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Background & Aims: Human milk is the optimal diet for very preterm infants (VPIs), but it requires nutrient fortification to support growth. Bovine colostrum (BC), rich in intact proteins and bioactive components, could serve as a novel fortifier with potential benefits to VPIs gut health. To evaluate a possible effect of feeding BC on intestinal metabolism, the gut microbiota, and their interaction, we studied the fecal metabolome of VPIs in the first month of life, as compared with a conventional fortifier (CF, based on infant formula ingredients)., Methods: Fecal samples were collected from VPIs recruited to the FortiColos trial (NCT03537365, BC, n = 107; CF, n = 112) before (FT0) and one (FT1) or two (FT2) weeks after start of fortification and analyzed using 1 H NMR spectroscopy. Abundances of metabolites were compared between BC versus CF groups. Further, temporal changes in metabolite levels after start of fortification, as well as correlations with specific gut bacterial genera were explored., Results: Infants in the BC group had higher levels of fecal acetoacetate, choline, methanol, uracil, creatine, creatinine, lysine and a lower leucine at both FT1 and FT2, relative to the CF group. Asparagine, tryptophan and phenylalanine levels were higher, and butyrate was lower in the BC group at FT1. At FT2, higher fecal succinate and lower isoleucine were found in the BC group. In addition, eight metabolites (asparagine, phenylalanine, tryptophan, lysine, creatinine, acetoacetate, methanol and uracil) had fortification-specific changes over time. Positive correlations were found between succinate and unclassified Enterobacteriaceae, butyrate and Clostridium, uracil and Staphylococcus, while negative correlation were found between uracil and unclassified Enterobacteriaceae members., Conclusion: Our study shows distinct fecal metabolome profiles in VPIs in the first weeks after fortification with BC versus CF. The fortification- and time-specific gut metabolite changes suggest that fortifiers influence luminal nutrient metabolism and microbiota activity in VPIs. Fortifier type for human milk affected gut health of VPIs via altered gut metabolite levels, interacting with microbiota in VPIs., Competing Interests: Conflict of interest The University of Copenhagen holds a patent on the use of colostrum for human infants (PCT/DK2013/050184). Biofiber Damino A/S is given options to license this patent. P.T.S. is listed as the sole inventor but has declined any share of potential revenue arising from commercial exploitation of such a patent. P.T.S. did not take part in any clinical work in the units involved in this study. Other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study examines the effectiveness of automatic speech recognition (ASR) for individuals with speech disorders, addressing the gap in performance between read and conversational ASR. We analyze the factors influencing this disparity and the effect of speech mode-specific training on ASR accuracy., Method: Recordings of read and conversational speech from 27 individuals with various speech disorders were analyzed using both (a) one speaker-independent ASR system trained and optimized for typical speech and (b) multiple ASR models that were personalized to the speech of the participants with disordered speech. Word error rates were calculated for each speech model, read versus conversational, and subject. Linear mixed-effects models were used to assess the impact of speech mode and disorder severity on ASR accuracy. We investigated nine variables, classified as technical, linguistic, or speech impairment factors, for their potential influence on the performance gap., Results: We found a significant performance gap between read and conversational speech in both personalized and unadapted ASR models. Speech impairment severity notably impacted recognition accuracy in unadapted models for both speech modes and in personalized models for read speech. Linguistic attributes of utterances were the most influential on accuracy, though atypical speech characteristics also played a role. Including conversational speech samples in model training notably improved recognition accuracy., Conclusions: We observed a significant performance gap in ASR accuracy between read and conversational speech for individuals with speech disorders. This gap was largely due to the linguistic complexity and unique characteristics of speech disorders in conversational speech. Training personalized ASR models using conversational speech significantly improved recognition accuracy, demonstrating the importance of domain-specific training and highlighting the need for further research into ASR systems capable of handling disordered conversational speech effectively.

Edaravone Dexborneol (EDB), comprised of edaravone and (+)- bornel, has been demonstrated to have synergistic effects of antioxidant and anti-inflammatory, which makes it to be applied for stroke as a protectant. However, the underlying mechanism of neuroprotection of EDB has not been fully elucidated. Increasing evidence has shown that neurotoxic A1 astrocytes were closely related to neuronal death after cerebral ischemia. However, whether EDB could provide neuroprotection by modulating the activation of astrocytes has not yet been elucidated. The present study aimed to explore whether EDB afforded neuroprotection by modulating A1 polarization of astrocytes and the down-stream signaling after cerebral ischemia. We first validated the neuroprotective effects of EDB in mice suffering focal cerebral ischemia via evaluating behavioral test, infarct volumes and neuronal survival. As for the down-stream signaling, our data further showed that EDB alleviated neuronal death by suppressing activation of neurotoxic A1 astrocytes via inhibition of NF-κB signaling pathway in vitro. Additionally, administration of EDB reduced the number of A1 reactive astrocytes in mice of focal cerebral ischemia. The above findings demonstrated that EDB provided neuroprotective effect by inhibiting neurotoxic activation of A1 astrocytes in animal model of cerebral ischemia, which indicated that EDB-mediated phenotypic regulation of astrocytes is a potential research direction to promote neurological recovery in central nervous system (CNS) diseases., Competing Interests: Declaration of Competing Interest All authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the association between early initiation of parenteral nutrition (PN) and body growth in preterm infants with very low birth weight (VLBW)., Design: Causal inference analysis with confounders preselected by causal diagram based on the NeoNutriNet cohort containing data of infants born between 2011 and 2014 from 13 hospitals from 5 continents., Patients: Neonates with birth weight ≤1500 g., Interventions: PN initiated within the first day of life (early PN) versus within day 2-5 (delayed PN)., Main Outcome Measures: The primary outcome was body weight z-scores at postmenstrual age (PMA) 36 weeks or early discharge or death, whichever comes first (WT z-score END). Secondary outcomes included WT z-scores at week 1 and 4 of life (WT z-scores CA1 and CA4), corresponding growth velocities (GVs), mortality and incidence of necrotising enterocolitis (NEC), and duration and episodes of antibiotic treatment., Results: In total, 2151 infants were included in this study and 2008 infants were in the primary outcome analysis. Significant associations of early PN were found with WT z-score END (adjusted mean difference, 0.14 (95% CI 0.05 to 0.23)), CA4 (β, 0.09 (0.04 to 0.14)) and CA1 (0.04 (0.01 to 0.08)), and GV PMA 36 weeks (1.02 (0.46 to 1.58)) and CA4 (1.03 (0.56 to 1.49), all p<0.001), but not with GV CA1 (p>0.05). No significant associations with mortality, incidence of NEC or antibiotic use was found (all p>0.05)., Conclusions: For VLBW infants, PN initiated within the first day of life is associated with improved in-hospital growth., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Preterm birth and formula feeding increase the risk of necrotizing enterocolitis (NEC), a gut inflammatory disease known to be associated with gut microbiota (GM) changes in infants. Supplemental bovine colostrum may protect against formula-induced NEC via GM changes. We hypothesised that feeding colostrum before, after, or during formula feeding affects NEC sensitivity via changes to GM., Methods: Colonic GM (profiled by 16S ribosomal RNA gene amplicon sequencing) was compared in preterm pigs fed colostrum for 4 days, either before, after, or together with formula feeding for 4 days. Correlations between GM and gut parameters were assessed on day 5 or 9., Results: Both exclusive and partial colostrum feeding induced higher GM diversity, lower Enterococcus abundance, and improved intestinal maturation parameters (villus structure, digestive enzyme activities, permeability), relative to exclusive formula feeding (all p < 0.05). Across feeding regimens, Enterococcus abundance was inversely correlated with intestinal maturation parameters. Conversely, there was no correlation between GM changes and early NEC lesions., Conclusion: Bovine colostrum inhibits formula-induced Enterococcus overgrowth and gut dysfunctions just after preterm birth but these effects are not causally linked. Optimising diet-related host responses, not GM, may be critical to prevent NEC in preterm newborn pigs and infants., Impact: Supplement of bovine colostrum to formula feeding modified the gut microbiota by increasing species diversity and reducing Enterococcus abundance, while concurrently improving intestinal functions in preterm pigs. Diet-related changes to the gut microbiota were not clearly associated with development of necrotizing enterocolitis (NEC) in preterm pigs, suggesting that diet-related gut microbiota effects are not critical for diet-related NEC protection. The study highlights the potential to use bovine colostrum as a supplement to formula feeding for preterm infants lacking human milk., (© 2024. The Author(s).)

