Perinatal factors impact gut microbiota development in early life, however, little is known on the effects of these factors on microbes in later life. Here we sequence DNA from faecal samples of ...children over the first four years and reveal a perpetual evolution of the gut microbiota during this period. The significant impact of gestational age at birth and delivery mode on gut microbiota progression is evident in the first four years of life, while no measurable effects of antibiotics are found in the first year. Microbiota profiles are also characteristic in children dependant on gestational age and maturity. Full term delivery is characterised by Bacteroides (year one), Parabacteroides (year two) and Christensenellaceae (year four). Preterm delivery is characterised by Lactobacillus (year one), Streptococcus (year two) and Carnobacterium (year four). This study reveals that the gut retains distinct microbial profiles of perinatal factors up to four years of age.
Summary
Objectives: Accurate diagnosis of neonatal seizures is critically important and is often made clinically, without EEG (electroencephalography) monitoring. This observational study aimed to ...determine the accuracy and interobserver reliability of healthcare professionals in distinguishing clinically manifested seizures from other neonatal movements, when presented with clinical histories and digital video recordings only.
Methods: Twenty digital video recordings of paroxysmal movements in term and preterm infants were selected from a video‐EEG database. The movements were categorized as seizure and nonseizure using EEG. Health care professionals (n = 137) from eight neonatal intensive care units (NICUs) were shown the video recordings with additional relevant clinical data, excluding EEG findings. The observers were asked to indicate which movements they considered to be seizure or nonseizure. A multirater Kappa statistic was used to assess agreement between observers and with the true diagnosis.
Results: Twenty video clips (11 seizure, 9 nonseizure) were evaluated by 91 doctors and 46 other professionals. The average number of correctly identified events was 10/20. Clonic seizures were correctly identified most frequently (range 36.5–95.6% of observers). Subtle seizures were poorly identified (range 20.4–49.6% of observers). The interobserver agreement (Kappa) for doctors and other health care professionals was poor at 0.21 and 0.29, respectively. Agreement with the correct diagnosis was also poor at 0.09 for doctors and −0.02 for other healthcare professionals.
Discussion: It is often impossible to accurately differentiate between seizure‐related and nonseizure movements in infants using clinical evaluation alone. In addition, doctors do not have a higher capacity for discriminating between neonatal paroxysmal events than other health care professionals. Until reliable continuous neurologic monitoring of newborn babies is available, it is likely that some babies with seizures will remain undetected and others with nonseizure movements will continue to be treated with potentially harmful anticonvulsants.
The association of the human microbiome with health outcomes has attracted much interest toward its therapeutic manipulation. The likelihood of modulating the human microbiome in early life is high ...and offers great potential to exert profound effects on human development since the early microbiota shows more flexibility compared to that of adults. The human microbiota, being similar to human genetics, can be transmitted from mother to infant, providing insights into early microbiota acquisition, subsequent development, and potential opportunities for intervention. Here, we review adaptations of the maternal microbiota during pregnancy, birth, and infancy, the acquisition and succession of early-life microbiota, and highlight recent efforts to elucidate mother-to-infant microbiota transmission. We further discuss how the mother-to-infant microbial transmission is shaped; and finally we address potential directions for future studies to promote our understanding within this field.
Changes in microbial communities inhabiting the maternal gut, vagina, and breast milk are observed during the period of pregnancy and throughout lactation.The seeding and development of the microbial communities in early life of humans differ among individuals, and may relate to host health status in later life.Being similar to human genetics, shared microbial strains have been observed among mothers and their babies, suggesting vertical transmission of microbiota mainly from the maternal gut, vagina, and breast milk.Human genetics, gestational age, mode of delivery, antibiotic exposure, and maternal diet during pregnancy all influence the developing microbiota of the infant.There may be an opportunity to address such influences through probiotic intervention with ’missing’ microbes.
More than half of all infants with neonatal hypoxic ischemic encephalopathy (HIE) are graded as mild and do not meet current criteria for therapeutic hypothermia. These infants are often not enrolled ...in follow-up, and hence our knowledge of their long-term outcome is sparse. We wished to compare 5-year outcomes in a group of infants with mild, moderate, and severe HIE, graded with both early EEG and clinical assessment, none of whom were treated with therapeutic hypothermia.
Term infants with HIE and a healthy comparison group were recruited at birth. Both groups had early continuous EEG recordings. Cognitive and motor outcome was assessed at 5 years.
Outcome was available in 53 infants with HIE and 30 infants in the comparison group at 5 years. Infants with mild HIE at birth (n = 22) had significantly lower full-scale IQ, verbal IQ, and performance IQ than comparison infants (n = 30) at 5 years (P = .001, .001, and 0.004, respectively). No difference in cognitive measures was seen between infants with mild and moderate grades HIE. Intact survival at 5 years varied across EEG grade HIE at 6 hours after birth; 75% in mild, 46% in moderate, 43% in major abnormalities, and 0% with inactive EEGs, compared with 97% in the comparison group.
Survivors of mild HIE, graded clinically or by early EEG, have higher rates of disability than their peers and have cognitive outcomes similar to that of children with moderate encephalopathy in an uncooled HIE cohort.
