"Random" gentamicin concentrations do not predict trough levels in neonates receiving once daily fixed dose regimens

BACKGROUND: Monitoring plasma gentamicin concentrations in neonates 24 hours after a once daily dose (4 mg/kg) often necessitates additional blood sampling. In adults a nomogram has been developed enabling evaluation of gentamicin doses by sampling concentrations with other blood tests, 4 – 16 hours after administration. We attempted to develop a similar nomogram for neonates. METHODS: In addition to standard 24 hour sampling to monitor trough concentrations, one additional "random" gentamicin concentration was measured in each of 50 neonates <4 days of age (median gestation 33 weeks [28–41]), when other blood samples were clinically necessary, 4 – 20 hours after gentamicin administration. 24 hour concentrations of >1 mg/L were considered high, and an indication to extend the dosing interval. RESULTS: Highest correlation (r(2 )= 0.51) of plasma gentamicin concentration against time (4 to 20 hours) was with logarithmic regression. A line drawn 0.5 mg/L below the true regression line resulted in all babies with 24 hr gentamicin concentrations >1 mg/L having the additional "random" test result above that line, i.e. 100% sensitivity for 24 hour concentrations>1 mg/L, though only 58% specificity. Having created the nomogram, 39 further babies (median gestation 34 weeks [28–41]), were studied and results tested against the nomogram. In this validation group, sensitivity of the nomogram for 24 hr concentrations >1 mg/L was 92%; specificity 14%, positive predictive value 66%, and negative predictive value 50%. Prematurity (≤ 37 weeks) was a more sensitive (94%) and specific (61%) indicator of high 24-hour concentrations. 62 (87%) of 71 preterm babies had high 24-hour concentrations. CONCLUSION: It was not possible to construct a nomogram to predict gentamicin concentrations at 24 hours in neonates with a variety of gestational ages. Dosage tailored to gestation with monitoring of trough concentrations remains management of choice

Retrospective study evaluating safety, clinical effect, and dosing of dalteparin for the treatment of venous thromboembolism in term neonates

Background: There is an increased risk of venous thromboembolism (VTE) among neonates due to their unique hemostatic system. However, there is lack of approved treatment options for VTE in neonatal population. Importantly, dalteparin, a low molecular weight heparin approved for pediatric VTE in children ≥1 month of age, has also been used for the treatment of neonatal VTE. Based on the request from the Food and Drug Administration, this retrospective study aimed to characterize the safety, clinical effects, and dosing of dalteparin for treatment of VTE among neonates. Procedure: Data from electronic medical records for neonates (born ≥35 weeks of gestation) treated with dalteparin for VTE between January 2010 and December 2021 were collected. The data assessed included bleeding and deterioration in hematological biomarkers among other adverse events, changes in relevant factor antifactor Xa (anti‐Xa) levels and VTE status, and dosing of dalteparin and corresponding anti‐Xa assay levels. Results: Sixteen neonates from five participating sites in the United Kingdom were included. There were no bleeding events or deaths. Only one serious adverse event of hypoglycemic brain injury (unrelated to dalteparin) was documented in a patient with a history of hyperinsulinism. Median (range) daily dose of dalteparin at initiation was 309 (297–314) IU/kg. Eight of 16 neonates achieved therapeutic anti‐Xa level, including two patients who did so after the first dose. Conclusions: Dalteparin treatment in neonates raised no major safety concerns. Larger cohort studies may help provide further insights on clinical effects of dalteparin for neonatal VTE

The impact of level of neonatal care provision on outcomes for preterm babies born between 27 and 31 weeks of gestation, or with a birth weight between 1000 and 1500 g: a review of the literature

© 2020 The Authors. Published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/bmjpo-2019-000583Objective:There is evidence that birth and care in a maternity service associated with a neonatal intensive care unit (NICU) is associated with improved survival in preterm babies born at <27 weeks of gestation. We conducted a systematic review to address whether similar gains manifested in babies born between 27+0 and 31+6 weeks (hereafter 27 and 31 weeks) of gestation, or in those with a birth weight between 1000 and 1500 g. Methods:We searched Embase, Medline and CINAHL databases for studies comparing outcomes for babies born between 27 and 31 weeks or between 1000 and 1500 g birth weight, based on designation of the neonatal unit where the baby was born or subsequently cared for (NICU vs non-NICU setting). A modified QUIPS (QUality In Prognostic Studies) tool was used to assess quality. Results:Nine studies compared outcomes for babies born between 27 and 31 weeks of gestation and 11 studies compared outcomes for babies born between 1000 and 1500 g birth weight. Heterogeneity in comparator groups, birth locations, gestational age ranges, timescale for mortality reporting, and description of morbidities facilitated a narrative review as opposed to a meta-analysis. Conclusion:Due to paucity of evidence, significant heterogeneity and potential for bias, we were not able to answer our question-does place of birth or care affect outcomes for babies born between 27 and 31 weeks? This supports the need for large-scale research to investigate place of birth and care for babies born in this gestational age range.This work is supported by the NIHR HS&DR Stream, Project number 15/70/104, and by the Royal Wolverhampton NHS Trust, Protocol number 2016NEO87. AQTI is undertaking a PhD with the University of Leicester, with funding from the OptiPrem project.Published versio

Neonatal health care costs of very preterm babies in England: a retrospective analysis of a national birth cohort

© 2023 The Authors. Due to be published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://bmjpaedsopen.bmj.com/content/7/1/e001818Objectives: Babies born between 27+0 and 31+6 weeks of gestation represent the largest group of very preterm babies requiring NHS care, however up-to-date cost figures for the UK are not currently available. This study estimates neonatal costs to hospital discharge for this group of very preterm babies in England. Design: Retrospective analysis of resource use data recorded within the National Neonatal Research Database (NNRD). Setting: Neonatal units in England. Patients: Babies born between 27+0 and 31+6 weeks of gestation in England and discharged from a neonatal unit between 2014 and 2018. Main outcome measures: Days receiving different levels of neonatal care were costed, along with other specialised clinical activities. Mean resource use and costs per baby are presented by gestational age at birth, along with total costs for the cohort. Results: Based upon data for 28,154 very preterm babies, the annual total costs of neonatal care were estimated to be £262 million, with 95% of costs attributable to routine daily care provided by units. The mean (SD) total cost per baby of this routine care varied by gestational age at birth; £75,594 (£34,874) at 27 weeks as compared with £27,401 (£14,947) at 31 weeks. Conclusions: Neonatal healthcare costs for very preterm babies vary substantially by gestational age at birth. The findings presented here are a useful resource to stakeholders including NHS managers, clinicians, researchers, and policy makers.This work is supported by the National Institute for Health Research, Health Services and Delivery Research Stream, project number 15/70/104 CRN accrual was approved by the NIHR for the period (1 August 2017 to 31 August 2018)

The Fornax Spectroscopic Survey: The Number of Unresolved Compact Galaxies

We describe a sample of thirteen bright (18.5<Bj<20.1) compact galaxies at low redshift (0.05<z<0.21) behind the Fornax Cluster. These galaxies are unresolved on UK Schmidt sky survey plates, so would be missing from most galaxy catalogs compiled from this material. The objects were found during initial observations of The Fornax Spectroscopic Survey. This project is using the Two-degree Field spectrograph on the Anglo-Australian Telescope to obtain spectra for a complete sample of all 14000 objects, stellar and non-stellar, with 16.5<Bj<19.7, in a 12 square degree area centered on the Fornax cluster of galaxies. The surface density of compact galaxies with magnitudes 16.5<Bj<19.7 is 7+/-3 /sq.deg., representing 2.8+/-1.6% of all local (z<0.2) galaxies to this limit. There are 12+/-3 /sq.deg. with 16.5<Bj<20.2. They are luminous (-21.5<Mb<-18.0, for H0=50 km/s/mpc) and most have strong emission lines (H alpha equivalent widths of 40-200 A) and small sizes typical of luminous HII galaxies and compact narrow emission line galaxies. Four out of thirteen have red colors and early-type spectra, so are unlikely to have been detected in any previous surveys.Comment: LaTeX source; 5 pages including 3 figures; uses emulateapj.st

Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the United Kingdom

Introduction: Methodologically robust clinical trials are required to improve neonatal care and reduce unwanted variations in practice. Previous neonatal research prioritisation processes have identified important research themes rather than specific research questions amenable to clinical trials. Practice-changing trials require well-defined research questions, commonly organised using the Population, Intervention, Comparison, Outcome (PICO) structure. By narrowing the scope of research priorities to those which can be answered in clinical trials and by involving a wide range of different stakeholders, we aim to provide a robust and transparent process to identify and prioritise research questions answerable within the National Healthcare System to inform future practice-changing clinical trials. Methods and analysis: A steering group comprising parents, doctors, nurses, allied health professionals, researchers and representatives from key organisations (Neonatal Society, British Association of Perinatal Medicine, Neonatal Nurses Association and Royal College of Paediatrics and Child Health) was identified to oversee this project. We will invite submissions of research questions formatted using the PICO structure from the following stakeholder groups using an online questionnaire: parents, patients, healthcare professionals and academic researchers. Unanswered, non-duplicate research questions will be entered into a three-round eDelphi survey of all stakeholder groups. Research questions will be ranked by mean aggregate scores. Ethics and dissemination: The final list of prioritised research questions will be disseminated through traditional academic channels, directly to key stakeholder groups through representative organisations and on social media. The outcome of the project will be shared with key research organisations such as the National Institute for Health Research. Research ethics committee approval is not required

Philosophy of the world and philosophy of Karl Löwith as a precursor and incentive to the idea of integrative bioethics

Traditional cosmology, once used to explain the world, was suppressed by the domination of science over philosophy which happened after their separation. Nowadays, scientific (in terms of natural sciences) cosmology is given the advantage in answering the question what is the world, while the "non-empirical" catholicity (the basic characteristic of traditional cosmology) became useless. Encouragement of one’s effort to re-establish the category of catholicity can be found in the idea of integrative bioethics on one side and in the philosophy of the world on the other. In this paper the relation between the idea of integrative bioethics and the philosophy of the world will be established through philosophical discussions which were held in Augsburg and in Zagreb (1988, 1990, 1993) and also with reliance on understanding the world in philosophy of Karl Löwith

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E₂(PGE₂) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE₂cell surface receptors (EP 1–4) to examine the mechanisms by which PGE₂regulates tumour progression.</p> <p>Methods</p> <p>Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue.</p> <p>Results</p> <p>EP4 was the most abundant subtype of PGE₂receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE₂generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE₂(1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21^WAF1/CIP1expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21^WAF1/CIP1was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted.</p> <p>Conclusion</p> <p>COX-2 regulates cell cycle transition via EP4 receptor and altered p21^WAF1/CIP1expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.</p