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis., (© 2024. The Author(s).)

Objective: To compare the role and importance of fibular fixation in tibiofibular fractures by Meta-analysis., Methods: The literature related to the comparison of the efficacy of fixation of the fibula with or without fixation on the treatment of tibiofibular fractures was searched through the databases of China Knowledge Network, Wipu, Wanfang, The Cochrane Library, Web of science and Pubmed, and statistical analysis was performed using RevMan 5.3 software. The rates of malrotation, rotational deformity, internal/external deformity, anterior/posterior deformity, non-union, infection, secondary surgery and operative time were compared between the fibula fixation and non-fixation groups., Results: A total of 11 publications were included, six randomised controlled trials and five case-control trials, eight of which were of high quality. A total of 813 cases were included, of which 383 were treated with fibula fixation and 430 with unfixed fibulae.Meta-analysis results showed that fixation of the fibulae in the treatment of tibiofibular fractures reduced the rates of postoperative rotational deformity[ RR =0.22, 95% CI (0.10, 0.45), P <0.000 1] and internal/external deformity[ RR =0.34, 95% CI (0.14, 0.84), P =0.02] and promoted fracture healing [ RR =0.76, 95% CI (0.58, 0.99), P =0.04]. In contrast, the rates of poor reduction [ RR =0.48, 95% CI (0.10, 2.33), P =0.36], anterior/posterior deformity[ RR =1.50, 95% CI (0.76, 2.96), P =0.24], infection[ RR =1.43, 95% CI (0.76, 2.72), P =0.27], secondary surgery[ RR =1.32, 95% CI (0.82, 2.11), P =0.25], and operative time[ MD =10.21, 95% CI (-17.79, 38.21), P =0.47] were not statistically significant ( P >0.05) for comparison., Conclusion: Simultaneous fixation of the tibia and fibula is clinically more effective in the treatment of tibiofibular fractures.

Objective: To investigate the value of uterine morphological parameters and endometrial T 2 signal intensity (T 2 -SI) in evaluating the degree of the fibrotic repair secondary to endometrial injury. Methods: From Sep. 2018 to Feb. 2023, this study prospectively enrolled 29 patients with fibrotic repair secondary to severe endometrial injury (severe group), 17 patients with fibrotic repair secondary to mild to moderate endometrial injury (mild to moderate group), and 40 healthy women of reproductive age (control group) in Nanjing Drum Tower Hospital. The length of uterine cavity (LUC), length of cervix and isthmus (LCI), width of upper uterine cavity (WUUC) and width of lower uterine cavity (WLUC) were measured using magnetic resonance imaging. T 2 -SI of endometrium and subcutaneous fat of buttocks were measured, and endometrial normalized T 2 -SI (nT 2 -SI; T 2 -SI of endometrium/T 2 -SI of subcutaneous fat of buttocks) was calculated. Statistical analyses of data were performed using one-way analysis of variance, Mann-Whitney U test, intraclass correlation coefficient, Spearman rho test, area under the receiver operating characteristic curve (AUC). Results: LUC, WUUC, WLUC and endometrial nT 2 -SI of severe group [(19.7±3.5) mm, (26.9±6.4) mm, (7.9±1.4) mm, 0.73±0.11, respectively] were significantly lower than those of the control group (all P <0.01), while LCI and WUUC/LUC [(51.3±7.3) mm and 1.38±0.34] were significantly higher than those of the control group (all P <0.001). LUC and WLUC of severe group were significantly lower than those of mild to moderate group [(32.4±5.1) mm and (8.8±1.2) mm; all P <0.05], while LCI and WUUC/LUC were significantly higher than those of mild to moderate group [(41.8±8.6) mm and 0.94±0.16; all P <0.001]. LUC and endometrial nT 2 -SI of mild to moderate group were significantly lower than those of the control group [ (32.4±5.1) vs (35.3±3.5) mm, 0.68±0.13 vs 0.80±0.12; all P <0.01]. LUC, WUUC, WLUC and endometrial nT 2 -SI were significantly negatively correlated to the degree of the fibrotic repair secondary to endometrial injury (Spearman rho:-0.794, -0.441, -0.471 and -0.316, respectively; all P <0.05), while LCI and WUUC/LUC were significantly positively correlated to the degree of the fibrotic repair secondary to endometrial injury (Spearman rho: 0.481 and 0.674, respectively; all P <0.05). LUC and WUUC/LUC showed high value in distinguishing severe group from the control group or mild to moderate group (all AUC>0.9, all P <0.001). Conclusion: As noninvasive and quantitative biomarkers, uterine morphological parameters and endometrial nT 2 -SI could evaluate the degree of the fibrotic repair secondary to endometrial injury.

Background & Aims: Gut immaturity leads to feeding difficulties in very preterm infants (<32 weeks gestation at birth). Maternal milk (MM) is the optimal diet but often absent or insufficient. We hypothesized that bovine colostrum (BC), rich in protein and bioactive components, improves enteral feeding progression, relative to preterm formula (PF), when supplemented to MM. Aim of the study is to determine whether BC supplementation to MM during the first 14 days of life shortens the time to full enteral feeding (120 mL/kg/d, TFF120)., Methods: This was a multicenter, randomized, controlled trial at seven hospitals in South China without access to human donor milk and with slow feeding progression. Infants were randomly assigned to receive BC or PF when MM was insufficient. Volume of BC was restricted by recommended protein intake (4-4.5 g/kg/d). Primary outcome was TFF120. Feeding intolerance, growth, morbidities and blood parameters were recorded to assess safety., Results: A total of 350 infants were recruited. BC supplementation had no effect on TFF120 in intention-to-treat analysis [n (BC) = 171, n (PF) = 179; adjusted hazard ratio, aHR: 0.82 (95% CI: 0.64, 1.06); P = 0.13]. Body growth and morbidities did not differ, but more cases of periventricular leukomalacia were detected in the infants fed BC (5/155 vs. 0/181, P = 0.06). Blood chemistry and hematology data were similar between the intervention groups., Conclusions: BC supplementation during the first two weeks of life did not reduce TFF120 and had only marginal effects on clinical variables. Clinical effects of BC supplementation on very preterm infants in the first weeks of life may depend on feeding regimen and remaining milk diet., Trial Registration: http://www., Clinicaltrials: gov: NCT03085277., Competing Interests: Conflict of Interest The study received support from a Danish company, Biofiber-Damino, which donated the bovine colostrum used for the study. University of Copenhagen holds a patent (Eur. Patent no. EP2858653A1) on the use of bovine colostrum for preterm infants. Per Torp Sangild is listed as the sole inventor but has declined any share of potential revenue arising from commercial exploitation of such a patent. All other authors have no conflicts of interest. All funding bodies had no role in the design, analysis or writing of this article., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bone defect (BD) caused by trauma, infection, congenital defects, or neoplasia is a major cause of physical limitation. Distraction osteogenesis (DO) is a highly effective procedure for bone regeneration, while the concrete mechanism remains unknown. In this study, canine DO and BD models of the mandible were established. The results of micro-computed tomography and histological staining revealed that DO led to an increased mineralized volume fraction and robust new bone formation; in contrast, BD demonstrated incomplete bone union. Mesenchymal stem cells (MSCs) from DO and BD calluses were isolated and identified. Compared with BD-MSCs, DO-MSCs were found to have a stronger osteogenic capability. Single-cell RNA sequencing analysis was further performed to comprehensively define cell differences between mandibular DO and BD calluses. Twenty-six clusters of cells representing 6 major cell populations were identified, including paired related homeobox 1-expressing MSCs ( PRRX1 + MSCs), endothelial cells (ECs), T cells, B cells, neutrophils, and macrophages. Interestingly, 2 subpopulations in PRRX1 + MSCs in the DO group were found to express the marker of neural crest cells (NCCs) and were associated with the process of epithelial-mesenchymal transition. The immunofluorescence assay was performed to further corroborate these results in vivo and in vitro, experimentally validating that continuous distraction maintained the PRRX1 + MSCs in an embryonic-like state. Finally, we used CRISPR/Cas9 to knock out (KO) PRRX1 in the context of DO, which significantly blunted the capability of jawbone regeneration, resulting in a diminished NCC-like program and reduction of new bone volume. In addition, the ability of osteogenesis, cell migration, and proliferation in cultured PRRX1 KO MSCs was inhibited. Taken together, this study provides a novel, comprehensive atlas of the cell fates in the context of DO regeneration, and PRRX1 + MSCs act essential roles.