Human breast milk is considered the optimum feeding regime for newborn infants due to its ability to provide complete nutrition and many bioactive health factors. Breast feeding is associated with ...improved infant health and immune development, less incidences of gastrointestinal disease and lower mortality rates than formula fed infants. As well as providing fundamental nutrients to the growing infant, breast milk is a source of commensal bacteria which further enhance infant health by preventing pathogen adhesion and promoting gut colonisation of beneficial microbes. While breast milk was initially considered a sterile fluid and microbes isolated were considered contaminants, it is now widely accepted that breast milk is home to its own unique microbiome. The origins of bacteria in breast milk have been subject to much debate, however, the possibility of an entero-mammary pathway allowing for transfer of microbes from maternal gut to the mammary gland is one potential pathway. Human milk derived strains can be regarded as potential probiotics; therefore, many studies have focused on isolating strains from milk for subsequent use in infant health and nutrition markets. This review aims to discuss mammary gland development in preparation for lactation as well as explore the microbial composition and origins of the human milk microbiota with a focus on probiotic development.
The gut is the most extensively studied niche of the human microbiome. The aim of this study was to characterise the initial gut microbiota development of a cohort of breastfed infants (n = 192) ...from 1 to 24 weeks of age.
V4-V5 region 16S rRNA amplicon Illumina sequencing and, in parallel, bacteriological culture. The metabolomic profile of infant urine at 4 weeks of age was also examined by LC-MS.
Full-term (FT), spontaneous vaginally delivered (SVD) infants' microbiota remained stable at both phylum and genus levels during the 24-week period examined. FT Caesarean section (CS) infants displayed an increased faecal abundance of Firmicutes (p < 0.01) and lower abundance of Actinobacteria (p < 0.001) after the first week of life compared to FT-SVD infants. FT-CS infants gradually progressed to harbouring a microbiota closely resembling FT-SVD (which remained stable) by week 8 of life, which was maintained at week 24. The gut microbiota of preterm (PT) infants displayed a significantly greater abundance of Proteobacteria compared to FT infants (p < 0.001) at week 1. Metabolomic analysis of urine at week 4 indicated PT-CS infants have a functionally different metabolite profile than FT (both CS and SVD) infants. Co-inertia analysis showed co-variation between the urine metabolome and the faecal microbiota of the infants. Tryptophan and tyrosine metabolic pathways, as well as fatty acid and bile acid metabolism, were found to be affected by delivery mode and gestational age.
These findings confirm that mode of delivery and gestational age both have significant effects on early neonatal microbiota composition. There is also a significant difference between the metabolite profile of FT and PT infants. Prolonged breastfeeding was shown to have a significant effect on the microbiota composition of FT-CS infants at 24 weeks of age, but interestingly not on that of FT-SVD infants. Twins had more similar microbiota to one another than between two random infants, reflecting the influence of similarities in both host genetics and the environment on the microbiota..
Establishing a diverse gut microbiota after birth is being increasingly recognised as important for preventing illnesses later in life. It is well established that bacterial diversity rapidly ...increases post-partum; however, few studies have examined the infant gut virome/phageome during this developmental period. We performed a metagenomic analysis of 20 infant faecal viromes at one year of age to determine whether spontaneous vaginal delivery (SVD) or caesarean section (CS) influenced viral composition. We find that birth mode results in distinctly different viral communities, with SVD infants having greater viral and bacteriophage diversity. We demonstrate that CrAssphage is acquired early in life, both in this cohort and two others, although no difference in birth mode is detected. A previous study has shown that bacterial OTU's (operational taxonomic units) identified in the same infants could not discriminate between birth mode at 12 months of age. Therefore, our results indicate that vertical transmission of viral communities from mother to child may play a role in shaping the early life microbiome, and that birth mode should be considered when studying the early life gut virome.
KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, ...cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.
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► A MEK inhibitor-based synthetic lethal screen in KRAS mutant cancers identified BCL-XL ► Combined inhibition of BCL-XL and MEK induces marked apoptosis in KRAS mutant cancers ► Epithelial-to-mesenchymal transition predicts insensitivity to BCL-XL/MEK inhibition ► Combined BCL-XL/MEK inhibition causes tumor regressions in KRAS mutant cancer models
Oral squamous cell carcinoma (OSCC) is one of the leading presentations of head and neck cancer (HNC). The first part of this review will describe the highlights of the oral microbiome in health and ...normal development while demonstrating how both the oral and gut microbiome can map OSCC development, progression, treatment and the potential side effects associated with its management. We then scope the dynamics of the various microorganisms of the oral cavity, including bacteria, mycoplasma, fungi, archaea and viruses, and describe the characteristic roles they may play in OSCC development. We also highlight how the human immunodeficiency viruses (HIV) may impinge on the host microbiome and increase the burden of oral premalignant lesions and OSCC in patients with HIV. Finally, we summarise current insights into the microbiome-treatment axis pertaining to OSCC, and show how the microbiome is affected by radiotherapy, chemotherapy, immunotherapy and also how these therapies are affected by the state of the microbiome, potentially determining the success or failure of some of these treatments.
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