Maternal Exposure to Endocrine-Disrupting Chemicals: Analysis of Their Impact on Infant Gut Microbiota Composition.

Endocrine disruptors (EDCs) are chemicals that interfere with the endocrine system. EDC exposure may contribute to the development of obesity, type 2 diabetes, and cardiovascular diseases by impacting the composition of an infant's gut microbiota during the first 1000 days of life. To explore the relationship between maternal urinary levels of Bisphenol-A and phthalates (UHPLC-MS/MS), and the composition of the infant gut microbiota (16S rDNA) at age 12 months (T3) and, retrospectively, at birth (T0), 1 month (T1), and 6 months (T2), stool samples from 20 infants breastfed at least once a day were analyzed. Metataxonomic bacteria relative abundances were correlated with EDC values. Based on median Bisphenol-A levels, infants were assigned to the over-exposed group (O, n = 8) and the low-exposed group (B, n = 12). The B-group exhibited higher gut colonization of the Ruminococcus torques group genus and the O-group showed higher abundances of Erysipelatoclostridium and Bifidobacterium breve. Additionally, infants were stratified as high-risk (HR, n = 12) or low-risk (LR, n = 8) exposure to phthalates, based on the presence of at least three phthalates with concentrations exceeding the cohort median values; no differences were observed in gut microbiota composition. A retrospective analysis of gut microbiota (T0-T2) revealed a disparity in ß-diversity between the O-group and the B-group. Considering T0-T3, the Linear Discriminant Effect Size indicated differences in certain microbes between the O-group vs. the B-group and the HR-group vs. the LR-group. Our findings support the potential role of microbial communities as biomarkers for high EDC exposure levels. Nevertheless, further investigations are required to deeply investigate this issue.

Anti-Inflammatory and Anti-Allergic Properties of Colostrum from Mothers of Full-Term and Preterm Babies: The Importance of Maternal Lactation in the First Days.

Our narrative review focuses on colostrum components, particularly those that influence the neonatal immune system of newborns. Colostrum is secreted in small volumes by the alveolar cells of the breast during the first two to five days after birth. Colostrum is poor in fat and carbohydrates, with larger protein and bioactive compounds than mature milk. It plays a crucial role in driving neonates' immunity, transferring those immunological factors which help the correct development of the neonatal immune system and support establishing a healthy gut microbiome. The newborn has an innate and adaptive immune system deficiency, with a consequent increase in infection susceptibility. In particular, neonates born prematurely have reduced immunological competencies due to an earlier break in the maternal trans-placenta transfer of bioactive components, such as maternal IgG antibodies. Moreover, during pregnancy, starting from the second trimester, maternal immune cells are conveyed to the fetus and persist in small quantities post-natal, whereby this transfer is known as microchimerism (MMc). Thus, preterm newborns are deficient in this maternal heritage, and have their own immune system under-developed, but colostrum can compensate for the lack. Early breastfeeding, which should be strongly encouraged in mothers of preterm and full-term babies, provides those immunomodulant compounds that can act as a support, allowing the newborn to face immune needs, including fronting infections and establishing tolerance. Moreover, making mothers aware that administering colostrum helps their infants in building a healthy immune system is beneficial to sustain them in the difficult post-partum period.

Exclusive breastfeeding at 6 months after assisted and spontaneous conceiving: a prospective study in Northern Italy.

Conceiving by assisted infertility treatments may influence breastfeeding duration. In one-year time, to evaluate the goal of 6 months breastfeeding, we recruited 55 consecutive mothers who conceived using assisted treatment compared to 45 mothers conceiving naturally, all giving birth to healthy, full-term, singleton infants, sharing the double-occupancy room. At birth, maternal/neonatal characteristics were obtained by medical records and interviews. Six months after, a telephonic interview was done about the exclusivity of breastfeeding, mood instability, and breastfeeding complications. All the women were supported by the same neonatal-pediatrician team, during the study period. The number of mothers who were exclusively breastfeeding at six months was not statistically different between the two groups, as well as, breastfeeding initiation, BMI, smoking habit, mood instability, co-morbidities. In the assisted group, the women were older, had fewer previous children, upper degree of education, higher rate of cesarean sections, their neonate's birthweight was lower; they reported more breastfeeding complications, but the distribution was not different between groups. The control women had higher number of previously breastfed siblings. Our experience highlights that the mode of conception may not be the defining factor influencing the goal of 6 months lactation. The support of healthcare professional team has a crucial role in maintaining breastfeeding.

