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Aim: After preterm birth, supine head midline position is supported for stable cerebral blood flow (CBF) and prevention of intraventricular haemorrhage (IVH), while prone position supports respiratory function and enables skin‐to‐skin care. The prone compared to supine position could lead to a change in near‐infrared derived cerebral tissue oxygen saturation (rScO2), which is a surrogate for cerebral blood flow (CBF). By monitoring rScO2 neonatologists aim to stabilise CBF during intensive care and prevent brain injury. In this systematic review and meta‐analysis, we investigate the effect of the body position on rScO2. Methods: A comprehensive literature search was performed to identify all trials that included preterm infants in the first 2 weeks after birth and compared rScO2 in the prone versus supine head in midline position of the infant. A meta‐analysis, including two subgroup analyses based on postnatal age (PNA) and gestational age (GA), was performed. Results: Six observational cohort studies were included. In the second, but not the first week after birth, a significant higher rScO2 in the prone position was found with a mean difference of 1.97% (95% CI 0.87–3.07). No rScO2 difference was observed between positions in the extremely preterm nor the preterm group. Conclusion: No consistent evidence was found that body position influences rScO2 in the first 2 weeks after preterm birth. Subgroup analysis suggests that in the second week after birth, the prone position might result in higher cerebral rScO2 than the supine position with head in midline. Multiple factors determine the best body position in preterms. [ABSTRACT FROM AUTHOR]

As the NAVA level increases, more support is given by the ventilator and the patient's respiratory workload is diminished. The breakpoint was at a mean (SD) NAVA level of 1.7 (0.4) cmH SB 2 sb O/ V with a range of 1-2 cmH SB 2 sb O/ V. The mean (SD) PIP at the breakpoint was 18.7 (3.5) cmH SB 2 sb O. In some patients, however, unexpected additional observations were done. Neurally adjusted ventilatory assist (NAVA) is a ventilation mode in which the patient's respiratory effort is unloaded by the ventilator in a synchronised and proportional way. [Extracted from the article]

Background: The use of analgesics and sedatives to alleviate pain and discomfort is common in end-of-life care in neonates and infants. However, to what extent those drugs are used in that context with the specific aim of bringing the infant in a state of continuous deep sedation (CDS) is currently unknown. Methods: We performed a nationwide mortality follow-back survey based on all deaths under the age of 1 over a period of 16 months in Flanders, Belgium. Data on CDS were linked to sociodemographic information from death certificates. Physicians completed an anonymous questionnaire. Questions measured whether CDS preceded death, and which clinical characteristics were associated with the sedation (e.g., type of drugs used and the duration of sedation). Results: The response rate was 83% (229/276). In 39% of all deceased neonates and infants, death was preceded by CDS. Physicians used a combination of morphine and benzodiazepines in 53%, or morphine alone in 45% of all sedation cases in order to continuously and deeply sedate the infant. In 89% of cases, death occurred within 1 week after sedation was begun, and in 92% of cases, artificial nutrition and hydration were administered until death. In 49% of cases there was no intention to hasten death, and in 40% of cases, the possibility of hastening was taken into account. Conclusions: CDS precedes about 2 in 5 neonatal and infant deaths. Guidelines for CDS in this age group are non-existent and it is unclear whether the same recommendations as in the adult population apply and can be considered a good practice. [ABSTRACT FROM AUTHOR]

Aims: Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next‐generation sequencing modalities, genotype‐histopathological correlations remain limited. This is the first systematic review of molecular and neuropathological findings in patients with MCD to provide a comprehensive overview of the literature. Methods: A systematic review was performed between November 2019 and February 2020. A MEDLINE search was conducted for 132 genes previously linked to MCD in order to identify studies reporting macroscopic and/or microscopic findings in patients with a confirmed genetic cause. Results: Eighty‐one studies were included in this review reporting neuropathological features associated with pathogenic variants in 46 genes (46/132 genes, 34.8%). Four groups emerged, consisting of (1) 13 genes with well‐defined histological‐genotype correlations, (2) 27 genes for which neuropathological reports were limited, (3) 5 genes with conflicting neuropathological features, and (4) 87 genes for which no histological data were available. Lissencephaly and polymicrogyria were reported most frequently. Associated brain malformations were variably present, with abnormalities of the corpus callosum as most common associated feature. Conclusions: Neuropathological data in patients with MCD with a defined genetic cause are available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardised thorough neuropathological assessment and reporting should be encouraged. Histological features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions. [ABSTRACT FROM AUTHOR]

In a first part of this paper, we prove constancy of the canonical graded Betti table among the smooth curves in linear systems on Gorenstein weak Fano toric surfaces. In a second part, we show that Green's canonical syzygy conjecture holds for all smooth curves of genus at most 32 or Clifford index at most 6 on arbitrary toric surfaces. Conversely we use known results on Green's conjecture (due to Lelli-Chiesa) to obtain new facts about graded Betti tables of projectively embedded toric surfaces. [ABSTRACT FROM AUTHOR]

