Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial.

IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02076373

Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial

IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02076373

Nutrient Intake in the First Two Weeks of Life and Brain Growth in Preterm Neonates.

BACKGROUND: Optimizing early nutritional intake in preterm neonates may promote brain health and neurodevelopment through enhanced brain maturation. Our objectives were (1) to determine the association of energy and macronutrient intake in the first 2 weeks of life with regional and total brain growth and white matter (WM) maturation, assessed by 3 serial MRI scans in preterm neonates; (2) to examine how critical illness modifies this association; and (3) to investigate the relationship with neurodevelopmental outcomes. METHODS: Forty-nine preterm neonates (21 boys, median [interquartile range] gestational age: 27.6 [2.3] weeks) were scanned serially at the following median postmenstrual weeks: 29.4, 31.7, and 41. The total brain, basal nuclei, and cerebellum were semiautomatically segmented. Fractional anisotropy was extracted from diffusion tensor imaging data. Nutritional intake from day of life 1 to 14 was monitored and clinical factors were collected. RESULTS: Greater energy and lipid intake predicted increased total brain and basal nuclei volumes over the course of neonatal care to term-equivalent age. Similarly, energy and lipid intake were significantly associated with fractional anisotropy values in selected WM tracts. The association of ventilation duration with smaller brain volumes was attenuated by higher energy intake. Brain growth predicted psychomotor outcome at 18 months\u27 corrected age. CONCLUSIONS: In preterm neonates, greater energy and enteral feeding during the first 2 weeks of life predicted more robust brain growth and accelerated WM maturation. The long-lasting effect of early nutrition on neurodevelopment may be mediated by enhanced brain growth. Optimizing nutrition in preterm neonates may represent a potential avenue to mitigate the adverse brain health consequences of critical illness

Neuroimaging in infants with congenital cytomegalovirus infection and its correlation with outcome: emphasis on white matter abnormalities

Objective: To evaluate the association between neuroimaging and outcome in infants with congenital cytomegalovirus (cCMV), focusing on qualitative MRI and quantitative diffusion-weighted imaging of white matter abnormalities (WMAs). Methods: Multicentre retrospective cohort study of 160 infants with cCMV (103 symptomatic). A four-grade neuroimaging scoring system was applied to cranial ultrasonography and MRI acquired at ≤3 months. WMAs were categorised as multifocal or diffuse. Temporal-pole WMAs (TPWMAs) consisted of swollen or cystic appearance. Apparent diffusion coefficient (ADC) values were obtained from frontal, parieto-occipital and temporal white matter regions. Available follow-up MRI at ≥6 months (N=14) was additionally reviewed. Neurodevelopmental assessment included motor function, cognition, behaviour, hearing, vision and epilepsy. Adverse outcome was defined as death or moderate/severe disability. Results: Neuroimaging scoring was associated with outcome (p<0.001, area under the curve 0.89±0.03). Isolated WMAs (IWMAs) were present in 61 infants, and WMAs associated with other lesions in 30. Although TPWMAs and diffuse pattern often coexisted in infants with IWMAs (p<0.001), only TPWMAs were associated with adverse outcomes (OR 7.8; 95% CI 1.4 to 42.8), including severe hearing loss in 20% and hearing loss combined with other moderate/severe disabilities in 15%. Increased ADC values were associated with higher neuroimaging scores, WMAs based on visual assessment and IWMAs with TPWMAs. ADC values were not associated with outcome in infants with IWMAs. Findings suggestive of progression of WMAs on follow-up MRI included gliosis and malacia. Conclusions: Categorisation of neuroimaging severity correlates with outcome in cCMV. In infants with IWMAs, TPWMAs provide a guide to prognosis

Neuronal autosis is Na+/K+-ATPase alpha 3-dependent and involved in hypoxic-ischemic neuronal death

Abstract Macroautophagy (hereafter called autophagy) is an essential physiological process of degradation of organelles and long-lived proteins. The discovery of autosis, a Na+/K+-ATPase (ATP1)-dependent type of autophagic cell death with specific morphological and biochemical features, has strongly contributed to the acceptance of a pro-death role of autophagy. However, the occurrence and relevance of autosis in neurons has never been clearly investigated, whereas we previously provided evidence that autophagy mechanisms could be involved in neuronal death in different in vitro and in vivo rodent models of hypoxia-ischemia (HI) and that morphological features of autosis were observed in dying neurons following rat perinatal cerebral HI. In the present study, we demonstrated that neuronal autosis could occur in primary cortical neurons using two different stimulations enhancing autophagy flux and neuronal death: a neurotoxic concentration of Tat-BECN1 (an autophagy-inducing peptide) and a hypoxic/excitotoxic stimulus (mimicking neuronal death induced by cerebral HI). Both stimulations induce autophagic neuronal death (dependent on canonical autophagic genes and independent on apoptotic, necroptotic or ferroptotic pathways) with all morphological and biochemical (ATP1a-dependent) features of autosis. However, we demonstrated that autosis is not dependent on the ubiquitous subunit ATP1a1 in neurons, as in dividing cell types, but on the neuronal specific ATP1a3 subunit. We also provided evidence that, in different in vitro and in vivo models where autosis is induced, ATP1a3-BECN1 interaction is increased and prevented by cardiac glycosides treatment. Interestingly, an increase in ATP1a3-BECN1 interaction is also detected in dying neurons in the autoptic brains of human newborns with severe hypoxic-ischemic encephalopathy (HIE). Altogether, these results suggest that ATP1a3-BECN1-dependent autosis could play an important role in neuronal death in HI conditions, paving the way for the development of new neuroprotective strategies in hypoxic-ischemic conditions including in severe case of human HIE

Clinical management of pregnant women exposed to Zika virus

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Hypomagnesaemia-hypercalciuria-nephrocalcinosis: a report of nine cases and a review

Background. The cardinal characteristics of primary hypomagnesaemia-hypercalciuria-nephrocalcinosis include renal magnesium wasting, marked hypercalciuria, renal stones, nephrocalcinosis, a tendency towards chronic renal insufficiency and sometimes even ocular abnormalities or hearing impairment. Methods. As very few patients with this syndrome have been described, we provide information on nine patients on follow‐up at our institutions and review the 42 cases reported in the literature (33 females and 18 males). Results. Urinary tract infections, polyuria-polydipsia, renal stones and tetanic convulsions were the main clinical findings at diagnosis. The clinical course was highly variable; renal failure was often reported. The concomitant occurrence of ocular involvement or hearing impairment was reported in a large subset of patients. Parental consanguinity was noted in some families. Conclusions. The results indicate an autosomal recessive inheritance. The diagnosis of primary hypomagnesaemia-hypercalciuria-nephrocalcinosis deserves consideration in any patient with nephrocalcinosis and hypercalciuri