Adenotonsillectomy for Obstructive Sleep Apnea in Children.

Obstructed breathing is the most common indication for tonsillectomy in children. Although tonsillectomy is performed frequently worldwide, the surgery is associated with a number of significant complications such as bleeding and respiratory failure. Complication risk depends on a number of complex factors, including indications for surgery, demographics, patient comorbidities, and variations in perioperative techniques. While polysomnography is currently accepted as the gold standard diagnostic tool for obstructive sleep apnea, studies evaluating outcomes following surgery suggest that more research is needed on the identification of more readily available and accurate tools for the diagnosis and follow-up of children with obstructed breathing.

An Economic Evaluation of a Web-Based Management Support System for Children With Urinary Incontinence: The eADVICE Trial.

PURPOSE: Children who require specialist outpatient care typically wait substantial periods during which their condition may progress, making treatment more difficult and costly. Timely and effective therapy during this period may reduce the need for lengthy specialist care. This study evaluated the cost-effectiveness of an individualized, evidence-informed, web-based program for children with urinary incontinence awaiting a specialist appointment (eADVICE) compared to usual care. eADVICE was supervised by a primary physician and delivered by an embodied conversational agent (ECA). MATERIALS AND METHODS: A trial-based cost-effectiveness analysis was performed from the perspective of the healthcare funder as a sub-study of eADVICE, a multicenter waitlist-controlled randomized trial. Outcomes measures were incremental cost per incremental change in continence status and quality of life on an intention-to-treat basis. Uncertainty was examined using cost-effectiveness planes, scenarios, and 1-way sensitivity analyses. Costs were valued in 2021 Australian dollars ($). RESULTS: The use of eADVICE was found to be cost-saving and beneficial (dominant) over usual care, with a higher proportion of children dry over 14 days at 6 months (RD 0.13; 95%CI 0.02-0.23, P = .03) and mean healthcare costs reduced by $188 (95%CI $61-$315) per participant. CONCLUSION: An individualized, evidence-informed web-based program delivered by an ECA is likely cost-saving for children with urinary incontinence awaiting a specialist appointment. The potential economic impact of such a program is favorable and substantial and may be transferable to outpatient clinic settings for other chronic health conditions.

A Randomized Controlled Trial of a Web-Based Management Support System for Children With Urinary Incontinence: The eADVICE Trial.

PURPOSE: Children referred to specialist outpatient clinics by primary care providers often have long waiting times before being seen. We assessed whether an individualized, web-based, evidence-informed management support for children with urinary incontinence while waiting reduced requests for specialist appointments. MATERIALS AND METHODS: A multicenter, waitlisted randomized controlled trial was conducted for children (5-18 years) with urinary incontinence referred to tertiary pediatric continence clinics. Participants were randomized to the web-based eHealth program electronic Advice and Diagnosis Via the Internet following Computerized Evaluation (eADVICE), which used an embodied conversational agent to engage with the child at the time of referral (intervention) or 6 months later (control). The primary outcome was the proportion of participants requesting a clinic appointment at 6 months. Secondary outcomes included persistent incontinence, and the Paediatric incontinence Questionnaire (PinQ) score. RESULTS: From 2018 to 2020, 239 children enrolled, with 120 randomized to eADVICE and 119 to the control arm. At baseline, participants' mean age was 8.8 years (SD 2.2), 62% were males, mean PinQ score was 5.3 (SD 2.2), 36% had daytime incontinence, and 97% had nocturnal enuresis. At 6 months, 78% of eADVICE participants vs 84% of controls requested a clinic visit (relative risk 0.92, 95% CI 0.79, 1.06, P = .3), and 23% eADVICE participants vs 10% controls were completely dry (relative risk 2.23, 95% CI 1.10, 4.50, P = .03). The adjusted mean PinQ score was 3.5 for eADVICE and 3.9 for controls (MD -0.37, 95% CI -0.71, -0.03, P = .03). CONCLUSIONS: The eADVICE eHealth program for children awaiting specialist appointments doubled the proportion who were dry at 6 months and improved quality of life but did not reduce clinic appointment requests.

