read more:

Pediatr Cardiol 2016 doi 10.1007/s00246-016-1411-x

J Am Soc Echocardiogr 2012; 25: 859-65

Circulation 200; 110: 2747-71 

1621 Outcomes for very low- and extremely low birthweight infants in Africa

A ‘flip-side’ to the recent summaries on the issues of wrongful pregnancy, life and birth (1618, 1619) is the extent to which healthcare providers should be considering the consequences of active interventions in high-risk situations such as preterm delivery of very low (VLBW <1,5kg) and extremely low (ELBW <0.5kg) birthweight infants. Decisions as to when and how aggressively one should treat must be informed by evidence of the outcomes of interventions, and ideally long term outcomes, not only short term measures such as early mortality or survival to discharge. Furthermore, the outcomes should be context-specific i.e. one cannot automatically take first-world outcomes as a justification for aggressive intervention in a third world environment in which resource constraints impact not only on the services provided to mothers during pregnancy but also on services during delivery and to the infant postnatally.  In this regard one should note a recent paper authored by researchers from Brazil and Mozambique which systematically reviewed literature from 2008-2015 for mainly sub-Saharan African VLBW and ELBW infants.  The restricted publication dates to some extent deals with the issue of changes in treatment strategies over time i.e. there is little point in comparing a pre-surfactant cohort with one treated in recent times.  An initial search of databases yielded ~1700 papers of which 12 were ultimately considered for analysis.  As always, final inclusion of articles for analysis was limited by the quality, sample sizes and/or lack of homogeneity in the studies, once again begging the question of why there is so little in the way of collaborative research in Africa, whether national between centres or regional (i.e. sub-Saharan Africa)?  The outcomes of interest were growth, neurodevelopment and under-5 mortality but the lack of data make it difficult to draw definite conclusions other than low gestation and low birthweight are inversely proportional to short-term mortality and developmental delay, and directly proportional to growth, body weight and length ‘regain’, and catch-up growth.  These are relatively intuitive and unhelpful findings and the authors comment on the extreme lack of African studies into long-term growth and development in such infants. The region is not short of eligible subjects, but is deficient in terms of research.  Importantly the authors also discuss the difference between catch-up growth in appropriately-grown vs. ‘growth retarded’ infants in which rapid catch-up may have a positive effect on neurodevelopmental outcomes but may increase the risk of childhood and adult obesity and subsequent metabolic disease (see summary 1603).

Read more:

J Dev Origins Health Dis, 2016 doi: 10.1017/S2040174416000131

Int J Epidemiol 2013; 42: 1215-22

BMC Pregnancy Childbirth 2012; 12, 1

1622 More on the relationship between foetal growth and ‘lifestyle’ diseases

Followers of this series of literature reviews will have noted that several relate to the relationship between the effects of maternal health on the foetus and its subsequent growth and development. For example summary 1501 comments on maternal Body Mass Index (BMI) and subsequent metabolic disease in offspring; 1502 looks at optimal growth trajectories for ‘small-for-gestational-age’ (SGA) infants, and 1603 notes the fairly recent evidence for the occurrence of early obesity that appears to be related to inappropriate feeding in children born SGA.  Epidemiological studies have related specific events such as periods of national famine (as in the Netherlands, China and Ukraine) to impaired foetal growth and subsequent development of type 2 diabetes, and the oft-cited Barker hypothesis links impaired foetal growth to constitutional renal and pancreatic consequences that result in insulin resistance and hypertension in later life.  The literature has focused mainly on the ‘nurture’ aspect of any ‘nature vs. nurture’ debate around the sequence of events i.e. environmental issues compromise the foetus and the body responds in a particular way.  However a body of literature is emerging that indicates that one should also consider ‘nature’ and a role for genetics in any discussion around the foetal origins of adult disease. For example in 2013 international collaborators reviewed population data on almost 70 000 subjects of European descent and found genomic loci linking low birthweight to subsequent type 2 diabetes, but also found several loci that affected prenatal growth as measured by anthropometry at birth, other genetic links between birthweight and adult blood pressure, and links between lower birthweight and adult height. A genetic link has also been found between higher birthweight and subsequent type 2 diabetes.  While such associations have been noted in epidemiological studies and are not new, the recent information shows that in some cases the relationships are genetic and not the result of the foetal milieu.  In another study based on two long-standing cohorts, the Nurses’ Health Study and the Health Professionals Follow-up Study, investigators reviewed data for 5928 males and 10 673 females with available genotype data.  Type 2 diabetes was confirmed in 3627 (i.e. 12 974 without diabetes). Birthweight was available for the subjects and a genetic risk score (GRS) was calculated for four birthweight categories based on frequency of five single nucleotide polymorphisms (SNPs) that had been shown to be associated with low birthweight. The GRS ranged from 0-10 within the subjects and there was a dose-related  association between the GRS and birthweight with each 1-point increase in GRS associated with a 6% higher risk of type 2 diabetes.  Lifestyle risk factors such as lack of exercise, BMI, alcohol and smoking were assessed and were similar across the range of genetic risk scores. Mendelian randomization showed an almost three-fold risk of type 2 diabetes per standard deviation lower birthweight. These results indicate that in addition to environmentally-induced intrauterine growth restriction and subsequent metabolic disease there are instances in which low birthweight and subsequent type 2 diabetes are genetically determined.

Read more:

Diabetologia 2016; DOI 10.1007/s00125-016-4019-z

JAMA 2016; 315: 1129-40

Nat Genet 2013; 45: 76-82

1623 Bariatric surgery for obese adolescents with type 2 diabetes

The emergence of non-communicable diseases in adolescence receives particular attention in the June edition of the South African Medical Journal and healthcare providers are urged to be cognizant of the problem.  Once again there is an emphasis on overweight and obesity and the attendant risk of type 2 diabetes. South African statistics for 2013 showed that overweight and obesity occurred in 18.8% of males and 26.3% of females before the end of the second decade of life. Physical inactivity and consumption of calorie-dense foods are regarded as key contributors to the ‘epidemic’ but cultural factors and genetics also come into play. In terms of the risk of diabetes, figures from the US, UK, India and Japan demonstrate the dramatic change in type 1 vs type 2 disease among adolescents. For example in the US, 25 years ago type 2 accounted for ~4% of new diagnoses whereas now at least 50% of new cases of teenage diabetes are type 2. Similar rates have been reported in India whereas in Japan type 2 is diagnosed twice as frequently as type 1 in teenagers. Aggravating the situation is the fact that the progression of disease appears to be far more aggressive among the youth, who develop comorbidities at a faster pace than type 1’s, and also appear to lose beta-cell function more rapidly than adults despite medical management.  The latter results were observed in the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) in which time to treatment failure was measured in three groups receiving metformin alone, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Failure (defined as HbA1c of >8% for 6 months or a requirement for insulin therapy) was observed in 40-50% of the subjects, and beta-cell function declined by 20-35% per year vs a reported rate of 7-11% per year in adults.  Cardiovascular and renal complications also progressed rapidly in the TODAY study in cases with BMI of ~35, for example hypertension prevalence trebled over 4 years from ~11% to 34% and microalbuminuria increased from 6 to 17% over three years of treatment.  The cornerstone of medical management in obese youth with type 2 diabetes is lifestyle intervention that includes diet and exercise, but in most cases adjunctive pharmacotherapy is ultimately required.  Bariatric surgery has been under investigation for some time in the Teen-LABS study (Teen Longitudinal Assessment of Bariatric Surgery) and results showed a 31% weight reduction after 1 year with only modest regain by years 2 and 3.  BMI loss was between 15 and 17 kg/m² between 1 and 5 years.  Hypertension remitted in 74%, dyslipidaemia in 66% and abnormal renal function in 86%.  Surgical complications include requirement for cholecystectomy, anastomotic strictures, reoperation and leaks, and nutritional deficiencies may also occur (vitamin D, B₁₂ and ferritin). So the procedure is not to be undertaken lightly and strict criteria for eligibility must be applied e.g. BMI >120% of the 95^th centile for age and sex. Also of note is that in a recently-presented comparison of the TODAY vs the Teen-LABS cohorts (63 vs 30 matched subjects) HbA1c increased over time in the former while declining among the latter, and BMI increased for the TODAY subjects while decreasing by 28% in the Teen-LABS group. Again, these results need to be seen in the context of rehospitalistion rates between the groups (5 vs 33% within 2 years), but surgery may well be here to stay as a treatment option for eligible patients.

Read more:

S Afr Med J 2016; 106: 662-5

Diabetes Care 2016; 39: 934-940

DG News docguide.com bariatric surgery June 17 2016

1624 On dysbiosis, transfaunation and ecotherapeutics

Not surprisingly, typing the above words results in Microsoft Word alerting one to the fact that these are not recognizable terms. However they all relate to a German quote that goes back at least 150 years when Ludwig Andreas Feuerbach wrote in an essay titled Concerning Spiritualism and Materialism that "Der Mensch ist, was er ißt." Translated this means Man is what Man eats.  We have all heard this saying in the context of numerous diets and lifestyles, but it is now coming to the fore in the context of the human biome or microbiome, and in paediatrics particularly in the context of the altered gut microbiome that follows delivery by caesarean section (c/s).  In this regard there is concern that failure to expose the neonate to the appropriate organisms that colonise the maternal genitourinary and alimentary tracts has consequences such as the development of obesity, asthma, atopy, inflammatory bowel disease and immune deficiencies.  Epidemiological associations between c/s and the various conditions have been found, resulting in endeavours to reduce the rate of elective caesarean sections and also initiatives to colonise babies with maternal organisms.  The latter has been popularised in the overseas media, leading to women requesting post-delivery ‘vaginal seeding’ which involves swabbing the baby with gauze that has been seeded by placement in the vagina prior to delivery. While there are data showing that this procedure results in vaginal microbes being partially restored in the short term, a recent editorial in the BMJ advocates against ‘seeding’ and denying women’s request to do so. The view is that too little is known about the subject, vaginal flora may contain pathogens, and alimentary and/or placental organisms may also be of important in the process of normal colonisation.  While infants born by c/s represent a significant population, one should also consider those born prematurely who might spend weeks or even months in the neonatal ICU and who are not only denied maternal contact but are also exposed to antibiotics, nosocomial infections and invasive instrumentation and procedures. All of these result in ‘dysbiosis’ which is defined as a state of imbalance in the gut microbial system with growth of some organisms and loss of others.  Perhaps the major focus of interventions in this population has been on prevention of necrotising enterocolitis by means of ‘transfaunation’ or introduction of organisms in the form of probiotics.   These concepts are discussed in a review by Grady and co-authors, not only going into probiotics which introduce desirable organisms, but also prebiotics which stimulate growth of existing organisms but are not particularly helpful if the gut is colonised with the wrong organisms. Ecotherapeutics refers to both FMT (fecal microbial transplant) which is from a screened and healthy donor to the host, and MET (microbial ecosystem therapeutics) which involves laboratory preparation of a ‘designer’ set of organisms. Both FMT and MET have found a place in the treatment of adults and children with Clostridial infection but have not been studied in neonates.  Bottom line is perhaps that while there are the concerns about infants and children delivered by c/s, surely the microbiomes of ‘ex-prems’ are far more disturbed, and do they therefore have similar risks for asthma, allergy, auto-immune conditions and irritable bowel disease?

Read more:

Nature Med 2016; 22: 250-3

BMJ 2016; 352: i227

Semin Fetal Neonatal Med 2016 http://dx.doi.org/10.1016/j.siny.2016.04.005        

1625 Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR)

A brief review of the literature covering ER stress and the UPR reveals that this is a field of interest that has occupied the minds of researchers in a number of fields for the past one-and-half decades. Adult onset metabolic disease, cancer and neurodegenerative conditions have come under the spotlight, while in the field of paediatrics articles have appeared covering congenital heart disease and foetal growth restriction and also enhanced foetal growth associated with gestational diabetes. Much of the interest lies in the possibility of targeting elements of or steps in the UFP in order to modulate or prevent disease. With the help of ‘chaperone proteins’ one third of all human proteins are folded inside the ER which also contains other protein-based factors that ‘quality control’ the various folded proteins. Those proteins not meeting the required standard are ‘referred’ for degrading and, under circumstances in which unfolded or misfolded proteins accumulate, the ER becomes stressed. This activates signaling pathways that collectively result in the UPR which attempts to restore ER homeostasis. Three pathways are involved, the first aims to reduce the burden of new proteins entering the ER lumen, the second enhances protein-folding capacity by increasing ER chaperone proteins, while the third promotes degradation of the remaining unfolded or misfolded proteins. If/when ER function is severely impaired, apoptosis is induced to eliminate damaged cells. In the context of intrauterine growth restriction, researchers from the UK, Switzerland and Italy hypothesized that abnormalities in the maternal spiral arteries supplying the placenta leads to repetitive low-grade ischaemic-reperfusion injury which in turn generates reactive oxygen species, depletes intracellular ATP and induces ER stress in the placenta. The researchers obtained both biochemical and cytological evidence of ER and inhibition of both placental protein synthesis and cellular proliferation. In addition the authors postulate that the intracellular damage may account for the increased microparticulate debris found in the circulation of patients with conditions such as pre-eclampsia, which may also lead to endothelial cell activation and impaired placental development.

