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Abstract. Background:. Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges. The study aimed to analyze the clinical characteristics of VLBW infants. Methods:. A retrospective cohort study was conducted in West China Second Hospital between January 2016 and December 2021. Neonates with a birth weight of

Introduction: Endothelial dysfunction indicates blood vessel injury and is a risk factor for cardiovascular diseases. Blueberry has been approved for its benefits on human health, especially on cardiovascular function. However, its effect on endothelial function remains unclear. We conducted a systematic review and meta-analysis to explore the impact of blueberries on endothelial function in adults.Methods: We searched PubMed, Web of Science, Embase, and the Cochrane Library, 16 studies were included in the systematic review, and 11 were used for the meta-analysis. Data associated with endothelial function were extracted and pooled as mean differences (MD) with 95% confidence intervals (CI).Results: Blueberry consumption significantly improved flow-mediated dilation (FMD) by 1.50% (95% CI: 0.81, 2.20; I2 = 87%) and reactive hyperemia index (RHI) by 0.26 (95% CI: 0.09, 0.42; I2 = 72%). A significant decrease in diastolic blood pressure (DBP) was also observed (MD: −2.20 mm Hg; 95% CI: −4.13, −0.27; I2 = 11%). Subgroup analysis indicated a significant decrease in blood pressure (Systolic blood pressure [SBP]: −3.92 mmHg; 95% CI: −6.88, −0.97; I2 = 20% and DBP: −2.20 mmHg; 95% CI: −4.13, −0.27; I2 = 11%) in the smoking population. However, SBP levels (MD: −1.43 mm Hg; 95% CI: −3.11, 0.26; I2 = 20%) and lipid status (high-density lipoprotein cholesterol [HDL-C]: 0.06; 95% CI: −0.04, 0.16; I2 = 77%; low-density lipoprotein cholesterol [LDL-C]: 0.05; 95% CI: −0.14, 0.24; I2 = 0%) did not significantly improve.Conclusion: Blueberry intervention improved endothelial function and DBP. Subgroup analysis revealed a notable improvement in blood pressure among the smoking population. However, no significant effects were observed on SBP, HDL-C, and LDL-C levels. Future research should delve into the mechanisms of endothelial improvement and verify blood pressure reduction in specific subpopulations through large-scale trials.Clinical Trial Registration:https://www.crd.york.ac.uk/PROSPERO/, Identifier CRD42023491277.

Abstract Early-life human gut microbiome is a pivotal driver of gut homeostasis and infant health. However, the viral component (known as “virome”) remains mostly unexplored. Here, we establish the Early-Life Gut Virome (ELGV), a catalog of 160,478 non-redundant DNA and RNA viral sequences from 8130 gut virus-like particles (VLPs) enriched or bulk metagenomes in the first three years of life. By clustering, 82,141 viral species are identified, 68.3% of which are absent in existing databases built mainly from adults, and 64 and 8 viral species based on VLPs-enriched and bulk metagenomes, respectively, exhibit potentials as biomarkers to distinguish infants from adults. With the largest longitudinal population of infants profiled by either VLPs-enriched or bulk metagenomic sequencing, we track the inherent instability and temporal development of the early-life human gut virome, and identify differential viruses associated with multiple clinical factors. The mother-infant shared virome and interactions between gut virome and bacteriome early in life are further expanded. Together, the ELGV catalog provides the most comprehensive and complete metagenomic blueprint of the early-life human gut virome, facilitating the discovery of pediatric disease-virome associations in future.

Abstract Background Extracorporeal membrane oxygenation (ECMO) has been widely used in severe neonatal diseases for approximately 50 years, while few studies have concentrated on the long-term follow-up of its neuropsychological development. Objective To assess the long-term neuropsychological complications in children who underwent ECMO in infancy. Methods The PubMed, Web of Science, Cochrane, and EMBASE databases were searched for retrieving studies published in the recent 10 years (until June 10, 2022). All studies were eligible that concentrated on the long-term follow-up of neuropsychological complications in neonates undergoing ECMO. Excluding animal studies, neonates with congenital craniocerebral dysplasia and studies with data from the same center performed at different times. Statistical analysis was performed using RevMan 5.3 and Stata/SE 12.0 software. A random-effects model was used to report results. The sensitivity analysis was utilized to identify sources of heterogeneity. Results The meta-analysis of 10 studies that enrolled 1199 patients was conducted, showing the pooled morbidity of intelligence (pooled morbidity: 20.3%, 95% CI: 0.16-0.25, I 2 : 9.5%, P=0.33), motor activity (pooled morbidity: 10.3%, 95%CI: 0.07-0.14, I 2 : 43.5%, P=0.15), learning (pooled morbidity: 9.0%, 95%CI: -0.03-0.21, I 2 : 63.2%, P=0.10), hearing (pooled morbidity: 15.7%, 95%CI: 0.02-0.29, I 2 : 94.2%, P=0.00), vision (pooled morbidity: 18.5%, 95%CI: 0.12-0.25, I 2 : 0%, P=0.46), cognition (pooled morbidity: 26.3%, 95%CI: 0.19-0.34, I 2 : 0%, P=0.32), attention (pooled morbidity: 7.4%, 95%CI: 0.02-0.13, I 2 : 38.9%, P=0.20), speed in attention (pooled morbidity: 69.9%, 95%CI: 0.62-0.78), and accuracy in attention (pooled morbidity: 39.0%, 95%CI: 0.30-0.48) in neonates undergoing ECMO. The results of the Begg's test and sensitivity analysis indicated that the heterogeneity was originated from factors other than sample size. Conclusion This systematic review and meta-analysis showed that neonates undergoing ECMO were associated with various neuropsychological complications. Additional randomized controlled trials (RCTs) with a larger sample size and a higher quality are needed.