Choline-acetyltransferase (ChAT) and acetylcholinesterase (AChE) in the human infant dorsal motor nucleus of the Vagus (DMNV), and alterations according to sudden infant death syndrome (SIDS) category.

Amongst other molecules, the cholinergic system consists of choline-acetyltransferase (ChAT, - synthesis enzyme), acetylcholinesterase (AChE - primary hydrolysis enzyme), and butyrylcholinesterase (BuChE - secondary hydrolysis enzyme). In the brainstem, the Dorsal Motor Nucleus of The Vagus (DMNV) has high cholinergic expression and is a region of interest in the neuropathology of sudden infant death syndrome (SIDS). SIDS is the unexpected death of a seemingly healthy infant, but postmortem brainstem abnormalities suggesting altered cholinergic regulation have been found. This study aimed to determine the percentage of positive ChAT and AChE neurons within the infant DMNV through immunohistochemistry at the three levels of the brainstem medulla (caudal, intermediate, and rostral), to investigate whether the proportion of neurons positive for these enzymes differs amongst the diagnostic subgroups of SIDS compared to those with an explained cause of Sudden unexpected death in infancy (eSUDI), and whether there were any associations with SIDS risk factors (male gender, cigarette smoke exposure, co-sleeping/bed sharing, and prone sleeping). Results showed that ChAT-positive neurons were lower in the rostral DMNV in the SIDS II cohort, and within the caudal and intermediate DMNV of infants who were exposed to cigarette smoke. These findings suggest altered cholinergic regulation in the brainstem of SIDS infants, with potential contribution of cigarette smoke exposure, presumably via the nicotinic acetylcholinergic receptor system.

Cell death in the lateral geniculate nucleus, and its possible relationship with nicotinic receptors and sudden infant death syndrome (SIDS).

The role of the lateral geniculate nucleus (LGN) in vision has been extensively studied, yet its extraretinal capacities are still being investigated, including its role in arousal from sleep. The ß2 nicotinic acetylcholine receptor (nAChR) subunit is involved in the laminal organisation of the LGN with magnocellular (MC) and parvocellular (PC) neurons. Sudden infant death syndrome (SIDS) occurs during a sleep period and, neuropathologically, is associated with increased neuronal cell death and altered nAChRs. A recent qualitative pilot study from our group implicates the possibility of increased neuronal death/apoptosis in the SIDS LGN. The present study used quantitative analysis to report the baseline expression of apoptotic and nAChR subunits α7 and ß2 in the PC and MC layers of the LGN, to determine correlations amongst these markers within layers and across layers, and to evaluate changes in the expression of these markers in the LGN of SIDS infants, along with associations with SIDS risk factors, such as age, sex, cigarette smoke exposure, bed-sharing, and presence of an upper respiratory tract infection (URTI). Tissue was immunohistochemically stained for cell death markers of active caspase-3 (Casp-3) and TUNEL, and for the α7 and ß2 nAChR subunits. Amongst 43 cases of sudden and unexpected deaths in infancy (SUDI), classifications included explained deaths (eSUDI, n = 9), SIDS I (n = 5) and SIDS II (n = 29). Results indicated a strong correlation of the apoptotic markers and ß2 nAChR subunit between the LGN layers, but not across the markers within the layers. Amongst the diagnostic groups, compared to eSUDI, the SIDS II cases had decreased Casp-3 expression while ß2 nAChR expression was increased in both PC and MC layers. Amongst the SIDS risk factors, URTI and bed-sharing were associated with changes in neuronal death but not in the α7 and ß2 markers. In conclusion, our findings do not support a role for the α7 and ß2 nAChRs in apoptotic regulation of the LGN layers during infancy. However, for SIDS victims, an inverse correlation between the changes for markers of apoptosis and the ß2 nAChR subunit expression suggests altered LGN function.

Patterns of Change in the Severity of Airway Obstruction with Robin Sequence in Early Infancy.

