Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease.

Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.

Thermoregulation and golden hour practices in extremely preterm infants: an international survey.

BACKGROUND: Are thermoregulation and golden hour practices in extremely preterm (EP) infants comparable across the world? This study aims to describe these practices for EP infants based on the neonatal intensive care unit's (NICUs) geographic region, country's income status and the lowest gestational age (GA) of infants resuscitated. METHODS: The Director of each NICU was requested to complete the e-questionnaire between February 2019 and August 2021. RESULTS: We received 848 responses, from all geographic regions and resource settings. Variations in most thermoregulation and golden hour practices were observed. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission, and having local protocols were the most consistent practices (>75%). The odds for the following practices differed in NICUs resuscitating infants from 22 to 23 weeks GA compared to those resuscitating from 24 to 25 weeks: respiratory support during resuscitation and transport, use of polyethylene plastic wrap and servo-control mode, commencing ambient humidity >80% and presence of local protocols. CONCLUSION: Evidence-based practices on thermoregulation and golden hour stabilisation differed based on the unit's region, country's income status and the lowest GA of infants resuscitated. Future efforts should address reducing variation in practice and aligning practices with international guidelines. IMPACT: A wide variation in thermoregulation and golden hour practices exists depending on the income status, geographic region and lowest gestation age of infants resuscitated. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission and having local protocols were the most consistent practices. This study provides a comprehensive description of thermoregulation and golden hour practices to allow a global comparison in the delivery of best evidence-based practice. The findings of this survey highlight a need for reducing variation in practice and aligning practices with international guidelines for a comparable health care delivery.

Skincare practices in extremely premature infants: A survey of tertiary neonatal intensive care units from Australia and New Zealand.

AIM: To investigate skincare practices in the first 2 weeks of life in extremely premature infants across tertiary neonatal intensive care units (NICUs). METHODS: A web-based secure survey invite was emailed to the medical directors of tertiary NICUs. The survey included questions on various aspects of skincare practices in the first 2 weeks of life in extremely premature infants (born before 28 weeks gestation). The person most familiar with local skincare practices was asked to complete the survey and only one response per unit was requested. We performed a descriptive analysis. RESULTS: We received responses from 30 out of 32 NICUs (response rate 93%). Twenty-five NICUs (89%) reported offering resuscitation and intensive care to infants born at ≥23 weeks gestation. All NICUs reported occurrences of skin breakdown, including medical adhesive-related skin injury (30%), abrasion/friction-associated skin injury (46%), perineal skin breakdown (55%), pressure site injury (47%) and diaper dermatitis (60%). A high level of consensus (≥75%) was observed for certain practices, such as the use of polyethylene occlusive plastic wraps at birth and aqueous chlorhexidine solution for sterile procedures, but a low level of consensus (<25%) was observed for many other practices, including the skin risk assessment tool used. CONCLUSIONS: Skin injuries in extremely premature infants are common and skincare practices vary considerably amongst NICUs. Clinical practice improvement projects and further clinical research will help improve consistency amongst NICUs. Further research is needed to assist the development of evidence-based guidelines and benchmarking for skincare practices in these vulnerable infants.

Sail sign in neonatal pneumomediastinum: a case report.

BACKGROUND: Pneumomediastinum is an uncommon cause of neonatal respiratory distress. Clinical history and examination of the neonate may be uninformative in determining the aetiology of the respiratory distress. Chest x-ray can be diagnostic of pneumomediastinum however is often difficult to interpret. CASE PRESENTATION: A 36 week gestation newborn was delivered by emergency caesarean section, intubated and given intermittent positive pressure ventilation via Neopuff™ for apnoea before being extubated to CPAP. Chest radiography initially showed bilateral upper zone opacities, presenting a diagnostic dilemma; however subsequent films demonstrated a pneumomediastinum which was managed conservatively and resolved. CONCLUSIONS: The "sail sign" describes an uncommon radiological appearance of a pneumomediastinum in neonates and infants. With careful conservative management, a spontaneous resolution without longterm sequelae can be expected.

Transient Neonatal Diabetes Mellitus followed by recurrent asymptomatic hypoglycaemia: a case report.