Methyltransferase-like 3 (METTL3), a component of the RNA N6-methyladenosine (m6A) modification with a specific catalytic capacity, controls gene expression by actively regulating RNA splicing, nuclear export, stability, and translation, determines the fate of RNAs and assists in regulating biological processes. Studies conducted in recent decades have demonstrated the pivotal regulatory role of METTL3 in liver disorders, including hepatic lipid metabolism disorders, liver fibrosis, nonalcoholic steatohepatitis, and liver cancer. Although METTL3’s roles in these diseases have been extensively investigated, the regulatory network of METTL3 and its potential applications remain unexplored. In this review, we provide a comprehensive overview of the roles and mechanisms of METTL3 implicated in these diseases, establish a regulatory network of METTL3, evaluate the potential for targeting METTL3 for diagnosis and treatment, and discuss avenues for future development and research. We found relatively upregulated expressions of METTL3 in these liver diseases, demonstrating its potential as a diagnostic biomarker and therapeutic target.

Abstract. Background:. Extreme temperature events, including extreme cold, are becoming more frequent worldwide, which might be harmful to pregnant women and cause adverse birth outcomes. We aimed to investigate the association between exposure to low ambient temperature in pregnant women and adverse birth outcomes, such as preterm birth, low birth weight, and stillbirth, and to summarize the evidence herein. Methods:. Relevant studies were searched in PubMed, Cochrane, and Embase electronic databases until November 2021. Studies involving low ambient temperature, preterm birth, birth weight, and stillbirth were included. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed to conduct this study risk of bias and methods for data synthesis. Results:. A total of 34 studies were included. First, pregnant women exposed to low ambient temperature had an increased risk of preterm birth (risk ratio [RR] 1.08; 95% confidence interval [CI] 1.04–1.13). Subgroup analyses revealed that exposure during late pregnancy was more likely to induce preterm birth. In addition, only pregnant women exposed to

Abstract Background Health problems in neonates with gestational age (GA) ≥ 32 weeks remain a major medical concern. Respiratory distress (RD) is one of the common reasons for admission of neonates with GA ≥ 32 weeks. Noninvasive ventilation (NIV) represents a crucial approach to treat RD, and currently, the most used NIV modes in neonatal intensive care unit include high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and nasal intermittent positive pressure ventilation. Although extensive evidence supports the use of NIPPV in neonates with a GA

Abstract Background The RNA m6A modification has been implicated in multiple neurological diseases as well as macrophage activation. However, whether it regulates microglial activation during hypoxic-ischemic brain damage (HIBD) in neonates remains unknown. Here, we aim to examine whether the m6A modification is involved in modulating microglial activation during HIBD. We employed an oxygen and glucose deprivation microglial model for in vitro studies and a neonatal mouse model of HIBD. The brain tissue was subjected to RNA-seq to screen for significant changes in the mRNA m6A regulator. Thereafter, we performed validation and bioinformatics analysis of the major m6A regulators. Results RNA-seq analysis revealed that, among 141 m6A regulators, 31 exhibited significant differential expression (FC (abs) ≥ 2) in HIBD mice. We then subjected the major m6A regulators Mettl3, Mettl14, Fto, Alkbh5, Ythdf1, and Ythdf2 to further validation, and the results showed that all were significantly downregulated in vitro and in vivo. GO analysis reveals that regulators are mainly involved in the regulation of cellular and metabolic processes. The KEGG results indicate the involvement of the signal transduction pathway. Conclusions Our findings demonstrate that m6A modification of mRNA plays a crucial role in the regulation of microglial activation in HIBD, with m6A-associated regulators acting as key modulators of microglial activation.

Abstract Background Mechanical ventilation (MV) is essential in the management of critically ill neonates, especially preterm infants. However, inappropriate or prolonged use of invasive MV may result in ventilator-associated lung injury. A systemic review comparing pressure control ventilation (PCV) with volume-targeted ventilation mode (VTV) approved that VTV reduces the incidence of death or bronchopulmonary dysplasia (BPD) in neonates; however, this study did not analyze subgroups of very low birthweight (VLBW) infants. Therefore, the aim of this study was to compare the use of VTV and PCV in VLBW infants and to provide clinical evidence for reducing mortality and complications of MV in VLBW infants. Method A single-center randomized controlled trial will be performed. All eligible infants will be randomized and assigned to either VTV or PCV group with 1:1 ratio using sealed envelopes. Death or BPD at 36 weeks’ postmenstrual age will be used as the primary outcome. Secondary outcomes include BPD, death, length of invasive MV, noninvasive mechanical ventilation, and oxygen use, length of hospital stay, failure of conventional MV, rate of using high-frequency oscillatory ventilation (HFOV) as rescue therapy, rate of reintubation within 48 h, and hospital expenses. Discussion Systemic review suggested that VTV decreases the incidence of death or BPD in neonates compared to PLV; however, this study did not specifically analyze subgroups of VLBW infants. We designed this single-center randomized controlled trials (RCT) to add a significant contribution regarding the benefits of VTV for VLBW patients.