Background: Human breast milk has a high microRNA (miRNA) content. It remains unknown whether and how milk miRNAs might affect intestinal gene regulation and homeostasis of the developing microbiome after initiating enteral nutrition. However, this requires that relevant milk miRNA amounts survive the gastrointestinal (GI) passage, are taken up by cells, and become available to the RNA interference machinery. It seems important to dissect the fate of these miRNAs after oral ingestion and GI passage., Objectives: Our goal was to analyze the potential transmissibility of milk miRNAs via the gastrointestinal system in neonate humans and a porcine model in vivo to contribute to the discussion of whether milk miRNAs could influence gene regulation in neonates and thus might vertically transmit developmental relevant signals., Methods: We performed cross-species profiling of miRNAs via deep sequencing and utilized dietary xenobiotic taxon-specific milk miRNA (xenomiRs) as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells using adenovirus-type 5-mediated miRNA gene transfer., Results: Mammals share many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced bovine-specific miRNAs from formula nutrition in human preterm stool and 9 d after the onset of enteral feeding in intestinal cells (ICs) of preterm piglets. Thereafter, several xenomiRs accumulated in the ICs. Moreover, a few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed their enrichment in blood serum and in argonaute RISC catalytic component 2 (AGO2)-immunocomplexes from intestinal biopsies., Conclusions: Milk-derived miRNAs survived GI passage in human and porcine neonates. Bovine-specific miRNAs accumulated in ICs of preterm piglets after enteral feeding with bovine colostrum/formula. In piglets, colostrum supplementation with cel-miR-39-5p/-3p resulted in increased blood concentrations of cel-miR-39-3p and argonaute RISC catalytic component 2 (AGO2) loading in ICs. This suggests the possibility of vertical transmission of miRNA signaling from milk through the neonatal digestive tract., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Dexmedetomidine is commonly used in hysteroscopy surgery due to its analgesia and sedation without respiratory depression. Many studies have shown that dexmedetomidine can reduce the consumption of sevoflurane. However, the optimal end-tidal concentration of sevoflurane when it is co-administered with dexmedetomidine has not been established. The primary purpose of this study was to investigate the minimal alveolar concentration (MAC) of sevoflurane for cervical dilatation combined with different doses of dexmedetomidine in patients with hysteroscopy surgery., Methods: One-hundred patients undergoing hysteroscopy surgery were enrolled in this clinical trial. All the patients were randomly assigned into four groups (C, D 1 , D 2 , D 3 ) and received a loading dose of dexmedetomidine (0, 0.6, 0.8 and 1.0 μg/kg) over 10 min before anaesthesia induction, respectively. Anaesthesia was induced in each patient with 5% sevoflurane in 100% oxygen via a facemask. A laryngeal mask (LMA) was inserted when the patient had lost consciousness and the BIS value decreased below 40. The response to cervical dilatation stimulus (movement vs non-movement) by the insert of hysteroscope was recorded. The MAC of sevoflurane was measured by up and down sequential method of Dixon and Mood and centred isotonic regression analysis., Results: The calculated MAC of sevoflurane using up-and-down method of Dixon and Mood in patients with hysteroscopy surgery was (1.90 ± 0.13)%, (1.23 ± 0.16)%, (1.03 ± 0.10)% and (0.93 ± 0.08)% in groups C, D 1 , D 2 and D 3 , respectively., Conclusions: The administration of dexmedetomidine can significantly decrease the MAC of sevoflurane for hysteroscopy surgery. However, a ceiling effect of the reduction was observed when the dose of dexmedetomidine was higher than 0.8 μg/kg., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Newborn infants are prone to sepsis and related inflammation of different organs. Neuroinflammation has been associated with long-term adverse neuronal (neuropsychiatric/neurodegenerative) outcomes, including attention deficit hyperactivity disorder (ADHD) or even Alzheimer's disease. Despite a vast number of findings on sepsis-induced inflammatory responses in the central nervous system (CNS), how neuroinflammation affects brain development remains largely elusive. In this study, neonates with clinical sepsis and screened for meningitis were included and classified by the neuroinflammation status based on cerebrospinal fluid (CSF) parameters (INF vs. NOINF). CSF samples collected from clinical screening were subjected to proteomics analysis. Proteins with differential abundance were subjected to enrichment analysis to reveal affected biological pathways. INF and NOINF infants had similar demographic data and hematological and biochemical parameters in blood and CSF. The CSF proteomes were essentially different between the two groups. All 65 proteins with differential abundance showed lower abundance in the INF group and functionally covered pivotal developmental processes, including axonal and synaptic function and extracellular homeostasis. CSF proteins, PTPRZ1 and IGFBP4, were correlated with C-reactive protein (CRP) and ratios of immature/total neutrophils in blood. In general, a substantial change in the CSF protein profile was found under neuroinflammation, and these changes are related to systemic conditions. The results suggest that changes in CSF proteins may be involved in sepsis-affected neurodevelopment, such as disturbances in circuit formation, which has the potential to predispose neonates to long-term adverse outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Peng, Pankratova, Luo, Zhou and Chen.)