We present various facts on the graded Betti table of a projectively embedded toric surface, expressed in terms of the combinatorics of its defining lattice polygon. These facts include explicit formulas for a number of entries, as well as a lower bound on the length of the quadratic strand that we conjecture to be sharp (and prove to be so in several special cases). We also present an algorithm for determining the graded Betti table of a given toric surface by explicitly computing its Koszul cohomology and report on an implementation in SageMath. It works well for ambient projective spaces of dimension up to roughly 25, depending on the concrete combinatorics, although the current implementation runs in finite characteristic only. As a main application we obtain the graded Betti table of the Veronese surface v6(P²) ⊆ P27 in characteristic 40 009. This allows us to formulate precise conjectures predicting what certain entries look like in the case of an arbitrary Veronese surface vd(P²). [ABSTRACT FROM AUTHOR]

We classify the unimodular equivalence classes of inclusion-minimal polygons with a certain fixed lattice width. As a corollary, we find a sharp upper bound on the number of lattice points of these minimal polygons. [ABSTRACT FROM AUTHOR]

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking.Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants.Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017.Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190).Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age.Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%).Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication.Trial Registration: Netherlands National Trial Register Identifier: NTR2768. [ABSTRACT FROM AUTHOR]

We prove that in the moduli space of genus- g metric graphs the locus of graphs with gonality at most d has the classical dimension min ⁡ { 3 g − 3 , 2 g + 2 d − 5 } . This follows from a careful parameter count to establish the upper bound and a construction of sufficiently many graphs with gonality at most d to establish the lower bound. Here, gonality is the minimal degree of a non-degenerate harmonic map to a tree that satisfies the Riemann–Hurwitz condition everywhere. Along the way, we establish a convenient combinatorial datum capturing such harmonic maps to trees. [ABSTRACT FROM AUTHOR]

Let C be an algebraic curve defined by a sufficiently generic bivariate Laurent polynomial with given Newton polygon Δ. It is classical that the geometric genus of C equals the number of lattice points in the interior of Δ. In this paper we give similar combinatorial interpretations for the gonality, the Clifford index, and the Clifford dimension, by removing a technical assumption from a recent result of Kawaguchi. More generally, the method shows that apart from certain well-understood exceptions, every base-point free pencil whose degree equals or slightly exceeds the gonality is combinatorial, in the sense that it corresponds to projecting C along a lattice direction. Along the way we prove various features of combinatorial pencils. For instance, we give an interpretation for the scrollar invariants associated with a combinatorial pencil, and show how one can tell whether the pencil is complete or not. Among the applications, we find that every smooth projective curve admits at most one Weierstrass semi-group of embedding dimension 2, and that if a non-hyperelliptic smooth projective curve C of genus g ≥ 2 can be embedded in the nth Hirzebruch surface Hn, then n is actually an invariant of C. [ABSTRACT FROM AUTHOR]

We give upper bounds on the minimal degree of a model in P 2 and the minimal bidegree of a model in P 1 × P 1 of the curve defined by a given Laurent polynomial, in terms of the combinatorics of the Newton polygon of the latter. We prove in various cases that this bound is sharp as soon as the polynomial is sufficiently generic with respect to its Newton polygon. [ABSTRACT FROM AUTHOR]

We give an explicit way of writing down a minimal set of generators for the canonical ideal of a nondegenerate curve, or of a more general smooth projective curve in a toric surface, in terms of its defining Laurent polynomial. [ABSTRACT FROM AUTHOR]

Linear pencils of tropical plane curves are parameterized by tropical lines (i.e. trees) in the space of coefficients. We study pencils of tropical curves with n-element support that pass through n−2 general points in the plane. Richter-Gebert et al. proved that such trees are compatible with their support set, and they conjectured that every compatible tree can be realized by a point configuration. In this article, we prove this conjecture. Our approach is based on a characterization of the fixed loci of tropical linear pencils. [ABSTRACT FROM AUTHOR]

Abstract: We produce Brill–Noether general graphs in every genus, confirming a conjecture of Baker and giving a new proof of the Brill–Noether Theorem, due to Griffiths and Harris, over any algebraically closed field. [Copyright &y& Elsevier]

In this paper, we classify all smooth threefolds , for which the Grassmann secant variety G1,2( X) ⊂⊂ (1, N) (i.e. the closure of the set of lines contained in the span of 3 independent points of X) has not the expected dimension. [ABSTRACT FROM AUTHOR]

The article provides information on a study which investigated the effectiveness of elective high-frequency oscillatory ventilation (HFOV) against conventional ventilation in preterm infants. Main outcome measures included death or bronchopulmonary dysplasia at 36 weeks' postmenopausal age and death or severe adverse neurological event. A detailed discussion on the research findings is offered. Identified limitations of the study include selection of preterm infants for HFOV on the basis of gestational age and birthweight for gestation, among others.