BackgroundHypoxia can threaten the metabolic functions of different systems in immature neonates, particularly the central nervous system. The red blood cell distribution width (RDW) has recently been reported as a prognostic factor in neurologic diseases. Herein, we examined the correlation between RDW and regional cerebral tissue oxygen saturation (rcSO2).MethodsThis cross-sectional study included 110 preterm infants born at a gestational age (GA) of

Here the authors present a large-scale resource of the early-life human gut microbiome from children under three years old, which comprises 32,277 metagenome-assembled gut genomes, representing 2172 species, and more than 80 million gut proteins representing >4 million protein clusters, spanning multiple clinical factors including age, delivery mode, gestational age, and feeding patterns.

Abstract. Background:. Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE. Methods:. A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen- activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope. Results:. First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N- terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats. Conclusions:. Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

BackgroundThe presence of meconium is associated with gestational age, and the incidence of meconium aspiration syndrome (MAS) increases with gestational age. Our study compared the differences in the clinical characteristics of patients with MAS at different gestational ages and discussed the risk factors for neurological injury and death from MAS.MethodsA total of 294 neonates diagnosed with MAS between 2013 and 2021 were included. Patients were divided into preterm, early-term, full-term, and late-term groups according to gestational age. We compared the patients’ basic demographic, treatment, complications, and clinical outcomes in the different groups. We also analyzed the risk factors of neurological injury and death in patients with MAS.ResultsThe mean age at admission (0.55 ± 0.9 h) was lower and the proportion of cesarean deliveries (90.00%, 27/30) was higher in the preterm group than in the other three groups. There was no statistically significant difference among the four groups regarding 1- and 5-min Apgar scores and the need for delivery room resuscitation. In terms of complications, early-term infants had the highest incidence of neurological injury (52.9%, 27/51), and late-term infants had the highest incidence of pneumothorax (37.8%, 17/45). The overall mortality rate of children with MAS was 7.80% (23/294), and the difference in mortality rates among the four groups was not significant. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were independent risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS.ConclusionThe clinical characteristics of MAS neonates of different gestational age are different mainly in complications. Early-term infants are more likely to complicate with neurological injury, and late-term infants are more likely to complicate with pneumothorax. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were established as risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS.

The authors uncover synthetic lethality between TP53 and ENDOD1, which contains an atypical endonuclease domain. Co-depleted G1 cells accumulate single stranded DNA and die. Combined with xenograft data the work identifies ENDOD1 as a potential cancer-specific SL drug discovery target.

Abstract. Background:. Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. Methods:. This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. Results:. A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. Conclusions:. In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

Background and aimAbdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in the early stages of abdominal TB. However, it remains unclear whether ADA serves as a diagnostic marker for abdominal TB.MethodsWe performed a systematic literature search for relevant articles published in PubMed, Web of Science, Cochrane Library, and Embase up to April 2022. First, we used the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2), to evaluate the quality of the included articles. Bivariate and hierarchical summary receiver operating characteristic (HSROC) models were then utilized to analyze pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC). In addition, we explored a subgroup analysis for potential heterogeneity and publication bias among the included literature.ResultsTwenty-four articles (3,044 participants, 3,044 samples) which met the eligibility criteria were included in this study. The pooled sensitivity and specificity of ADA for abdominal TB detection were 93% [95% confidence interval (CI): 0.89–0.95] and 95% (95% CI: 0.93–0.96), respectively. PLR and NLR were 18.6 (95% CI: 14.0–24.6) and 0.08 (95% CI: 0.05–0.12), respectively. DOR and AUROC were 236 (95% CI: 134–415) and 0.98 (95% CI: 0.96–0.99), respectively. Furthermore, no heterogeneity or publication bias was found.ConclusionsOur meta-analysis found ADA to be of excellent diagnostic value for abdominal TB and could be used as an auxiliary diagnostic tool.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022297931.

Extracorporeal membrane oxygenation (ECMO) is a frequently used mechanical cardiopulmonary support for rescuing critically ill patients for whom conventional medical therapies have failed. However, ECMO is associated with several complications, such as acute kidney injury, hemorrhage, thromboembolism, and acute brain injury (ABI). Among these, ABI, particularly intracranial hemorrhage (ICH) and infarction, is recognized as the primary cause of mortality during ECMO support. Furthermore, survivors often suffer significant long-term morbidities, including neurocognitive impairments, motor disturbances, and behavioral problems. This review provides a comprehensive overview of the different subtypes of ECMO-related ABI and the updated advance mechanisms, which could be helpful for the early diagnosis and potential neuromonitoring of ECMO-related ABI.

Preterm birth remains a major maternal and infant health issue worldwide particularly with an increase in the global preterm birth rate, which requires more interventions to manage the consequences of preterm birth. In addition to traditional complications, recent studies have shown that the succession of gut microbiota of preterm infants is disordered due to the systemic physiological immaturity, which confers negative influences on the growth, development, and health of infants. In the present study, we briefly discussed the prevalence of preterm birth worldwide and then highlighted the signatures of gut microbiota in preterm infants within the first 1000 days of life after the birth categorized into birth, infancy, and childhood. Afterward, we focused on the potential association of clinical phenotypes typically associated with preterm birth (i.e., necrotizing enterocolitis) with gut microbiota, and the potential directions for future studies in this field are finally discussed.