LIMIT: LIfestyle and Microbiome InTeraction Early Adiposity Rebound in Children, a Study Protocol.

Childhood obesity is a strong predictor of adult obesity with health and economic consequences for individuals and society. Adiposity rebound (AR) is a rise in the Body Mass Index occurring between 3 and 7 years. Early adiposity rebound (EAR) occurs at a median age of 2 years and predisposes to a later onset of obesity. Since obesity has been associated with intestinal dysbiosis, we hypothesize that EAR could be related to early microbiome changes due to maternal/lifestyle changes and environmental exposures, which can increase the unhealthy consequences of childhood obesity. LIMIT is a prospective cohort study that aims at identifying the longitudinal interplay between infant gut microbiome, infant/maternal lifestyle, and environmental variables, in children with EAR vs. AR. Methods. The study evaluated 272 mother-infant pairs, enrolled at an Italian neonatal unit, at different time points (T0, at delivery; T1, 1 month; T2, 6 months; T3, 12 months; T4, 24 months; T5, 36 months after birth). The variables that were collected include maternal/infant anthropometric measurements, lifestyle habits, maternal environmental endocrine disruptor exposure, as well as infant AR. The LIMIT results will provide the basis for early identification of those maternal and infant modifiable factors on which to act for an effective and personalized prevention of childhood obesity.

The establishment of the gut microbiota in 1-year-aged infants: from birth to family food.

PURPOSE: With the aim of characterizing the gastrointestinal (GI) microbiota and contextually determine how different prenatal, perinatal, and postnatal factors affected its composition in early childhood, infants were enrolled in a longitudinal-prospective study named "A.MA.MI." (Alimentazione MAmma e bambino nei primi MIlle giorni; NCT04122612, October 2019). METHODS: Forty-five fecal samples were collected at 12 months of infants' age, identified as the 3rd follow-up (T3). The evaluated variables were pre-gestational weight and weight gain during pregnancy, delivery mode, feeding, timing of weaning, and presence/absence of older siblings. Fecal alpha and beta-diversities were analyzed. Noteworthy, to determine the impact of the influencing factors, multivariate analyses were conducted. RESULTS: At T3, all prenatal and perinatal variables did not result to be significant whereas, among the postnatal variables, type of milk-feeding and weaning showed the greatest contribution in shaping the microbiota. Although aged 1 year, infants exclusively breastfed until 6 months were mainly colonized by Lactobacillaceae and Enterobacteriaceae. Differently, Bacteroidaceae characterized the microbiota of infants that were never breastfed in an exclusive way. Moreover, although an early introduction of solid foods determined higher values of Faith's PD, high abundances of Ruminococcaceae and Faecalibacterium mainly associated with infants weaned after the 4th month of age. CONCLUSION: The microbial colonization during the first year of life is likely affected by a simultaneous effect of multiple variables playing a significant role at different times. Therefore, these data contribute to add evidence concerning the complex multifactorial interaction between GI microbiota and various stimuli affecting infants during the early stages of life.

Early Life Microbiota Colonization at Six Months of Age: A Transitional Time Point.

