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Preterm infants have higher nutritional requirements than term neonates and are vulnerable to extrauterine growth restriction. Providing adequate nutritional support during the initial few weeks of life plays a crucial role in improving the short- and long-term outcomes of these infants. Emerging evidence on enteral feeding emphasises rapid feed advancement, early total enteral feeding and early human milk (HM) fortification for preterm babies. The objective of this review was to summarise the latest evidence around enteral nutrition in very low birth weight or very preterm infants (<32 weeks’ gestation) and provide evidence-based recommendations for practice. The strength of recommendations was graded using the Oxford Centre for Evidence-Based Medicine criteria. This review provides clinical practice guidelines on the following key domains: (1) feed initiation strategies including oral immune therapy, minimal enteral nutrition and early total enteral feeds; (2) type of milk for feeding preterm infants; (3) feed advancement strategies and standardised feeding regimen; (4) various approaches to HM fortification and (5) multivitamin and mineral supplementation. This updated review will serve as a practical guide for clinicians and dietitians in handling the difficulties related to the nutritional management of preterm infants and improving clinical outcomes.
Maternal infections contracted during pregnancy may be without fetal consequence, or they may have serious adverse effects on the fetus. These adverse effects may include fetal death, stillbirth, intrauterine growth restriction, and congenital infection. Congenitally infected neonates may be symptomatic or asymptomatic at birth. Those who are symptomatic at birth are at risk for significant long-term sequelae. Those who are asymptomatic at birth may never manifest evidence of damage, or they may develop clinically evident sequelae later in life. This chapter discusses the neurologic consequences of congenital and perinatal infections, including Toxoplasma gondii, varicella-zoster virus (VZV), Treponema pallidum(syphilis), rubella virus, cytomegalovirus (CMV), and herpes simplex virus (HSV). Brief consideration is also given to Zika virus (ZIKV) and human parechovirus (HPeV).
Cytomegalovirus (CMV) is a ubiquitous virus with significant public health implications, including severe morbidity and mortality in neonates and immunosuppressed individuals. Substantial variation in CMV prevalence has been reported globally, and local epidemiological data are important to inform public health interventions. In this study, we estimated CMV seroprevalence and seroconversion rates among blood donors to provide baseline data on CMV epidemiology in Ireland. Seroprevalence was estimated in 74,821 donors, and seroconversion rates were calculated among returning donors, with associations assessed by demographic and geographical factors. Overall CMV seroprevalence in 2020 was 26.0% [95%CI: 25.7–26.3]. Female donors had higher odds of seropositivity than males (adjusted OR: 1.38, [95%CI: 1.34–1.43]). Among first-time donors, CMV seroprevalence was 23.82% [95% CI; 22.79–24.86], whereas within Sample Only New Donors (SOND), who are first-time donors born outside of Ireland and the UK, the seroprevalence was significantly higher, at 46.49% [95% CI; 40.41–52.98, p < 0.001]. The estimated annual seroconversion rate was 0.76% [95% CI: 0.68–0.85], with CMV DNA detected in 6.5% of seroconverters. These findings highlight a low CMV seroprevalence in Ireland, suggesting increased susceptibility to primary infection. Analysis of blood donor CMV data is a useful epidemiological tool to assess population-level risk.
The most common viral cause of congenital infection is CMV, a double-stranded DNA herpesvirus, affecting 0.2–2.2% of all neonates. It is the leading nongenetic cause of congenital deafness and a major cause of neurologic disability in children. Of previously seronegative women, 1–4% will become infected during pregnancy, and while most are asymptomatic, some patients may experience a mononucleosis-like syndrome. The diagnosis of primary CMV infection in pregnancy can be made by IgG seroconversion or detection of CMV IgM and IgG antibodies and low IgG avidity. Routine serologic screening of pregnant women for CMV is not recommended. Pregnant patients, particularly those who care for young children, should be counseled about behavioral measures to reduce the risk of CMV infection.