Abstract Background Enterovirus (EV) is a common cause of infection in neonates. Neonates are at high risk of enterovirus infection with serious clinical manifestations and high lethality. This review systematically summarized the clinical characteristics of neonates with severe enteroviral infection to provide evidence for the identification and treatment of severe neonatal EV infection. Methods PubMed, Embase, and Web of Science were searched for original studies on neonates with severe EV infections from January 1, 2000, to November 27, 2020. Two reviewers independently screened the literature, extracted the data, and performed a descriptive analysis. Results In total, 66 articles with 237 cases of severe neonatal enterovirus infection were included. All neonates developed severe complications. Among them, 46.0% neonates had hepatitis or coagulopathy, 37.1% had myocarditis, 11.0% had meningoencephalitis, and 5.9% had other complications such as hemophagocytic lymphohistiocytosis and pulmonary hemorrhage. The lethality rate of neonates with severe infection was 30.4%. The highest lethality rate was 38.6%, which was observed in neonates with myocarditis. In 70.5% neonates, the age at the onset of symptoms was less than 7 days. Coxsackievirus B infection was seen in 52.3% neonates. The most common symptoms included temperature abnormalities (127, 53.6%), rash (88, 37.1%), poor feeding (58, 24.5%), and respiratory symptoms (52, 21.9%). The main treatment included transfusion of empirical antibiotics (127, 53.6%), blood components (100, 42.2%), intravenous immunoglobulin (IVIG; 97, 40.9%), mechanical ventilation (51, 21.5%), and extracorporeal membrane oxygenation (ECMO; 43, 18.1%). Additionally, antiviral medications pleconaril (14, 5.9%) and pocapavir (3, 1.3%) were administered. Conclusions Lethality was high in neonates with severe enterovirus infection, especially in those complicated with myocarditis. The most common symptoms included temperature abnormalities, rash, and poor feeding. The chief supportive treatment consisted of transfusion of blood components, mechanical ventilation, and ECMO. Empirical antibiotics and IVIG were widely used. Antiviral medications included pocapavir and pleconaril; however, more clinical evidence regarding their efficacy is needed.

Methyltransferase-like 3 (METTL3) is a typical component of N6-methyladenosine writers that exhibits methyltransferase activity and deposits methyl groups on RNA. Currently, accumulating studies have demonstrated the involvement of METTL3 in the regulation of neuro-physiological and pathological events. However, no reviews have comprehensively summarized and analyzed the roles and mechanisms of METTL3 in these events. Herein, we are focused on reviewing the roles of METTL3 in regulating normal neurophysiological (Neurogenesis, Synaptic Plasticity and Glial Plasticity, Neurodevelopment, Learning and Memory,) and neuropathological (Autism Spectrum Disorder, Major Depressive Disorder, Neurodegenerative disorders, Brain Tumors, Brain Injuries, and Other Brain Disorders) events. Our review found that although the down-regulated levels of METTL3 function through different roles and mechanisms in the nervous system, it primarily inactivates neuro-physiological events and triggers or worsens neuropathological events. In addition, our review suggests that METTL3 could be used as a diagnostic biomarker and therapeutic target in the nervous system. Collectively, our review has provided an up-to-date research outline of METTL3 in the nervous system. In addition, the regulatory network for METTL3 in the nervous system has been mapped, which could provide directions for future research, biomarkers for clinical diagnosis, and targets for disease treatment. Furthermore, this review has provided a comprehensive view, which could improve our understanding of METTL3 functions in the nervous system.

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed as having the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) is known to be expressed on type II pneumocytes. As a counter-regulatory arm of the renin–angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury.The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 for human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have shown that regulating the ACE2/RAS system is effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor for both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.

BackgroundVitamin A plays an important role in the development and maintenance of the normal function of organs and systems. Premature infants have low levels of vitamin A, which may be associated with an increased risk of developing disease. This study aimed to evaluate the effects of vitamin A supplementation on short-term morbidity and mortality in very-low-birth-weight (VLBW) infants.MethodsWe used PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science to conduct a literature search of studies published before January 1, 2022, to be included in our meta-analysis. The analysis included randomized controlled trials that compared the effects of vitamin A supplementation on VLBW infants (birth weight

Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.

Abstract Preterm infants with periventricular–intraventricular hemorrhage (PV–IVH) have a high risk of neurological sequelae, with severity depending on the severity of the PV–IVH. Previous studies on the pathogenesis of PV–IVH have focused mainly on comparisons of perinatal risk factors between patients with and without PV–IVH. Notably, most cases of PV–IVH occur within the first 3 days after birth, and the condition may worsen within 1 week following the initial diagnosis. However, the risk factors that contribute to the deterioration of PV–IVH have not been investigated. In this cohort study, 514 PV–IVH infants with a gestational age (GA)

Hypertensive disorders in pregnancy are prevalent perinatal diseases. Here the authors report an association between ambient temperature before or after conception and risk of preeclampsia or eclampsia and gestational hypertension.