Abstract: A point P on a smooth hypersurface X of degree d in is called a star point if and only if the intersection of X with the embedded tangent space is a cone with vertex P. This notion is a generalization of total inflection points on plane curves and Eckardt points on smooth cubic surfaces in . We generalize results on the configuration space of total inflection points on plane curves to star points. We give a detailed description of the configuration space for hypersurfaces with two or three star points. We investigate collinear star points and we prove that the number of star points on a smooth hypersurface is finite. [Copyright &y& Elsevier]

Let X ⊂ PN be an irreducible non-degenerate variety. If the (h, k)-Grassmann secant variety Gh,k(X) of X is not the whole Grassmannian G(h, N), we have that the singular locus of Gh,k(X) contains Gh,k-1(X). Moreover, if X is a smooth curve without (2k +2)-secant 2k-space divisors, we obtain the equality Sing(Gh,k(X)) = Gh,k-1(X). [ABSTRACT FROM AUTHOR]

Abstract: In this article, we will prove that the set of 4-dissimilarity vectors of -trees is contained in the tropical Grassmannian . We will also propose three equivalent conjectures related to the set of -dissimilarity vectors of -trees for the case . Using a computer algebra system, we can prove these conjectures for . [Copyright &y& Elsevier]

Abstract: Let T be a weighted tree with n numbered leaves and let be its distance matrix, so is the distance between the leaves i and j. If m is an integer satisfying , we prove a tropical formula to compute the m-dissimilarity map of T (i.e. the weights of the subtrees of T with m leaves), given D. For , we present a tropical description of the set of m-dissimilarity maps of trees. For , a partial result is given. [Copyright &y& Elsevier]

In this paper we give a sharp lower bound on the dimension of Grassmann secant varieties of a given variety and we classify varieties for which the bound is attained. [ABSTRACT FROM AUTHOR]

We give a rough characterization for n-dimensional varieties with Gk-1,k-defect equal to a > 0 if k ≥ n. Then we apply this in the case that a ≥ n - 2 to become a fine classification. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess how frequently end-of-life decisions (ELDs) with a possible or certain life-shortening effect in neonates and infants were discussed with parents, and to determine if consultation of parents was associated with the type of ELD, (clinical) characteristics of the patient, and socio-demographic characteristics of the physician. A retrospective study of all deaths of live born infants under the age of one year was conducted in Flanders, Belgium. For 292 of all 298 deaths in a 1-year period (between 1 August 1999 and 31 July 2000) the attending physician could be identified and was sent an anonymous questionnaire. All cases with an ELD and containing information regarding the consultation of parents were included. The response rate was 87% (253/292). In 136 out of 143 cases, an ELD was made and information on the consultation of parents was obtained. According to the physician, the ELD was discussed with parents in 84% (114/136) of cases. The smaller the gestational age of the infant, the more the parental request for an ELD was explicit (p=0.025). When parents were not consulted, the ELD was based more frequently on the fact that the infant had no chance to survive and less on quality-of-life considerations (p=0.001); the estimated shortening of life due to the ELD was small in all cases, but significantly smaller (p<0.001) if parents were not consulted. It is concluded that the majority of parents of children dying under the age of one year are consulted in ELD-making, especially for decisions based on quality-of-life considerations (95.1%). Parents of infants with a small gestational age more often explicitly requested an ELD. [ABSTRACT FROM AUTHOR]

Objective: The purpose was to describe the use of drugs with a possible or certain life-shortening effect in end-of-life care in infants and to evaluate the possibly lethal effect.Design: For 292/298 deaths of live born infants (<1 year), in a 1-year period (between 1 August 1999 and 31 July 2000) in Flanders, Belgium, the attending physician could be identified and was sent an anonymous questionnaire. The questionnaires relating to deaths directly preceded by the administration of drugs were reviewed by a multi-disciplinary panel.Results: The response rate was 86.6% (253/292). In 57 cases (22.5%), drugs were administered directly before death. In 17/57 cases, the physician explicitly intended to hasten death. In 16/17 cases information about the drug(s) was available: opioids were administered in 14, a muscle relaxant in 5 and potassium chloride in 3 cases. In 13 cases where the lethal effect could be evaluated, the panel judged that the drugs were effective in hastening death in 10 cases. In most cases the estimated life-shortening was <24 h. In 40/57 cases the physician administered drugs to alleviate pain and/or symptoms, taking into account a possible life-shortening effect without explicitly intending it. Opioids were administered in all 30 cases where information about the drug(s) was supplied. In 13 cases the lethal effect could be evaluated, and in 6 cases the panel judged that the drugs had hastened death.Conclusions: When life-shortening was explicitly intended, (dosages of) drugs were likely to be lethal. Drugs administered also clearly hastened death in some cases where life-shortening was not explicitly intended. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we prove a rough characterization for -defective -dimensional non-degenerate varieties if . In the case of smooth surfaces or threefolds, we give a fine classification. [Copyright &y& Elsevier]