BACKGROUND: Transient Neonatal Diabetes Mellitus is the commonest cause of diabetes presenting in the first week of life. Majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes later on in life. This condition is usually due to genetic aberrations at the 6q24 gene locus, and can be sporadic or inherited. This disorder has three phases: neonatal diabetes, apparent remission, relapse of diabetes. CASE PRESENTATION: Our case, a neonate presented with low birth weight and growth retardation along with the metabolic profile consistent with transient diabetes mellitus at birth. We report a novel clinical observation of recurrent asymptomatic hypoglycaemia detected on pre-feed blood glucose level monitoring in our case with transient neonatal diabetes mellitus at 6 weeks of age, 4 weeks after the remission of diabetes mellitus. CONCLUSION: This case demonstrates that neonates in remission following transient diabetes mellitus can present with recurrent asymptomatic hypoglycaemia without any other obvious congenital malformations seen. This asymptomatic hypoglycaemia may persist for weeks and may be missed if pre-feed blood glucose level monitoring is not done in these infants. Also, these infants may require an aggressive enteral feeding regimen with high glucose delivery rate to maintain normoglycemia.

Is it feasible to identify preterm infants with respiratory distress syndrome for early extubation to continuous positive airway pressure post-surfactant treatment during retrieval?

AIM: Preterm infants with respiratory distress syndrome (RDS) requiring surfactant treatment are often retrieved mechanically ventilated to the receiving hospital. INSURE (INtubate, SURfactant, Extubate) technique is not routinely performed by Newborn and Pediatric Emergency Transport Services NSW (NETS) during retrieval. This study aims to evaluate the likelihood of using INSURE technique during retrieval. We attempted to study the clinical characteristics of preterm infants with RDS who were favourably extubated (FE) shortly after admission to the receiving hospital. METHODS: Retrospective study of preterm infants, gestational age (GA) > 28 weeks with RDS requiring retrieval by NETS. RESULTS: Two hundred twenty-three infants, median GA of 33 weeks (range 29-36), median birthweight 2200 g (1000-4080) were examined. A percentage of 49.7 received CPAP, and 50.3% required MV. Eighteen (16%) infants were FE (<6 h) at receiving hospital. FiO2 on stabilisation (FiO2 (st)) by NETS correlated with FiO2 on admission to receiving hospital (r = 0.863). A percentage of 81 of ventilated infants received premedications including morphine. No significant differences were noted for GA, stabilisation ventilator settings, surfactant dose (mean 155 mg/kg) and mode of transport between FE and non-FE groups. FiO2 (st) post-surfactant treatment was significantly lower in FE compared with non-FE group (mean 0.28 vs. 0.41 respectively). The area under the curve from receiver operating characteristic based on FiO2 (st) was 0.646 (P = 0.050), the sensitivity and specificity of FiO2 (st) cut-off points (between 0.25 and 0.30) was low. CONCLUSION: FiO2 on stabilisation post-surfactant treatment has a weak predictive value and may not be adequate to be used as sole criteria to extubate to CPAP prior to transport. FiO2 at stabilisation should be included as an eligibility criteria for a randomised trial of INSURE during retrieval, but other clinical assessments are needed.

Randomised study of a new inline respiratory function monitor (Juno) to improve mask seal and delivered ventilation with neonatal manikins.

BACKGROUND: Respiratory function monitors (RFMs) have been used extensively in manikin and infant studies yet have not become the standard of training. We report the outcomes of a new portable, lightweight RFM, the Juno, designed to show mask leak and deflation tidal volume to assist in positive pressure ventilation (PPV) competency training using manikins. METHODS: Two leak-free manikins (preterm and term) were used. Participants provided PPV to manikins using two randomised devices, self-inflating bag (SIB) and T-piece resuscitator (TPR), with Juno display initially blinded then unblinded in four 90 s paired sequences, aiming for adequate chest wall rise and target minimal mask leak with appropriate target delivered volume when using the monitor. RESULTS: 49 experienced neonatal staff delivered 15 569 inflations to the term manikin and 14 580 inflations to the preterm. Comparing blinded to unblinded RFM display, there were significant reductions in all groups in the number of inflations out of target range volumes (preterm: SIB 22.6-6.6%, TPR 7.1-4.2% and term: SIB 54.8-37.8%, TPR 67.2-63.8%). The percentage of mask leak inflations >60% was reduced in preterm: SIB 20.7-7.2%, TPR 23.4-7.4% and in term: SIB 8.7-3.6%, TPR 23.5-6.2%). CONCLUSIONS: Using the Juno monitor during simulated resuscitation significantly improved mask leak and delivered ventilation among otherwise experienced staff using preterm and term manikins. The Juno is a novel RFM that may assist in teaching and self-assessment of resuscitation PPV technique.