Women infected during pregnancy with TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes simplex viruses) pathogens have a higher risk of adverse birth outcomes including stillbirth / miscarriage because of mother-to-child transmission. To investigate these risks in pregnant women in Kenya, we analyzed serum specimens from a pregnancy cohort study at three healthcare facilities. A sample of 481 participants was selected for TORCH pathogen antibody testing to determine seroprevalence. A random selection of 285 from the 481 participants was selected to measure seroconversion. These sera were tested using an IgG enzyme-linked immunosorbent assay against 10 TORCH pathogens. We found that the seroprevalence of all but three of the 10 TORCH pathogens at enrollment was >30%, except for Bordetella pertussis (3.8%), Treponema pallidum (11.4%), and varicella zoster virus (0.5%). Conversely, very few participants seroconverted during their pregnancy and were herpes simplex virus type 2 (n = 24, 11.2%), parvovirus B19 (n = 14, 6.2%), and rubella (n = 12, 5.1%). For birth outcomes, 88% of the participant had live births and 12% had stillbirths or miscarriage. Cytomegalovirus positivity at enrolment had a statistically significant positive association with a live birth outcome (p = 0.0394). Of the 10 TORCH pathogens tested, none had an association with adverse pregnancy outcome.
Children with unilateral hearing loss (UHL) have difficulty hearing in noisy environments and localizing sounds, impacting learning and social opportunities across contexts. Using a visible device like a cochlear implant (CI) may improve functioning but can also create psychological risk. Audiological measures alone are insufficient for predicting social, emotional, educational, adaptive, and quality-of-life post-operative outcomes, which are highly variable in this population and can also be impacted by a secondary diagnosis. Extending beyond audition to consider the “whole child” through neuropsychological evaluation may produce a sharper picture of potential outcomes, with or without surgical/audiological intervention. Given recent FDA approval for CI in children with UHL, more are receiving this elective surgery despite difficulties predicting who will experience significant benefit. Here we describe neuropsychological profiles of children with UHL who underwent CI candidacy evaluation at a tertiary pediatric hospital.
Participants and Methods:
During pre-operative clinical care, CI candidates completed targeted neuropsychological evaluation to identify patient- and family-level factors that could impact CI use and outcomes from surgery. Cognitive, language, attention/executive, visuoperceptual/visuomotor, academic, adaptive, and emotional/behavioral functioning were assessed. Evaluations integrated history, observations, caregiver report forms, and performance-based test data.
Results:
18 individuals were evaluated (age 7-months to 16-years). Most had left-sided UHL (67%) and were male (61%). Known hearing loss etiologies were congenital cytomegalovirus (n=5), enlarged vestibular aqueduct (n=1), traumatic brain injury (n=1), meningitis (n=1), cholesteatoma (n=1), neurofibromatosis type 1 (n=1), and Waardenburg syndrome (n=1). Indices of general cognitive ability were generally low average to average. Patterns of cognitive impairment were not restricted to language-based tasks (e.g., Beery VMI-6 range 56-109, M=89.42, SD=16.27). Standardized parent ratings of everyday executive functioning, social/emotional/behavioral functioning, and adaptive skills were collected. Eight (44%) had a behavioral health diagnosis: Attention Deficit Hyperactivity Disorder (n=2), Global Developmental Delay (n=2), Unspecified Neurodevelopmental Disorder (n=2), Autism Spectrum Disorder (n=1), and Depression (n=1). Thirteen (72%) received or will receive a CI, of whom 38% had a behavioral health diagnosis. Average Area Deprivation Index (a marker of socio-economic status) was lower for individuals who ultimately received CIs (M=18%tile) compared to those who did not (M=25%tile).
Conclusions:
There may be increased rates of neurodevelopmental/psychological conditions among children with UHL, especially when the etiology involves the central nervous system. Albeit preliminary, results align with findings from bilateral hearing loss samples. Findings highlight the importance of routine neuropsychological screening in children with UHL and close interdisciplinary collaboration for optimal outcomes. Socio-economic disparities among those who do and do not receive CI need further exploration as those who did not receive CIs tended to be from less resourced neighborhoods. Additional research is warranted to understand the full range of risk and protective factors for children with UHL and how these relate to outcomes for those who opt for cochlear implantation.
Various intestinal and extraintestinal conditions may complicate inflammatory bowel disease (IBD). Intestinal complications include infections, strictures, obstruction, fistulas, dysplasia, and malignancy. Extraintestinal complications or associations include cutaneous disease, arthropathy, ocular problems, primary sclerosing cholangitis, and other forms of liver disease. The intestinal complications whose diagnosis and assessment relies most heavily on histopathology are cytomegalovirus (CMV) infection, dysplasia, and malignancy. Reactivation of latent CMV is more likely in ulcerative colitis than Crohn’s disease, is more common in those with immunosuppression and/or severe disease, and is associated with a worse clinical outcome. CMV inclusions are often detectable on H&E examination. Immunohistochemistry for CMV is specific and sensitive. Histopathology may also play a role in recognising other infections such as amoebiasis and TB and may contribute to the assessment of fissures and fistulas. Confident recognition of dysplasia depends on histology, although endoscopic methods of detection are becoming more reliable. Colorectal carcinoma (CRC) is the most common malignancy to complicate IBD and is more likely than non-IBD CRC to present at a younger age and to be right-sided and is more likely to show signet ring cell differentiation, a peritumoral lymphocytic reaction, and a mucinous phenotype. Small bowel cancer may complicate Crohn’s disease but is rare overall. A lymphoproliferative disorder may complicate IBD, especially in the setting of thiopurine therapy.