Background: Paediatricians are increasingly confronted with end-of-life decisions in critically ill neonates and infants. Little is known about the frequency and characteristics of end-of-life decisions in this population, nor about the relation with clinical and patients' characteristics. Methods: A death-certificate study was done for all deaths of neonates and infants in the whole of Flanders over a 12-month period (August, 1999, to July, 2000). We sent an anonymous questionnaire by mail to the attending physician for each of the 292 children who died under the age of 1 year. Information on patients was obtained from national registers. An attitude study was done for all physicians who attended at least one death during the study period. Findings: 253 (87%) of the 292 questionnaires were returned, and 121 (69%) of the 175 physicians involved completed the attitude questions. An end-of-life decision was possible in 194 (77%; 95% CI 70.4-82.4) of the 253 deaths studied, and such a decision was made in 143 cases (57%; 48.9-64.0). Lethal drugs were administered in 15 cases among 117 early neonatal deaths and in two cases among 77 later deaths (13% vs 3%; p=0.018). The attitude study showed that 95 (79%; 70.1-85.5) of the 121 physicians thought that their professional duty sometimes includes the prevention of unnecessary suffering by hastening death and 69 (58%; 48.1-66.5) of 120 supported legalization of life termination in some cases. Interpretation: Death of neonates and infants is commonly preceded by an end-of-life decision. The type of decision varied substantially according to the age of the child. Most physicians favour legalization of the use of lethal drugs in some cases. [ABSTRACT FROM AUTHOR]

Objective. To compare the pharmacokinetics of two dosing regimens of cisapride and their effects on QTc interval. Design. Thirty-one pre-term infants were enrolled in two neonatal intensive care units. In 16 infants, cisapride was started at 0.2 mg/kg orally every 6 h (group A) and in 15 infants at 0.1 mg/kg orally every 3 h (group B). Electrocardiograms were performed before and after 72 h of treatment to calculate the QTc interval according to the Bazett formula. After 72 h of treatment, cisapride and norcisapride trough concentrations, and concentrations 1 h after the next cisapride administration were quantified in serum. A linear regression analysis was performed to analyse the effect of postnatal and postconception age. Results. At the start of cisapride treatment, mean postnatal age was 22.9±13.9 days (mean±SD) for group A and 23.3±15.0 days for group B, and mean postconception age was 34.0±1.8 weeks for group A and 33.3±0.8 weeks for group B. The QTc interval increased equally in both groups (group A: +37±20 ms, and group B: + 38±25 ms; P=0.9). Mean concentration of cisapride 1 h after administration was, as expected from the dosing regimen, significantly higher in group A than in group B (123.7±43.2 ng/ml versus 86.7±27.8 ng/ml; P=0.03).The difference in trough concentration was not significant (107.4±44.3 ng/ml versus 78.2±35.4 ng/ml; P=0.09). There was a positive correlation between QTc prolongation and cisapride serum concentration (peak: R2=0.20, P=0.015; trough: R2=0.24, P=0.008) and an inverse correlation between postnatal age and concentration 1 h after administration concentration of cisapride (R2=0.19, P=0.02). No correlation was found for postconception age. Conclusion. Postnatal age has an inverse relationship with cisapride serum concentration in premature infants, whereas postconception age is not correlated. The maturation process of the biotransformation system of cisapride during the first weeks of life, triggered by birth, but independent of gestational age at birth can explain this observation. The effect of cisapride on cardiac repolarisation is positively related with the cisapride serum concentration. Administering cisapride every 3 h instead of every 6 h could be advantageous, as it is associated with lower peak cisapride serum concentrations. Further investigations are required to confirm this and its potential clinical benefit on QTc and arrhythmia risk. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate changes over time in cause of death and making end-of-life decisions in preterm infants. Methods: A follow-back survey was conducted of all preterm infants who died between September 2016 and December 2017 in Flanders and Brussels, Belgium. Cause of death was obtained from the death certificate and information on end-of-life decisions (ELDs) through an anonymous questionnaire of the certifying physician. Results were compared with a previous study performed between August 1999 and July 2000. Results: In the cohort 1999-2000 and 2016-2017, respectively, 150 and 135 deaths were included. A significantly higher proportion of infants born before 26 weeks of gestation was found in the 2016-2017 cohort (53% vs. 24% in 1999-2000, p < 0.001). Extreme immaturity (<26 weeks) remained the most prevalent cause with a significant increase in the 2016-2017 cohort (48% vs. 28% in 1999-2000, p < 0.001). The overall prevalence of ELDs was similar across study periods (61%). Non-treatment decisions remained the most common ELD (36% and 37%). Conclusion: Infants born at the limits of viability have become more prevalent among infant deaths, possibly due to a change in attitude towards periviable births. Neither the process of making ELDs nor the cause of death has changed over time. [ABSTRACT FROM AUTHOR]

