Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Searches for Neutrinos from LHAASO ultra-high-energy {\gamma}-ray sources using the IceCube Neutrino Observatory

Galactic PeVatrons are Galactic sources theorized to accelerate cosmic rays up to PeV in energy. The accelerated cosmic rays are expected to interact hadronically with nearby ambient gas or the interstellar medium, resulting in {\gamma}-rays and neutrinos. Recently, the Large High Altitude Air Shower Observatory (LHAASO) identified 12 {\gamma}-ray sources with emissions above 100 TeV, making them candidates for PeV cosmic-ray accelerators (PeVatrons). While at these high energies the Klein-Nishina effect suppresses exponentially leptonic emission from Galactic sources, evidence for neutrino emission would unequivocally confirm hadronic acceleration. Here, we present the results of a search for neutrinos from these {\gamma}-ray sources and stacking searches testing for excess neutrino emission from all 12 sources as well as their subcatalogs of supernova remnants and pulsar wind nebulae with 11 years of track events from the IceCube Neutrino Observatory. No significant emissions were found. Based on the resulting limits, we place constraints on the fraction of {\gamma}-ray flux originating from the hadronic processes in the Crab Nebula and LHAASOJ2226+6057

Search for Astrophysical Neutrinos from 1FLE Blazars with IceCube

The majority of astrophysical neutrinos have undetermined origins. The IceCube Neutrino Observatory has observed astrophysical neutrinos but has not yet identified their sources. Blazars are promising source candidates, but previous searches for neutrino emission from populations of blazars detected in ≳GeV gamma rays have not observed any significant neutrino excess. Recent findings in multimessenger astronomy indicate that high-energy photons, coproduced with high-energy neutrinos, are likely to be absorbed and reemitted at lower energies. Thus, lower-energy photons may be better indicators of TeV–PeV neutrino production. This paper presents the first time-integrated stacking search for astrophysical neutrino emission from MeV-detected blazars in the first Fermi Large Area Telescope low energy (1FLE) catalog using ten years of IceCube muon–neutrino data. The results of this analysis are found to be consistent with a background-only hypothesis. Assuming an E$^{-2}$ neutrino spectrum and proportionality between the blazars MeV gamma-ray fluxes and TeV–PeV neutrino flux, the upper limit on the 1FLE blazar energy-scaled neutrino flux is determined to be 1.64 × 10^-12} TeV cm$^{-2}$ s$^{-1}$ at 90% confidence level. This upper limit is approximately 1% of IceCube\u27s diffuse muon–neutrino flux measurement

A Search for Coincident Neutrino Emission from Fast Radio Bursts with Seven Years of IceCube Cascade Events

This paper presents the results of a search for neutrinos that are spatially and temporally coincident with 22 unique, non-repeating Fast Radio Bursts (FRBs) and one repeating FRB (FRB121102). FRBs are a rapidly growing class of Galactic and extragalactic astrophysical objects that are considered a potential source of high-energy neutrinos. The IceCube Neutrino Observatory's previous FRB analyses have solely used track events. This search utilizes seven years of IceCube's cascade events which are statistically independent of the track events. This event selection allows probing of a longer range of extended timescales due to the low background rate. No statistically significant clustering of neutrinos was observed. Upper limits are set on the time-integrated neutrino flux emitted by FRBs for a range of extended time-windows