Quantification of Maceration Changes using Post Mortem MRI in Fetuses

BACKGROUND: Post mortem imaging is playing an increasingly important role in perinatal autopsy, and correct interpretation of imaging changes is paramount. This is particularly important following intra-uterine fetal death, where there may be fetal maceration. The aim of this study was to investigate whether any changes seen on a whole body fetal post mortem magnetic resonance imaging (PMMR) correspond to maceration at conventional autopsy. METHODS: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla Siemens Avanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to the clinical history and autopsy data using a numerical severity scale (0 = no maceration changes to 2 = severe maceration changes) for 6 different visceral organs (total 12). The degree of maceration at autopsy was categorized according to severity on a numerical scale (1 = no maceration to 4 = severe maceration). We also generated quantitative maps to measure the liver and lung T2. RESULTS: The mean PMMR maceration score correlated well with the autopsy maceration score (R(2) = 0.93). A PMMR score of ≥4.5 had a sensitivity of 91%, specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver and lung T2 were increased in fetuses with maceration scores of 3-4 in comparison to those with 1-2 (liver p = 0.03, lung p = 0.02). CONCLUSIONS: There was a good correlation between PMMR maceration score and the extent of maceration seen at conventional autopsy. This score may be useful in interpretation of fetal PMMR

Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy

We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage)

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 in mild neonatal encephalopathy: a national survey of practice in the UK

Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy

Energy efficiency measures for buildings in Hebron city and their expected impacts in the distribution grid

Theenergye ffi ciencyinbuildingscouldrepresentoneofthemainopportunity,withinawidestrategicscenario,toachieveenergy independenceofPalestine.Infact,thereductionofbuildingenergydemandduetotheimplementationofenergye ffi ciency measuresleadstoaconsequentdecreaseoftheenergyprovisionneeds.Forthisreasonananalysisofthepotentialreduction oftheenergyconsumptioninbuildingneedtobeperformedandapossibleestimationofcostsshouldbeidentifiedfordefining aenergystrategicplanofPalestine.Thispaperintendstohighlightthepotentialoftheenergye ffi ciencymeasuresindi ff erent buildingtypologiesofHebroncityinPalestineandtheirimpactintheelectricaldistributiongrid.Thee ff ectivenessofthedi ff erent measuresareestimatedbymeansofsoftwaresimulationsandtheiroptimalcombinationisalsoidentifiedinordertomaximize thereductionofenergydemands.Finally,thevariationofpowerlossesinthedistributiongridduetotheretrofitactionanda preliminaryestimationofpossibleeconomice ff ortfortheimplementationoftheproposedactionsarealsoexpose

Human metapneumovirus driven IFN-β production antagonizes macrophage transcriptional induction of IL1-β in response to bacterial pathogens

Human metapneumovirus (HMPV) is a pneumovirus that may cause severe respiratory disease in humans. HMPV infection has been found to increase susceptibility to bacterial superinfections leading to increased morbidity and mortality. The molecular mechanisms underlying HMPV-mediated increase in bacterial susceptibility are poorly understood and largely understudied. Type I interferons (IFNs), while critical for antiviral defenses, may often have detrimental effects by skewing the host immune response and cytokine output of immune cells. It is currently unknown if HMPV skews the inflammatory response in human macrophages triggered by bacterial stimuli. Here we report that HMPV pre-infection impacts production of specific cytokines. HMPV strongly suppresses IL-1β transcription in response to LPS or heat-killed Pseudomonas aeruginosa and Streptococcus pneumonia, while enhancing mRNA levels of IL-6, TNF-α and IFN-β. We demonstrate that in human macrophages the HMPV-mediated suppression of IL-1β transcription requires TANK-binding kinase 1 (TBK1) and signaling via the IFN-β-IFNAR axis. Interestingly, our results show that HMPV pre-infection did not impair the LPS-stimulated activation of NF-κB and HIF-1α, transcription factors that stimulate IL-1β mRNA synthesis in human cells. Furthermore, we determined that sequential HMPV-LPS treatment resulted in accumulation of the repressive epigenetic mark H3K27me3 at the IL1B promoter. Thus, for the first time we present data revealing the molecular mechanisms by which HMPV shapes the cytokine output of human macrophages exposed to bacterial pathogens/LPS, which appears to be dependent on epigenetic reprogramming at the IL1B promoter leading to reduced synthesis of IL-1β. These results may improve current understanding of the role of type I IFNs in respiratory disease mediated not only by HMPV, but also by other respiratory viruses that are associated with superinfections.</p

NK cells and other innate lymphoid cells in hematopoietic stem cell transplantation

Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34+ cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT

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