Previous studies suggest that infants with Robin sequence show a pattern of steady improvement in the severity of airway obstruction, and of their treatment requirements, during infancy. Methods: Three infants with Robin sequence and severe obstructive sleep apnea were managed with nasal continuous positive airways pressure (CPAP). Multiple measures of airway obstruction were made during infancy, including CPAP pressure evaluations and sleep studies (screening and polysomnography studies). Parameters reported include obstructive apnea-hypopnea index, oxygen desaturation parameters, and CPAP pressures required for effective airway management. Results: CPAP pressure requirements increased in all three infants during their first weeks of life. Apnea indices on polysomnography did not track with the CPAP pressure requirements. Peak pressure requirements were at 5 and 7 weeks for two patients, with subsequent gradual decline and cessation of therapy CPAP at 39 and 74 weeks, respectively. The third patient had a complicated course, jaw distraction at 17 weeks, and biphasic CPAP pressure requirement (first peak at 3 weeks, but maximum pressure at 74 weeks), with cessation of CPAP at 75 weeks. Conclusions: The observed pattern of early increases in CPAP pressure requirements for infants with Robin sequence adds to the complexities of managing this disorder. Factors that may lead to this pattern of change in airway obstruction are discussed.

The management of upper airway obstruction in Pierre Robin Sequence.

Pierre Robin Sequence (PRS) is defined by a constellation of characteristics including micrognathia, glossoptosis and airway obstruction. PRS can occur in isolation or can be associated with syndromes and another anomalies. Airway obstruction and feeding difficulties are the major presenting issues, and the severity of the condition ranges from mild, with minimal to no symptoms, to severe, with overt obstruction resulting in apnoeas, severe respiratory distress and cyanosis. The presence of airway obstruction can result in obstructive sleep apnoea and abnormalities in gas exchange, as well as exacerbation of already present feeding difficulties and failure to thrive, secondary to mismatch of caloric intake to energy usage associated with increased effort of breathing. Management of airway obstruction for infants with PRS varies between centres. This paper explores the surgical and non-surgical management options available, their effectiveness and pitfalls in children with PRS. Despite the pros and cons of each management option, it is evident that resource availability and multidisciplinary clinical support are key factors to successful management.

Three-dimensional orthodontic imaging in children across the age spectrum and correlations with obstructive sleep apnea.

STUDY OBJECTIVES: To determine baseline facial convexity measurements in children with obstructive sleep apnea (OSA) across the age spectrum. METHODS: Polysomnogram, stereophotogrammetry, and biometric data were collected from children aged 0-18 years who were being investigated for OSA. Analyses evaluated differences in facial convexity according to OSA severity and other sleep parameters, while adjusting for age, ethnicity, and sex. RESULTS: Ninety-one children, aged 0.05-16.02 years, met the inclusion criteria for this study. Initial analysis showed that the logarithm of age had a significant effect on facial convexity (P = 8.3·10-7) with significant effects of sex (P = 1.3·10-2), while excluding OSA. Ordinal logistic regression taking into consideration age, sex, weight, height, and ethnicity with OSA severity categorized as obstructive apnea-hypopnea index negative, mild, moderate, or severe showed that facial convexity was associated with OSA severity (P = 2.2·10-3); an increasing obtuse angle of convexity increased the tendency to be classified as having severe OSA. CONCLUSIONS: Using three-dimensional imaging, we found an added impact of infancy on changes of facial convexity with age. While modeling could describe facial convexity without any OSA-associated sleep parameters, differences in facial convexity were present among groups with different levels of OSA severity adjusted for growth (age, weight, and height), sex, and ethnicity. The method provides a safer and cheaper alternative to other medical imaging techniques in children and holds potential for future use in studies of craniofacial structure. CITATION: Tyler G, Machaalani R, Waters KA. Three-dimensional orthodontic imaging in children across the age spectrum and correlations with obstructive sleep apnea. J Clin Sleep Med. 2023;19(2):275-282.

Sleep in children and young adults with cystic fibrosis.

Large gains have been made in the management of respiratory diseases associated with cystic fibrosis (CF). Initial studies evaluating sleep issues in CF focused on respiratory problems of nocturnal hypoxia, alveolar hypoventilation and risk of airway obstruction from nasal polyps with treatment evaluations including long term oxygen therapy or noninvasive ventilation in case of nocturnal hypercapnia. More recent studies include patients whose lung function is better preserved, and have permitted more focus on sleep patterns and sleep quality. This literature identified that reduced sleep duration and poor sleep quality are common and may be explained by chronic pain and cough, frequent stools, gastro-oesophageal reflux, nasal obstruction or sinusitis, and drugs such as corticosteroids or beta-agonists. In the teenage years, poor sleep hygiene, sleep debt and poor sleep quality are associated with depression, poor academic performance, less physical activity, and a decrease in quality of life. Restless leg syndrome also seems to be common in adult patients with CF. These sleep problems seem more important in patients with a low lung function but may also be observed in patients with preserved lung function. The consequences of poor sleep may potentially exaggerate the multi-organ morbidity of CF, such as pain, inflammation, susceptibility to infection, and glucose intolerance, but these aspects are largely under-evaluated. Sleep should be evaluated on a routine basis in CF and prospective studies assessing the benefits of interventions aiming at improving sleep duration and sleep quality urgently needed.

Immunohistochemistry for acetylcholinesterase and butyrylcholinesterase in the dorsal motor nucleus of the vagus (DMNV) of formalin-fixed, paraffin-embedded tissue: comparison with reported literature.

The majority of research regarding the expression of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain has been conducted using histochemistry to identify enzymatic activity in frozen fixed tissue. However, retrospective human neurochemistry studies are generally restricted to formalin-fixed, paraffin-embedded (FFPE) tissues that are not suitable for histochemical procedures. The availability of commercially available antibody formulations provides the means to study such tissues by immunohistochemistry (IHC). In this study, we optimised IHC conditions for evaluating the expression of AChE and BuChE in the brainstem, focusing on the dorsal motor nucleus of the vagus, in human and piglet FFPE tissues, using commercially available antibodies. Our results were compared to published reports of histochemically determined AChE and BuChE expression. We varied antibody concentrations and antigen retrieval methods, and evaluated different detection systems, with the overall aim to optimise immunohistochemical staining. The primary findings, consistent across both species, are: (1) AChE and BuChE expression dominated in the neuronal somata, specifically in the neuronal cytoplasm; and (2) no change in the protocol resulted in axonal/neuropil expression of AChE. These results indicate that IHC is a suitable tool to detect AChE and BuChE in FFPE tissue using commercial antibodies, albeit the staining patterns obtained differed from those using histochemistry in frozen tissue. The underlying cause(s) for these differences are discussed in detail and may be associated with the principal components of the staining method, the antibody protein target and/or limitations to the detection of epitopes by tissue fixation.

Impact of adenotonsillectomy on growth trajectories in preschool children with mild-moderate obstructive sleep apnea.