Background: Early life gut microbiota is involved in several biological processes, particularly metabolism, immunity, and cognitive neurodevelopment. Perturbation in the infant's gut microbiota increases the risk for diseases in early and later life, highlighting the importance of understanding the connections between perinatal factors with early life microbial composition. The present research paper is aimed at exploring the prenatal and postnatal factors influencing the infant gut microbiota composition at six months of age. Methods: Gut microbiota of infants enrolled in the longitudinal, prospective, observational study "A.MA.MI" (Alimentazione MAmma e bambino nei primi MIlle giorni) was analyzed. We collected and analyzed 61 fecal samples at baseline (meconium, T0); at six months of age (T2), we collected and analyzed 53 fecal samples. Samples were grouped based on maternal and gestational weight factors, type of delivery, type of feeding, time of weaning, and presence/absence of older siblings. Alpha and beta diversities were evaluated to describe microbiota composition. Multivariate analyses were performed to understand the impact of the aforementioned factors on the infant's microbiota composition at six months of age. Results: Different clustering hypotheses have been tested to evaluate the impact of known metadata factors on the infant microbiota. Neither maternal body mass index nor gestational weight gain was able to determine significant differences in infant microbiota composition six months of age. Concerning the type of feeding, we observed a low alpha diversity in exclusive breastfed infants; conversely, non-exclusively breastfed infants reported an overgrowth of Ruminococcaceae and Flavonifractor. Furthermore, we did not find any statistically significant difference resulting from an early introduction of solid foods (before 4 months of age). Lastly, our sample showed a higher abundance of clostridial patterns in firstborn babies when compared to infants with older siblings in the family. Conclusion: Our findings showed that, at this stage of life, there is not a single factor able to affect in a distinct way the infants' gut microbiota development. Rather, there seems to be a complex multifactorial interaction between maternal and neonatal factors determining a unique microbial niche in the gastrointestinal tract.

Literature Review and an Italian Hospital Experience about Post-Natal CMV Infection Acquired by Breast-Feeding in Very Low and/or Extremely Low Birth Weight Infants.

Breastfeeding is recommended for all neonates due to a known variety of beneficial effects, but infants can be infected by cell-associated bacteria and viruses from breast milk, such as cytomegalovirus (CMV). The majority of CMV-seropositive breastfeeding women have a viral, self-restricted reactivation, can shed the virus in the milk for about 12 weeks after delivery, and can transmit the infection to their offspring. Post-natal CMV-infected term infants are mainly asymptomatic, while very low birth weight (VLBW, <1500 g) and extremely low birth weight (ELBW, <1000 g) infants may present with severe disease, short-term sequelae ranging from abnormalities in laboratory indexes to sepsis-like syndrome, and long-term sequelae such as developmental problems. Thus, the use of thermally treated maternal milk for VLBW/ELBW infants may be indicated to prevent/reduce the risk of CMV transmission. Different techniques, with varying efficacy in eradicating CMV and maintaining the activity of biological compounds in milk are available: long/short pasteurization, freeze-thawing, the use of microwaves, and ultraviolet-C irradiation. In our NICU, the use of maternal raw milk is always strongly recommended for term/preterm infants, but to reduce risk of CMV transmission, freeze-thawing mother's own milk is used in neonates with GA ≤ 30 weeks or/and weight ≤ 1000 g, usually regardless of serological maternal condition, as CMV screening is not routinely offered to pregnant women and the milk of seroimmune mothers is not evaluated for CMV reactivation, as its rate is similar to seroprevalence. Over the last 4 years, we had 10 VLBW/ELBW newborns in our NICU with late-onset sepsis and negative cultures. In these cases, the research of CMV DNA in neonatal urine or saliva, for the diagnosis of post-natal symptomatic infection (once congenital transmission has been excluded) may be useful and not invasive. The take-home message we would like to share is that acquired CMV infection should be considered in VLBW/ELBW infants breastfed by seropositive mothers and presenting severe symptoms-particularly sepsis with negative cultures. This could allow pediatricians to make better-quality diagnoses, perform supportive therapy, provide antiviral treatment if needed, or establish a "pre-emptive" therapy for these high-risk neonates.

Correction to: Probiotics' efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics.

An amendment to this paper has been published and can be accessed via the original article.

Probiotics' efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics.

During the last decade several paediatric studies have been published with different possible indications for probiotics, leading to a global increase of probiotics' market. Nevertheless, different study designs, multiple single/combined strains and small sample size still leave many uncertainties regarding their efficacy. In addition, different regulatory and quality control issues make still very difficult the interpretation of the clinical data. The objective of this review is to critically summarise the current evidence on probiotics' efficacy and safety on a different number of pathologies, including necrotizing enterocolitis, acute infectious diarrhoea, allergic diseases and functional gastrointestinal disorders in order to guide paediatric healthcare professionals on using evidence-based probiotics' strains. To identify relevant data, literature searches were performed including Medline-PubMed, the Cochrane Library and EMBASE databases. Considering probiotics strain-specific effects, the main focus was on individual probiotic strains and not on probiotics in general.