Aims: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Methods: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed‐effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range. Results: Sixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1‐compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Conclusion: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model‐informed precision dosing. [ABSTRACT FROM AUTHOR]

For parenteral nutrition (PN) of newborns, the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) 2018 guidelines recommend standardized solutions over individual PN (IPN) solutions for most patients. This retrospective study assessed if a shift from IPN to standardized PN was feasible at the UZ Brussel. Using prescription data of 145 neonates, we calculated the nutrient provision for IPN and for standardized PN of the same volumes. We compared the macronutrient intakes with ESPGHAN 2018 recommendations to assess the feasibility. For neonates of a gestational age (GA) <32 or >36 weeks, standardized PN reached recommendations as least as fast as IPN. For neonates with a GA of 32 to 36 weeks, the administration protocol requires further adjustments as amino acid provision was lacking compared to IPN. Overall, the results support the feasibility of a shift from IPN to standardized PN at the UZ Brussel. [ABSTRACT FROM AUTHOR]

This follow-up to the STOP-BPD randomized clinical trial, which investigated the efficacy and safety of systemic hydrocortisone treatment initiated 7 to 14 days after birth in ventilator-dependent, very preterm infants in the Netherlands and Belgium at 36 weeks' postmenstrual age, examines the prespecified composite of death and neurodevelopmental impairment among these infants at 2 years' corrected age. [ABSTRACT FROM AUTHOR]

The INtubation-SURfactant-Extubation (INSURE) procedure is a widely-used surfactant administration method to treat preterm infants with respiratory distress syndrome (RDS) but is not always successful. We conducted a systematic review to identify early predictive factors for failure of this procedure. A systematic literature search was performed until July 2018 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Original studies comparing INSURE success with INSURE failure in preterm infants with RDS were included. A predefined data extraction form was used to retrieve data from articles, and methodological quality was assessed using the SIGN checklists. Fifteen studies out of 690 identified records met inclusion criteria. Methodological quality varied, only 8 studies performed multivariate analysis. We identified 20 different risk factors in total. Evidence for birth weight (BW) as a predictor for INSURE failure was inconsistent, but there was a significant association between decreasing gestational age (GA) and failure risk. RDS severity was assessed in multiple ways, using arterial blood gas values, imaging, and scoring systems. In conclusion, extremely low BW, low GA, and severe RDS appear to be risk factors for INSURE failure. However, evidence is inconsistent due to important methodological heterogeneity. Therefore, clinical applicability of these results is limited and implies the need for future large cohort studies on this subject. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9–8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2–1.2) and pembrolizumab (1.1%; 95% CI, 0.5–2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction – particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4–9.8; pembrolizumab, 8.5%; 95% CI, 7.5–9.7; PD-L1, 5.5%; 95% CI, 4.4–6.8; ipilimumab, 3.8%; 95% CI, 2.6–5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2–16.4%), hyperthyroidism (9.4–10.4%), hypophysitis (8.8–10.5%), and primary adrenal insufficiency (5.2–7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment. [ABSTRACT FROM AUTHOR]

The author discusses surfactant administration in preterm infants. He notes that surfactant treatment has improved results for preterm infants with respiratory distress syndrome. He cites a multicentre randomised controlled trial investigation by Wolfgang Göpel and colleagues, published in the issue, which showed the efficacy of a minimally invasive method of early surfactant administration in infants supported with continuous positive airway pressure.

Background: Mortality and end-of-life decision-making can occur in newborns, especially within the Neonatal Intensive Care Unit. For parents, participating in end-of-life decision-making is taxing. Knowledge is lacking on what support is helpful to parents during decision-making. Aim: To identify barriers and facilitators experienced by parents in making an end-of-life decision for their infant. Design: Qualitative study using face-to-face semi-structured interviews. Setting/participants: We interviewed 23 parents with a child that died after an end-of-life decision at a Neonatal Intensive Care Unit between April and September 2018. Results: Parents stated barriers and facilitators within 4 themes: 1. Clinical knowledge and prognosis; 2. Quality of information provision; 3. Emotion regulation; and 4. Psychosocial environment. Facilitators include knowing whether the prognosis includes long-term negative quality of life, knowing all treatment options, receiving information according to health literacy level, being able to process intense emotions, having experienced counseling and practical help. Barriers include a lack of general medical knowledge, being unprepared for a poor prognosis, having an uninformed psychologist. Conclusions: We found that clinical information and psychosocial support aid parents in decision-making. Information is best tailored to health literacy. Psychosocial support can be provided by experienced, informed counselors, social services and sibling support, distinguishing between verbal and non-verbal coping preferences, and calm, familiar architecture. Intense emotions may hinder absorption of clinical information, therefore interventions to aid emotion regulation and reduce cognitive load may be looked at in further research. Adjustment of the Situations, Opinions and Options, Parents, Information, Emotions framework based on our results can be evaluated. [ABSTRACT FROM AUTHOR]