Chorioamnionitis (CA) is a risk factor for preterm birth and is associated with neurodevelopmental delay and cognitive disorders. Prenatal inflammation-induced brain injury may resolve during the immediate postnatal period when rapid brain remodeling occurs. Cerebrospinal fluid (CSF) collected at birth may be a critical source of predictive biomarkers. Using pigs as a model of preterm infants exposed to CA, we hypothesized that prenatal lipopolysaccharide (LPS) exposure induces proteome changes in the CSF and brain at birth and postnatally. Fetal piglets (103 days gestation of full-term at 117 days) were administered intra-amniotic (IA) lipopolysaccharide (LPS) 3 days before preterm delivery by caesarian section. CSF and brain tissue were collected on postnatal Days 1 and 5 (P1 and P5). CSF and hippocampal proteins were profiled by LC-MS-based quantitative proteomics. Neuroinflammatory responses in the cerebral cortex, periventricular white matter and hippocampus were evaluated by immunohistochemistry, and gene expression was evaluated by qPCR. Pigs exposed to LPS in utero showed changes in CSF protein levels at birth but not at P5. Complement protein C3, hemopexin, vasoactive intestinal peptide, carboxypeptidase N subunit 2, ITIH1, and plasminogen expression were upregulated in the CSF, while proteins associated with axon growth and synaptic functions (FGFR1, BASP1, HSPD1, UBER2N, and RCN2), adhesion (talin1), and neuronal survival (Atox1) were downregulated. Microglia, but not astrocytes, were activated by LPS at P5 in the hippocampus but not in other brain regions. At this time, marginal increases in complement protein C3, LBP, HIF1a, Basp1, Minpp1, and FGFR1 transcription indicated hippocampal proinflammatory responses. In conclusion, few days exposure to endotoxin prenatally induce proteome changes in the CSF and brain at birth, but most changes resolve a few days later. The developing hippocampus has high neuronal plasticity in response to perinatal inflammation. Changes in CSF protein expression at birth may predict later structural brain damage in preterm infants exposed to variable types and durations of CA-related inflammation in utero., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Compare with preterm formula, donor human milk (DM) is associated with a lower risk of mortality and morbidity in preterm infants. It is thus deemed superior to preterm formula as the sole diet or supplement to own mother's milk (OMM) for preterm infants, especially for those with very low birthweight (VLBW). This historic cohort study investigated the relationship between DM availability, and enteral feeding, body growth of VLBW infants by comparing two cohorts before and after the establishment of a human milk bank. A sub-analysis was also conducted between small-for-gestational-age (SGA) and non-SGA infants in our cohorts. Our results showed that DM availability was associated with earlier initiation and faster advancement of enteral feeding, earlier attainment of full enteral feeding, and a higher proportion of OMM in enteral feeding. DM availability was also associated with earlier regain of birthweight, but not with better body growth. SGA and non-SGA infants responded differently to DM availability with only the non-SGA group showing improved enteral feeding associated with DM availability. The poor growth of VLBW infants with fortified DM warrants further investigations on better fortification strategies to further improve body growth. Studies are also needed on long-term effects of DM feeding on the development of VLBW infants., (© 2022 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background: Treatment of antenatal corticosteroids (ACSs) to women at risk of preterm labor can decrease neonatal mortality and morbidity. However, effect of ACS exposure on enteral feeding and body growth of preterm infants remains elusive., Methods: This retrospective study collected information of eligible singleton infants born between 22 +0 and 36 +6 weeks' gestation from 2017 to 2019. Logistic regression and multivariate linear regression were adopted to examine the associations of the ACS exposure with various outcomes of enteral feeding and growth considering potential confounders. Stratified analysis was performed based on gestational age (GA) (<34 vs ≥34 weeks)., Results: Of the 1694 preterm infants included, 1222 (72.1%) were exposed to ACSs. Infants with ACS exposure had a higher incidence of feeding intolerance (odds ratio 1.51; 95% CI, 1.05 to 2.20; P = .03), slower advancement of enteral feeding (β coefficient -0.86; 95% CI, -1.48 to -0.25; P = .01), and lower delta body-weight z-scores (β coefficient-0.13; 95% CI, -0.18 to -0.08; P < .001). Unlike in infants with GA <34 weeks, ACS exposure was associated with slower advancement of enteral feeding, longer time to regain birth weight, and lower delta body-weight z-scores in the ones with GA ≥34 weeks., Conclusion: ACS exposure is associated with poorer enteral feeding process and body growth in our study population, which is more prominent in late preterm infants. A multicenter prospective study and mechanistic studies using animal models are required., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Background: In the first weeks after birth, enteral feeding and bacterial colonization interact to influence gut maturation in preterm infants. Bovine colostrum (BC) has been suggested as a relevant supplementary diet when own mother's milk (MM) is insufficient or absent. This pilot trial tests whether the supplement type, BC or donor human milk (DM), affects gut colonization in preterm infants during the first week of life., Methods: On day 7, fecal samples were collected from preterm infants (n = 24) fed BC or DM as a supplement to MM. The gut microbiome (GM) was analyzed by 16S ribosomal RNA amplicon sequencing. Correlations between the relative abundance of specific bacterial taxa and blood chemistry variables, including amino acids, were explored., Results: BC-supplemented infants showed a lower relative abundance of the families Lactobacillaceae and Enterococcaceae than DM infants. Planococcaceae were more abundant in infants delivered by cesarean birth vs vaginally. The relative abundance of bacterial families, specifically Enterobacteriaceae, correlated negatively with plasma levels of multiple essential and nonessential amino acids (valine, isoleucine, lysine, histidine, and arginine)., Conclusion: The nature of nutrition supplements (BC or DM) just after birth may affect GM development and nutrient metabolism in the neonatal period of preterm infants. The exploratory nature of our study calls for confirmation of these results and their possible long-term clinical implications for preterm infants., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Breast milk has neurodevelopmental advantages compared to infant formula, especially in low-birth-weight infants, which may in part relate to the fat source. This study compared neurodevelopmental outcomes in three-day-old normal birth weight (NBW) and intrauterine growth restricted (IUGR) piglets fed a formula diet with either vegetable oil (VEG) or bovine milk fat sources (MILK) for three weeks in a 2 × 2 factorial design. Behavioural tests, lipidomics, MRI and RNA sequencing analyses of plasma and brain tissue were conducted. The absolute levels of 82% and 11% of lipid molecules were different between dietary groups in plasma and hippocampus, respectively. Of the lipid molecules with differential abundance in the hippocampus, the majority were upregulated in MILK versus VEG, and they mainly belonged to the group of glycerophospholipids. Lower absolute brain weights, absolute grey and white matter volumes and behaviour and motor function scores, and higher relative total brain weights were present in IUGR compared to NBW with minor influence of diet. Cognitive function and cerebellar gene expression profiles were similar for dietary and weight groups, and overall only minor interactive effects between diet and birth weight were observed. Overall, we show that the dietary fat source influences the plasma and to a lesser degree the hippocampal lipidome and is unable to improve on IUGR-induced brain structural and functional impairments., (© 2022. The Author(s).)

Skin-mountable capacitive-type strain sensors with great linearity and low hysteresis provide inspiration for the interactions between human and machine. For practicality, high sensing performance, large stretchability, and self-healing are demanded but limited by stretchable electrode and dielectric and interfacial compatibility. Here, we demonstrate an extremely stretchable and self-healing conductor via both hard and soft tactics that combine conductive nanowire assemblies with double dynamic network based on π-π attractions and Ag-S coordination bonds. The obtained conductor outperforms the reported stretchable conductors by delivering an elongation of 3250%, resistance change of 223% at 2000% strain, high durability, and multiresponsive self-healability. Especially, this conductor accommodates large strain of 1500% at extremely knotted and twisted deformations. By sandwiching hydrogel conductors with a newly developed dielectric, ultrahigh stretchability and omni-healability are simultaneously achieved for the first time for a capacitive strain sensor inspired by metal-thiolate coordination chemistry, showing great potentials in wearable electronics and soft robotics.

Enterotoxigenic Escherichia coli (ETEC) is closely associated with diarrhoea in children in resource-limited countries. This study aims to investigate the change of the mucosal microbiome and protein expression in the ileum induced by E. coli K88 (ETEC) using pigs as a model. Seven weaned male pigs were orally given ETEC (1 × 10 9 CFU, n = 7), and the other seven received saline (CON, n = 7). Ileal tissues were obtained 48 hours after the ETEC challenge for both proteomic and mucosal microbiome analyses. Nine proteins were found with altered abundance between the two groups, including a decrease in FABP1 and FABP6, involved in bile acid circulation. The TLR-9 mediated pathway was also affected showing increased transcription of genes SIGIRR and MyD88. Correlations between the ileal proteins and mucosal bacterial taxa found included a positive correlation between Lactobacilllus and PPP3CA (r = 0.9, p < 0.001) and a negative correlation between Prevotella with CTNND1 (r = -0.7, p < 0.01). In conclusion, ETEC infection caused inflammation and impaired the circulation of bile acids and the mucosal microbiome may affect the expression of intestinal proteins. Further studies are needed to explain the exact roles of these affected processes in the pathogenesis of ETEC-triggered diarrhoea.

Background: Antibiotics are widely prescribed by obstetricians, which exposes a large number of infants to antenatal antibiotics (AAB). The effect of AAB on various aspects of neonatal development of preterm infants remains unclear. Methods: In this retrospective study, infants born with gestational age (GA) between 22 +0 and 36 +6 weeks at our unit from 2017 to 2019 were included. Multivariable analysis was adopted to examine the associations between AAB exposure and various outcomes related to enteral feeding process, body growth, and neonatal infection after adjusting for potential confounders. Further subanalysis on the exposure level of AAB and stratified analysis by GA (<34 vs. ≥34 weeks) were also conducted. Results: In this cohort comprising 2,543 preterm infants, AAB was associated with decreased risks of feeding intolerance (odds ratio [OR]: 0.63, 95% confidence interval [CI]: 0.48-0.82) and neonatal infection (OR: 0.63, 95% CI: 0.41-0.94). Higher AAB exposure level was associated with higher Z scores of birth weight (β = 0.37, 95% CI: 0.27-0.47), but lower Δbodyweight Z-scores (β = -0.20, 95% CI: -0.27 to -0.13). AAB was positively associated with the parameters related to body growth in infants with GA <34 weeks but negatively associated in those with GA ≥34 weeks. Conclusions: AAB exposure affects the enteral feeding process and neonatal infection. The effects on body growth vary by the exposure level of AAB and GA of infants. A well-designed prospective and preferably multi-centre study with predefined parameters is required to confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Zhang, Chen, Geng, Wu, Li, Zhou, Jiang and Ma.)