STUDY OBJECTIVES: Adenotonsillectomy (AT) forms part of first-line management for pediatric obstructive sleep apnea. In nonrandomized studies of preschool-aged children, postoperative weight gain has been seen following AT, raising concerns regarding later obesity. Using longitudinal data from a multicenter randomized controlled trial, we assessed the impact of AT on growth trajectories in preschool-aged children with mild-moderate obstructive sleep apnea. METHODS: A total of 190 children (aged 3-5 years) with obstructive apnea-hypopnea index ≤ 10 events/h were randomly assigned to early (within 2 months) or routine (12-month wait) AT. Anthropometry and polysomnography were performed at baseline, 12-month, and 24-month time points for 126 children. Baseline characteristics were compared using a Mann-Whitney or t test for continuous variables and Fisher's exact test for categorical variables. Longitudinal data underwent linear mixed modeling. RESULTS: For body mass index (BMI) z-score there was a significant increase in the early surgery group between 0 and 12 months (0.4, 95% confidence interval 0.1-0.8) but not from 12-24 months. For the routine surgery group there was an identical significant BMI z-score increase in the first 12 months following surgery, ie, between 12- and 24-month time points (0.45, 95% confidence interval 0.1-0.8) but not from 0-12 months (preoperative time). Final BMI z-score was similar between groups. Findings for weight-for-age z-score were similar to the findings for BMI z-score. Height-for-age z-score was not significantly different between different time points or intervention groups. CONCLUSIONS: This study provides randomized controlled trial evidence of notable, but time-limited, increase in the BMI and weight of preschool children with mild-moderate obstructive sleep apnea in the months immediately following AT. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: POSTA Child Study (Preschool Obstructive Sleep Apnea Tonsillectomy Adenoidectomy Study); URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336273&isReview=true; Identifier: ACTRN12611000021976. CITATION: Kevat A, Bernard A, Harris M-A, et al. Impact of adenotonsillectomy on growth trajectories in preschool children with mild-moderate obstructive sleep apnea. J Clin Sleep Med. 2023;19(1):55-62.

COVID-19 Vaccination in Young People with Functional Neurological Disorder: A Case-Control Study.

BACKGROUND: The emergence of acute-onset functional neurological symptoms, the focus of this study, is one of three stress responses related to immunisation. This case-control study documents the experience of 61 young people with past or current functional neurological disorder (FND) in relation to the COVID-19 vaccination program in Australia. METHODS: Information about the young person's/parent's choice and response pertaining to COVID-19 vaccination was collected as part of routine clinical care or FND research program follow-up. RESULTS: 61 young people treated for FND (47 females, mean age = 16.22 years) and 46 healthy controls (34 females, mean age = 16.37 years) were included in the study. Vaccination rates were high: 58/61 (95.1%) in the FND group and 45/46 (97.8%) in the control group. In the FND group, 2 young people (2/61, 3.3%) presented with new-onset FND following COVID-19 vaccination; two young people with resolved FND reported an FND relapse (2/36, 5.56%); and two young people with unresolved FND (2/20, 10.0%) reported an FND exacerbation. In the control group no FND symptoms were reported. CONCLUSIONS: Acute-onset FND symptoms following COVID-19 vaccination are uncommon in the general population. In young people prone to FND, COVID-19 vaccination can sometimes trigger new-onset FND, FND relapse, or FND exacerbation.

Early Postnatal Exposure to Intermittent Hypercapnic Hypoxia (IHH), but Not Nicotine, Decreases Reelin in the Young Piglet Hippocampus.

This study evaluated the expression of reelin, an extracellular protein involved in lamination and migration of neurons, in the hippocampus of young piglets, and quantified to examine the following: (i) baseline levels within layers of the hippocampus and dentate gyrus (DG); (ii) differences between ventral and dorsal hippocampi; and (iii) changes attributable to postnatal exposure to continuous nicotine for 12 days, or intermittent hypercapnic hypoxia (IHH), with further analysis according to duration of IHH (1 vs 4 days). Additionally, we analysed whether any exposure altered DG morphology and whether it is related to altered reelin expression. Reelin was visualised via immunohistochemistry, and the number of positive reelin cells/mm2 was measured in the CA4/Hilus, layers of the DG, and the CA1. The dorsal DG had significantly more reelin within the subgranular zone compared to the ventral DG (p < 0.01). There was no difference in reelin between nicotine (n = 5) and controls (n = 5). IHH exposed piglets (n = 10) had significantly lowered reelin in the CA1 (p = 0.05), specifically the stratum pyramidale (p = 0.04) and the hippocampal fissure (p = 0.02), compared to their controls (n = 7); the duration of IHH had no effect. No exposure was associated with an alteration in DG morphology. This study shows that postnatal IHH exposure decreased reelin expression in the developing piglet hippocampal CA1, suggesting that IHH may result in altered neuronal migration.