Read more:

eLife 2016;5:e18431

J Clin Investig 2002; 110: 1389-98

Am J Path 2008; 173: 451-62

1626  Endoplasmic reticulum (ER) stress in gestational diabetes mellitus (GDM)

Gestational diabetes mellitus is a subtype of diabetes that arises de novo late in the second trimester or early in the third trimester of pregnancy. It represents a global health challenge, affecting up to 18% of pregnancies. Predisposing factors include maternal obesity, metabolic dysfunction and genetic susceptibility. Decreased insulin sensitivity and inadequate insulin secretion are two common causative factors. Women with GDM are at increased risk for complications such as pregnancy-induced hypertension and an increased lifetime risk for type 2 diabetes. For the foetus and offspring, GDM poses an increased risk of stillbirth, perinatal complications, macrosomia or growth restriction, and subsequent predisposition to type 2 diabetes, obesity and metabolic and cardiovascular diseases.  Pregnancy is a diabetogenic state due to changes in the endocrine regulation of maternal carbohydrate and lipid metabolism which elevate circulating blood glucose to meet foetal demands. Consequently, maternal organs and peripheral tissues are adapted for glucose intolerance and insulin resistance. As pregnancy advances, the placenta drives the maternal metabolic adaptations through secretion of polypeptide hormones, growth factors, cytokines and adipokines that modulate maternal metabolism and fetal growth. For example human placental lactogen and prolactin induce beta cell expansion in the maternal pancreas, while human placental growth hormone and adipokines cause peripheral insulin resistance. In normal pregnancy these factors redistribute maternal energy resources, increasing their availability for the foetus. However, perturbation of placental function potentially disrupts their bioactivity, altering the normal balance of maternal metabolism and resulting in GDM.  As an ‘organ’ with high polypeptide endocrine activity the placenta is susceptible to ER stress, so any disturbance of the ER environment can severely affect the bioactivity of secreted proteins through activation of the unfolded protein response (UPR). Research on the role of ER stress in human diabetes has advanced rapidly, and therapeutic ‘targeting’ to ameliorate ER stress has become a focus of research. In this regard researchers from the UK, Norway, Brazil and Germany have provided biochemical evidence of stress and dilatation of ER cisternae in placental tissue, and an in-vitro model of GDM. Furthermore, challenge of the model with high glucose activated the biochemical pathways of ER stress.  Addition of chemical chaperones or vitamins (E or C) ameliorated the response, again suggesting that ER stress and its consequential UPR may be amenable to therapeutic interventions.

Read more:

Diabetologia 2016; DOI 10.1007/s00125-016-4040-2   and DOI 10.1007/s00125-016-4048-7

eLife 2016;5:e18431

Expert Opin Ther Targets 2015; 19: 1203-18  and  2013; 17: 437-8

1627 Breastfeeding: A key to sustainable development

The title of this summary is how the WABA (the World Alliance for Breastfeeding Action) announced World Breastfeeding Week which ran from 1-7 August 2016 and which WABA linked to the 17 Sustainable Development Goals (SDGs) announced in 2015.  These SDGs are broadly aimed at ending poverty, protecting the planet and ensuring prosperity.  Breastfeeding is stated to be the cornerstone of a child’s health development as well as the foundation of a country’s development, and WABA links breastfeeding to all 17 SDGs ranging from zero hunger, to good health and wellbeing, gender equality, peace, justice, industry innovation and marine life!  Considerable support to the initiative to promote breastfeeding comes from a Lancet series published earlier this year, with one of the articles focusing on epidemiology, pathophysiology and lifelong effects of breastfeeding.  Outcomes of interest in children included mortality, gastrointestinal and respiratory infections, allergies, growth, and dental malocclusion, and in adolescents and adults included blood pressure, overweight and obesity, cholesterol, type 2 diabetes, and breast and ovarian cancer.  The authors reviewed data from 28 meta-analyses and systematic reviews and conclude that scaling up breastfeeding to near-universal levels could prevent 823 000 annual deaths in children younger than 5 years, and 20 000 annual deaths from breast cancer.  These impressive survival statistics are based on well-established relationships between breastfeeding and protection against infections in the first two years of life (mostly in LMIC’s i.e. low- and middle-income countries), and protection against breast cancer in women who breast feed for extended periods of time.  Benefits of breastfeeding are also seen for IQ (some 2-3 points higher), otitis media (fewer infections in under-two’s), malocclusion (during primary dentition phase), sudden infant death during the risk period) and necrotizing enterocolitis (fewer cases in high-income country studies). However relationships are weaker for effects on growth and subsequent blood pressure, type 2 diabetes and ovarian cancer.  Breastfeeding rates are typically higher in LMIC’s, but in high-income countries, while breastfeeding rates are generally low, the better-educated breastfeed more commonly than the less-educated.  On the other hand, an interesting feature of the analysis is the very strong inverse relationship between breastfeeding at 6 months and gross domestic product (GDP). For each doubling of GDP, breastfeeding prevalence at 12 months decreases by 10 percentage points.  Certainly for high income countries this flies in the face of an argument that breastfeeding results in smarter and healthier children and adults and greater national productivity, although one must acknowledge that high income countries suffer from an increasing burden of non-communicable diseases, so high GDP does not automatically equate with population well-being and sustainability.

Read more:

2016 worldbreastfeedingweek.org

Lancet 2016; 387: 475-90

Pediatrics 1984; 74: 579-762

1628 Why the difference in HIV transmission between exclusively-breastfed and mixed-fed infants?

 The short answer to the above question is that we don’t fully understand why HIV-exposed infants exclusively breastfed for 6 months are protected when compared against infants fed a mixed diet of breast milk plus artificial feeds.  Given that HIV is excreted in breast milk, the early dictum was that breastfeeding should be discouraged and infant formula should be available at public health facilities in order to prevent transmission of HIV from mother to child.  Apart from the fact that many mothers were unwilling to accept this ‘benefit’ because it identified them as HIV-positive, this policy was overturned when researchers in KwaZulu-Natal (KZN) showed that exclusively-breastfed HIV-exposed infants were at significantly lower risk of acquiring the virus (<10% vs. previous risk estimates of 30-40%).  This phenomenon is stated as representing “one of the major enigmas of HIV transmission via breast milk” particularly because daily oral and gastrointestinal exposure in at-risk infants is calculated to be at least 700 000 viral particles per day.  The evidence suggests that anti-infective factors are active in the milk of infected mothers as well as in HIV-exposed breastfed infants.  For example, French researchers in collaboration with the University of KZN explored why residual transmission occurs despite chemoprophylaxis. They identified changes in breast milk fatty acids, their case control study showing that inverse relationships exist between HIV acquisition and two fatty acids: eicosatrienoic acid (polyunsaturated) and cis-vaccenic acid (monounsaturated), with dose effects going in opposite directions.  Cis-vaccenic acid concentrations correlated positively with HIV RNA load while this relationship was in the opposite direction for eicosatrienoic acid.  The authors conclude that increased mammary gland synthesis of cis-vaccenic acid plays a role in HIV-transmission, but are silent on what actually triggers the response.  Other research has found that in a mouse model, milk from HIV-infected women protected against HIV challenge. However a similar rate of protection was found using milk from HIV-negative mothers, thus excluding a direct role of HIV-specific immunity. Furthermore, this protection was limited to human milk and was not found in milk from other mammals.  Also of note is that pasteurization or other processes that remove protein, sugars or fat do not affect the protective effects.  Another variable in transmission appears to relate to whether the virus is cell-free or cell-associated, and studies have shown that increases in levels of cell-associated virus in breast milk are predictive of postnatal transmission during lactation.  Returning to the title of this summary, while we know that exclusive breastfeeding for at least 6 months is protective, exactly how this works is far from clear.