What Is Known and Objective: Remifentanil can effectively decrease the sevoflurane concentration to block sympathetic adrenergic response to CO 2 pneumoperitoneum stimulus,and liver dysfunction will significantly reduce the MAC BAR (minimum alveolar concentration for blocking adrenergic response) of sevoflurane. However, the effects of different remifentanil concentrations on the MAC BAR of sevoflurane in patients with liver dysfunction are unclear. The aim of this study was to observe the effects of different remifentanil concentrations by intravenous target-controlled infusion on the MAC BAR of sevoflurane in patients with grade B liver dysfunction under carbon dioxide pneumoperitoneum stimulus., Methods: Seventy-five patients with grade B liver dysfunction undergoing elective laparoscopic surgery were selected, and randomly divided into three groups with remifentanil plasma target concentrations of 0 (group R 0 ), 1 (group R 1 ) and 2 (group R 2 ) ng/ml. Anaesthesia was induced by intravenous injection of propofol 2-3 mg/kg, remifentanil 2 μg/kg and cisatracurium 0.15 mg/kg. All groups were inhaled different concentrations of sevoflurane. The determination of sevoflurane MAC BAR in each group was used a method of sequential-allocation technique, and venous blood samples were taken before and after the creation of carbon dioxide pneumoperitoneum to determine plasma adrenaline and noradrenaline concentrations., Results and Discussions: The MAC BAR of sevoflurane in groups R 0 , R 1 and R 2 was 4.83%, 3.00% and 2.10%, respectively. The MAC BAR of sevoflurane was significantly difference among the three groups. When a similar effect of MAC BAR had achieved in each group, no significant differences were found in the changes of plasma adrenaline and noradrenaline concentrations before and after the creation of pneumoperitoneum. What is new and conclusion Target-controlled infusion of different concentrations of remifentanil can reduce sevoflurane MAC BAR during pneumoperitoneum stimulation in patients with liver dysfunction in some degree. However, the changes of plasma adrenaline and noradrenaline concentrations are consistent in the three groups when patient's stress response was inhibited at the same degree., (© 2021 John Wiley & Sons Ltd.)

To explore the influence of human activities on the Yangtze River water chemistry, water samples were obtained from a representative section the main river stem/branch in wet and normal seasons in 2016. Ion ratio analysis, principal component analysis(PCA), and chemical ion balance calculations were performed, and carbonate rock dissolution rates were determined based on carbonate and exogenous acids. The result show that HCO 3 -Ca is the dominant hydrochemistry type, indicating that the dissolution of carbonate rocks in the basin is the main process affecting hydrochemistry, and carbonate acid is significant in the weathering of carbonate rocks. In addition, the proportion of carbonate acid dissolution in the wet and normal seasons accounted for 60.33% and 59.14% of the total dissolution, respectively. The dissolution ratio among the different sampling points was notable, which indicates that the carbon sink effect of exogenous acid cannot be ignored. In addition, cation exchange some influence on hydrochemistry but was not the main reaction process. Compared with hydrological monitoring data for the last few years, the weathering of rocks by sulfuric and nitrate acids has strengthened, and the negative effects of anthropogenic pollution in the Yangtze River have increased.

Background: To investigate the effects of different plasma target concentrations of remifentanil on the minimum alveolar concentration (MAC) for blocking adrenergic response (BAR) of sevoflurane in children with laparoscopic herniorrhaphy., Methods: Seventy-five children with 3-7 years old scheduled for laparoscopic herniorrhaphy were randomly divided into group R 0 , group R 1, and group R 2 according to different remifentanil plasma target concentration (0, 1, and 2 ngml -1 ), respectively. The MAC BAR of sevoflurane was determined by the up-and-down and sequential method in each group. The concentrations of epinephrine and noradrenaline were also determined at corresponding time points., Results: A total of 52 child patients were used among the anticipated 75 patients. In groups R 0 , R 1, and R 2 , the MAC BAR of sevoflurane was (3.29 ± 0.17) %, (2.12 ± 0.10) % and (1.29 ± 0.11) %, respectively, and a significant difference was found among the three groups (P<0.05). The changes of epinephrine and noradrenaline concentrations in each group before and after insufflation of carbon dioxide pneumoperitoneum showed no significant differences., Conclusion: Remifentanil by target-controlled infusion can effectively reduce the MAC BAR of sevoflurane during laparoscopic surgery in children. At a similar effect of MAC BAR , both the changes of epinephrine and noradrenaline concentrations are not affected by the infusion of different remifentanil target concentrations., Trial Registration: The trial was registered at http://www.chictr.org.cn ( ChiCTR1800019393 , 8, Nov, 2018)., (© 2021. The Author(s).)

Mucositis is a serious adverse effect of chemotherapeutic treatment. During intestinal mucositis, the mucosal barrier is compromised, increasing the risk of severe infections. Mucositis necessitates dose reduction or pauses in treatment, which affect the outcome of the treatment. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We have previously shown that jejunal DMBT1 expression is increased in piglets during chemotherapeutic treatment. We hypothesized that DMBT1 ameliorates doxorubicin-induced mucositis. Individually-caged Dmbt1 +/+ (WT) and Dmbt1 -/- (KO) female mouse littermates received intraperitoneal injections of either doxorubicin or saline. They were euthanized after three (D3) or seven days (D7). Weight loss was monitored every day, and serum citrulline levels were measured at termination. Intestinal tissue was analyzed for the expression of DMBT1 and proinflammatory cytokines (IL-1β, IL-6, and TNF). Specimens from the small intestines and colon were scored for inflammation and epithelial and mucosal architecture changes. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. We detected a significant increase in crypt depth in WT mice compared to that in KO mice on D3. In conclusion, DMBT1 does not affect doxorubicin-induced mucositis in mice., (© 2021. The Author(s).)

Necrotising enterocolitis (NEC) is a microbiome-dependent gut disease in preterm infants in early life. Antibiotic treatment is a common intervention for NEC. How NEC lesions, with or without antibiotics, affect plasma metabolome was explored in this study. Formula-fed preterm pigs were used as a model for human NEC and treated with saline, parenteral or oral antibiotics ( n = 15-17) for four days after delivery. Gut tissues were collected for evaluation of NEC-like lesions and plasma for metabolomic analysis by proton nuclear magnetic resonance spectroscopy ( 1 H-NMR). Metabolites were annotated, quantified and subjected to statistical modelling to delineate the effects of NEC and antibiotic treatment. Presence of severe NEC lesions, not antibiotic treatment, was the main drive for plasma metabolite changes. Relative to other pigs, pigs with severe NEC lesions had higher levels of alanine, histidine and myo -inositol, and lower levels of 3-hydroxybutyric acid and isobutyric acid. Across NEC lesion states (healthy, mild, severe), antibiotics directly affected only a few metabolites (tryptophan, 3-phenyllactic acid). Together and independently, NEC and antibiotic treatment affected circulating metabolites in preterm pigs. Amino acids and plasma metabolites, partly related to the gut microbiome, may be helpful to monitor progression of NEC lesions after proper validation.

Aster pekinensis is a perennial herb that distributes widely in China, Korea, and Eeastern Russia. The complete plastome of A. pekinensis is reported here. It is a circular molecular of 152,815 bp in length and consists of a large single-copy region (LSC: 84,530 bp), a small single-copy region (SSC: 18,219 bp), and two inverted repeats (IR: 25,033 bp) regions. GC content is 37.3%. This plastome encodes 113 unique genes, including 79 protein-coding genes, 30 tRNAs, and 4 rRNAs. Phylogenomic analysis of 17 plastomes within Aster and closely related genera revealed that A. pekinensis was sister to the clade comprising A. flaccidus and A. altaicus ., Competing Interests: No potential conflict of interest was reported by the authors., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To explore whether probiotic supplementation could attenuate serum trimethylamine-N-oxide (TMAO) level and impact the intestinal microbiome composition., Design: Forty healthy males (20-25 years old) were randomized into the probiotic group (1.32 × 10 11  CFU live bacteria including strains of Lactobacillus acidophilus, Lactobacillus rhamnosus GG, Bifidobacterium animalis, and Bifidobacterium longum daily) or the control group for 4 weeks. All participants underwent a phosphatidylcholine challenge test (PCCT) before and after the intervention. Serum TMAO and its precursors (TMA, choline and betaine) were measured by UPLC-MS/MS. The faecal microbiome was analyzed by 16S rRNA sequencing., Results: Serum TMAO and its precursors were markedly increased after the PCCT. No statistical differences were observed in the probiotic and the control group in area under the curve (AUC) (14.79 ± 0.97 μmol/L 8 h vs. 19.17 ± 2.55 μmol/L 8 h, P = 0.106) and the pre- to post-intervention AUC alterations (∆AUC) (- 6.33 ± 2.00 μmol/L 8 h vs. - 0.73 ± 3.04 μmol/L 8 h, P = 0.131) of TMAO; however, higher proportion of participants in probiotic group showed their TMAO decrease after the intervention (78.9% vs. 45.0%, P = 0.029). The abundance of Faecalibacterium prausnitzii (P = 0.043) and Prevotella (P = 0.001) in the probiotic group was significantly increased after the intervention but without obvious differences in α- and β-diversity., Conclusions: The current probiotic supplementation resulted in detectable change of intestinal microbiome composition but failed to attenuate the serum TMAO elevation after PCCT. CLINICALTRIALS., Gov Identifier: NCT03292978. CLINICALTRIALS.GOV WEBSITE: https://clinicaltrials.gov/ct2/show/NCT03292978 .

The enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.

Importance: Expert-level artificial intelligence (AI) algorithms for prostate biopsy grading have recently been developed. However, the potential impact of integrating such algorithms into pathologist workflows remains largely unexplored., Objective: To evaluate an expert-level AI-based assistive tool when used by pathologists for the grading of prostate biopsies., Design, Setting, and Participants: This diagnostic study used a fully crossed multiple-reader, multiple-case design to evaluate an AI-based assistive tool for prostate biopsy grading. Retrospective grading of prostate core needle biopsies from 2 independent medical laboratories in the US was performed between October 2019 and January 2020. A total of 20 general pathologists reviewed 240 prostate core needle biopsies from 240 patients. Each pathologist was randomized to 1 of 2 study cohorts. The 2 cohorts reviewed every case in the opposite modality (with AI assistance vs without AI assistance) to each other, with the modality switching after every 10 cases. After a minimum 4-week washout period for each batch, the pathologists reviewed the cases for a second time using the opposite modality. The pathologist-provided grade group for each biopsy was compared with the majority opinion of urologic pathology subspecialists., Exposure: An AI-based assistive tool for Gleason grading of prostate biopsies., Main Outcomes and Measures: Agreement between pathologists and subspecialists with and without the use of an AI-based assistive tool for the grading of all prostate biopsies and Gleason grade group 1 biopsies., Results: Biopsies from 240 patients (median age, 67 years; range, 39-91 years) with a median prostate-specific antigen level of 6.5 ng/mL (range, 0.6-97.0 ng/mL) were included in the analyses. Artificial intelligence-assisted review by pathologists was associated with a 5.6% increase (95% CI, 3.2%-7.9%; P < .001) in agreement with subspecialists (from 69.7% for unassisted reviews to 75.3% for assisted reviews) across all biopsies and a 6.2% increase (95% CI, 2.7%-9.8%; P = .001) in agreement with subspecialists (from 72.3% for unassisted reviews to 78.5% for assisted reviews) for grade group 1 biopsies. A secondary analysis indicated that AI assistance was also associated with improvements in tumor detection, mean review time, mean self-reported confidence, and interpathologist agreement., Conclusions and Relevance: In this study, the use of an AI-based assistive tool for the review of prostate biopsies was associated with improvements in the quality, efficiency, and consistency of cancer detection and grading.

The pathogenesis of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is highly heterogeneous and still unclear. Additional novel variants have been recently detected in the population. The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization. To address this problem, we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency. Marked deficiencies in fatty acid oxidation (FAO) and other mitochondrial defects were observed in cells carrying one of these six variants (c.541C>T, c.863T>G, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A), including reductions in mitochondrial respiratory-chain function and adenosine triphosphate (ATP) production, and increased levels of mitochondrial reactive oxygen species (ROS). Intriguingly, higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress. Moreover, the stability of the mutant homodimer was disturbed, and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics (MD) simulation. The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.

Background: Most hospitalized preterm infants receive antibiotics in the first days of life to prevent or treat infections. Short-term, early antibiotic treatment may also prevent the microbiota-dependent gut inflammatory disorder, necrotizing enterocolitis (NEC). It remains a challenge to predict NEC, and a few early blood diagnostic markers exist. Using preterm pigs as model for infants, blood parameters and plasma proteins affected by early progression of NEC were profiled in preterm pigs subjected to oral, systemic, or no antibiotics after preterm birth. Methods: Preterm newborn pigs were treated with saline (CON) or antibiotics (ampicillin, gentamicin, and metronidazole) given enterally (ENT) or parenterally (PAR), and fed formula for 4 days to induce variable microbiome-dependent sensitivities to NEC. The gut was collected for macroscopic scoring of NEC lesions and blood for hematology, blood biochemistry, and LC/MS-based plasma proteomics. Statistical modeling was applied to detect plasma proteins affected by NEC and/or antibiotics. Results: Analyzed across different antibiotic regimens, NEC progression was associated with altered blood parameters and abundance of 89 plasma proteins that were functionally involved in extracellular membrane destruction, lipid metabolism, coagulopathy, and acute phase response. Large NEC-related changes were observed in abundance of RBP4, FGA, AHSG, C5, PTPRG, and A-1-antichymotrypsin 2, indicating potential serving as early markers of NEC. Conversely, antibiotic treatment, independent of NEC, affected only 4 proteins with main differences found between ENT and CON pigs. Conclusion: Early postnatal development of NEC lesions is associated with marked plasma protein changes that may be used for early NEC diagnosis., (Copyright © 2020 Jiang, Muk, Stensballe, Nguyen, Sangild and Jiang.)

Chorioamnionitis (CA) predisposes to preterm birth and affects the fetal mucosal surfaces (i.e., gut, lungs, and skin) via intra-amniotic (IA) inflammation, thereby accentuating the proinflammatory status in newborn preterm infants. It is not known if CA may affect more distant organs, such as the kidneys, before and after preterm birth. Using preterm pigs as a model for preterm infants, we investigated the impact of CA on fetal and neonatal renal status and underlying mechanisms. Fetal pigs received an IA dose of lipopolysaccharide (LPS), were delivered preterm by cesarean section 3 days later (90% gestation), and compared with controls (CON) at birth and at postnatal day 5. Plasma proteome and inflammatory targets in kidney tissues were evaluated. IA LPS-exposed pigs showed inflammation of fetal membranes, higher fetal plasma creatinine, and neonatal urinary microalbumin levels, indicating renal dysfunction. At birth, plasma proteomics revealed LPS effects on proteins associated with renal inflammation (up-regulated LRG1, down-regulated ICA, and ACE). Kidney tissues of LPS pigs at birth also showed increased levels of kidney injury markers ( LRG1 , KIM1 , NGLA , HIF1A , and CASP3 ), elevated molecular traits related to innate immune activation (infiltrated MPO + cells, complement molecules, oxidative stress, TLR2 , TLR4, S100A9 , LTF , and LYZ ), and Th1 responses (CD3 + cells, ratios of IFNG/IL4 , and TBET/GATA3 ). Unlike in plasma, innate and adaptive immune responses in kidney tissues of LPS pigs persisted to postnatal day 5. We conclude that prenatal endotoxin exposure induces fetal and postnatal renal inflammation in preterm pigs with both innate and adaptive immune activation, partly explaining the potential increased risks of kidney injury in preterm infants born with CA., (Copyright © 2020 Muk, Jiang, Stensballe, Skovgaard, Sangild and Nguyen.)

Background: Neonatal infection and sepsis are common for preterm infants due to their immature immune system. Early diagnosis is important for effective treatment, but few early markers of systemic and neuro-inflammatory responses in neonates are known. We hypothesised that systemic infection with Staphylococcus epidermidis (SE), a Gram-positive bacteria, induces acute changes to proteins in the plasma and cerebrospinal fluid (CSF), potentially affecting the immature brain of preterm neonates. Methods: Using preterm pigs as a model for preterm infants, plasma and CSF samples were collected up to 24 h after SE infection and investigated by untargeted mass spectrometry (MS)-based proteomics. Multiple differentially expressed proteins were further studied in vitro . Results: The clinical signs of sepsis and neuroinflammation in SE-infected piglets were associated with changes of multiple CSF and plasma proteins. Eight plasma proteins, including APOA4, haptoglobin, MBL1, vWF, LBP, and sCD14, were affected 6 h after infection. Acute phase reactants, including complement components, showed a time-dependent activation pattern after infection. Feeding bovine colostrum reduced the sepsis-related changes in clinical indices and plasma proteins. Neuroinflammation-related neuropeptide Y (NPY), IL-18, and MMP-14 showed distinct changes in the CSF and several brain regions (the prefrontal cortex, PVWM, and hippocampus) 24 h after infection. These changes were verified in TLR2 agonist-challenged primary microglia cells, where exogenous NPY suppressed the inflammatory response. Conclusion: Systemic infection with SE induces inflammation with rapid proteome changes in the plasma and CSF in preterm newborn pigs. The observed early markers of sepsis and neuroinflammation in preterm pigs may serve as novel biomarkers for sepsis in preterm infants., (Copyright © 2019 Muk, Stensballe, Pankratova, Nguyen, Brunse, Sangild and Jiang.)