Prenatal and postnatal determinants in shaping offspring's microbiome in the first 1000 days: study protocol and preliminary results at one month of life.

BACKGROUND: Fetal programming during in utero life defines the set point of physiological and metabolic responses that lead into adulthood; events happening in "the first 1,000 days" (from conception to 2-years of age), play a role in the development of non-communicable diseases (NCDs). The infant gut microbiome is a highly dynamic organ, which is sensitive to maternal and environmental factors and is one of the elements driving intergenerational NCDs' transmission. The A.MA.MI (Alimentazione MAmma e bambino nei primi MIlle giorni) project aims at investigating the correlation between several factors, from conception to the first year of life, and infant gut microbiome composition. We described the study design of the A.MA.MI study and presented some preliminary results. METHODS: A.MA.MI is a longitudinal, prospective, observational study conducted on a group of mother-infant pairs (n = 60) attending the Neonatal Unit, Fondazione IRCCS Policlinico San Matteo, Pavia (Italy). The study was planned to provide data collected at T0, T1, T2 and T3, respectively before discharge, 1,6 and 12 months after birth. Maternal and infant anthropometric measurements were assessed at each time. Other variables evaluated were: pre-pregnancy/gestational weight status (T0), maternal dietary habits/physical activity (T1-T3); infant medical history, type of feeding, antibiotics/probiotics/supplements use, environment exposures (e.g cigarette smoking, pets, environmental temperature) (T1-T3). Infant stool samples were planned to be collected at each time and analyzed using metagenomics 16S ribosomal RNA gene sequence-based methods. RESULTS: Birth mode (cesarean section vs. vaginal delivery) and maternal pre pregnancy BMI (BMI < 25 Kg/m2 vs. BMI ≥ 25 Kg/m2), significant differences were found at genera and species levels (T0). Concerning type of feeding (breastfed vs. formula-fed), gut microbiota composition differed significantly at genus and species level (T1). CONCLUSION: These preliminary and explorative results confirmed that pre-pregnancy, mode of delivery and infant factors likely impact infant microbiota composition at different levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04122612.

Safety, growth, and support to healthy gut microbiota by an infant formula enriched with functional compounds.

BACKGROUND & AIMS: Safety and growth adequacy of infant formulae enriched by functional ingredients need stringent evaluation by means of randomized controlled trials (RCTs), therefore we performed a double-blind RCT to evaluate an infant formula enriched with galacto-oligosaccharides, beta-palmitate, and acidified milk vs. a standard infant formula. METHODS: Weight, length, head circumference and fecal bacteria (Bifidobacteria, BIF/Clostridia, CLO) were measured in healthy full term infants, at baseline - as before 21 days of life - at 60 and 135 days thereafter. A group of 51 neonates received the enriched formula (ENR), 59 the standard one (ST). Parents were trained to daily register gastrointestinal diseases. RESULTS: All the infants grew homogeneously increasing the anthropometric parameters and complying with WHO and Italian standards: the mean (SD) difference in daily weight between ENR and ST groups was -0.74 (1.13) g/day, corresponding to a 90% CI of -2.62 to 1.13 g/day, well within the postulated interval of equivalence of -3.9 to +3.9 g/day. A statistical improvement in BIF concentration in the microbiota of infants fed by ENR was recorded. There was no between-group change in log10CLO, but log10BIF increase was higher at T2 vs. T0 in ENR (treatment × time interaction = 0.71, 95% CI 0.08-1.34, p = 0.028) than in ST neonates. This corresponds to estimated mean (95% CI) values of 8.37 (8.04-8.69) log10-units for ENR vs. 8.08 (7.77-8.39) log10-units for ST neonates. Gastrointestinal effects were mild and similar, with no statistical difference between two groups. CONCLUSION: Safety and growth ability of the enriched formula has been confirmed. A positive effect on neonatal gut microbiota, consisting of increased fecal BIF counts at T2 vs. baseline has been shown too. Nonetheless, larger RCTs are needed to estimate with greater precision the effective potential attributable to the enriched formula on neonatal microbiota, with particular reference to the mode of delivery.

Impact of Early Postnatal Nutrition on the NMR Urinary Metabolic Profile of Infant.