Read more:

J Virus Eradic 2016; 2: 112-3

Prostagland Leukotrienes Essential Fatty Acids 2016; 105: 35-42

J Virol 2015; 89: 10868-78           

1629 Sublingual immunotherapy (SLIT) for management of allergic rhinitis

An elegant and recently-published study from Japan evaluated the safety and effectiveness of sublingual house dust mite (HDM) immunotherapy for patients with HDM-related allergic rhinitis (AR).  The intervention itself is not new, in fact SLIT was approved by the WHO in 1988 and Cochrane Reviews in 2003 and 2010 confirmed the value of SLIT for management of AR.  However there are a number of unique elements in the double-blinded 50-centre Japanese study, specifically the randomization of almost 1000 subjects into the three groups (placebo and two study groups, one employing a 300 IR (index of reactivity) dose and the other a 500 IR dose).  The SLIT tablet contained extracts of both D pteronyssinus and D farinae, and patients were treated for 52 weeks.  Eligible subjects were aged between 12 and 64 years with a clinical history of HDM-induced AR for at least 2 years, a positive HDM-specific IgE, a positive response to nasal provocation with a house dust disc, and an Average Rhinitis Total Symptom Score of ≥6 of 15 for 7 days before randomization.  Patients were assessed for nasal symptoms (sneezing, rhinorrhea, congestion), ocular symptoms (itching or watering), troubles with daily life and use of rescue medication (antihistamine or steroid) during interim periods and the primary evaluation period which was during study weeks 44-52.  In addition an intranasal examination was carried out and quality of life was assessed by means of the JRQLQ (Japanese Rhinoconjunctivitis Quality of Life Questionnaire).  Specific IgE and IgG4, and total IgE were also measured and increased over the 52 weeks. The 44-52 week symptom scores were significantly improved in both study groups vs the placebo group, with an onset of action 8-10 weeks.  Rescue medication use and JRQOL outcome also improved in the 300 IR group. As with previous studies, adverse events were absent or mild and the authors conclude that while both 300IR and 500IR tablets were effective, the recommended dose is the 300 IR.  Of note is that the placebo group also showed improvement during the 52 weeks, possibly related to the fact that all three groups had access to rescue medication which could have ameliorated symptoms in the placebo group.  In this regard it has been recommended that where such studies measure and score both symptoms and medication use, the two outcomes should be combined into a single score and not treated independently because the two are interrelated. Current treatment guidelines, both national and international, highlight the value of SLIT in eligible patients, particularly those who are mono-sensitised, e.g. to HDM. In such patients it would make sense to administer earlier rather than only after most/all other treatment modalities have failed. Unfortunately in South Africa, despite the evidence base access to SLIT is problematic.

Read more:

Allergy 2016 doi:10.1111/all.12996 and 2007; 62: 1023-8

J Allergy Clin Immunol 2013; 132: 99-100

Curr Allergy Clin Immunol 2015; 28: 282-95

1630 Is it safe to vaccinate pregnant women with influenza vaccine?

The global 2009 A/H1N1 pandemic drew attention to the morbidity and mortality risks of infection with the influenza virus during pregnancy and strengthened recommendations for vaccination of pregnant women, not only during epidemics but also to protect against adverse effects during seasonal influenza infection.  Despite strong recommendations by national and international health bodies, healthcare providers are often dissuaded by package insert information that warns that vaccination should only be given when clearly needed.  Added to this are many mothers’ concerns about risk of vaccines to the developing foetus, so it is not particularly surprising that vaccination targets are not achieved. For example, in the USA a recent article in Vaccine cited coverage rates of around 50% during the 2012/3 and 2013/4 seasons in a CDC-driven survey of pregnant and ‘soon-to-be-pregnant’ women. Infection during seasonal influenza is associated with maternal morbidity and mortality, while newborns and infants <6 months of age are respectively at risk for preterm birth and low birthweight, and hospitalization and death.  In the wake of the 2009 pandemic in which 2.4million American women were immunized, only 294 adverse events were recorded on the system with none regarded as being due to the vaccine. South African researchers have contributed much to the safety debate, and a recent meta-analysis of 5 inactivated influenza vaccine (IIV) studies and 13 monovalent A/H1N1 studies showed that preterm birth and low birthweight were lower in the IIV group than in unvaccinated women (Odds Ratios 0.87 and 0.77 respectively), while the H1N1 vaccine showed ratios of 0.92 and 0.88 for preterm birth and low birthweight in vaccinated vs unvaccinated groups.  There has also been a randomized controlled study from Bangladesh showing an increase in mean birthweight and fewer small-for-gestational age infants born to vaccinated vs unvaccinated women.  While the evidence for safety abounds, articles such as the aforementioned one from Vaccine continue to appear; in this particular case showing a possible increase in relative risk of birth defects in 25/457 infants of first-trimester vaccine-exposed vs 13/427 unexposed women (RR 1.87; 95%CI 0.97-3.59). However since the confidence interval included 1, the authors conclude that their findings could be due to chance (and relatively small numbers). Statistically-speaking one should discount such a study and perhaps await results of yet another meta-analysis, but the doubters and nay-sayers will no doubt find support for their arguments against immunisation.