Sepsis, the clinical manifestation of serious infection, may disturb normal brain development, especially in preterm infants with an immature brain. We hypothesized that neonatal sepsis induces systemic metabolic alterations that rapidly affect metabolic signatures in immature brain and cerebrospinal fluid (CSF). Cesarean-delivered preterm pigs systemically received 10⁸ CFU/kg Staphylococcus epidermidis (SE) and were provided total parenteral nutrition ( n = 9) or enteral supplementation with bovine colostrum ( n = 10) and compared with uninfected pigs receiving parenteral nutrition ( n = 7). Plasma, CSF, and brain tissue samples were collected after 24 h and analyzed by ¹H NMR-based metabolomics. Both plasma and CSF metabolomes revealed SE-induced changes in metabolite levels that reflected a modified energy metabolism. Hence, increased plasma lactate, alanine, and succinate levels, as well as CSF lactate levels, were observed during SE infection (all p < 0.05, ANOVA analysis). Myo -inositol, a glucose derivative known for beneficial effects on lung maturation in preterm infants, was also increased in plasma and CSF following SE infection. Enteral colostrum supplementation attenuated the lactate accumulation in blood and CSF. Bloodstream infection in preterm newborns was found to induce a rapid metabolic shift in both plasma and CSF, which was modulated by colostrum feeding., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the epidemiological characteristics, phenotype, genotype, and prognosis of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in the Chinese population., Methods: A retrospective analysis was performed for the clinical data of the neonates who underwent screening with high-performance liquid chromatography-tandem mass spectrometry from January 2009 to June 2018 and were diagnosed with MCADD by gene detection., Results: A total of 2 674 835 neonates underwent neonatal screening, among whom 12 were diagnosed with MCADD. Gene detection was performed for 10 neonates with MCADD and found 13 mutation types at 16 mutation sites of the ACADM gene, among which there were 7 reported mutations (p.T150Rfs*4, p.M1V, p.R206C, p.R294T, p.G310R, p.M328V, and p.G362E), 5 novel mutations (p.N194D, p.A324P, p.N366S, c.118+3A>G, and c.387+1del G), and 1 exon 11 deletion; p.T150Rfs*4 was the most common mutation (4/16). The detection rate of mutation sites in the ACADM gene was 80%. No phenotype-genotype correlation was observed. Dietary guidance and symptomatic treatment were given after confirmed diagnosis. No acute metabolic imbalance was observed within 4-82 months of follow-up. All neonates had good prognosis except one who had brain dysplasia., Conclusions: MCADD is relatively rare in southern China, and p.T150Rfs*4 is a common mutation in the Chinese population. Cases with positive screening results should be evaluated by octanoylcarnitine C8 value and gene detection.

[This corrects the article DOI: 10.1371/journal.pgen.1007394.].

Background: Distal radius metaphyseal (DRM) fractures are very frequent childhood fractures. Whether additional percutaneous pinning improves the outcome remains controversial. In this review, we tried to systematically evaluate the effect of percutaneous pinning on re-displacement, secondary reduction, radiographs, function, and complications in children with displaced DRM fractures., Methods: PubMed, Medline, Embase, Cochrane Library, and Web of Science databases were explored systematically to identify randomized controlled trials (RCTs) and clinical controlled trials (CCTs) comparing cast immobilization alone or following reduction to additional percutaneous pinning in the treatment of pediatric displaced DRM fractures. Two reviewers independently screened eligible articles and extracted relevant information from each article. The methodological quality of eligible articles was evaluated using the Cochrane Collaboration risk assessment tool (RCTs) and modified Jadad scale (CCTs)., Results: A total of 4 RCTs and 3 CCTs met the inclusion criteria, with a total patient count of 1144 children. The results showed that additional percutaneous pinning significantly reduced the rate of re-placement (Chi-square tests, P < .001) and complications (Chi-square tests, P = .030). The superior results, both radiographically and functionally seemed to be temporary. No difference was found between the 2 groups after longer-term follow-up., Conclusions: This systematic review suggested that compared with casting following reduction, percutaneous pinning had a positive effect on maintaining the initial reduction and reducing fracture complication rate of displaced DRM fractures in children, but with no significant improvement in function and radiographic outcome at the long-term follow-up. We suggest clinicians think twice before percutaneous pinning of displaced pediatric DRM fractures.

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB., Competing Interests: The 23andMe authors are employees of and hold stock or stock options in 23andMe, Inc.

Background: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations., Methods: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 -8 ) or an association with suggestive significance (P<1.0×10 -6 ) in the discovery set., Results: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome., Conclusions: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).

Reconstruction following devastating hand injuries, with amputations of the thumb plus multiple digits, is challenging. Double flap or combined flap transfers may be options in such cases. Between 2012 and 2014, 6 patients underwent hand reconstruction following devastating injuries with amputations of the thumb and multiple digits. Sensate anterolateral thigh free flaps and superficial circumflex iliac artery osteocutaneous flaps were microsurgically fabricated as sequential chimeric flaps. Basic hand function, including pulp-to-palm distance, pinch strength, sensation recovery and modified DASH scores, were evaluated. Anterolateral thigh flaps were used as "piggyback" flaps, and their size ranged from 8 cm × 16 cm to 10 cm × 25 cm. Cutaneous portions of superficial circumflex iliac artery osteocutaneous flaps ranged in size from 4 cm × 5 cm to 7 cm × 15 cm, and bone flap size ranged from 1 cm × 3 cm × 0.8 cm to 1 cm × 4 cm × 1 cm. All of the flaps survived uneventfully. All patients were able to perform basic hand functions after a median follow-up of 1.8 years. Microsurgically fabricated chimeric iliac osteocutaneous flaps may restore basic hand function to some extent. This procedure is an option worth considering for hand reconstruction following devastating injuries in carefully selected patients., (Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this report is to present the clinical results of using free chimeric iliac osteocutaneous flaps based on the periosteal branch of the superficial circumflex iliac artery (SCIA) in complex metacarpal reconstructions., Methods: Reconstruction using free chimeric iliac osteocutaneous flaps was performed in a series of seven patients who underwent metacarpal reconstruction for complex metacarpal defects between March 2009 and March 2012. The procedure was performed for bone and soft tissue losses associated with posttraumatic infections (four patients) and posttraumatic bone and soft tissue defects (three patients)., Results: The skin paddles of the chimeric flaps had a median size of 3 × 7 cm, and the iliac segments had a mean size of 1 × 1 × 3 cm. The median follow-up time was 18 months. All the flaps survived completely with no signs of infection. Osseous union occurred within a mean period of 3 months, and the range of motion achieved for the metacarpal phalangeal joints was 0-80°. The patients were satisfied with the aesthetic outcome., Conclusions: Chimeric iliac osteocutaneous flaps may be a useful alternative for treating complex metacarpal defects because they yield a thinner skin paddle and less bulky bone segment than traditional flaps.

Mitochondrial DNA (mtDNA) mutations cause a variety of mitochondrial DNA-based diseases which have been studied using Lymphoblastoid cell lines (LCLs) and transmitochondrial cybrids. Individual genetic information is preserved permanently in LCLs while the development of transmitochondrial cybrids provide ex-vivo cellular platform to study molecular mechanism of mitochondrial DNA-based diseases. The cytoplasmic donor cells for previous transmitochondrial cybrids come from patient's tissue or platelet directly. Here, we depicted in details the principle, methods and techniques to establish LCLs from frozen peripheral bloods harboring mitochondrial 4401G > A mutation by infection of Epstein Barr virus, and then to generate cybrids using ρ 0 206 and LCLs. The process of establishing these two cellular models was summarized into four steps as follows: (1) Generation of LCLs; (2) Transformation; (3) Selection; (4) Verification. To faithfully represent the function of mtDNA mutation, we analyzed and identified the sites of mtDNA mutations and copy numbers of each cellular models as well as the karyotype of transmitochondrial cybrids. Those clones with consistent parameters were selected for preservation and future analysis of the function of point mutations of mtDNA. Although these two cellular models play important roles in understanding molecular mechanism of mitochondrial DNA-based diseases on the cellular level, their limitations should be considered when elucidating the character of tissue specificity of mitochondrial DNA-based diseases.