Abstract Background Isolated sulfite oxidase deficiency (ISOD) is an autosomal recessive disorder caused by a deficiency of sulfite oxidase, which is encoded by the sulfite oxidase gene (SUOX). Clinically, the disorder is classified as one of two forms: the late-onset mild form or the classic early-onset form. The latter is life-threatening and always leads to death during early childhood. Mild ISOD cases are rare and may benefit from dietary therapy. To date, no cases of ISOD have been reported to recover spontaneously. Here, we present three mild ISOD cases in one family, each with a stable clinical course and spontaneous recovery. Case presentation All three siblings had two novel compound heterozygous mutations in the SUOX gene (NM_000456; c.1096C > T [p.R366C] and c.1376G > A [p.R459Q]). The siblings included two males and one female with late ages of onset (12–16 months) and presented with specific neuroimaging abnormalities limited to the bilateral globus pallidus and substantia nigra. The three patients had decreased plasma homocysteine levels. They exhibited a monophasic clinical course continuing up to 8.5 years even without dietary therapy. Conclusion This is the first report of mild ISOD cases with a stable clinical course and spontaneous recovery without dietary therapy. Our study provides an expansion for the clinical spectrum of ISOD. Furthermore, we highlight the importance of including ISOD in the differential diagnosis for patients presenting with late-onset symptoms, bilaterally symmetric regions of abnormal intensities in the basal ganglia, and decreased plasma homocysteine levels.

Psoriasis is a complex, chronic relapsing and inflammatory skin disorder with a prevalence of approximately 2% in the general population worldwide. Psoriasis can be triggered by infections, physical injury and certain drugs. The most common type of psoriasis is psoriasis vulgaris, which primarily features dry, well-demarcated, raised red lesions with adherent silvery scales on the skin and joints. Over the past few decades, scientific research has helped us reveal that innate and adaptive immune cells contribute to the chronic inflammatory pathological process of psoriasis. In particular, dysfunctional helper T cells (Th1, Th17, Th22, and Treg cells) are indispensable factors in psoriasis development. When stimulated by certain triggers, antigen-presenting cells (APCs) can release pro-inflammatory factors (IL-23, IFN-α and IL-12), which further activate naive T cells and polarize them into distinct helper T cell subsets that produce numerous cytokines, such as TNF, IFN-γ, IL-17 and IL-22, which act on keratinocytes to amplify psoriatic inflammation. In this review, we describe the function of helper T cells in psoriasis and summarize currently targeted anti-psoriatic therapies.

Abstract Background The aim of this study was to follow the growth and hematological indicators of preterm infants during their first year. Methods Neonates below 37 gestational weeks had routine follow-ups up through 1 year from January 2012 to December 2015 at West China 2nd University Hospital, Sichuan University. Weight, length and head circumference (HC) were measured monthly during the first 6 months, followed by monitoring every second month until 12 months. The catch-up growth defined as a gain of Z-score > 0.67 according to previous study. All preterm infants were prescribed iron prophylaxis based on national guideline. The hemoglobin concentration was examined at 6 and 12 months. Results Altogether, 132 very-low-birth-weight (VLBW), 504 low-birth-weight (LBW) and 198 normal-birth-weight (NBW) infants were followed. The rates of catch-up growth for weight, length and HC 12 months of corrected age (CA) were 22.6, 29.1 and 14.6%, respectively. SGA and VLBW infants showed higher catch-up growth rates. The overall prevalence of anemia was 6.8% at 6 months and 7.8% at 12 months. The Z-scores for weight-for-length, length and HC were lower in the VLBW and SGA preterm infant groups than in the other preterm groups throughout the first year of life. The incidences of stunting, microcephaly and wasting changed from 5, 1.3 and 3.7% to 2, 1.1, 0.9 and 2.4%, respectively, during the first year. However, the incidences of wasting and stunting were higher for the VLBW infants than for the LBW and NBW infants at 12 months (9.3% vs. 1.4%, p

Abstract Background Sepsis is a critical disease associated with extremely high mortality. Some severe forms of sepsis can induce brain injury, thus causing behavioral and cognitive dysfunction. Pyroptosis is a type of cell death that differs from apoptosis and plays an important role in the occurrence and development of infectious diseases, nervous system-related diseases. A recent study has found that there is pyroptosis in the hippocampus of sepsis-induced brain injury, but its mechanism and treatment scheme have not been evaluated. Methods We established immediately a septic rat model by cecal ligation and perforation (CLP) after administration with recombinant club cell protein (rCC16) and/or U46619 in different groups. The clinical performance, survival percentage, vital signs, and neurobehavioral scores were monitored at different time points. Cortical pathological changes were also examined. The expression of cortical nucleotide-binding domain leucine-rich repeat-containing pyrin domain-containing 3 (NLRP3), caspase-1, (p)-p38 mitogen-activated protein kinase (MAPK), and (p)-extracellular signal-related kinase (ERK) was detected by western blotting and immunofluorescence analysis. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha in the cortical supernatant were detected by enzyme-linked immunosorbent assay. Results Compared with the sham group, the clinical performance, survival percentage, vital signs, and severe cortical pathological changes in the CLP group were worse; NLRP3, caspase-1, and inflammatory factor levels were increased; and phosphorylation of p38 MAPK and ERK was also increased. Meanwhile, multiple indicators were deteriorated further after administration of U46619 in CLP rats. The clinical performance of CLP rats, however, was better after rCC16 administration; cortical pathological changes were attenuated; and NLRP3, caspase-1, and inflammatory factor levels and the phosphorylation of signaling pathway proteins (p38 MAPK and ERK) were reduced. Interestingly, the CLP rats showed the opposite changes in all indicators after administration with both rCC16 and U46619 when compared with those administered rCC16 alone. Conclusions In sepsis, rCC16 inhibits cortical pyroptosis through p38 MAPK and ERK signaling pathways. Meanwhile, rCC16 has a protective effect on newborn rats with sepsis, but it is not clear whether its mechanism is directly related to pyroptosis.