Read more:

Vaccine 2016; 34: 4443-9

Hum Vacc Immunother http://dx.doi.org/10.1080/21645515.2016.1222341

Am J Perinatol 2016;33: 1104-14  

1631 Is there a role for endoplasmic reticulum (ER) stress in the initiation of labour?

In summaries 1625 and 1626 the subject of ER stress is introduced with a number of examples of disease states in which sustained stress and the UPR (unfolded protein response) are possibly responsible for the adverse outcomes. In the field of paediatrics ER stress has been implicated as a non-genetic cause of congenital heart disease, but on the other hand there is experimental evidence from work in mice that there are protective mechanisms in foetal myocardial cells that render them less susceptible to insults than is the case for adult myocardium.  The focus of research into ER stress in various disease states is ultimately the identification of mediators that might block the UPR and its potential to cause tissue damage and/or cell death via apoptosis.  In the field of perinatal medicine ER stress and the UPR have not only been studied in the context of growth restriction, pre-eclampsia and gestational diabetes but also in the context of labour, whether spontaneous at term or affected by chorioamnionitis before term, and also where delivery was by caesarean section without labour.  The interest in this area is driven by the evidence that labour involves an inflammatory response.  The essential features of the UPR are reduced protein burden, increased folding, and enhanced degradation of misfolded protein. Key mediators are IRE1, PERK and ATF6 which are normally bound to glucose-regulated protein 78 (GRP78) but are ‘liberated’ and activated when unfolded or misfolded proteins accumulate.  In a series of elegant studies, researchers from Australia sought evidence of ER stress in foetal membranes and myometrial biopsies obtained after informed maternal consent. Samples were obtained from women delivering at term or preterm, whether by spontaneous vaginal delivery or caesarean section without labour. In the preterm group samples were taken from women with and without evidence of chorioamnionitis. The markers of ER stress (e.g. GRP78, IRE1) were significantly increased in foetal membranes and myometrium after term and preterm labour compared to non-labouring samples. To explore whether infection-induced inflammation would achieve similar results the researchers used bacterial endotoxin lipopolysaccharide (LPS) as a model for preterm chorioamnionitis. In term non-laboured foetal membranes and myometrium, LPS- induced UPR activation was shown by a significant increase in the expression of GRP78 and IRE1 in both foetal membranes and myometrium. The use of the chemical chaperones 4-phenylbutyric acid (4-PBA) and taurodeoxycholic acid (TUDCA) alleviated ER stress induced by LPS. These mediators also ameliorated the increase in LPS-induced prolabour mediators. The data suggest that the UPR may regulate the inflammatory responses associated with labour and also with infection in foetal membranes and myometrium of pregnant term and preterm women. While the authors propose that the ER stress inhibitors, in particular 4-PBA or TUDCA, may represent an intervention strategy for the prevention of infection-mediated spontaneous preterm birth, one should perhaps be concerned about maintaining the foetus in an infected and potentially hostile environment.

Read more:

Biol Reprod 2014 DOI 10.1095/biolreprod.114.120741

Development 2016; 143: 2561-72

J Molec Cell Cardiol 2016; 97: 1-14

1632 Should routine transvaginal cervical length measurement be the standard of care?

One can almost hear the critics once again shouting “First world problem, we have more important issues to deal with.”  But is that altogether true, given that globally spontaneous preterm birth is one of the most pressing problems facing healthcare providers dealing with mothers and newborn babies?  Spontaneous preterm birth is one of the leading causes of perinatal morbidity and mortality in infants without congenital abnormalities, and is associated with adverse long term outcomes, particularly if birth occurred before 34 weeks.  Many such births occur in women without identifiable risk factors, so an appropriate screening tool for asymptomatic women would likely be advantageous.  There is considerable evidence that pregnant women with a cervical length ≤15mm to ~25mm at screening with transvaginal ultrasound are at risk of preterm delivery, and over the past decade there have been studies into the value of administering topical (vaginal) progesterone to asymptomatic women who are ‘positive’ on ultrasound examination.  Such studies have shown benefits in terms of reduced rates of preterm birth and improved neonatal outcomes (e.g. fewer admissions to neonatal ICU, less respiratory distress and reduced length of hospital stay).  While there continues to be debate around the definition of short cervical length and also around the timing of the screening, there would obviously be an advantage in combining the cervical screen with the fairly routine ‘anomaly screen’ (so as not to add an extra consultation), and using the cervical length measurement that best identifies those asymptomatic women at highest risk for spontaneous birth at <34 weeks.  A number of multi-centre trials and meta-analyses have shown that the intervention has positive outcomes, however conclusions range from those that show no beneficial effects for the neonate or infant to one that recommends that this is effective both clinically and in terms of cost, and the intervention should therefore be the standard of care.  Based on data from one of the studies that covered a similar population, researchers in Ireland assessed the risk of spontaneous preterm birth in their population and the cost effectiveness of screening for cervical length of ≤15mm at the time of the routine ‘anomaly screen’.  Twelve years of obstetric data covering some 95 000 deliveries were analysed. Relative risk of adverse outcome was calculated, based on the results from the applicable randomized controlled trial, and the possible number of women requiring intervention was calculated.  Locally-relevant clinical and cost data were utilized to estimate the costs of providing the service and of providing neonatal care. The authors calculated that 1.7% of the historical study sample would have had a cervical length of ≤15mm and that the delivery rate before 34 weeks would have been reduced by 27.7% if vaginal progesterone had been given to all those who were eligible.  In their environment, based on the cost of treating fewer preterm neonates, this could have resulted in a saving of ~270 000 Euros per annum. The authors conclude that the intervention appears to be justifiable in terms of cost effectiveness, but suggest that units should ‘do the local maths’ before considering implementation.

Read more:

Acta Obstet Gynecol Scand doi: 10.1111//aogs.13021

Cochrane Database Syst Rev 2013; (7): CD004947

Am J Obstet Gynecol 2010; 202: (6): 548 e1-8          

1633 Is erythropoietin of value in treating cerebral palsy?

In developed countries the incidence of cerebral palsy has increased with advances in neonatology that have enhanced the survival of high risk neonates.  The risk amongst term infants in developing countries is also substantial, usually related to deficiencies in pre- and perinatal care.  Despite advancements in neonatal care, neurological impairments, skeletal deformities and activity limitations of cerebral palsy remain.  Hypoxic-ischemic injury in neonates is one of the major causes of cerebral palsy, involving disturbances in neuronal function and initiation of inflammatory responses that differ from those of adults due to an immature immune system and ongoing apoptosis of developmental neurons. Erythropoietin (Epo) receptors exist on neurons, astrocytes, microglia, and oligodendrocytes in the brain. Epo is considered to be neuroprotective, having anti-apoptotic and anti-inflammatory properties. In addition, the neurogenic and angiogenic properties of Epo favour neuro-regeneration. MRI studies have shown improvements in white matter development and reduced risk of white matter injury in preterm infants who receive recombinant human Epo early on.  More recently a case has been made for delayed Epo administration in treating white matter injuries in term infants who received recombinant human Epo 48 hours after birth and who showed better neurodevelopmental outcomes than a control group at 18 months of age.  While studies suggest that Epo should ideally be administered before or immediately after neuronal injury, it is possible that it could be expected to provide some benefits for young children diagnosed with cerebral palsy through its anti-apoptotic and other effects on persistent neuro-inflammation, pre-oligodendrocyte maturation and neurogenic and angiogenic processes. To test this hypothesis, researchers in South Korea conducted a small study on 10 cerebral palsy patients aged between 6 and 36 months of age (mean 19.2 mths). All except three were born at ≥34 weeks.  Subjects received 2 doses of Epo at 250IU/kg for 4 weeks, physiotherapy for 8 weeks and were reassessed using motor and developmental scales 4 and 8 weeks later. Adverse events, vital signs and haematologic tests were monitored up to 8 weeks. Functional measures of development at 4 and 8 weeks post-injection were compared with baseline values and compared with those of 21 age-matched historical controls. Nine participants completed the trial. No adverse events were related to Epo. Erythropoiesis was noted, although within normal range. Increases in motor function were higher in the Epo group than the control group on both the Gross Motor Performance Measure and Bayley motor scale. The study has several limitations, including small sample size and lack of concurrent controls, but does ask the question of whether there is an extended therapeutic window during which Epo may be beneficial. Additional insight may be derived from another (again small) South Korean study in which infants with cerebral palsy were given Epo at around 6 months of age and were shown to perform better motor-wise than controls. However the effects were not sustained when the groups were compared after 6 months.

Read more:

J Child Neurol 2016; 31: 1227-34

Brain and Develop 2014; 36: 764-9

Pediatrics 2009; 124: e218-226

1634 Next-generation gene sequencing

As is well known, initial sequencing of the human genome required 15 years and $3billion. In contrast the HiSeqX^TM instrument which was released in 2014 was able to sequence over 45 genomes in a day for approximately $1000.  Clearly science has come a long way from technology based on two-dimensional chromatography to that based on ‘short-read massively parallel sequencing’ of multiple gene fragments.  The ‘$1000 genome’ has transformed the way scientists and societies think about genetic information, opening the door to population-scale sequencing, personalized genomic medicine as part of standard medical care, and the cataloging of genes responsible for a range of diseases and also for patients’ responses to therapeutic interventions for those diseases.  One example of a database resides within Vanderbilt University in the USA, feeding the institution’s BioVu project (http://victr.vanderbilt.edu/pub/biovu/). Patient data are fed into the system in order to match clinical presentations to genetic profiles, some resent examples showing that genetic variations are linked to differences in pain perception, or that there are genetic determinants for the development of retinopathy in diabetics. The Vanderbilt Institute also has international collaborations involving tens of thousands of patients, studying the genetics of conditions such as multiple sclerosis, inflammatory bowel disease, blood pressure, body mass index and osteoporotic bone fractures.  These studies are mostly based on the whole genome (known as GWASs - genome-wide association studies).  Another modality under the heading of ‘next-generation gene sequencing’ is WES or whole exome sequencing which focuses on the protein-coding regions of the genome.  It is estimated that protein-coding genes constitute only 1% of the genome but are home to 85% of mutations underlying monogenic disorders.  Variations in non-coding loci have only a small impact on phenotype.   Whole exome sequencing was reviewed rather negatively in the South African Medical Journal earlier this year, but in the context of WES becoming directly available to consumers through membership of their medical aid scheme and its collaboration with an American laboratory.  The editorial commented on WES not being available in the country as a result of “technological constraints, insufficient storage for the resulting large datasets, ethical considerations and limitations of our understanding of the impact of human genetic variants on health in terms of clinical utility.” Essentially there were concerns about why people would opt to have the test, whether they would be adequately counseled on implications of a ‘positive’ result, and whether in an asymptomatic individual one would in fact know when a variation is clinically significant.  There were also concerns that while the test would be relatively inexpensive ($250), the major beneficiary of such a database would be the laboratory which would likely use the data (albeit anonymous or unlinked) for commercial gain.  Contrasting with these negative opinions are two recent articles that lead one to rue the fact that WES is not available in South Africa.  Both articles refer to paediatric (monogenic) disorders.  In one the focus was on 57 neurology patients, while the other studied 80 infants with multiple congenital abnormalities and dysmorphic features (e.g. neurometabolic conditions and skeletal dysplasias).  Both studies address the question of the role of WES, its predictive value and in particular whether it should be used as an initial test or only after the usual ‘genetic workup’ has failed to identify a problem. In both cases WES performed significantly better than standard/routine workup. Definite results were obtained in 50-60% of cases, assisting with mode of inheritance, recurrence risk, and modification of treatment in several cases.   

Read more:

J Child Neurol 2016; doi: 10.1177/0883073816664836

Genetics in Med 2016; doi: 10.1038/gim.2016.1

S Afr Med J 2016; 106: 139-140

1635 Parlous state of congenital disorder (CD) data in South Africa

As most will know, the MDGs (Millennium Development Goals) have been supplemented and complemented by the 17 SDGs (Sustainable Development Goals) for 2030.  The latter goals include the ending of poverty and hunger; healthy lives for all; education and lifelong learning; gender equality; water, sanitation and energy for all; employment and economic growth; resilient infrastructure, industrialization and innovation; reduction of inequality within and between countries; safe cities and settlements; combating of climate change; marine and terrestrial conservation; and revitalized global partnerships.  As these goals were being formulated by the United Nations, in September 2015 stakeholders from 37 countries, including several delegates from South Africa, were in Tanzania attending the 7^th International Conference on Birth Defects. A focus of debate was the acceleration of strategies to prevent birth defects and improve the care of affected children, especially those in high-burden, low-resource settings.  In many of these the proportion of deaths due to CDs in children is rising and disability rates are increasing, this usually because neonatal survival is up but subsequent healthcare lags behind.  It was stated at the conference that 7.9 million children are born each year with a genetic or partially genetic congenital disorder, and hundreds of thousands more CDs are due to intrauterine insults from infections or teratogens such as alcohol.  In the under-5’s there are almost 500 000 deaths due to CDs each year, with almost 200 000 of the annual stillbirths the result of an underlying congenital disorder.  Under optimal circumstances up to 70% of CDs are preventable, their effects substantially mitigated and quality of life improved, but the reality is that families, infants and children have been left behind in policies, programmes, research and funding.  Conference attendees therefore drafted a consensus statement to emphasise the importance of including those affected by CDs within the SDGs.  Their call to action includes the improvement of data quality (e.g. via registries and surveillance systems), risk reduction (e.g. by ensuring that folic acid is supplemented in the diet and teratogenic substances such as alcohol are removed), and care should be improved (e.g. by training healthcare providers and providing services such as newborn screening).  South Africa embarked on CD surveillance in 1980 in order to plan prevention and rehabilitation programmes, and in 2001 the National Department of Health published Policy Guidelines for the Management and Prevention of Genetic Disorders, Birth Defects and Disabilities.  This was followed by the introduction of the BDNT (Birth Defect Notification Tool).  Utilisation of the tool at national level between 2006 and 2014 was covered in a recent issue of the South African Medical Journal and shown to be abysmal, reporting on less than 2% of CDs expected for the population.  If the country is serious about such an initiative we clearly have a long way to go!