The recognition of specific oesophageal infections and the distinction between gastro-oesophageal reflux disease and rarer forms of oesophagitis are key tasks for gastrointestinal pathologists reading mucosal biopsies. Infections can involve the oesophagus either primarily or as part of a wider process. This chapter highlights their features, discussing in detail the common infections including herpes simplex, cytomegalovirus, and Candida, and summarises the features of the rarer ones. A few additional types of oesophagitis have emerged recently, including eosinophilic oesophagitis and lymphocytic oesophagitis. This chapter reviews the recent literature and will discuss the controversies surrounding some of these new entities. There is an emphasis on the need for correlation between clinical/endoscopic information and microscopic appearances, and there is discussion of supplementary special studies including immunohistochemistry where relevant.
Life course research embraces the complexity of health and disease development, tackling the extensive interactions between genetics and environment. This interdisciplinary blueprint, or theoretical framework, offers a structure for research ideas and specifies relationships between related factors. Traditionally, methodological approaches attempt to reduce the complexity of these dynamic interactions and decompose health into component parts, ignoring the complex reciprocal interaction of factors that shape health over time. New methods that match the epistemological foundation of the life course framework are needed to fully explore adaptive, multilevel, and reciprocal interactions between individuals and their environment. The focus of this article is to (1) delineate the differences between lifespan and life course research, (2) articulate the importance of complex systems science as a methodological framework in the life course research toolbox to guide our research questions, (3) raise key questions that can be asked within the clinical and translational science domain utilizing this framework, and (4) provide recommendations for life course research implementation, charting the way forward. Recent advances in computational analytics, computer science, and data collection could be used to approximate, measure, and analyze the intertwining and dynamic nature of genetic and environmental factors involved in health development.
Cytomegalovirus (CMV) enters latency after primary infection and can reactivate periodically with virus excreted in body fluids which can be called shedding. CMV shedding during the early stage of pregnancy is associated with adverse pregnancy outcome. The shedding pattern in healthy seropositive women who plan to have babies has not been well characterised. Vaginal swabs, urine and blood were collected from 1262 CMV IgG-positive women who intended to have babies and tested for CMV DNA by fluorogenic quantitative PCR method. Serum IgM was also detected. The association between sociodemographic characteristics and CMV shedding prevalence was analysed. Among 1262 seropositive women, 12.8% (161/1262) were detected CMV DNA positive in at least one body fluid. CMV DNA was more frequently detected in vaginal secretion (10.5%) than in urine (3.2%) and blood (0.6%) also with higher viral loads (P < 0.00). CMV shedding was more likely detected in IgM-positive women than IgM-negative women (29.5% (13/44) vs. 12.2% (148/1218); OR 3.03, 95% CI 1.55–5.93; P = 0.001). CMV shedding in vaginal secretion was highly correlated with shedding in urine, the immune state of IgM, the adverse pregnant history and younger age. CMV shedding was more commonly detected in vaginal secretion than in urine or blood with higher viral loads among healthy seropositive women of reproductive age. Further studies are needed to figure out whether the shedding is occasional or continuous and whether it is associated with adverse pregnancy outcomes.
Aetiology of protein-losing enteropathy in single-ventricle type CHD is multi-factorial.
Report:
We describe two Fontan patients with protein-losing enteropathy who presented with cytomegalovirus-associated colitis.
Discussion:
Fontan patients display risk factors for cytomegalovirus-induced gastroenteropathy that may affect lymph angiogenesis, disease development, and progression.
Conclusion:
Cytomegalovirus enteropathy may be common among Fontan patients who suffer from protein-losing enteropathy. Polymerase chain reaction is important for detection.