Abstract Backgrounds Pulmonary tuberculosis (PTB) is a major health and economic burden. Accurate PTB detection is an important step to eliminating TB globally. Interferon gamma-induced protein 10 (IP-10) has been reported as a potential diagnostic marker for PTB since 2007. In this study, a meta-analysis approach was used to assess diagnostic value of IP-10 for PTB. Methods Web of Science, PubMed, the Cochrane Library, and Embase databases were searched for studies published in English up to February 2019. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), the area under the curve (AUC) and hierarchical summary receiver operating characteristic (HSROC) curve were estimated by the HSROC model and random effect model. Results Eighteen studies including 2836 total participants met our inclusion criteria. The pooled sensitivity, specificity, PLR, and NLR of IP-10 for PTB detection were 86, 88%, 7.00, and 0.16, respectively. The pooled DOR was 43.01, indicating a very powerful discriminatory ability of IP-10. The AUC was 0.93 (95% CI: 0.91–0.95), showed the accuracy of IP-10 was good. Meta-regression showed that there was no heterogeneity with respect to TB burden, study design type, age, IP-10 assay method, IP-10 condition and HIV-infection status. Conclusions Our results showed that IP-10 is a promising marker for differentiating PTB from non-TB.

Abstract Tuberculin skin test and interferon-gamma release assay are not good at differentiating active tuberculosis from latent tuberculosis. Interferon-gamma-induced protein 10 (IP-10) has been widely used to detect tuberculosis infection. However, its values of discriminating active and latent tuberculosis is unknown. To estimate the diagnostic potential of IP-10 for differentiating active tuberculosis from latent tuberculosis, we searched PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang, VIP and CBM databases. Eleven studies, accounting for 706 participants (853 samples), were included. We used a bivariate diagnostic random-effects model to conduct the primary data. The overall pooled sensitivity, specificity, negative likelihood rate, positive likelihood rate, diagnostic odds ratio and area under the summary receiver operating characteristic curve were 0.72 (95% CI: 0.68–0.76), 0.83 (95% CI: 0.79–0.87), 0.32 (95% CI: 0.22–0.46), 4.63 (95% CI: 2.79–7.69), 17.86 (95% CI: 2.89–38.49) and 0.8638, respectively. This study shows that IP-10 is a potential biomarker for differentiating active tuberculosis from latent tuberculosis.

Abstract Background The training of neonatal resuscitation is an important part in the clinical teaching of neonatology. This study aimed to identify the educational efficacy of high-fidelity simulation compared with no simulation or low-fidelity simulation in neonatal resuscitation training. Methods The PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, Chinese databases (CBM, CNKI, WanFang, and Weipu), ScopeMed and Google Scholar were searched. The last search was updated on April 13, 2019. Studies that reported the role of high-fidelity simulation in neonatal resuscitation training were eligible for inclusion. For the quality evaluation, we used the Cochrane Risk of Bias tool for RCTs and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for non-RCTs. A standardized mean difference (SMD) with a 95% confidence interval (CI) was applied for the estimation of the pooled effects of RCTs. Results Fifteen studies (10 RCTs and 5 single arm pre-post studies) were ultimately included. Performance bias existed in all RCTs because participant blinding to the simulator is impossible. The assessment of the risk of bias of single arm pre-post studies showed only one study was of high quality with a low risk of bias whereas four were of low quality with a serious risk of bias. The pooled results of single arm pre-post studies by meta-analysis showed a large benefit with high-fidelity simulation in skill performance (SMD 1.34; 95% CI 0.50–2.18). The meta-analysis of RCTs showed a large benefit in skill performance (SMD 1.63; 95% CI 0.49–2.77) and a moderate benefit in neonatal resuscitation knowledge (SMD 0.69; 95% CI 0.42–0.96) with high-fidelity simulation when compared with traditional training. Additionally, a moderate benefit in skill performance (SMD 0.64; 95% CI 0.06–1.21) and a small benefit was shown in knowledge (SMD 0.39; 95% CI 0.08–0.71) with high-fidelity simulation when compared with low-fidelity simulation. Conclusions Improvements of efficacy were shown both in resuscitation knowledge and skill performance immediately after training. However, in current studies, the long-time retention of benefits is controversial, and these benefits may not transfer to the real-life situations.

Glial cells are the most abundant and widely distributed cells that maintain cerebral homeostasis in the central nervous system. They mainly include microglia, astrocytes, and the oligodendrocyte lineage cells. Moreover, glial cells may induce pathological changes, such as inflammatory responses, demyelination, and disruption of the blood–brain barrier, to regulate the occurrence and development of neurological diseases through various molecular mechanisms. Furthermore, RNA m6A modifications are involved in various pathological processes associated with glial cells. In this review, the roles of glial cells in physiological and pathological states, as well as advances in understanding the mechanisms by which glial cells regulate neurological diseases under RNA m6A modification, are summarized, hoping to provide new perspectives on the deeper mechanisms and potential therapeutic targets for neurological diseases.

