A relativistic eikonal description of nucleon propagation through nuclei

The main focus of my PhD thesis is on exclusive proton-induced A(p,pN) reactions. A relativistic and cross-section factorized framework for computing quasielastic $A(p,pN)$ observables is presented. To model the propagation of the nucleons through the nuclear medium, the eikonal approximation is used. Our eikonal model is very flexible as it can be used either in conjunction with relativistic optical potentials (relativistic optical model eikonal approximation, ROMEA) or within its Glauber multiple-scattering extension (relativistic multiple-scattering Glauber approximation, RMSGA). The major difference between both approaches is that the ROMEA framework describes the initial- and final-state interactions (IFSI) in terms of a nucleon-nucleus picture, whereas the RMSGA framework is essentially a nucleon-nucleon model. At lower nucleon energies, the former is preferred; while the latter is more suitable at higher energies. The ROMEA formalism has been put to a stringent test by comparing the calculations with A(p,pN) cross-section data from a wide variety of experiments. A fair description of the data is obtained, thereby demonstrating that the ROMEA model can be applied in a wide energy range. The RMSGA approach has been used to account for the IFSI in the study of A(p,2p) nuclear transparencies at GeV energies. To explain the oscillatory energy dependence of the nuclear transparency data, the A(p,2p) formalism has been extended to incorporate the Ralston-Pire model for the pp scattering amplitude and the concepts of color transparency (CT) and nuclear filtering (NF). Introducing the concept of NF brings the calculations in qualitative agreement with the data. Furthermore, the calculations indicate that CT is imperative to increase the predictions to the level of the data. The quantitative description of the data, however, is far from perfect and a number of uncertainties involving the A(p,2p) transparency remain. Finally, we have studied the accuracy of the eikonal approximation at lower energies by developing an extension of the ROMEA model which accounts for second-order eikonal corrections. The calculations show that the effect of the second-order eikonal corrections on A(e,e'p) observables is rather limited for Q^2 >= 0.2 (GeV/c)^2

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial):statistical analysis plan

Abstract 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

Recommendations for neonatologist performed echocardiography in Europe: Consensus Statement endorsed by European Society for Paediatric Research (ESPR) and European Society for Neonatology (ESN)

Contains fulltext : 171351.pdf (Publisher’s version ) (Open Access

Laboratory validation and field usability assessment of a point-of-care test for serum bilirubin levels in neonates in a tropical setting [version 1; referees: 2 approved]

Background: Screening and monitoring serum bilirubin (SBR) in neonates is crucial to prevent neonatal hyperbilirubinemia (NH)-associated morbidity and mortality worldwide. A lack of resources is often a barrier for measuring SBR in developing countries. Reliable, cost-effective, easy to use point-of-care (POC) SBR tests are needed. This study aimed to evaluate the technical accuracy and usability of the Bilistick System (BS), a new bilirubin POC test, in a tropical setting. Methods: This was a mixed-methods study, including laboratory validation of the BS, direct observation of technical procedures as performed by the midwives and midwives’ assessment of the device’s easiness of use through focus group discussions (FGD) and a self-administered questionnaire. The study was conducted in a field clinic of the Shoklo Malaria Research Unit along the Thailand-Myanmar border between January and December 2017. Results: A total of 173 samples were tested at a median age of 4 days. BS generated an error message—providing no SBR readout—in 48.6% of the tests performed. For the tests that yielded a result, the correlation coefficient (95% CI) between BS and routine laboratory bilirubinometer SBR was 0.87 (0.77-0.93). The accuracy decreased with increasing haematocrit and at higher humidity (≥75%). Direct observation of the operators using the device and analysis of the focus group discussions and questionnaires indicated that the BS was considered easy to use and required limited training. Conclusions: This evaluation showed that the BS, in its current formulation, does not provide reliable results for measuring SBR in a tropical, low-resource setting  but has acceptable usability features

Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.

BACKGROUND: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. METHODS: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. RESULTS: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. CONCLUSIONS: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy

Early treatment versus expectative management of patent ductus arteriosus in preterm infants

_Background:_ Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. _Methods:_ This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA1.5mm. Early treatment (between 24 and 72h postnatal age) with the cyclooxygenase inhibitor(COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. _Discussion:_ As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36weeks