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

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 ± 8; p = 0.53), and cognitive scores (95 ± 21 vs. 99 ± 13; p = 0.56) at 22 months. Adverse neurodevelopmental outcome (adjusted for severity of encephalopathy) was seen in 26 (18%) of the morphine group, and none of the nonmorphine group (p = 0.11). Preemptive morphine sedation during TH does not offer any neuroprotective benefits and may be associated with increased hospital stay. Optimal sedation during induced hypothermia requires further evaluation in clinical trials

White matter injury after neonatal encephalopathy is associated with thalamic metabolite perturbations

Background Although thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes. Methods We performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome. Findings Of the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18–0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45–7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16–1.00); specificity 0.95 (95% CI 0.84–0.99)). Interpretation Thalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes. Funding The National Institute for Health Research (NIHR)

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

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

Early improvement of glycaemic control after virus clearance in patients with chronic hepatitis C and severe liver fibrosis: a cohort study

HCV has been recognized as the cause of chronic hepatitis C (CHC) since 1990. CHC is associated with progressive liver damage and extrahepatic conditions. Direct antiviral agents (DAAs), approved in 2014, have shown effectiveness in eradicating HCV in most patients. However, little is known about the effect of viral eradication on hepatic and extra-hepatic damage. We performed a historical cohort study of patients with HCV-related liver diseases who achieved SVR from March 2015 to October 2016 at INMI Lazzaro Spallanzani liver Unit in Rome (Italy). Repeated measures of glycaemia were analysed through a multilevel analysis framework to assess short time kinetics of blood glucose level at different times after therapy and for different levels of HCV viremia. The analysis included 205 patients. A model assessing temporal kinetics and variation of glycaemia according to HCV viremia provided evidence that blood glucose levels significantly dropped in patients with diabetes achieving SVR. Most of the variations occurred at 3-5 weeks of therapy (-17.96 mg/dL; p<0.001) and in coincidence with HCV clearance (-13.92 mg/dL; p<0.001). A weak, non-statistically significant reduction was observed in normoglycemic patients. Our study provides evidence that DAAs therapy may significantly improve glycaemic control in patients with CHC achieving SVR even when liver diseases are already established

Looking for pathways related to COVID-19: confirmation of pathogenic mechanisms by SARS-CoV-2-host interactome

In the last months, many studies have clearly described several mechanisms of SARS-CoV-2 infection at cell and tissue level, but the mechanisms of interaction between host and SARS-CoV-2, determining the grade of COVID-19 severity, are still unknown. We provide a network analysis on protein–protein interactions (PPI) between viral and host proteins to better identify host biological responses, induced by both whole proteome of SARS-CoV-2 and specific viral proteins. A host-virus interactome was inferred, applying an explorative algorithm (Random Walk with Restart, RWR) triggered by 28 proteins of SARS-CoV-2. The analysis of PPI allowed to estimate the distribution of SARS-CoV-2 proteins in the host cell. Interactome built around one single viral protein allowed to define a different response, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, the network-based approach highlighted a possible direct action of ORF3a and NS7b to enhancing Bradykinin Storm. This network-based representation of SARS-CoV-2 infection could be a framework for pathogenic evaluation of specific clinical outcomes. We identified possible host responses induced by specific proteins of SARS-CoV-2, underlining the important role of specific viral accessory proteins in pathogenic phenotypes of severe COVID-19 patients

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial

IMPORTANCE: The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown. OBJECTIVE: To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn). Design, Setting, and PARTICIPANTS: This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks' gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020. Exposure: 3T MR imaging, MR spectroscopy, and diffusion tensor imaging. MAIN OUTCOMES AND MEASURES: Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months. RESULTS: Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], -0.28; 95% CI, -1.62 to 1.07; P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, -0.62 to 0.71; P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08; P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09; P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41). CONCLUSIONS AND RELEVANCE: In this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02387385

Prospective research on infants with mild encephalopathy: the PRIME study.

OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.Journal of Perinatology advance online publication, 2 November 2017; doi:10.1038/jp.2017.164

Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device

Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC. Design: We recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge. Results: Eighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality. Conclusions: The low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs. Clinical trial registration number: NCT01760629

COVID-19 disease - Temporal analyses of complete blood count parameters over course of illness, and relationship to patient demographics and management outcomes in survivors and non-survivors: a longitudinal descriptive cohort study

Background. Detailed temporal analyses of complete (full) blood count (CBC) parameters, their evolution and relationship to patient age, gender, co-morbidities and management outcomes in survivors and non-survivors with COVID-19 disease, could identify prognostic clinical biomarkers. Methods. From 29 January 2020 until 28 March 2020, we performed a longitudinal cohort study of COVID-19 inpatients at the Italian National Institute for Infectious Diseases, Rome, Italy. 9 CBC parameters were studied as continuous variables [neutrophils, lymphocytes, monocytes, platelets, mean platelet volume, red blood cell count, haemoglobin concentration, mean red blood cell volume and red blood cell distribution width (RDW %)]. Model-based punctual estimates, as average of all patients' values, and differences between survivors and non-survivors, overall, and by co-morbidities, at specific times after symptoms, with relative 95% CI and P-values, were obtained by marginal prediction and ANOVA- style joint tests. All analyses were carried out by STATA 15 statistical package. Main findings. 379 COVID-19 patients [273 (72% were male; mean age was 61.67 (SD 15.60)] were enrolled and 1,805 measures per parameter were analysed. Neutrophils' counts were on average significantly higher in non-survivors than in survivors (P&lt;0.001) and lymphocytes were on average higher in survivors (P&lt;0.001). These differences were time dependent. Average platelets' counts (P&lt;0.001) and median platelets' volume (P&lt;0.001) were significantly different in survivors and non-survivors. The differences were time dependent and consistent with acute inflammation followed either by recovery or by death. Anaemia with anisocytosis was observed in the later phase of COVID-19 disease in non-survivors only. Mortality was significantly higher in patients with diabetes (OR = 3.28; 95%CI 1.51-7.13; p = 0.005), obesity (OR = 3.89; 95%CI 1.51-10.04; p = 0.010), chronic renal failure (OR = 9.23; 95%CI 3.49-24.36; p = 0.001), COPD (OR = 2.47; 95% IC 1.13-5.43; p = 0.033), cardiovascular diseases (OR = 4.46; 95%CI 2.25-8.86; p = 0.001), and those &gt;60 years (OR = 4.21; 95%CI 1.82-9.77; p = 0.001). Age (OR = 2.59; 95%CI 1.04-6.45; p = 0.042), obesity (OR = 5.13; 95%CI 1.81-14.50; p = 0.002), renal chronic failure (OR = 5.20; 95%CI 1.80-14.97; p = 0.002) and cardiovascular diseases (OR 2.79; 95%CI 1.29-6.03; p = 0.009) were independently associated with poor clinical outcome at 30 days after symptoms' onset. Interpretation. Increased neutrophil counts, reduced lymphocyte counts, increased median platelet volume and anaemia with anisocytosis, are poor prognostic indicators for COVID19, after adjusting for the confounding effect of obesity, chronic renal failure, COPD, cardiovascular diseases and age &gt;60 years

Siderophore-Mediated Zinc Acquisition Enhances Enterobacterial Colonization of the Inflamed Gut

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or “Nissle”) exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin’s affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae