Amniotic Fluid: A Perspective on Promising Advances in the Prevention and Treatment of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a common and potentially fatal disease that typically affects preterm (PIs) and very low birth weight infants (VLBWIs). Although NEC has been extensively studied, the current therapeutic approaches are unsatisfactory. Due to the similarities in the composition between human amniotic fluid (AF) and human breast milk (BM), which plays a protective role in the development of NEC in PIs and VLBWIs, it has been postulated that AF has similar effects on the outcome of NEC and potential therapeutic implications. AF has been long used for its diagnostic purposes and is often discarded after birth as “biological waste”. However, researchers have started to elucidate its therapeutic potential. Experimental studies in animal models have shown that diseases of various organ systems can possibly benefit from AF-based therapy. Hence, we have identified three approaches which show promising results for future clinical application in the prevention and/or treatment of NEC: (1) administration of processed AF (PAF) isolated from donor mothers, (2) administration of AF stem cells (AFSCs), and (3) administration of simulated AF (SAF) formulated to mimic the composition of physiological AF. We have highlighted the most important aspects that should be taken into account to guide further research on the clinical application of AF-based therapy. We hope that this review can provide a framework to identify the challenges of AF-based therapy and help to design future studies to better evaluate AF-based approaches for the treatment and/or prevention of NEC in PIs and VLBWIs

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic–pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic–pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation

Adverse differences in cardiometabolic risk factor levels between individuals with pre-diabetes and normal glucose metabolism are more pronounced in women than in men : The Maastricht Study

Objective To investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing individuals with and without diabetes, are also present before type 2 diabetes onset. Research design and methods In a population-based cohort study of individuals aged 40-75 years (n=3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated associations with cardiometabolic and lifestyle risk factors of (1) pre-diabetes and type 2 diabetes (reference category: normal glucose metabolism) and (2) among non-diabetic individuals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms. Results In pre-diabetes, adverse differences in cardiometabolic risk factors were greater in women than men for systolic blood pressure (difference, 3.02 mm Hg; 95% CI:-0.26 to 6.30), high-density lipoprotein (HDL) cholesterol (difference,-0.10 mmol/L; 95% CI:-0.18 to-0.02), total-to-HDL cholesterol ratio (difference, 0.22; 95% CI:-0.01 to 0.44), triglycerides (ratio: 1.11; 95% CI: 1.01 to 1.22), and inflammation markers Z-score (ratio: 1.18; 95% CI: 0.98 to 1.41). In type 2 diabetes, these sex differences were similar in direction, and of greater magnitude. Additionally, HbA1c among non-diabetic individuals was more strongly associated with several cardiometabolic risk factors in women than men: per one per cent point increase, systolic blood pressure (difference, 3.58 mm Hg; 95% CI:-0.03 to 7.19), diastolic blood pressure (difference, 2.10 mm Hg; 95% CI:-0.02 to 4.23), HDL cholesterol (difference,-0.09 mmol/L; 95% CI:-0.19 to 0.00), and low-density lipoprotein cholesterol (difference, 0.26 mmol/L; 95% CI: 0.05 to 0.47). With regard to lifestyle risk factors, no consistent pattern was observed. Conclusion Our results are consistent with the concept that the more adverse changes in cardiometabolic risk factors in women (than men) arise as a continuous process before the onset of type 2 diabetes