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  • Journal article
    Cartwright JH, Aziz Q, Harmer SC, Thayyil S, Tinker A, Munroe PBet al., 2020,

    Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function

    , Human Molecular Genetics, Vol: 29, Pages: 1797-1807, ISSN: 0964-6906

    INTRODUCTION: Stillbirth is the loss of a foetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing foetus. We observed four heterozygous, nonsynonymous variants in TRPM7, a ubiquitously expressed ion channel known to regulate cardiac development and repolarisation in mice. METHODS: We used site-directed mutagenesis and single-cell patch-clamp to analyse the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. RESULTS: Our results show that two TRPM7 variants, p.G179V and p.T860M lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents, however siRNA knockdown did not directly affect action potential morphology. CONCLUSION: TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.

  • Journal article
    Kariholu U, Montaldo P, Markati T, Lally PJ, Teiserskas J, Liow N, Oliveira V, Soe A, Shankaran S, Thayyil Set al., 2020,

    Therapeutic hypothermia for mild neonatal encephalopathy: A systematic review and meta-analysis

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 105, Pages: 225-228, ISSN: 1359-2998

    Objectives To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).Data source MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using ‘hypoxic ischaemic encephalopathy’, ‘newborn’ and ‘hypothermia’, and ‘clinical trials’ as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.Study selection Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.Data extraction Safety and efficacy data extracted independently by two reviewers and analysed.Results We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).Conclusions Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.

  • Journal article
    Montaldo P, Vakharia A, Ivain P, Mendoza J, Oliveira V, Markati T, Shankaran S, Thayyil Set al., 2020,

    Pre-emptive opioid sedation during therapeutic hypothermia

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 105, Pages: 108-109, ISSN: 1359-2998
  • Journal article
    Thayyil S, 2019,

    Cooling therapy for the management of hypoxic-ischaemic encephalopathy in middle-income countries: we can, but should we?

    , Paediatrics and International Child Health, Vol: 39, Pages: 231-233, ISSN: 2046-9047

    In the past decade a large number of studies of cooling for the treatment of hypoxic-ischaemic encephalopathy have been reported from middleincome countries (MIC), yet credible evidence of its safety and efficacy is still lacking. Although cooling therapy should not be considered in settings which lack basic neonatal care, many neonatal units in India and other MIC have excellent tertiary neonatal intensive care facilities. Most of these centres now routinely offer cooling therapy in clinical practice using a wide range of devices including ice and phase-change material (PCM). A large trial (HELIX: Hypothermia for Encephalopathy in Low- and Middle-Income Countries) involving 408 infants with moderate and severe encephalopathy in seven tertiary academic neonatal units in India, Sri Lanka and Bangladesh recently completed recruitment, and assessment of the neurodevelopmental outcome is ongoing. Considering the differences in population co-morbidities and the strong association between increased neonatal mortality and hypothermia, it would be prudent for clinicians in tertiary neonatal units in MIC to await the results of the HELIX trial before offering cooling therapy as standard care.

  • Journal article
    Montaldo P, Lally P, Oliveira V, Swamy R, Mendoza J, Atreja G, Kariholu U, Shivamurthappa V, Liow N, Teiserskas J, Pryce R, Soe A, Shankaran S, Thayyil Set al., 2019,

    Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic ischemic encephalopathy: a non-randomised cohort study

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 104, Pages: F515-F520, ISSN: 1359-2998

    Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE).Design Non-randomised cohort study.Setting Eight tertiary neonatal units in the UK and the USA.Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth.Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours).Main outcome measures MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years.Results The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).Conclusions Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.

  • Journal article
    Oliveira V, von Rosenberg W, Montaldo P, Adjei T, Mendoza J, Shivamurthappa V, Mandic D, Thayyil Set al., 2019,

    Early postnatal heart rate variability in healthy newborn infants

    , Frontiers in Physiology, Vol: 10, Pages: 1-12, ISSN: 1664-042X

    Background: Despite the increasing interest in fetal and neonatal heart rate variability (HRV) analysis and its potential use as a tool for early disease stratification, no studies have previously described the normal trends of HRV in healthy babies during the first hours of postnatal life.Methods: We prospectively recruited 150 healthy babies from the postnatal ward and continuously recorded their electrocardiogram during the first 24 h after birth. Babies were included if born in good condition and stayed with their mother. Babies requiring any medication or treatment were excluded. Five-minute segments of the electrocardiogram (non-overlapping time-windows) with more than 90% consecutive good quality beats were included in the calculation of hourly medians and interquartile ranges to describe HRV trends over the first 24 h. We used multilevel mixed effects regression with auto-regressive covariance structure for all repeated measures analysis and t-tests to compare group differences. Non-normally distributed variables were log-transformed.Results: Nine out of 16 HRV metrics (including heart rate) changed significantly over the 24 h [Heart rate p < 0.01; Standard deviation of the NN intervals p = 0.01; Standard deviation of the Poincaré plot lengthwise p < 0.01; Cardiac sympathetic index (CSI) p < 0.01; Normalized high frequency power p = 0.03; Normalized low frequency power p < 0.01; Total power p < 0.01; HRV index p = 0.01; Parseval index p = 0.03], adjusted for relevant clinical variables. We observed an increase in several HRV metrics during the first 6 h followed by a gradual normalization by approximately 12 h of age. Between 6 and 12 h of age, only heart rate and the normalized low frequency power changed significantly, while between 12 and 18 h no metric, other than heart rate, changed significantly. Analysis with multilevel mixed effects regression analysis (multivariable) revealed that gestational age, reduced fetal movements, cardi

  • Journal article
    Montaldo P, Swamy R, Bassett P, Lally PJ, Shankaran S, Thayyil Set al., 2019,

    Pitfalls in using neonatal brain NAA to predict infant development - Authors' reply.

    , The Lancet Neurology, Vol: 18, Pages: 423-424, ISSN: 1474-4422
  • Journal article
    Thayyil S, Liow N, Montaldo P, Lally P, Teiserskas J, Bassett P, Oliveira V, Mendoza J, Slater R, Shankaran Set al., 2019,

    Pre-emptive morphine during therapeutic hypothermia after neonatal encephalopathy: a secondary analysis

    , Therapeutic Hypothermia and Temperature Management, Vol: 10, Pages: 45-52, ISSN: 2153-7658

    Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate (n = 150) or severe NE (n = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion (n = 141) were more hypotensive (49% vs. 25%, p = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days, p = 0.009) than those who did not (n = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group (p > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5; p = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12–0.21] vs. 0.13 [0.11–0.18]; p = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10; p = 0.98), language (89 ± 22 vs. 93 ± 

  • Journal article
    Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil Set al., 2019,

    Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study

    , Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422

    BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after

  • Journal article
    Montaldo P, Kaforou M, Pollara G, Hervás-Maríne D, Calabria I, Panadero J, Pedrola L, Lally PJ, Oliveira V, Kage A, Atreja G, Mendoza J, Soe A, Pattnayak S, Shankaranh S, Vento M, Herberg J, Thayyil Set al., 2019,

    Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy

    , Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800

    BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.

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