Efficient depolymerization of lignin to biobased chemicals using a two-step approach involving ozonation in a continuous flow microreactor followed by catalytic hydrotreatment

Lignin is a promising feedstock for the replacement of conventional carbon sources for the production of chemicals and fuels. In this paper, results are reported for the depolymerization of various residual lignins in the absence of a catalyst by utilizing ozone. Reactions were performed in a microreactor setup ensuring high gas-liquid mass transfer rates, a low inventory of ozone, and straightforward scale-up possibilities. The ozonation is demonstrated using a representative model compound (vanillin) and various lignins (pyrolytic and organosolv) dissolved in methanol (2.5 wt %). Experiments were performed under ambient conditions, at gas-liquid flow ratios ranging from 30 to 90 and short residence times on the order of 12-24 s. Analyses of the products after methanol removal revealed the presence of (di)carboxylic acids, methyl esters, and acetals. Extensive depolymerization was achieved (i.e., up to 30% for pyrolytic lignin and 70% for organosolv lignins). Furthermore, a two-step approach in which the ozonated lignin is further hydrotreated (350-400 degrees C, 100 bar H-2, 4 h, Pd/C as catalyst) showed a substantial increase in depolymerization efficiency, yielding a 2.5-fold increased monomer yield in the product oil compared to a hydrotreatment step only

Stratified Management for Bacterial Infections in Late Preterm and Term Neonates:Current Strategies and Future Opportunities Toward Precision Medicine

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a “one size fits all” approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.</p

Zebrafish larvae as experimental model to expedite the search for new biomarkers and treatments for neonatal sepsis

Neonatal sepsis is a major cause of death and disability in newborns. Commonly used biomarkers for diagnosis and evaluation of treatment response lack sufficient sensitivity or specificity. Additionally, new targets to treat the dysregulated immune response are needed, as are methods to effectively screen drugs for these targets. Available research methods have hitherto not yielded the breakthroughs required to significantly improve disease outcomes, we therefore describe the potential of zebrafish (Danio rerio) larvae as preclinical model for neonatal sepsis. In biomedical research, zebrafish larvae combine the complexity of a whole organism with the convenience and high-throughput potential of in vitro methods. This paper illustrates that zebrafish exhibit an immune system that is remarkably similar to humans, both in terms of types of immune cells and signaling pathways. Moreover, the developmental state of the larval immune system is highly similar to human neonates. We provide examples of zebrafish larvae being used to study infections with pathogens commonly causing neonatal sepsis and discuss known limitations. We believe this species could expedite research into immune regulation during neonatal sepsis and may hold keys for the discovery of new biomarkers and novel treatment targets as well as for screening of targeted drug therapies.Pharmacolog

A Pooled Population Pharmacokinetic Study of Oral and Intravenous Administration of Clavulanic Acid in Neonates and Infants:Targeting Effective Beta-Lactamase Inhibition

Data published on the oral clavulanic acid pharmacokinetics in the pediatric population is lacking. This research aimed to describe clavulanic acid disposition following oral and intravenous administration and to provide insights into clavulanic acid exposure based on threshold concentrations for (pre-)term neonates and infants. This pooled population pharmacokinetic study combined four datasets for analysis in NONMEM v7.4.3. Clavulanic acid exposure was simulated using the percentage of time above the threshold concentrations (%fT &gt; C T). Multiple dosage regimens and amoxicillin/clavulanic acid dosage ratios were evaluated. The cohort consisted of 89 (42 oral, 47 intravenous) subjects (403 samples) with a median (range) postnatal age 54.5 days (0–365), gestational age 37.4 weeks (23.0–41.7), and current bodyweight 3.9 kg (0.6–9.0). A one-compartment model with first-order absorption best described clavulanic acid pharmacokinetics with postnatal age as a covariate on the inter-individual variability of clearance. Oral bioavailability was 24.4% in neonates up to 10 days of age. An oral dosing regimen 90 mg/kg/day amoxicillin/clavulanic acid (4:1 ratio) resulted in 40.2% of simulated patients achieving 100% fT &gt; C T,2mg/L. An amoxicillin/clavulanic acid ratio of 4:1 is preferred for neonatal oral regimens due to the higher exposure along the entire %fT &gt; C T range (0–100%) as ratios higher than 4:1 might result in inadequate exposure. Our results highlight substantial exposure differences (%fT &gt; C T) when using threshold concentrations of 1 mg/L vs. 2 mg/L. This first population pharmacokinetic model for clavulanic acid in neonates may serve as a foundational step for future research, once more precise clavulanic acid targets become available.</p

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates:A Pooled Population Pharmacokinetic Study

BACKGROUND: There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI.METHODS: In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling. In order to evaluate amoxicillin exposure following oral and intravenous administration, pharmacokinetic profiles for different dosing regimens were simulated with the developed population pharmacokinetic model. A target of 50% time of the free fraction above the minimal inhibitory concentration (MIC) with an MICECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used.RESULTS: The cohort consisted of 261 (79 oral, 182 intravenous) neonates with a median (range) gestational age of 35.8 weeks (range, 24.9-42.4) and bodyweight of 2.6 kg (range, 0.5-5). A 1-compartment model with first-order absorption best described amoxicillin pharmacokinetics. Clearance (L/h/kg) in neonates born after 30 weeks' gestation increased with increasing postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was 87%. We found that a twice-daily regimen of 50 mg/kg/day is superior to a 3- or 4-times daily schedule in the first week of life for both oral and intravenous administration.CONCLUSIONS: This pooledpopulation pharmacokinetic description of intravenous and oral amoxicillin in neonates provides age-specific dosing recommendations. We conclude that neonates treated with oral amoxicillin in the first weeks of life reach adequate amoxicillin levels following a twice-daily dosing regimen. Oral amoxicillin therapy could therefore be an adequate, cost-effective, and more patient-friendly alternative for neonates worldwide.</p

Acculturation and use of health care services by Turkish and Moroccan migrants: a cross-sectional population-based study

<p>Abstract</p> <p>Background</p> <p>There is insufficient empirical evidence which shows if and how there is an interrelation between acculturation and health care utilisation. The present study seeks to establish this evidence within first generation Turkish and Moroccan migrants, two of the largest migrant groups in present-day Western Europe.</p> <p>Methods</p> <p>Data were derived from the Amsterdam Health Monitor 2004, and were complete for 358 Turkish and 288 Moroccan foreign-born migrants. Use of health services (general practitioner, outpatient specialist and health care for mental health problems) was measured by means of self-report. Acculturation was measured by a structured questionnaire grading (i) ethnic self-identification, (ii) social interaction with ethnic Dutch, (iii) communication in Dutch within one's private social network, (iv) emancipation, and (v) cultural orientation towards the public domain.</p> <p>Results</p> <p>Acculturation was hardly associated with the use of general practitioner care. However, in case of higher adaptation to the host culture there was less uptake of outpatient specialist care among Turkish respondents (odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.82-0.99) and Moroccan male respondents (OR = 0.81, 95% CI = 0.71-0.93). Conversely, there was a higher uptake of mental health care among Turkish men (OR = 0.81, 95% CI = 0.71-0.93) and women (OR = 0.81, 95% CI = 0.71-0.93). Uptake of mental health care among Moroccan respondents again appeared lower (OR = 0.74, 95% CI = 0.55-0.99). Language ability appeared to play a central role in the uptake of health care.</p> <p>Conclusion</p> <p>Some results were in accordance with the popular view that an increased participation in the host society is concomitant to an increased use of health services. However, there was heterogeneity across ethnic and gender groups, and across the domains of acculturation. Language ability appeared to play a central role. Further research needs to explore this heterogeneity into more detail. Also, other cultural and/or contextual aspects that influence the use of health services require further identification.</p

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data