Polysomnography in infants with clinical suspicion of sleep-related breathing disorders.

STUDY OBJECTIVES: Limited data exist concerning the indications, parameters, utility of daytime polysomnography, and treatment of infants with suspected sleep-related breathing disorders. METHODS: We retrospectively reviewed all polysomnography undertaken in a quaternary pediatric hospital for term infants up to 6 months of age between January 2017 and December 2019. Outcomes were evaluated, including a comparison among diagnostic groups. RESULTS: Of 161 infants (58% male), 77 (48%) were ≤ 2 months old, and 103 (61%) were referred for either craniofacial abnormalities or an airway malformation. Daytime (n = 100) vs nighttime (n = 61) studies showed no differences in sleep architecture or treatment rates. Apnea-hypopnea index was > 10 events/h in 137 (85%) and was similar across different diagnostic groups, and 97 (78%) were prescribed noninvasive ventilation, with a mean treatment duration of 13.4 ± 9 months. Of the infants who were commenced on noninvasive ventilation 75% did not require it beyond 24 months. CONCLUSIONS: Polysomnographic sleep parameters and the number of treatments prescribed were equivalent whether the polysomnography was performed during daytime or nighttime. Treatment with noninvasive ventilation was required in the short term for most infants with sleep-related breathing disorders, regardless of the indication for referral. CITATION: Singh J, Yeoh E, Castro C, Uy C, Waters K. Polysomnography in infants with clinical suspicion of sleep-related breathing disorders. J Clin Sleep Med. 2022;18(12):2803-2812.

Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome.

BACKGROUND: Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death. METHODS: In this case-control study we measured BChE activity and total protein in the eluate of 5µL spots punched from the dried blood spots taken at birth as part of the newborn screening program. Results for each of 67 sudden unexpected deaths classified by the coroner (aged 1 week-104 weeks) = Cases, were compared to 10 date of birth - and gender-matched surviving controls (Controls), with five cases reclassified to meet criteria for SIDS, including the criterion of age 3 weeks to 1 year. FINDINGS: Conditional logistic regression showed that in groups where cases were reported as "SIDS death" there was strong evidence that lower BChE specific activity (BChEsa) was associated with death (OR=0·73 per U/mg, 95% CI 0·60-0·89, P=0·0014), whereas in groups with a "Non-SIDS death" as the case there was no evidence of a linear association between BChEsa and death (OR=1·001 per U/mg, 95% CI 0·89-1·13, P=0·99). INTERPRETATION: BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. We conclude that a previously unidentified cholinergic deficit, identifiable by abnormal -BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. FUNDING: All funding provided by a crowd funding campaign https://www.mycause.com.au/p/184401/damiens-legacy.

Cheyne-stokes respiration in children with heart failure.

Cheyne-Stokes respiration (CSA-CSR) is a form of central sleep apnea characterized by alternating periods of hyperventilation and central apneas or hypopneas. CSA-CSR develops following a cardiac insult resulting in a compensatory increase in sympathetic activity, which in susceptible patients causes hyperventilation and destabilizes respiratory control. The physiological changes that occur in CSA-CSR include hyperventilation, a reduced blood gas buffering capacity, and circulatory delay. In adults, 25% to 50% of patients with heart failure are reported to have CSA-CSR. The development of CSA-CSR in this group of patients is considered a poor prognostic sign. The prevalence, progression, and treatment outcomes of CSA-CSR in children remain unclear with only 11 children being described in the literature. The lack of data is possibly not due to the paucity of children with severe heart failure and CSA-CSR but because they may be under-recognized, compounded by the absence of routine polysomnographic assessment of children with moderate to severe heart failure. Building on much broader experience in the diagnosis and management of CSA-CSR in adult sleep medicine and our limited experience in a pediatric quaternary center, this paper will discuss the prevalence of CSA-CSR, its' treatment options, outcomes in children, and the potential future direction for research in this understudied area of pediatric sleep medicine.

