Auditory maturation and congenital hearing loss in NICU infants

The number of preterm births has increased over the past decades as a result of increasing maternal age and in vitro fertilization (1). At the same time the survival of preterm infants has increased due to advances in perinatal and neonatal care. For example, antenatal corticosteroids for women with threatened preterm delivery, high-frequency oscillatory ventilation and inhaled nitric oxide have now become standard therapy (1). Unfortunately, these improvements sometimes come at a price. Neonatal intensive care unit (NICU) survivors have an increased risk of neurodevelopmental impairment, such as cerebral palsy, cognitive delay, blindness and deafness (2). Infants admitted to the NICU have an increased risk of congenital (present at birth) and acquired hearing loss compared to infants admitted to the well-baby nursery (3). Multiple risk factors have been associated with congenital hearing loss (Table 1) (4). Many of these risk factors occur in daily NICU care. The increased knowledge of the etiology of congenital hearing loss has put the emphasis not only on treating, but also on preventing congenital hearing loss. For example, bilirubin serum levels are kept within a very strict range in NICU infants. While prevention may not always be possible, the increased awareness has resulted in earlier diagnosis and careful counseling. Between 2002 and 2006 the universal newborn hearing screening (UNHS) program was introduced in the Netherlands. This has resulted in earlier identification and referral of infants with congenital hearing loss. Several studies have shown that early and adequate intervention of infants with congenital hearing loss minimizes future problems with speech and language development (5-6). Treatment before the age of six months results in better speech and language development at school age

STROOPWAFEL: Simulating rare outcomes from astrophysical populations, with application to gravitational-wave sources

Gravitational-wave observations of double compact object (DCO) mergers are providing new insights into the physics of massive stars and the evolution of binary systems. Making the most of expected near-future observations for understanding stellar physics will rely on comparisons with binary population synthesis models. However, the vast majority of simulated binaries never produce DCOs, which makes calculating such populations computationally inefficient. We present an importance sampling algorithm, STROOPWAFEL, that improves the computational efficiency of population studies of rare events, by focusing the simulation around regions of the initial parameter space found to produce outputs of interest. We implement the algorithm in the binary population synthesis code COMPAS, and compare the efficiency of our implementation to the standard method of Monte Carlo sampling from the birth probability distributions. STROOPWAFEL finds $\sim$25-200 times more DCO mergers than the standard sampling method with the same simulation size, and so speeds up simulations by up to two orders of magnitude. Finding more DCO mergers automatically maps the parameter space with far higher resolution than when using the traditional sampling. This increase in efficiency also leads to a decrease of a factor $\sim$3-10 in statistical sampling uncertainty for the predictions from the simulations. This is particularly notable for the distribution functions of observable quantities such as the black hole and neutron star chirp mass distribution, including in the tails of the distribution functions where predictions using standard sampling can be dominated by sampling noise.Comment: Accepted. Data and scripts to reproduce main results is publicly available. The code for the STROOPWAFEL algorithm will be made publicly available. Early inquiries can be addressed to the lead autho

Common-Envelope Episodes that lead to Double Neutron Star formation

Close double neutron stars have been observed as Galactic radio pulsars, while their mergers have been detected as gamma-ray bursts and gravitational-wave sources. They are believed to have experienced at least one common-envelope episode during their evolution prior to double neutron star formation. In the last decades there have been numerous efforts to understand the details of the common-envelope phase, but its computational modelling remains challenging. We present and discuss the properties of the donor and the binary at the onset of the Roche-lobe overflow leading to these common-envelope episodes as predicted by rapid binary population synthesis models. These properties can be used as initial conditions for detailed simulations of the common-envelope phase. There are three distinctive populations, classified by the evolutionary stage of the donor at the moment of the onset of the Roche-lobe overflow: giant donors with fully-convective envelopes, cool donors with partially-convective envelopes, and hot donors with radiative envelopes. We also estimate that, for standard assumptions, tides would not circularise a large fraction of these systems by the onset of Roche-lobe overflow. This makes the study and understanding of eccentric mass-transferring systems relevant for double neutron star populations.Comment: 26 pages, 10 figures. Includes bug fix. Two new figures and an appendix adde

Incidence and clinical value of prolonged I–V interval in NICU infants after failing neonatal hearing screening

Infants admitted to neonatal intensive care units (NICUs) have a higher incidence of perinatal complications and delayed maturational processes. Parameters of the auditory brainstem response (ABR) were analyzed to study the prevalence of delayed auditory maturation or neural pathology. The prevalence of prolonged I–V interval as a measure of delayed maturation and the correlation with ABR thresholds were investigated. All infants admitted to the NICU Sophia Children’s Hospital between 2004 and 2009 who had been referred for ABR measurement after failing neonatal hearing screening with automated auditory brainstem response (AABR) were included. The ABR parameters were retrospectively analyzed. Between 2004 and 2009, 103 infants were included: 46 girls and 57 boys. In 58.3% (60 infants) of our population, the I–V interval was recordable in at least one ear at first diagnostic ABR measurement. In 4.9%, the I–V interval was severely prolonged. The median ABR threshold of infants with a normal or mildly prolonged I–V interval was 50 dB. The median ABR threshold of infants with a severely prolonged I–V interval was 30 dB. In conclusion, in case both peak I and V were measurable, we found only a limited (4.9%) incidence of severely prolonged I–V interval (≥0.8 ms) in this high-risk NICU population. A mild delay in maturation is a more probable explanation than major audiologic or neural pathology, as ABR thresholds were near normal in these infants