Feasibility of umbilical cord blood collection in neonates at risk of brain damage - a step toward autologous cell therapy for a high-risk population. Umbilical cord blood (UCB)-derived cells have shown promise as a treatment for preterm brain injury in pre-clinical models, including neuro-inflammation4, hypoxia-ischaemia5 and perinatal stroke6. Adjusted for confounding factors, the implementation of outreach education was associated with a significant reduction in the rate of composite death and/or severe brain injury (AOR 0.36, 95% CI, 0.15-0.85, P=0.02), severe brain injury (AOR 0.34, 95% CI, 0.14-0.83, P=0.02), moderate to severe post hemorrhagic ventricular dilatation (AOR 0.21, 95% CI, 0.08-0.61, P=0.004), and brain injury of any grade (AOR 0.41, 95% CI, 0.21-0.83, P=0.01). Effects of combined treatment of Inter-Alpha Inhibitor Proteins (IAIPs) with hypothermia in n... B Chen X b B SP a sp b , Wu Y, Kim B, Domonoske R, Lim Y, Stonestreet B I SP a sp Women & Infants' Hospital Of RI, 101 Dudley Street, Providence, United States i B BACKGROUND: b Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems observed in infants. [Extracted from the article]

We aimed to examine the effect of changing levels of support (NAVA level) during non-invasive neurally adjusted ventilatory assist (NIV-NAVA) in preterm infants with respiratory distress syndrome (RDS) on electrical diaphragm activity. This is a prospective, single-centre, interventional, exploratory study in a convenience sample. Clinically stable preterm infants supported with NIV-NAVA for RDS were eligible. Patients were recruited in the first 24 h after the start of NIV-NAVA. Following a predefined titration protocol, NAVA levels were progressively increased starting from a level of 0.5 cmH2O/µV and with increments of 0.5 cmH2O/µV every 3 min, up to a maximum level of 4.0 cmH2O/µV. We measured the evolution of peak inspiratory pressure and the electrical signal of the diaphragm (Edi) during NAVA level titration. Twelve infants with a mean (SD) gestational age at birth of 30.6 (3.5) weeks and birth weight of 1454 (667) g were enrolled. For all patients a breakpoint could be identified during the titration study. The breakpoint was on average (SD) at a level of 2.33 (0.58) cmH2O/µV. With increasing NAVA levels, the respiratory rate decreased significantly. No severe complications occurred. Conclusions: Preterm neonates with RDS supported with NIV-NAVA display a biphasic response to changing NAVA levels with an identifiable breakpoint. This breakpoint was at a higher NAVA level than commonly used in this clinical situation. Immature neural feedback mechanisms warrant careful monitoring of preterm infants when supported with NIV-NAVA. Trial registration: clinicaltrials.gov NCT03780842. Date of registration December 12, 2018. What is Known: • Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) is a safe, feasible and effective way to support respiration in preterm infants. • Intact neural feedback mechanisms are needed to protect the lung from overdistension in neurally adjusted ventilatory assist. What is New: • Preterm infants with acute RDS have a similar pattern of respiratory unloading as previously described. • Neural feedback mechanisms seem to be immature with the risk of insufficient support and lung injury due to overdistension of the lung. [ABSTRACT FROM AUTHOR]

Background: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/design: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial Registration: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28. [ABSTRACT FROM AUTHOR]

Background: Moral distress and burnout related to end-of-life decisions in neonates is common in neonatologists and nurses working in neonatal intensive care units. Attention to their emotional burden and psychological support in research is lacking. Aim: To evaluate perceived psychological support in relation to end-of-life decisions of neonatologists and nurses working in Flemish neonatal intensive care units and to analyse whether or not this support is sufficient. Design/participants: A self-administered questionnaire was sent to all neonatologists and neonatal nurses of all eight Flemish neonatal intensive care units (Belgium) in May 2017. The response rate was 63% (52/83) for neonatologists and 46% (250/527) for nurses. Respondents indicated their level of agreement (5-point Likert-type scale) with seven statements regarding psychological support. Results: About 70% of neonatologists and nurses reported experiencing more stress than normal when confronted with an end-of-life decision; 86% of neonatologists feel supported by their colleagues when they make end-of-life decisions, 45% of nurses feel that the treating physician listens to their opinion when end-of-life decisions are made. About 60% of both neonatologists and nurses would like more psychological support offered by their department when confronted with end-of-life decisions, and 41% of neonatologists and 50% of nurses stated they did not have enough psychological support from their department when a patient died. Demographic groups did not differ in terms of perceived lack of sufficient support. Conclusion: Even though neonatal intensive care unit colleagues generally support each other in difficult end-of-life decisions, the psychological support provided by their department is currently not sufficient. Professional ad hoc counselling or standard debriefings could substantially improve this perceived lack of support. [ABSTRACT FROM AUTHOR]

