Sickle Cell Disease Treatment with Arginine Therapy (STArT): Study protocol for a phase 3 randomized controlled trial

BACKGROUND: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. METHODS: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant\u27s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. DISCUSSION: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. TRIAL REGISTRATION: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354)

Do deep neural networks have an inbuilt Occam's razor?

The remarkable performance of overparameterized deep neural networks (DNNs) must arise from an interplay between network architecture, training algorithms, and structure in the data. To disentangle these three components, we apply a Bayesian picture, based on the functions expressed by a DNN, to supervised learning. The prior over functions is determined by the network, and is varied by exploiting a transition between ordered and chaotic regimes. For Boolean function classification, we approximate the likelihood using the error spectrum of functions on data. When combined with the prior, this accurately predicts the posterior, measured for DNNs trained with stochastic gradient descent. This analysis reveals that structured data, combined with an intrinsic Occam's razor-like inductive bias towards (Kolmogorov) simple functions that is strong enough to counteract the exponential growth of the number of functions with complexity, is a key to the success of DNNs

Gedanken Worlds without Higgs: QCD-Induced Electroweak Symmetry Breaking

To illuminate how electroweak symmetry breaking shapes the physical world, we investigate toy models in which no Higgs fields or other constructs are introduced to induce spontaneous symmetry breaking. Two models incorporate the standard SU(3)_c x SU(2)_L x U(1)_Y gauge symmetry and fermion content similar to that of the standard model. The first class--like the standard electroweak theory--contains no bare mass terms, so the spontaneous breaking of chiral symmetry within quantum chromodynamics is the only source of electroweak symmetry breaking. The second class adds bare fermion masses sufficiently small that QCD remains the dominant source of electroweak symmetry breaking and the model can serve as a well-behaved low-energy effective field theory to energies somewhat above the hadronic scale. A third class of models is based on the left-right--symmetric SU(3)_c x SU(2)_L x SU(2)_R x U(1)_{B-L} gauge group. In a fourth class of models, built on SU(4)_{PS} x SU(2)_L x SU(2)_R gauge symmetry, lepton number is treated as a fourth color. Many interesting characteristics of the models stem from the fact that the effective strength of the weak interactions is much closer to that of the residual strong interactions than in the real world. The Higgs-free models not only provide informative contrasts to the real world, but also lead us to consider intriguing issues in the application of field theory to the real world.Comment: 20 pages, no figures, uses RevTeX; typos correcte

Minkowski's Object: A Starburst Triggered by a Radio Jet, Revisited

We present neutral hydrogen, ultraviolet, optical and near-infrared imaging, and optical spectroscopy, of Minkowski's Object (MO), a star forming peculiar galaxy near NGC 541. The observations strengthen evidence that star formation in MO was triggered by the radio jet from NGC 541. Key new results are the discovery of a 4.9E8 solar mass double HI cloud straddling the radio jet downstream from MO, where the jet changes direction and decollimates; strong detections of MO, also showing double structure, in UV and H-alpha; and numerous HII regions and associated clusters in MO. In UV, MO resembles the radio-aligned, rest-frame UV morphologies in many high redshift radio galaxies (HzRGs), also thought to be caused by jet-induced star formation. MO's stellar population is dominated by a 7.5 Myr-old, 1.9E7 solar mass instantaneous burst, with current star formation rate 0.52 solar masses per year (concentrated upstream from where the HI column density is high). This is unlike the jet-induced star formation in Centaurus A, where the jet interacts with pre-existing cold gas; in MO the HI may have cooled out of a warmer, clumpy intergalactic or interstellar medium as a result of jet interaction, followed by collapse of the cooling clouds and subsequent star formation (consistent with numerical simulations). Since the radio source that triggered star formation in MO is much less luminous, and therefore more common, than powerful HzRGs, and because the environment around MO is not particularly special in terms of abundant dense, cold gas, jet-induced star formation in the early universe might be even more prevalent than previously thought.Comment: 52 pages, 15 figures, accepted for publication in Ap

Magnetohydrodynamic Simulations of Shock Interactions with Radiative Clouds

We present results from two-dimensional numerical simulations of the interactions between magnetized shocks and radiative clouds. Our primary goal is to characterize the dynamical evolution of the shocked clouds. We perform runs in both the strong and weak magnetic field limits and consider three different field orientations. For the geometries considered, we generally find that magnetic fields external to, but concentrated near, the surface of the cloud suppress the growth of destructive hydrodynamic instabilities. External fields also increase the compression of the cloud by effectively acting as a confinement mechanism driven by the interstellar flow and local field stretching. This can have a dramatic effect on both the efficiency of radiative cooling, which tends to increase with increasing magnetic field strength, and on the size and distribution of condensed cooled fragments. In contrast, fields acting predominately internally to the cloud tend to resist compression, thereby inhibiting cooling. We observe that, even at modest strengths, internal fields can completely suppress low-temperature cooling.Comment: 21 pages, 9 figures, to appear in The Astrophysical Journa

Computerised speechreading training for deaf children: A randomised controlled trial

Purpose: We developed and evaluated in a randomised controlled triala computerised speechreading training programme to determine a) whether it is possible to train speechreading in deaf children and b) whether speechreading training results in improvements in phonological and reading skills.Previous studies indicate a relationship between speechreading and reading skill and further suggest this relationshipmay be mediated by improved phonological representations. This is important since many deaf children find learning to read to be very challenging. Method: Sixty-six deaf 5-7 year olds were randomised into speechreading and maths training arms. Each training programme was comprised of10 minutesessionsa day, 4 days a week for 12 weeks. Children were assessed on a battery of language and literacy measures before training, immediately after training, 3 months and 10 months after training. Results: We found no significant benefits for participants who completed the speechreading training, compared to those who completed the maths training, on the speechreading primary outcome measure. However, significantly greater gains were observed in the speechreading training group on one of the secondary measures of speechreading. There was also some evidence of beneficial effects of the speechreading training on phonological representations, however these effects were weaker. No benefits were seen toword reading. Conclusions: Speechreading skill is trainable in deaf children. However, to support early reading, training may need to be longer or embedded in a broader literacy programme. Nevertheless, a training tool that can improve speechreading is likely to be of great interest to professionals working with deaf children