Comparison of simultaneous auscultation and ultrasound for clinical assessment of bowel peristalsis in neonates.

Introduction: Assessment of bowel health in ill preterm infants is essential to prevent and diagnose early potentially life-threatening intestinal conditions such as necrotizing enterocolitis. Auscultation of bowel sounds helps assess peristalsis and is an essential component of this assessment. Aim: We aim to compare conventional bowel sound auscultation using acoustic recordings from an electronic stethoscope to real-time bowel motility visualized on point-of-care bowel ultrasound (US) in neonates with no known bowel disease. Methods: This is a prospective observational cohort study in neonates on full enteral feeds with no known bowel disease. A 3M™ Littmann® Model 3200 electronic stethoscope was used to obtain a continuous 60-s recording of bowel sounds at a set region over the abdomen, with a concurrent recording of US using a 12l high-frequency Linear probe. The bowel sounds heard by the first investigator using the stethoscope were contemporaneously transferred for a computerized assessment of their electronic waveforms. The second investigator, blinded to the auscultation findings, obtained bowel US images using a 12l Linear US probe. All recordings were analyzed for bowel peristalsis (duration in seconds) by each of the two methods. Results: We recruited 30 neonates (gestational age range 27-43 weeks) on full enteral feeds with no known bowel disease. The detection of bowel peristalsis (duration in seconds) by both methods (acoustic and US) was reported as a percentage of the total recording time for each participant. Comparing the time segments of bowel sound detection by digital stethoscope recording to that of the visual detection of bowel movements in US revealed a median time of peristalsis with US of 58%, compared to 88.3% with acoustic assessment (p < 0.002). The median regression difference was 26.7% [95% confidence interval (CI) 5%-48%], demonstrating no correlation between the two methods. Conclusion: Our study demonstrates disconcordance between the detection of bowel sounds by auscultation and the detection of bowel motility in real time using US in neonates on full enteral feeds and with no known bowel disease. Better innovative methods using artificial intelligence to characterize bowel sounds, integrating acoustic mapping with sonographic detection of bowel peristalsis, will allow us to develop continuous neonatal bowel sound monitoring devices.

Ensemble Approach on Deep and Handcrafted Features for Neonatal Bowel Sound Detection.

For the care of neonatal infants, abdominal auscultation is considered a safe, convenient, and inexpensive method to monitor bowel conditions. With the help of early automated detection of bowel dysfunction, neonatologists could create a diagnosis plan for early intervention. In this article, a novel technique is proposed for automated peristalsis sound detection from neonatal abdominal sound recordings and compared to various other machine learning approaches. It adopts an ensemble approach that utilises handcrafted as well as one and two dimensional deep features obtained from Mel Frequency Cepstral Coefficients (MFCCs). The results are then refined with the help of a hierarchical Hidden Semi-Markov Models (HSMM) strategy. We evaluate our method on abdominal sounds collected from 49 newborn infants admitted to our tertiary Neonatal Intensive Care Unit (NICU). The results of leave-one-patient-out cross validation show that our method provides an accuracy of 95.1% and an Area Under Curve (AUC) of 85.6%, outperforming both the baselines and the recent works significantly. These encouraging results show that our proposed Ensemble-based Deep Learning model is helpful for neonatologists to facilitate tele-health applications.

Neonatologist-performed point-of-care abdominal ultrasound: What have we learned so far?

This review describes the sonographic appearances of the neonatal bowel in Necrotising enterocolitis. It compares these findings to those seen in midgut-Volvulus, obstructive intestinal conditions such as milk-curd obstruction, and slow gut motility in preterm infants on continuous positive airway pressure (CPAP)-CPAP belly syndrome. Point-of-care bowel ultrasound is also helpful in ruling out severe and active intestinal conditions, reassuring clinicians when the diagnosis is unclear in a non-specific clinical presentation where NEC cannot be excluded. As NEC is a severe disease, it is often over-diagnosed, mainly due to a lack of reliable biomarkers and clinical presentation similar to sepsis in neonates. Thus, the assessment of the bowel in real-time would allow clinicians to determine the timing of re-initiation of feeds and would also be reassuring based on specific typical bowel characteristics visualised on the ultrasound.