Sudden Unexpected Death in Infancy [SUDI]: What the clinician, pathologist, coroner and researchers want to know.

The loss of an apparently healthy infant is confronting for any family, puzzling for a clinician and challenging for the pathologist charged with the task of demonstrating a cause for death. The term "cot death" evolved to "sudden infant death syndrome" [SIDS] and now "sudden unexpected death in infancy [SUDI]" as the epidemiology and pathology of infant death changed. Community interventions were successful in changing sleep practices for young babies. The current research focus is on understanding genetic predispositions to unexpected death in early childhood. Whilst much has been achieved in reducing the infant mortality rate from SUDI by between 50%, and 80% in some countries, over the last 30 years, there remain challenges for improving rates of accurate diagnosis and reaching out to more vulnerable families with clearly modifiable risk factors for SUDI. These challenges directly involve the clinician through taking a systematic and detailed history and better standardised death scene evaluations with specifically accredited assessors. Better knowledge regarding circumstances of SUDI cases will help Coroners and researchers provide answers for grieving families now, and in the future contribute to further reductions in the rate of SUDI in communities across the world.

Genes involved in paediatric apnoea and death based on knockout animal models: Implications for sudden infant death syndrome (SIDS).

The mechanism of death in Sudden infant death syndrome (SIDS) remains unknown but it is hypothesised that cardiorespiratory failure of brainstem origin results in early post-natal death. For a subset of SIDS infants, an underlying genetic cause may be present, and genetic abnormalities affecting brainstem respiratory control may result in abnormalities that are detectable before death. Genetic knockout mice models were developed in the 1990s and have since helped to elucidate the physiological roles of a number of genes. This systematic review aimed to identify which genes, when knocked out, result in the phenotypes of abnormal cardiorespiratory control and/or early post-natal death. Three major genes were identified: Pet1- a serotonin transcription factor, the neurotrophin pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor (PAC1). Knockouts targeting these genes had blunted hypercapnic and/or hypoxic responses and early post-natal death. The hypothesis that these genes have a role in SIDS is supported by their being identified as abnormal in SIDS cohorts. Future research in SIDS cohorts will be important to determine whether these genetic abnormalities coexist and their potential applicability as biomarkers.

Morphology of the Dentate Gyrus in a Large Cohort of Sudden Infant Deaths-Interrelation Between Features but Not Diagnosis.

Morphological differences in the dentate gyrus (DG) have been reported in sudden unexpected deaths in infancy (SUDI), with the feature of focal granule cell (GC) bilamination (FGCB) reported as increased in unexplained SUDI, including sudden infant death syndrome (SIDS), compared with explained SUDI (eSUDI). However, it remains to be determined how these morphologies relate to each other and their extent along the anteroposterior length. This retrospective study evaluated the prevalence of FGCB, single or clustered ectopic GCs, granule cell dispersion (GCD), heterotopia, hyperconvolution, gaps, thinning, blood vessel dissection (BVD), and cuffing (BV cuffing), in an Australian SUDI cohort, and compared the prevalence of these features in eSUDI and unexplained SUDI. We analyzed 850 formalin-fixed paraffin-embedded serial and subserial sections of the hippocampus at the level of the lateral geniculate nucleus from 90 infants, and identified GCD in 97% of infants, single ectopic cells, hyperconvolution, thinning, and BVD in 60%-80%, heterotopia in 36%, gaps, clusters of ectopic cells and BV cuffing in 9%-15%, and FGCB in 18%. These features are clustered within 3-5 serial sections. The presence of FGCB correlated with single ectopic GCs and hyperconvolution. There were no differences in the prevalence of these features between unexplained SUDI (n = 74) and eSUDI (n = 16). Our findings highlight that DG morphological features are highly localized, extending 14-35 µm at their focal location(s) along the anteroposterior length. Consequently, multiple sections along the longitudinal extent are required to identify them. No feature differentiated SUDI from eSUDI in our cohort, thus we cannot conclude that any of these features are abnormal and it remains to be determined their functional significance.