Read more

United Nations 2015; http://www.un.org/pga/wp-content/uploads/sites/3/2015/08/120815_outcome-document-of-Summit-for-adoption-of-the-post-2015-development-agenda.pdf

JAMA Pediatr 2016 doi: 10.1001/jamapediatrics.2016.0388

S Afr Med J 2016; 106: 992-5

1636 Therapeutic clowns in paediatrics

Since August 2016 there has been considerable mainstream media coverage overseas of the trauma and anxiety created around ‘scary clowns.’ The phenomenon started in the US, apparently linked to a gruesomely made-up clown carrying black balloons who was advertising a horror movie.  This was followed by reports of clowns flashing laser lights so as to lure children into the woods. Similar reports of sinister clowns appeared in at least 20 US states, subsequently crossing the ocean to the UK to the point that clowns who intimidate others now risk criminal prosecution. The Guardian newspaper in the UK recently reported that in the build-up to Halloween (another import from the US) there were 462 calls from children to Childline counsellors expressing fears about clowns, and clown costumes have been banned in several places.  On balance it would seem that clowns are not universally associated with laughter, joy and happiness but there is also extensive medical literature on the value of clown therapy administered by ‘therapeutic clowns’ ‘hospital clowns’ or ‘clown doctors’ in formal programmes in the Americas, Europe, Australia, New Zealand, Canada and Israel.  There have been International Congresses of Hospital Clowns and there are published guidelines from organisations such as Therapeutic Clowns International covering issues ranging from hygiene in the hospital environment to ethics, appropriate props and behaviour with patients and parents.  Clown doctors parody the hospital routine to help children adapt to their surroundings and distract from and demystify painful procedures. Comedo-therapeutic techniques include magic, music, storytelling and other skills, ideally delivered by individuals who have a background in acting, street theatre and/or physical clowning and are trained to work in hospitals.  Many will have seen the 1998 movie in which Robin Williams played the character of Dr Patch Adams and his ‘laugh therapy.’  In terms of whether the techniques are effective, an article recently published in the European Journal of Pediatrics reports on a systematic review and meta-analysis of 19 eligible randomized and controlled studies of clown therapy vs standard care in children admitted to hospital or undergoing an invasive procedure such as intravenous cannulation, blood collection or minor surgery under anaesthesia.  In almost all the reviewed studies both child and parental anxiety were significantly reduced by clown therapy.  In contrast to the ‘scary clowns’ cited above, if one ‘Googles’ a term such as clown care/therapy one sees an abundance of jovial clowns in white coats and minimalist but smiling make-up, some with and others without the ‘signature’ red nose.  Hopefully the current fearful climate will not detract from the excellent work done by the medical clowning community, which no doubt would find a place in South Africa, particularly in public hospitals in which there are many children whose caregivers are absent and who alienated by an unfamiliar environment and frequently surrounded by other patients and staff who are unable to communicate meaningfully with them.

Read more:

Eur J Pediatr 2016; 175: 1353-60

J Holist Nurs 2013; 32: 226-31

eCAM 2008; 5: 17-25    

1637 ‘Low-tech’ screening for hyperbilirubinaemia in neonates

This subject is addressed in a recent article from China in which bilirubin levels were assessed at between 3 and 30 days of age (67% at 11-20 days).  The authors custom-developed a ‘jaundice colour card’ (JCard) that has 8 coloured blocks which are based on serum bilirubin levels and computer-assessed skin colour.  The blocks show 2mg/dl bilirubin increments between 5 and 19mg/dl.  The card was tested with mothers as the ‘operators’ to assess whether the device could be used as a low-tech screening tool at home.  Colours on the card were matched against skin colour on the forehead, cheek and sternum and were correlated with serum bilirubin levels.  Results were found to correlate extremely well.  The best correlation was found on the cheek where the difference between the JCard and serum measures were only 0.3mg/dl.  In a commentary in the same journal, Jeffrey Maisels, an acknowledged guru in the area of  neonatal hyperbilirubinaemia, has several concerns about the claimed accuracy of the device, given that a very similar methodology was devised by Gosset in the 1950’s and data shown for his study showed wide bilirubin ranges for each of 9 ‘icterometer’ readings.  Maisels also questions whether the device could be used in neonates with pigment levels that differ from those of the study population.  While various paediatric and neonatal guidelines advocate against the use of these low-tech devices, almost invariably recommending transcutaneous bilirubinometers as the screening tools of choice, such devices are not universally available and certainly not appropriate for home use in the developing world. A smartphone ‘app’ has also been developed which utilizes the phone’s camera and installed software, but is complex, more expensive and does not appear to have been ‘field tested.’  While the Gosset icterometer had coloured bars on a clear perspex or plastic strip, the JCard has the bars on a strip with a computer-generated ‘population appropriate’ background.  The smartphone app adjusts for skin pigmentation, as do the transcutaneous bilirubinometers.  Given the current pressure on South Africa’s paediatric specialists-in-training to produce a research report, it might be worthwhile for a candidate to perform a study similar to that of the Chinese in which a group of similarly-pigmented neonates is selected and a number of colour bars (e.g. from commercial paint charts) are matched according to neonatal bilirubin levels. Once developed for one group the device could be tested on another. This would take time and planning, but would not cost much and make for an interesting project.

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Acta Paed 2016; DOI:10.1111/apa.13542 and 13599