Objective: To investigate associations between health-promoting lifestyle and suboptimal health status (SHS) in the population of Guangdong province., Methods: A cross-sectional survey was conducted in a clustered sample of 24 159 individuals aged 12-80 years from 2012 to 2013. Health-promoting lifestyle was assessed via the Health-Promoting Lifestyle Profile (HPLP-II), and SHS was evaluated using the medical examination report and Sub-health Measurement Scale V1.0 (SHMS V1.0)., Results: Of the 24159 participants, subjects with SHS (46.0%) and disease status (35.2%) accounted for a much higher percentage than healthy subjects (18.8%). Regression analyses revealed a significant association between health status and healthy lifestyle (P<0.001). Unhealthy lifestyle was an important risk factor for SHS and disease, especially the former. Compared with the participants with a healthy lifestyle (minimal exposure), after demographic adjustment, subjects with a 'poor' lifestyle (maximal exposure) were at a 43 times higher risk of developing SHS (OR: 42.825, 95% CI: 30.567-59.997), those with a general lifestyle were at a 21 times higher risk of SHS (OR: 21.072, 95%CI: 17.258-25.729), and those with a suboptimal lifestyle had a 4 times higher risk (OR: 4.085, 95%CI: 3.352-4.979). In the general population, the major risk factors for SHS included poor stress management, poor self-actualization, inactive exercise and poor interpersonal relationship., Conclusion: s Unhealthy lifestyles are significantly related to an increased risk of SHS. Intervention of unhealthy lifestyles, controlling the risk factors of SHS, and rigorous management of the time window of SHS are necessary to promote the heath status.

A total of 121 sampling sites were selected to study the C, N, P stoichiometric characteristics among the leaves of tree, shrub, herb and the litter of the majority forest community of Shaanxi Province, China. We also studied their relationships with geographical factors. The results showed that C, N concentrations were highest in tree leaf, P concentration was highest in herb leaf, and the C, N, P concentrations were lowest in litter. Leaf C: N: P ratios of tree, shrub, herb leaves and litter were 439.4:14.2:1, 599.2:13.5:1, 416.5:13.3:1, 504.8:15.5:1, respectively. The N:P ratios of tree, shrub and herb leaves were not significantly different, but they were all significantly higher than that of litter layer, indicating N:P ratio of different living life forms' leaves was stable. Compared with N, C and P had better relationships in each layer, and the relationships of leaf C, N, P stoichiometry between tree and herb leaves were better than those between tree and shrub leaves. The correlations of C, N, P stoichiometry between litter and the tree or herb leaves were highly significantly positive, and the correlations of P stoichiometry between litter and shrub leaves were highly significantly positive. Shrub leaf N, P concentration increased with the increasing latitude, and herb leaf N, P concentrations decreased with the increasing longitude. Compared with the longitude and latitude, the effect of altitude was smaller, and only tree leaf N:P decreased with the increasing latitude. Multivariate linear regression analysis results showed that the influence of geographical factors on herb leaf was longitude > latitude > altitude, while was latitude > longitude > altitude for tree, shrub leaves and litter.

High-frequency sampling was conducted at the outlet of Guangxi Bishuiyan karst subterranean river using an automatic sampler during the rainfall events. The hydrochemical drymanic variation characteristics of trace metals (Cu, Pb, Zn, Cd) at the outlet of Guangxi Bishuiyan karst subterranean river were analyzed, and the sources of the trace metals in the subterranean river as well as their response to rainfall were explored. The results showed that the rainfall provoked a sharp decrease in the major elements (Ca²⁺, Mg²⁺, HCO₃⁻, etc.) due to dilution and precipitation, while it also caused an increase in the concentrations of dissolved metals including Al, Mn, Cu, Zn and Cd, due to water-rock reaction, sediment remobilization, and soil erosion. The water-rock reaction was more sensitive to rainfall than the others, while the sediment remobilization and soil erosion took the main responsibility for the chemical change of the heavy metals. The curves of the heavy metal concentrations presented multiple peaks, of which the maximum was reached at 9 hours later after the largest precipitation. Different metal sources and the double-inlet structure of the subterranean river were supposed to be the reasons for the formation of multiple peaks. During the monitoring period, the average speed of the solute in the river reached about 0.47 km · h⁻¹, indicating fast migration of the pollutants. Therefore, monitoring the chemical dynamics of the karst subterranean river, mastering the sources and migration characteristics of trace metal components have great significance for the subterranean river environment pollution treatment.

The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Next-generation sequencing (NGS) has the potential to transform the discovery of viruses causing unexplained acute febrile illness (UAFI) because it does not depend on culturing the pathogen or a priori knowledge of the pathogen's nucleic acid sequence. More generally, it has the potential to elucidate the complete human virome, including viruses that cause no overt symptoms of disease, but may have unrecognized immunological or developmental consequences. We have used NGS to identify RNA viruses in the blood of 195 patients with UAFI and compared them with those found in 328 apparently healthy (i.e., no overt signs of illness) control individuals, all from communities in southeastern Nigeria. Among UAFI patients, we identified the presence of nucleic acids from several well-characterized pathogenic viruses, such as HIV-1, hepatitis, and Lassa virus. In our cohort of healthy individuals, however, we detected the nucleic acids of two novel rhabdoviruses. These viruses, which we call Ekpoma virus-1 (EKV-1) and Ekpoma virus-2 (EKV-2), are highly divergent, with little identity to each other or other known viruses. The most closely related rhabdoviruses are members of the genus Tibrovirus and Bas-Congo virus (BASV), which was recently identified in an individual with symptoms resembling hemorrhagic fever. Furthermore, by conducting a serosurvey of our study cohort, we find evidence for remarkably high exposure rates to the identified rhabdoviruses. The recent discoveries of novel rhabdoviruses by multiple research groups suggest that human infection with rhabdoviruses might be common. While the prevalence and clinical significance of these viruses are currently unknown, these viruses could have previously unrecognized impacts on human health; further research to understand the immunological and developmental impact of these viruses should be explored. More generally, the identification of similar novel viruses in individuals with and without overt symptoms of disease highlights the need for a broader understanding of the human virome as efforts for viral detection and discovery advance.

Background: Limited clinical and laboratory data are available on patients with Ebola virus disease (EVD). The Kenema Government Hospital in Sierra Leone, which had an existing infrastructure for research regarding viral hemorrhagic fever, has received and cared for patients with EVD since the beginning of the outbreak in Sierra Leone in May 2014., Methods: We reviewed available epidemiologic, clinical, and laboratory records of patients in whom EVD was diagnosed between May 25 and June 18, 2014. We used quantitative reverse-transcriptase-polymerase-chain-reaction assays to assess the load of Ebola virus (EBOV, Zaire species) in a subgroup of patients., Results: Of 106 patients in whom EVD was diagnosed, 87 had a known outcome, and 44 had detailed clinical information available. The incubation period was estimated to be 6 to 12 days, and the case fatality rate was 74%. Common findings at presentation included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness (in 60%), diarrhea (in 51%), abdominal pain (in 40%), and vomiting (in 34%). Clinical and laboratory factors at presentation that were associated with a fatal outcome included fever, weakness, dizziness, diarrhea, and elevated levels of blood urea nitrogen, aspartate aminotransferase, and creatinine. Exploratory analyses indicated that patients under the age of 21 years had a lower case fatality rate than those over the age of 45 years (57% vs. 94%, P=0.03), and patients presenting with fewer than 100,000 EBOV copies per milliliter had a lower case fatality rate than those with 10 million EBOV copies per milliliter or more (33% vs. 94%, P=0.003). Bleeding occurred in only 1 patient., Conclusions: The incubation period and case fatality rate among patients with EVD in Sierra Leone are similar to those observed elsewhere in the 2014 outbreak and in previous outbreaks. Although bleeding was an infrequent finding, diarrhea and other gastrointestinal manifestations were common. (Funded by the National Institutes of Health and others.).