Aim: Perinatal death is often preceded by an end-of-life decision (ELD). Disparate hospital policies, complex legal frameworks and ethically difficult cases make attitudes important. This study investigated attitudes of neonatologists and nurses towards perinatal ELDs.Methods: A survey was handed out to all neonatologists and neonatal nurses in all eight neonatal intensive care units in Flanders, Belgium in May 2017. Respondents indicated agreement with statements regarding perinatal ELDs on a Likert-scale and sent back questionnaires via mail.Results: The response rate was 49.5% (302/610). Most neonatologists and nurses found nontreatment decisions such as withholding or withdrawing treatment acceptable (90-100%). Termination of pregnancy when the foetus is viable in cases of severe or lethal foetal problems was considered highly acceptable in both groups (80-98%). Physicians and nurses do not find different ELDs equally acceptable, e.g. nurses more often than physicians (74% vs 60%, p = 0.017) agree that it is acceptable in certain cases to administer medication with the explicit intention of hastening death.Conclusion: There was considerable support for both prenatal and neonatal ELDs, even for decisions that currently fall outside the Belgian legal framework. Differences between neonatologists' and nurses' attitudes indicate that both opinions should be heard during ELD-making. [ABSTRACT FROM AUTHOR]

Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2–5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9–2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth. [ABSTRACT FROM AUTHOR]

Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population. Study design: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008–2010 (SHIVER) and 2010–2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants. Results: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C– 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C– 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia. Conclusions: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect. Trial registration: . [ABSTRACT FROM AUTHOR]

Aim: Infants born preterm are at risk of cerebral palsy (CP) and motor or cognitive developmental delay. For clinicians, it is essential to know the relative predictive accuracy of the most commonly used neuroimaging and neurophysiological tests for the early prediction of adverse neurodevelopmental outcome. The aim of this study was to compare the accuracy of these tests in survivors of a population of infants born very preterm.Method: A retrospective cohort study was performed in 163 children born before 32 weeks gestational age. We compared the accuracy in predicting adverse neurodevelopmental outcome at the age of 2 years 6 months of early and late cranial ultrasound (CUS), magnetic resonance imaging, somatosensory evoked potentials after stimulation of the posterior tibial nerve, and electroencephalography by calculating positive and negative likelihood ratios.Results: An abnormal early CUS is the best predictor of the presence of CP (positive likelihood ratio 6.09), motor developmental delay (positive likelihood ratio 3.11), and cognitive developmental delay (positive likelihood ratio 5.66). Overall, negative likelihood ratios were poor, ranging between 0.49 and 0.98, meaning that a normal test result had only minimal influence on the probability of adverse neurological outcome.Interpretation: None of the diagnostic tests had a good performance in predicting future neurodevelopmental problems in infants born preterm. A normal test result provided very little clinically useful information.What This Paper Adds: An abnormal early cranial ultrasound (positive test result) is the best predictor of adverse neurodevelopmental outcome. All negative results have poor predictive value of future neurodevelopmental problems. [ABSTRACT FROM AUTHOR]

Background Identifying patients with heart failure (HF) in general practice is challenging. Our aim was to provide an overview of methods used to identify patients with HF in general practice and to assess their impact on patient characteristics. Methods and results A systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Taken together, 105 studies on HF in general practice were included, totalling 196,105 patients. Five main identification methods for HF were distinguished, including 1) echocardiographic assessments, 2) results of echocardiography in general practitioner (GP) charts, 3) GP judgment after chart review, 4) GP judgment of consecutive patients and 5) only chart review. Only 30% of studies used the results of echocardiography. Despite a large heterogeneity between studies the pooled data revealed a predominant phenotype of older women with hypertension rather than ischaemic heart disease. Linear regression analysis showed that the impact of the identification method on patient characteristics was limited. However, study design had a greater impact, with randomized-controlled trials (RCTs) including younger, male patients with ischaemic heart disease and higher HF drug prescription rates at baseline. Conclusion Pooled data of 196,105 patients with HF confirmed a phenotype of older women with hypertension rather than ischaemic heart disease as the predominant HF population in general practice. The lack of a gold standard definition of HF introduced a large heterogeneity in identification methods with remarkably limited impact on patient characteristics. However, RCTs did include patients with a different phenotype, emphasizing the need to promote inclusion of real-world HF patients. [ABSTRACT FROM AUTHOR]