Cytomegalovirus (CMV) infection is endemic worldwide but its seroprevalence varies widely. The goal of this study was to estimate the age-specific seroprevalence of CMV infection in Belgium based on two cross-sectional serological datasets from 2002 and 2006. The seroprevalence was estimated relying on diagnostic test results based on cut-off values pre-specified by the manufacturers of the tests as well as relying on mixture models applied to continuous pathogen-specific immunoglobulin G antibody titre concentrations. The age-specific seroprevalence of hepatitis A virus (HAV), based on three Belgian cross-sectional serological datasets from 1993, 2002 and 2006, was used as a comparator since individuals acquire lifelong immunity upon recovery, implying an increasing seroprevalence with age. The age group weighted overall CMV seroprevalence derived from the mixture model was 32% (95% confidence interval (CI) 31–34%) in 2002 and 31% (95% CI 30–32%) in 2006. We demonstrated that CMV epidemiology differs from the immunizing infection HAV. This was the first large-scale study of CMV and HAV serial datasets in Belgium, estimating seroprevalence specified by age and birth cohort.
A cytomegalovirus-associated heart failure in a young infant with atrial and ventricular septal defects is reported in this case report. The patient recovered by an anti-congestive and anti-viral therapy with an extra percutaneous transcatheter treatment strategy. In the context of bi-ventricular predominant right heart failure associated with supra-systemic pulmonary hypertension, the already closed arterial duct was re-opened and stented to unload the right ventricle and thereby augment the systemic blood flow. Either the left-to-right shunting atrial septal defect or bi-directional shunting ventricular septal defect was involved in the disease process and was not able to avoid global heart failure. After clinical improvement, the stented duct was shunted left-to-right and was occluded with an ADO-II-AS. During the same procedure the atrial septal defect was closed with an Amplatzer-ASD occluder, while the peri-membranous ventricular septal defect was closed with an ADO-II occluder 2 months later.
The probability of a Black African finding a matched unrelated donor for a hematopoietic stem cell transplant is minimal due to the high degree of genetic diversity amongst individuals of African origin. This problem could be resolved in part by the establishment of a public cord blood (CB) stem cell bank. The high prevalence of human immunodeficiency virus (HIV) amongst women attending antenatal clinics in sub-Saharan Africa together with the risk of mother-to-child transmission increases the risk of transplant transmissible infection. In addition to screening the mother in a period inclusive of 7 days prior to the following delivery, we propose that all CB units considered for storage undergo rigorous and reliable screening for HIV. The Ultrio-plus® assay is a highly specific and sensitive test for detecting HIV, hepatitis-B and hepatitis-C viruses in peripheral blood. We validated the Ultrio-plus® assay for analytical sensitivity in detecting HIV in CB at the level of detection of the assay. Until more comprehensive and sensitive methods are developed, the sensitivity and reliability of the Ultrio-plus® assay suggest that it could be used for the routine screening of CB units in conjunction with currently recommended maternal screening to reduce the risk of transplant transmissible infection.
Several infections have been linked to telomere shortening and in some cases these associations have varied by sex. We assessed the association between seropositivity to four persistent pathogens (cytomegalovirus (CMV), herpes simplex virus-1, Helicobacter pylori, Chlamydia pneumoniae), and total pathogen burden on leukocyte telomere length in a diverse US sample. Data came from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study. We utilized cross-sectional survey data, and biological samples from participants tested for pathogens and telomere length (N = 163). Linear regression was used to examine the association between seropositivity for individual pathogens as well as total pathogen burden and telomere length, adjusting for various confounders. CMV seropositivity and increased total pathogen burden level were significantly associated with shorter telomere length among females (β = −0·1204 (standard error (s.e.) 0·06), P = 0·044) and (β = −0·1057 (s.e. = 0·05), P = 0·033), respectively. There was no statistically significant association among males. Our findings suggest that prevention or treatment of persistent pathogens, in particular CMV, may play an important role in reducing telomere shortening over the life course among women. Future research is needed to confirm these novel findings in larger longitudinal samples.
Cytomegalovirus (CMV) infection remains the leading cause of congenital virus infection in developed countries. Measuring the national prevalence of this infection, especially among women of childbearing age, is of great value to estimate the risk of congenital CMV infection, as well as to identify risk groups that should be targeted for behavioural interventions and/or vaccination once a CMV vaccine finally becomes available. In order to fulfil these objectives, a seroprevalence survey was conducted in 2010, using a nationally representative, population-based sample of 2536 people aged between 15 and 49 years, living in metropolitan France and attending private microbiological laboratories for blood testing. All blood samples were analysed in the same laboratory and screened for CMV-specific IgG using an enzyme-linked immunoassay technique (Elisa PKS Medac Enzyme immunoassay). The overall point estimate of CMV infection seroprevalence for individuals aged 15–49 years was 41.9%. The estimates were higher in women than in men (respectively 45.6% and 39.3%), and people born in a non-Western country were more likely to be CMV seropositive than those born in France or in another Western country (93.7% vs. 37.7%). Our results showed that a substantial percentage of women of childbearing age in France are CMV seronegative and therefore at risk of primary CMV infection during pregnancy. Educational measures and future vaccine are key issues to prevent infection in pregnant women and congenital CMV disease.