Ubicomp 2014; http://dx.doi.org/10.1145/2632048.2632076          

Lancet 1960; 1: 87-8

1638 Neonatal telomere length (TL) in stressed pregnancies

It probably bears repeating that telomeres are non-coding repetitive DNA sequences at the end of each chromosome, their primary function being the maintenance of genomic stability. However DNA polymerase is unable to fully replicate the chromosomal ends, with the result that telomeres shorten with each cell division. Once telomeres are reduced to critical lengths the cell enters a state of arrest i.e. senescence.  Various factors influence TL including oxidative stress, DNA damage, psychosocial stressors, chronic diseases and genetic factors. Shorter infant telomere length has also been associated with a number of perinatal factors such as intrauterine growth restriction, preterm rupture of membranes, gestational diabetes and prenatal exposure to anti-retroviral therapy. Summaries 1625 and 1626 in this series deal with the phenomenon of endoplasmic reticulum (ER) stress in situations such as gestational diabetes and maternal hypertension and the relationship between ER stress and intrauterine growth restriction.  Summary 1502 addresses the issue of postnatal growth in growth-restricted neonates and infants, and identifies optimal and sub-optimal growth patterns.  This suggests that with optimal care one might be able to mitigate the risk of subsequent conditions such as hypertension and the metabolic syndrome that are known to be more prevalent in individuals who have been stressed in utero. But if such fetuses and neonates also have shortened telomeres at birth, is it possible to reverse that process and lengthen telomeres?  While in vitro studies have demonstrated that prevention of aging by reversal of the process might be possible with certain chemical agents, we do not have supporting in vivo data.  It therefore appears that the best one can do is slow the process, something that is dealt with in summary 1504 in which it is shown that healthy lifestyles are associated with longer TLs than lifestyles involving high energy and unsaturated fat intakes.  A recent article in the American Journal of Obstetrics and Gynecology has once again brought the issue of telomere shortening into focus by showing an inverse relationship between newborn TL and maternal stress as measured on the Social Readjustment Rating Scale, and also showing how the distribution curve of newborns subjected to high stress is different from that of neonates exposed to less stress.  In another study the chromosomal consequence of early stress is shown by researchers from the UK and the Netherlands who measured TL in 470 young adults, 186 born preterm and 284 born at term.  Gestational age was positively associated with TL, the difference between the term and preterm groups being significant at p=0.003. An area that clearly requires more work emanates from research from Baltimore and New Orleans in which 42 black term neonates were shown to have significantly longer TLs than 24 white neonates.  The authors make the point that longer initial TL is predictive of greater attrition across the life course, so one not only needs to explore the inter-racial situation for stressed black and white neonates but also the progression thereafter.

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Am J Obstet Gynecol 2016; http://dx.doi.org/10.1016/j.ajog.2016.01.177

PLOS One 2015; DOI:10.1371/journal.pone.0143951

J Pediatr 2015; 166: 1181-6

1639 Electronic cervical auscultation (ECA) to diagnose aspiration in children

Uncoordinated swallowing and resultant reflux and aspiration are fairly common in paediatric patients e.g. those born prematurely or suffering from neurological conditions. Management strategies range from symptomatic treatment involving sleeping position and thickening of feeds to formal diagnosis by means of a videoflouroscopic swallow study (VFSS).  Speech pathologists may also use ECA in conjunction with a clinical feeding evaluation when assessing dysphagia in children in order to assess acoustic parameters (e.g. peak frequency or amplitude) or ‘perceptual sounds’ (such as ‘wet breathing’ or ‘clicks’) that are categorised after playing back the recordings.  Acoustic swallowing sound differences between preterm infants with and without chronic neonatal lung disease have been demonstrated by variations in the shape of the swallowing waveform pattern when captured by ECA. Similarly, differences in amplitude of the swallow have been found between healthy children and those with dysphagia.  However this is far from a perfect science and much needs to be done in terms of standardization of terminology and the sound features associated with aspiration, as well as on the interpretation of perceptual sounds heard.  On the other hand, given the current clinical utilization of devices such as the smartphone and the ability to develop sensors and capture normal and pathological ‘signals,’ perhaps paediatricians should be working with relevant professionals and acquiring skills that could enhance bedside diagnosis.  In this regard a number of Australian researchers collaborated on a study of 50 subjects referred to a tertiary centre for feeding/swallowing difficulties.  The gold standard for aspiration was the VFSS, although it is acknowledged that a negative VFSS at one point in time does not rule out reflux/aspiration at some other time.  Twenty-seven of the children had VFSS evidence of aspiration while 23 did not.  There was no relationship between aspiration and the acoustic parameters (duration, peak amplitude or peak frequency), however when the recorded sound clips were analysed by two experienced speech pathologists, there were indeed important and significant relationships between the perceptual clinical parameters and aspiration after swallowing.  Particular importance is attached to the glottal release sound (GRS) which is essentially the normal expiratory sound after a swallow has taken place.  In deriving receiver operator curves (ROCs), values >0.79 were obtained when an absent GRS plus absence of normal breathing post-swallow were combined with ≥1 of the following: ‘wet breathing,’ cough, wheeze, crackles, throat clearing and/or stridor.  The technological aspects of ECA do not appear to be particularly challenging, so it might be worthwhile investing in the development of the requisite clinical skills in order to introduce and evaluate the modality as another relatively ‘low-tech’ screening tool for children with possible aspiration.

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Ann Oto Rhino Laryngol 2016; 125: 1001-9

Dysphagia 1995; 10: 27-31

Dev Med Child Neurol 2003; 45: 442-6       

1640 Gender ratio at birth as a sentinel health indicator

Under normal circumstances the ratio of male to female births is slightly biased towards males, the typical ratio being around 1.05:1. Where ethnicity is a reflection of factors such as socio-economic status or pathophysiological factors, the ratio may be different. For example in the USA whites have higher ratios than African Americans and Native Americans. It has also been established that under stressful circumstances the ratio changes as a result of fewer male births.  Historical events ranging from the US Recession to more recent events such as economic collapse of East Germany after reunification and the 9/11 attacks on the World Trade Center’s Twin Towers have all shown an effect on the proportion of male births.  Catalano and Bruckner from California have published extensively on the subject and have concluded that there is ‘culling’ of ‘fragile’ males during times of stress. In one analysis they found the ratio dropping to 0.79:1. There is also evidence that the survivors of the culling process are hardier and have greater life expectancy than males conceived under non-stressful circumstances, and research goes further to show that in the most extreme cases the ‘survivors’ themselves produce almost 10% more offspring than do males born in years where the ratio was around 1:1.  In the South African context a recent article published in Early Human Development tracked the ratio between 2003 and 2014, the objective being to show a positive impact during this period of improving conditions as measured by available health indicators.  Using a slightly different metric viz. M/T (total males born/total births) the authors showed an annual increase from 0.5022 in 2003 until around 0.5045 in 2010 and a leveling off thereafter.  Health indicators that improved over the period included life expectancy increasing from 53.9 to 62.5 years, infant mortality decreasing from 51.3/1000 live births to 35.3/1000, and under-5 mortality reducing from 77.9 to 46.5/1000 live births.  The authors acknowledge that greater access to anti-retrovirals may have played the major role in these results and go further to suggest that the M/T ratio may be used as a sentinel health indicator for HIV/AIDS interventions.  Meanwhile one must consider that factors such as currency devaluation, increasing CPI (consumer price index), rising unemployment and the worst drought in decades might cause the M/T ratio to once again retreat.  Linking this subject to recent summaries in this series on foetal determinants of adult disease and also on the subject of telomere length (TL), it would be interesting to know how telomere length relates to whether the males who survive culling have longer telomeres at birth than those born under more-normal circumstances, possibly even approximating the TL of females who under normal circumstances are born with longer TLs.

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Early Hum Dev 2016; 103: 225-7

Int J Epidemiol 2014; 43: 1799-1805

Am J Hum Biol 2006; 18: 783-90   and 2007; 19: 763-73          

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