Objective Hyperbilirubinemia is one of the most common clinical symptoms in newborns. To improve patient outcomes, evidence-based and implementable guidelines are required. However, clinical guidelines may vary in quality, criteria and recommendations among regions and countries. In this study, we aimed to systematically assess the quality of guidelines using the Appraisal of Guidelines for Research & Evaluation (AGREE)-II instrument and summarise the specific recommendations for neonatal hyperbilirubinemia in order to provide suggestions for future guideline development.Design Systematic review.Interventions We searched the PubMed, Embase, Medline and guideline databases for relevant articles on 10 April 2020. The studies were screened by two independent reviewers according to our inclusion criteria. Two reviewers independently extracted the descriptive data. Four appraisers assessed the guidelines using the AGREE-II instrument.Results Our systematic review appraised 12 clinical practice guidelines for the diagnosis and management of neonatal hyperbilirubinemia. The 12 guidelines achieved an average score of 36%–89%. The guidelines received the highest scores for clarity of presentation and lowest scores for rigour of development. Most recommendations for diagnosis were relatively consistent, but recommendations regarding risk factors, the initiating threshold of treatment and pharmacotherapy varied.Conclusions Our study revealed that current guidelines vary in the quality of the developing process and are inconsistent with regards to recommendations. Future guidelines should afford more attention to the quality of methodologies in guideline development, and more qualified evidence is needed to standardise the initiating threshold of treatment for neonatal hyperbilirubinemia.

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.

Ischemic brain injuries are common diseases with high morbidity, disability, and mortality rates, which have significant impacts on human health and life. Microglia are resident cells of the central nervous system (CNS). The inflammatory responses mediated by microglia play an important role in the occurrence and development of ischemic brain injuries. This article summarizes the activation, polarization, depletion, and repopulation of microglia after ischemic brain injuries, proposing new treatment strategies for such injuries through the modulation of microglial function.

Objective This study aimed to describe drug utilisation in a large Chinese neonatal unit and to compare the findings with those from other countries. Methods Data were collected from electronic medical records. Prescription drugs were defined as the number of unique medication names for each patient. Medicine doses were defined as the total number of doses of all medicines administered. Information was collected regarding drugs prescribed to inpatients between March 1 and April 1 2018 in the neonatal intensive care unit and the general neonatal ward of West China Second University Hospital. Results The 319 neonates received 1276 prescription drugs and 11,410 medicine doses involving 81 drugs. Vitamin K1, hepatitis B vaccine, and cefoperazone-sulbactam were the three most frequently prescribed drugs. Antimicrobials were the most frequently used group of medicines, with cefoperazone-sulbactam and piperacillin-tazobactam the most frequently used in an off-label manner. Domperidone and simethicone were both widely used. Conclusions The most commonly prescribed antimicrobials differed greatly from those reported for other countries. The evidence base for the use of some medicines is poor, and is indicative of irrational prescribing.

Introduction Seizures are one of the most common neurological disorders of neonates, which is also an emergency in the neonatal intensive care unit. For neonates, the recommended first-line antiepileptic drugs (AEDs) include phenobarbitone, which may be effective in only 50% of seizures. Some new AEDs, such as levetiracetam, have been shown to be effective in adults and older children. However, their efficacy for neonatal seizures remains uncertain. The aim of this investigation is to conduct a systematic review to evaluate the efficacy of all AEDs in neonates. Additionally, the long-term outcomes following neonatal seizures, in relation to the development of cerebral palsy and epilepsy, will be studied.Method We will perform a systematic review including randomised controlled studies (RCTs), cohort studies, case-controlled studies and case series studies which evaluated the efficacy of AEDs and short-term and long-term outcomes in neonatal seizures. PubMed, Embase, Web of Science, Cochrane Library and Clinical trial.gov will be searched. There will be no language restriction. Risk bias in RCTs will be evaluated by the Cochrane risk-of-bias tool, while cohort and case-control studies will be evaluated by the Newcastle-Ottawa Scale. A network meta-analysis will be performed by the Bayesian model using WinBUGS V.1.4.3 and R software if there is a high degree of homogeneity among studies. Otherwise, we will perform a narrative review without pooling. Subgroup analyses will be performed in different AEDs and dosage groups.Outcome The primary outcomes will be seizure cessation confirmed by electroencephalogram and long-term neurodevelopmental outcome. Secondary outcomes will be neonatal mortality during hospitalisation and suspected drug toxicity.Ethics and dissemination Formal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication.

Abstract Background To provide a synopsis of the current understanding of the association between variants of HNF1B and cancer susceptibility, we conducted a comprehensive research synopsis and meta-analysis to evaluate associations between HNF1B variants and prostate and endometrial cancers. Results Eighteen studies totaling 34,937 patients and 55,969 controls were eligible for this meta-analysis. Four variants showed a significant association with the risk of individual cancer. Strong significant associations were found between rs4430796 A and the risk of both prostate cancer (OR = 1.247, p = 2.21 × 10− 77) and endometrial cancer (OR = 1.217, p = 8.98 × 10− 16); the AA, AG genotypes also showed strong significant associations with the risk of prostate cancer (OR1 = 1.517, p = 4.46 × 10− 22; OR2 = 1.180, p = 0.002). There was a strong significant association between rs7501939 G and the risk of prostate cancer (OR = 1.201, p = 9.31 × 10− 31). Strong significant association was found between rs11649743 G (OR = 1.138, p = 1.08 × 10− 12), rs3760511 C (OR = 1.214, p = 1.57 × 10− 19) and the prostate cancer risk;the GG, AG genotypes of rs11649743 also showed strong significant associations with the risk of prostate cancer (OR1 = 1.496, p = 3.32 × 10− 6; OR2 = 1.276, p = 7.82 × 10− 6). All the cumulative epidemiological evidence of associations was graded as strong. Conclusions Our study summarizes the evidence and helps to reveal that common variants of HNF1B are associated with risk of prostate and endometrial cancer.