Cytomegalovirus (CMV) is the leading cause of congenital infection and non-genetic sensorineural hearing loss in children. There are no recent data on the incidence of CMV infection during pregnancy in Canada. This present study was undertaken to determine the seroprevalence of CMV IgG antibodies and the rate of seroconversion in a cohort of pregnant women in the province of Québec, Canada. We used serum samples and questionnaire data collected as part of the 3D Pregnancy and Birth Cohort Study (2010–2013) conducted in Québec, Canada. CMV IgG antibodies were determined in serum samples collected at the first and third trimesters. Associations between independent variables and seroprevalence were assessed using logistic regression, and associations with seroconversions, by Poisson regression. Of 1938 pregnant women tested, 40·4% were seropositive for CMV at baseline. Previous CMV infection was associated with: working as a daycare educator, lower education, lower income, having had children, first language other than French or English, and being born outside Canada or the United States. Of the 1122 initially seronegative women, 24 (2·1%) seroconverted between their first and third trimesters. The seroconversion rate was 1·4 [95% confidence interval (CI) 0·9–2·1]/10 000 person-days at risk or 3·9 (95% CI 2·5–5·9)/100 pregnancies (assuming a 280-day gestation). The high proportion of pregnant women susceptible to CMV infection (nearly 60%) and the subsequent rate of seroconversion are of concern.
Congenital cytomegalovirus infection (cCMV) may lead to symptoms at birth and long-term consequences. We present a nationwide, retrospective cohort study on the outcome of cCMV up to age 6 years. For this study we identified cCMV, using polymerase chain reaction, by analysing dried blood spots, which are taken shortly after birth for neonatal screening. The group of children with cCMV were compared to a group of children who were cCMV negative at birth. Data were collected about their health and development up to age 6 years. Parents of 73 693 children were invited to participate, and 32 486 (44·1%) gave informed consent for testing of their child's dried blood spot for CMV. Of the 31 484 dried blood spots tested, 156 (0·5%) were positive for cCMV. Of these, four (2·6%) children had been diagnosed with cCMV prior to this study. This unique retrospective nationwide study permits the estimation of long-term sequelae of cCMV up to the age of 6 years. The birth prevalence of cCMV in this study was 0·5%, which is in line with prior estimates. Most (97·4%) children with cCMV had not been diagnosed earlier, indicating under-diagnosis of cCMV.
A ‘black box’ paradigm has prevailed in which researchers have focused on the association between the total number of pathogens for which individuals are seropositive (i.e. total pathogen burden) and various chronic diseases, while largely ignoring the role that seropositivity for specific combinations of pathogens may play in the aetiology of such outcomes and consequently mortality. We examined the association between total pathogen burden as well as specific pathogen combinations and all-cause mortality in the United States. Data were from individuals aged ⩾25 years tested for cytomegalovirus (CMV), herpes simplex virus (HSV)-1, HSV-2 and Helicobacter pylori, with mortality follow-up to 31 December 2006 in the National Health and Nutrition Examination Survey (NHANES) III (N = 6522). We did not observe a statistically significant graded relationship between total pathogen burden level and all-cause mortality. Furthermore, compared to those seronegative for all four pathogens, the greatest statistically significant rate of all-cause mortality was for those CMV+/HSV-2+ (hazard ratio 1·95, 95% confidence interval 1·13–3·35) adjusting for age, gender, race/ethnicity, education level, body mass index (kg/m2) and smoking status. Interventions targeting prevention or treatment of particular pathogens may be more effective for reducing mortality than those focused solely on reducing overall pathogen burden.
Little is known about the main routes of human cytomegalovirus (HCMV) transmission in young adult populations. This study investigated risk factors for HCMV transmission in young adults attending university over a 3-year period. Blood samples were tested for HCMV specific viral capsid antigen IgG by enzyme immunoassay. Being born in a developing country and having lived in Africa were associated with HCMV seropositivity at study onset. No risk factors were associated with HCMV seroconversion over the 3-year follow-up. In contrast to previous reports, sexual activity was not associated with HCMV seroprevalence or seroconversion.