Impact of Massive Binary Star and Cosmic Evolution on Gravitational Wave Observations I: Black Hole-Neutron Star Mergers

Mergers of black hole-neutron star (BHNS) binaries have now been observed by GW detectors with the recent announcement of GW200105 and GW200115. Such observations not only provide confirmation that these systems exist, but will also give unique insights into the death of massive stars, the evolution of binary systems and their possible association with gamma-ray bursts, $r$-process enrichment and kilonovae. Here we perform binary population synthesis of isolated BHNS systems in order to present their merger rate and characteristics for ground-based GW observatories. We present the results for 420 different model permutations that explore key uncertainties in our assumptions about massive binary star evolution (e.g. mass transfer, common-envelope evolution, supernovae), and the metallicity-specific star formation rate density, and characterize their relative impacts on our predictions. We find intrinsic local BHNS merger rates spanning $\mathcal{R}_{\rm{m}}^0 \approx 4$-$830\,\rm{Gpc}^{-3}\,\rm{yr}^{-1}$ for our full range of assumptions. This encompasses the rate inferred from recent BHNS GW detections, and would yield detection rates of $\mathcal{R}_{\rm{det}} \approx 1$-$180\, \rm{yr}^{-1}$ for a GW network consisting of LIGO, Virgo and KAGRA at design sensitivity. We find that the binary evolution and metallicity-specific star formation rate density each impact the predicted merger rates by order $\mathcal{O}(10)$. We also present predictions for the GW detected BHNS merger properties and find that all 420 model variations predict that $\lesssim 5\%$ of the BHNS mergers have BH masses $\gtrsim 18\,M_{\odot}$, total masses $\gtrsim 20\,M_{\odot}$, chirp masses $\gtrsim 5.5\,M_{\odot}$, mass ratios $\gtrsim 12$ or $\lesssim 2$. Moreover, we find that massive NSs $\gtrsim 2\,M_{\odot}$ are expected to be commonly detected in BHNS mergers in almost all our model variations.Comment: 38 pages, 18 figures, accepted to MNRAS. The authors welcome suggestions and feedback. All data and code to reproduce the results in this paper are publicly availabl

In Reply: Neoadjuvant TKI Study in Early- and Intermediate Stage Hepatocellular Carcinoma

This letter to the editor responds to comments from Rizzo et al on recently reported results of a phase II study of dovitinib therapy for hepatocellular carcinoma.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Development and validation of a dynamic survival prediction model for patients with acute-on-chronic liver failure

Background & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality. Current prediction models fail to adequately estimate prognosis and need for liver transplantation (LT) in ACLF. This study develops and validates a dynamic prediction model for patients with ACLF that uses both longitudinal and survival data.Methods: Adult patients on the UNOS waitlist for LT between 11.01.2016-31.12.2019 were included. Repeated model for end-stage liver disease-sodium (MELD-Na) measurements were jointly modelled with Cox survival analysis to develop the ACLF joint model (ACLF-JM). Model validation was carried out using separate testing data with area under curve (AUC) and prediction errors. An online ACLF-JM tool was created for clinical application.Results: In total, 30,533 patients were included. ACLF grade 1 to 3 was present in 16.4%, 10.4% and 6.2% of patients, respectively. The ACLF-JM predicted survival significantly (p <0.001) better than the MELD-Na score, both at baseline and during follow-up. For 28- and 90-day predictions, ACLF-JM AUCs ranged between 0.840-0.871 and 0.833-875, respectively. Compared to MELD-Na, AUCs and prediction errors were improved by 23.1%-62.0% and 5%-37.6% respectively. Also, the ACLF-JM could have prioritized patients with relatively low MELD-Na scores but with a 4-fold higher rate of waiting list mortality.Conclusions: The ACLF-JM dynamically predicts outcome based on current and past disease severity. Prediction performance is excellent over time, even in patients with ACLF-3. Therefore, the ACLF-JM could be used as a clinical tool in the evaluation of prognosis and treatment in patients with ACLF.Lay summary: Acute-on-chronic liver failure (ACLF) progresses rapidly and often leads to death. Liver transplantation is used as a treatment and the sickest patients are treated first. In this study, we develop a model that predicts survival in ACLF and we show that the newly developed model performs better than the currently used model for ranking patients on the liver transplant waiting list. (C) 2021 The Author(s). Published by Elsevier B.V.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of Heart Failure with Preserved Ejection Fraction

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. METHODS & RESULTS: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. CONCLUSIONS: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF. TRANSLATIONAL PERSPECTIVE: The failure of many treatment modalities for HFpEF may -at least in part- be explained by the lack of an adequate animal model. The diverse etiology of HFpEF is still largely neglected in pre-clinical research. In this study we developed a murine model that includes advanced age, female sex, in concert with co-morbidities: elevated blood pressure, obesity and T2DM. We demonstrate that this model recapitulates the human cardiometabolic HFpEF phenotype. We showed that contemporary glucose lowering drugs, liraglutide and dapagliflozin, which are both under study for HFpEF, have positive results. Our model may be useful to evaluate novel cardiometabolic, anti-fibrotic, and anti-inflammatory treatments for HFpEF