Background: Pancreatic agenesis is an extremely rare cause of neonatal diabetes mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development. Case presentation: We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder. Although the sequences of a selected set of genes related to pancreas agenesis or HPE were wild-type, the patient's phenotype suggests a genetic defect that emerges early in embryonic development of brain, gallbladder and pancreas. Conclusions: Developmental defects of the pancreas and brain can occur together. Identifying the genetic defect may identify a novel key regulator in beta cell development. [ABSTRACT FROM AUTHOR]

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria.Methods/design: In this study, 206 spontaneously breathing infants born at 24(+0)-27(+6) weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation.Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge.Trial Registration: ClinicalTrials.gov identifier: NCT02482766 . Registered on 1 June 2015. [ABSTRACT FROM AUTHOR]

Background: The Thompson encephalopathy score is a clinical score to assess newborns suffering from perinatal asphyxia. Previous studies revealed a high sensitivity and specificity of the Thompson encephalopathy score for adverse outcomes (death or severe disability). Because the Thompson encephalopathy score was developed before the use of therapeutic hypothermia, its value was reassessed.Objective: The purpose of this study was to assess the association of the Thompson encephalopathy score with adverse short-term outcomes, defined as death before discharge, development of severe epilepsy, or the presence of multiple organ failure in asphyxiated newborns undergoing therapeutic hypothermia.Methods: The study period ranged from November 2010 to October 2014. A total of 12 tertiary neonatal intensive care units participated. Demographic and clinical data were collected from the "PharmaCool" multicenter study, an observational cohort study analyzing pharmacokinetics of medication during therapeutic hypothermia. With multiple logistic regression analyses the association of the Thompson encephalopathy scores with outcomes was studied.Results: Data of 142 newborns were analyzed (male: 86; female: 56). Median Thompson score was 9 (interquartile range: 8 to 12). Median gestational age was 40 weeks (interquartile range 38 to 41), mean birth weight was 3362 grams (standard deviation: 605). All newborns manifested perinatal asphyxia and underwent therapeutic hypothermia. Death before discharge occurred in 23.9% and severe epilepsy in 21.1% of the cases. In total, 59.2% of the patients had multiple organ failure. The Thompson encephalopathy score was not associated with multiple organ failure, but a Thompson encephalopathy score ≥12 was associated with death before discharge (odds ratio: 3.9; confidence interval: 1.3 to 11.2) and with development of severe epilepsy (odds ratio: 8.4; confidence interval: 2.5 to 27.8).Conclusion: The Thompson encephalopathy score is a useful clinical tool, even in cooled asphyxiated newborns. A score ≥12 is associated with adverse outcomes (death before discharge and development of severe epilepsy). The Thompson encephalopathy score is not associated with the development of multiple organ failure. [ABSTRACT FROM AUTHOR]

Aim(s): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. Methods: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non‐linear mixed‐effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. Results: A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post‐natal age (PNA)) was 0.06 l kg−1 h−1 (inter‐individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). Conclusions: This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively. [ABSTRACT FROM AUTHOR]

Highlights: [•] We present an analytical method for amikacin, gentamicin, and vancomycin in plasma. [•] Only 25μL of plasma is used with this method. [•] All preset specifications of validation parameters are met. [•] The method is applied to 3 patients included in the Pharmacool trial. [•] It will be used to describe pharmacokinetics and dynamics of hypothermic newborns. [ABSTRACT FROM AUTHOR]

Objective This systematic review assesses the effectiveness and side effects of celiac plexus neurolysis ( CPN) in the treatment of upper abdominal cancer pain, and evaluates whether there are any differences between the percutaneous and endoscopic ultrasound-guided ( EUS) denervation techniques. Methods Five databases were searched, expanded by assessing the reference lists of all retrieved papers. Sixty-six publications fulfilled the inclusion/exclusion criteria and were included in the systematic review. Randomized controlled trials were available for the percutaneous CPN, and therefore meta-analyses were performed for pain, opioid consumption, and specific side effects. The quality of life data were too heterogeneous to be assessed by a meta-analysis, and evidence for EUS CPN could only be evaluated by observational studies. Results Meta-analyses show that percutaneous CPN significantly improves pain in patients with upper abdominal cancer, with a decrease in opioid consumption and side effects. It is unclear whether there is any change in quality of life. Case series suggest that EUS CPN improves pain. No conclusion can be made about EUS CPN's influence on opioid consumption. Although CPN is a safe procedure, side effects and complications can occur with both the percutaneous and EUS techniques. Conclusions Following this review, evidence suggests that CPN should be considered in patients with upper abdominal cancer where the pain is not adequately controlled with systemic analgesics or when significant opioid-induced side effects are present. The percutaneous approach remains the standard technique as robust evidence for EUS CPN is lacking. [ABSTRACT FROM AUTHOR]