Prereplicative complex (pre-RC) formation during G1 is fundamental for cell replication. Here the authors report a role for cyclin K in regulating pre-RC formation in mammalian cells by affecting cyclin E1 activity.

Pericytes are functional components of the neurovascular unit (NVU) that are located around the blood vessels, and their roles in the regulation of cerebral health and diseases has been reported. Currently, the potential properties of pericytes as emerging therapeutic targets for cerebrovascular diseases have attracted considerable attention. Nonetheless, few reviews have comprehensively discussed pericytes and their roles in cerebrovascular diseases. Therefore, in this review, we not only summarized and described the basic characteristics of pericytes but also focused on clarifying the new understanding about the roles of pericytes in the pathogenesis of cerebrovascular diseases, including white matter injury (WMI), hypoxic–ischemic brain damage, depression, neovascular insufficiency disease, and Alzheimer’s disease (AD). Furthermore, we summarized the current therapeutic strategies targeting pericytes for cerebrovascular diseases. Collectively, this review is aimed at providing a comprehensive understanding of pericytes and new insights about the use of pericytes as novel therapeutic targets for cerebrovascular diseases.

The epidemic due to the novel coronavirus (SARS-CoV-2) is now a global concern, posing a severe threat to the health of populations. At present, all countries in the world are stepping up the development of vaccines and antiviral agents to prevent the infection and further transmission of SARS-CoV-2. An in-depth investigation of the target organs and pathogenesis regarding SARS-CoV-2 infection will be beneficial for virus therapy. Besides pulmonary injury, SARS-CoV-2 also causes cardiac injury, but the exact mechanisms are unclear. This review summarizes the essential structural characteristics of SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2), describes the cardiac manifestations following SARS-CoV-2 infection, and explores the mechanisms of cardiac injury targeting ACE2 after the viral invasion. We aim to help the timely detection of related symptoms and implementation of therapeutic measures by clinicians for SARS-CoV-2 infection.

Objective: To determine factors associated with late preterm births in an underdeveloped region of China, and search for relevant reports in other underdeveloped regions by a systematic review. Materials and methods: Data of births occurring between January 2004 and December 2008 from eight hospitals in Western Sichuan Province, China, were analyzed. Late preterm birth was defined as delivery at 34–36 6/7 weeks' gestation. Medline, Cochrane Library, and Google Scholar were searched for studies which reported the risk factors of late preterm births in undeveloped regions until January 31, 2014. Results: During the study period there were 4711 late preterm births and 54,574 term births. The odds ratios (ORs) for a late preterm birth of mothers

Activin A belongs to the transforming growth factor superfamily and has a variety of biological functions. Studies have revealed that activin A can regulate the body's immune and inflammatory responses and participate in the regulation of cell death. In addition, activin A also has neurotrophic function and plays an important role in the repair of brain damage. This article summarizes recent advances in understanding the role and mechanism of action of activin A in brain injury and provides new hints into the application of activin A in the treatment of brain injury.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to child mortality and morbidity. Reliable prognostication for HIE is of key importance. Proton magnetic resonance spectroscopy (1H-MRS) is a quantitative, non-invasive method that has been demonstrated to be a suitable complementary tool for prediction. The aim of this study was to investigate the prognostic capability of 1H-MRS in the era of therapeutic hypothermia (TH).Methods: Databases, namely MEDLINE, Embase, Web of Science, and the Cochrane library (Cochrane Center Register of Controlled Trials), were searched for studies published before July 17, 2017. Study selection and data extraction were performed by two independent reviewers. The mean difference (MD) or standardized MD (SMD) and 95% confidence interval (CI) were calculated using random-effects models. Subgroup analyses were conducted based on the use of TH.Results: Among the 1,150 relevant studies, seven were included for meta-analysis, but only two small studies were conducted under TH. For 1H-MRS measurement, three peak area ratios revealed predictive values for adverse outcomes in TH subgroup and the combined results (with and without TH): N-acetylaspartate (NAA)/creatine in basal ganglia/thalamus (BG/T) in TH (MD −0.31, 95%CI −0.55 to −0.07) and combined results (MD −0.37, 95% CI −0.49 to −0.25); NAA/choline in BG/T in TH (MD −0.89, 95%CI −1.43 to −0.35) and combined results (MD −0.25, 95%CI −0.42 to −0.07); and myo-inositol/choline in cerebral cortex in TH (MD −1.94, 95%CI −3.69 to −0.19) and combined results (MD −1.64, 95%CI −2.64 to −0.64). Moreover, NAA relative concentration is associated with adverse outcomes: in TH (MD −0.04, 95%CI −0.06 to −0.02) and combined results (MD −0.06, 95%CI −0.11 to −0.01) in white matter; in TH (MD −0.04, 95%CI −0.07 to −0.01) and combined results (MD −0.05, 95%CI −0.07 to −0.02) in gray matter.Conclusions: NAA may be a potential marker in outcome prediction for all HIE subjects. It seems that MDs for the ratios including NAA are larger than for its relative concentration, and therefore are more likely to be measurable in a clinical context. Larger prospective multicenter studies with a standardized protocol for both measurement protocols and analysis methods are required in future studies.