NMR-based metabolomics was used to compare the metabolic urinary profiles of exclusively breast-fed term infants (n = 11) with those of a double-blinded controlled trial with 49 formula-fed term newborns randomized to receive either an infant formula enriched by functional ingredients (n = 24) or a standard formula (n = 25). Anthropometric measurements and urine samples were taken at enrollment (within the first month of life), at around 60 days of life, and at the end of study period (average age of 130 days). The metabolic profiles were examined in relation to time and diet strategy. A common age-dependent modification of the urine metabolome was observed for the three types of nutrition, mainly characterized by similar temporal trends of choline, betaine, myoinositol, taurine, and citrate. Contrariwise, differences in the metabolic profiles were identified according to the type of diet (human versus formula milk), while no significant difference was observed between the two formulas. These modifications are discussed mainly in terms of the different milk compositions. Despite the low number of enrolled infants (n = 60), these findings pointed out the potential of the metabolomics approach for neonatal nutritional science, in particular to provide important contributions to the optimization of formula milk.

Enteral nutrition and infections: the role of human milk.

Human milk (HM) is known as the best nutrition for newborns and support the optimal growth of infants, providing essential substances, nutrients, bioactive and immunologic constituents. HM also grants a favorable microbial colonization with attendant priming/maturation of the gut. The bioactive and immunologic elements of HM demonstrated to protect offspring against infection and inflammation and contribute to immune maturation. Some of these elements are being investigated in order to be used to ameliorate formula milk. A formula milk similar to breast milk may help neonatal gut to build a microbiota near to the one of the breast fed infants, improving the neonate's protection against pathogens. The aim of this review is to summarize the most significant bioactive constituents of HM that own natural anti-infectious properties and contribute to neonatal immune defense.

The early administration of Lactobacillus reuteri DSM 17938 controls regurgitation episodes in full-term breastfed infants.

Forty breastfed full-term infants were randomly, double blind assigned to receive orally Lactobacillus reuteri (L. reuteri) DSM 17938, 5 drops/daily (10(8) colony-forming units), for 4 weeks (n = 20) or an identical placebo (n = 20), starting before third day of life. They underwent basal and final visit to monitor growth parameters and gastrointestinal (GI) disease. Parents registered daily: crying minutes, stool frequency and consistency, numbers of regurgitations, adverse events. Secretory IgA (sIgA) has been measured in saliva on 28th day. Treated infants demonstrated a reduction in daily regurgitations at the end of treatment (p = 0.02), three neonates in the placebo group only needed simethicone for GI pain, sIgA level was similar in both groups. Random casualty produced an unbalanced gender distribution in the groups, but this bias did not affect the results. Therefore, early administration of L. reuteri DSM 17938 resulted beneficial in preventing regurgitation episodes during the first month of life.

Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial.

IMPORTANCE: Infantile colic, gastroesophageal reflux, and constipation are the most common functional gastrointestinal disorders that lead to referral to a pediatrician during the first 6 months of life and are often responsible for hospitalization, feeding changes, use of drugs, parental anxiety, and loss of parental working days with relevant social consequences. OBJECTIVE: To investigate whether oral supplementation with Lactobacillus reuteri DSM 17938 during the first 3 months of life can reduce the onset of colic, gastroesophageal reflux, and constipation in term newborns and thereby reduce the socioeconomic impact of these conditions. DESIGN: A prospective, multicenter, double-masked, placebo-controlled randomized clinical trial was performed on term newborns (age <1 week) born at 9 different neonatal units in Italy between September 1, 2010, and October 30, 2012. SETTING: Parents were asked to record in a structured diary the number of episodes of regurgitation, duration of inconsolable crying (minutes per day), number of evacuations per day, number of visits to pediatricians, feeding changes, hospitalizations, visits to a pediatric emergency department for a perceived health emergency, pharmacologic interventions, and loss of parental working days. PARTICIPANTS: In total, 589 infants were randomly allocated to receive L reuteri DSM 17938 or placebo daily for 90 days. INTERVENTIONS: Prophylactic use of probiotic. MAIN OUTCOMES AND MEASURES: Reduction of daily crying time, regurgitation, and constipation during the first 3 months of life. Cost-benefit analysis of the probiotic supplementation. RESULTS: At 3 months of age, the mean duration of crying time (38 vs 71 minutes; P < .01), the mean number of regurgitations per day (2.9 vs 4.6; P < .01), and the mean number of evacuations per day (4.2 vs 3.6; P < .01) for the L reuteri DSM 17938 and placebo groups, respectively, were significantly different. The use of L reuteri DSM 17938 resulted in an estimated mean savings per patient of €88 (US $118.71) for the family and an additional €104 (US $140.30) for the community. CONCLUSIONS AND RELEVANCE: Prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the onset of functional gastrointestinal disorders and reduced private and public costs for the management of this condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01235884.