Young stars and non-stellar emission in the aligned radio galaxy 3C 256

We present ground-based images of the z=1.824 radio galaxy 3C 256 in the standard BVRIJHK filters and an interference filter centered at 8800A, a Hubble Space Telescope image in a filter dominated by Ly-alpha emission (F336W), and spectra covering rest-frame wavelengths from Ly-alpha to [O III] 5007. Together with published polarimetry observations, we use these to decompose the overall spectral energy distribution into nebular continuum emission, scattered quasar light, and stellar emission. The nebular continuum and scattered light together comprise half (one third) of the V-band (K-band) light within a 4-arcsec aperture, and are responsible for the strong alignment between the optical/near-infrared light and the radio emission. The stellar emission is dominated by a population estimated to be 100-200 Myr old (assuming a Salpeter IMF), and formed in a short burst with a peak star formation rate of 1-4x10^3 Msun/yr. The total stellar mass is estimated to be no more than 2x10^{11} Msun, which is far less than other luminous radio galaxies at similar redshifts, and suggests that 3C 256 will undergo further star formation or mergers.Comment: 35 pages including 10 figures; to appear in Nov 10 Ap

Catchment land use effects on fluxes and concentrations of organic and inorganic nitrogen in streams

We present annual downstream fluxes and spatial variation in concentrations of dissolved inorganic nitrogen (NH4+ and NO3−) and dissolved organic nitrogen (DON) in two adjacent Scottish catchments with contrasting land use (agricultural grassland vs. semi-natural moorland). Inter- and intra-catchment variation in N species and the relation to spatial differences in agricultural land use were studied by determining catchment N input through agricultural activities at the field scale and atmospheric inputs at a 25 m grid resolution. The average agricultural N input of 52 kg N ha−1 yr−1 to the grassland catchment was more than 4 times higher than the input of 12 kg N ha−1 yr−1 to the moorland catchment, supplemented by 12.3 and 8.2 kg N ha−1 yr−1 through atmospheric deposition, respectively. The grassland catchment was associated with an annual downstream total dissolved nitrogen (TDN) flux of 14.4 kg N ha−1 yr−1, which was 66% higher than the flux of 8.7 kg ha−1 yr−1 from the moorland catchment. This difference was largely due to the NO3− flux being one order of magnitude higher in the grassland catchment. Dissolved organic N fluxes were similar for the two catchments (7.0 kg ha−1 yr−1) with DON contributing 49% to the TDN flux in the grassland compared with 81% in the moorland catchment. The results highlight the importance of diffuse agricultural N inputs to stream NO3− concentrations and the importance of quantifying all the major aquatic N species for developing a better understanding of N transformations and transport in the atmosphere-soil-water system

Heterogeneity of atmospheric ammonia at the landscape scale and consequences for environmental impact assessment

We examined the consequences of the spatial heterogeneity of atmospheric ammonia (NH3) by measuring and modelling NH3 concentrations and deposition at 25 m grid resolution for a rural landscape containing intensive poultry farming, agricultural grassland, woodland and moorland. The emission pattern gave rise to a high spatial variability of modelled mean annual NH3 concentrations and dry deposition. Largest impacts were predicted for woodland patches located within the agricultural area, while larger moorland areas were at low risk, due to atmospheric dispersion, prevailing wind direction and low NH3 background. These high resolution spatial details are lost in national scale estimates at 1 km resolution due to less detailed emission input maps. The results demonstrate how the spatial arrangement of sources and sinks is critical to defining the NH3 risk to semi-natural ecosystems. These spatial relationships provide the foundation for local spatial planning approaches to reduce environmental impacts of atmospheric NH3

Delivering clinical studies of exercise in the COVID-19 pandemic: challenges and adaptations using a feasibility trial of isometric exercise to treat hypertension as an exemplar.

The COVID-19 pandemic has significantly impacted on the delivery of clinical trials in the UK, posing complicated organisational challenges and requiring adaptations, especially to exercise intervention studies based in the community. We aim to identify the challenges of public involvement, recruitment, consent, follow-up, intervention and the healthcare professional delivery aspects of a feasibility study of exercise in hypertensive primary care patients during the COVID-19 pandemic. While these challenges elicited many reactive changes which were specific to, and only relevant in the context of 'lockdown' requirements, some of the protocol developments that came about during this unprecedented period have great potential to inform more permanent practices for carrying out this type of research. To this end, we detail the necessary adaptations to many elements of the feasibility study and critically reflect on our approach to redesigning and amending this ongoing project in order to maintain its viability to date. Some of the more major protocol adaptations, such as moving the study to remote means wherever possible, had further unforeseen and undesirable outcomes (eg, additional appointments) with regards to extra resources required to deliver the study. However, other changes improved the efficiency of the study, such as the remote informed consent and the direct advertising with prescreening survey. The adaptations to the study have clear links to the UK Plan for the future of research delivery. It is intended that this specific documentation and critical evaluation will help those planning or delivering similar studies to do so in a more resource efficient and effective way. In conclusion, it is essential to reflect and respond with protocol changes in the current climate in order to deliver clinical research successfully, as in the case of this particular study. [Abstract copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.