Microorganisms in human milk: lights and shadows.

Human milk has been traditionally considered germ free, however, recent studies have shown that it represents a continuous supply of commensal and potentially probiotic bacteria to the infant gut. Mammary microbioma may exercise anti-infective, anti-inflammatory, immunomodulatory and metabolic properties. Moreover human milk may be a source of pathogenic microorganism during maternal infection, if contaminated during expression or in case of vaccination of the mother. The non-sterility of breast milk can, thus, be seen as a protective factor, or rarely, as a risk factor for the newborn.

Viral outbreaks in neonatal intensive care units: what we do not know.

BACKGROUND: Nosocomial infection is among the most important causes of morbidity, prolonged hospital stay, increased hospital costs, and mortality in neonates, particularly those born preterm. The vast majority of scientific articles dealing with nosocomial infections address bacterial or fungal infections, and viral agents are often disregarded. This analysis reviews the medical literature in an effort to establish the incidence, types of pathogens, and clinical features of noncongenital neonatal viral infections. METHODS: This analysis was performed using the worldwide database of health care-associated outbreaks (http://www.outbreak-database.com). Items analyzed included causative pathogens, types of infection, source of outbreaks, and measures taken to stop outbreaks. RESULTS: The outbreak database contained a total of 590 neonatal outbreaks, of which 64 were originated by viruses, 44 of which (68.75%) were reported from neonatal intensive care units (NICUs). The 5 most frequent viral agents were rotavirus (23.44%), respiratory syncytial virus (17.19%), enterovirus (15.63%), hepatitis A virus (10.94%), and adenovirus (9.38%). CONCLUSION: Our analysis of the viral origins of nosocomial infections in NICUs can be a valuable tool in the investigation of neonatal infections. The mortality rates reported in this analysis demonstrate the significance of noncongenital viral infections in NICUs and the need for more effective outbreak prevention strategies.

Emerging viral infections in neonatal intensive care unit.

Nosocomial infections are the most important cause of morbidity and mortality among neonates and mostly in infants admitted to neonatal intensive care units (NICU). The total number of neonates who develop nosocomial infections per admission varies from 6.2 to 30%. The role of nosocomial virus infections is generally neglected in the actual epidemiologic scenario mostly due to the lack of data in the medical literature. Based on a worldwide database of health care-associated outbreaks (http://www.outbreak-database.com) we performed an analysis of the incidence, type of pathogens and clinical features of neonatal viral outbreaks especially those reported in NICUs. We also describe, as an example of emerging virus in NICU, a Norovirus outbreak along with clinical presentation that varies from mild to moderate clinical symptoms like vomiting, gastric remainder, diarrhoea, abdominal distension or severe presentation like necrotizing enterocolitis. and measures implemented for terminating the outbreak. In conclusion, our study analyses the viral origins of nosocomial infections in NICU and underline that the role of viral agents in neonatal nosocomial infections needs to be further investigated even in diseases traditionally considered of bacterial origin like necrotizing enterocolitis.

Nutritional needs of premature infants.

Preterm birth is the leading cause of perinatal morbidity and mortality in developed countries. Many innovation in neonatology have raised survival rates in the two past decades, but despite progress in neonatal intensive care, nutrition and growth of preterm infants are still critical points for neonatologists around the world and extrauterine growth restriction remains a common problem. Since growth is recognized as a major problem, in 2010, the European Society of Pediatric Gastroenterology and Nutrition published recommendations on enteral nutrition for preterm infants. The aim of this review is to revise nutritional needs of premature infants, taking into consideration the recommendations of ESPGHAN and the recent international literature.