Background: Late-onset Pompe disease (LOPD) is caused by a deficiency of acid α-glucosidase (GAA), leading to progressive muscle and respiratory decline. Cipaglucosidase alfa (cipa), a recombinant human GAA naturally enriched with bis-mannose-6-phosphate, exhibits improved muscle uptake but is limited by inactivation at near-neutral blood pH. Miglustat (mig), an enzyme stabiliser, binds competitively and reversibly to cipa, enhancing its stability and activity. Methods: In dose-finding studies, Gaa-/- mice were treated with cipa (20 mg/kg) +/- mig (10 mg/kg; equivalent human dose ~260 mg). Clinical study methodologies have been published (Schoser et al. Lancet Neurol 2021:20;1027–37; Schoser et al. J Neurol 2024:271;2810–23). Results: In Gaa-/- mice, cipa+mig improved muscle glycogen reduction more than cipa alone and grip strength to levels approaching wild-type mice. LOPD patients (n=11) treated with cipa alone showed dose-dependent decreases in hexose tetrasaccharide (Hex4) levels by ~15% from baseline, decreasing another ~10% with added mig (260 mg). In a head-to-head study, cipa+mig had a similar safety profile to alglucosidase alfa. Among 151 patients (three trials), mig-related adverse events occurred in 21 (13.9%), none serious. Conclusions: Mig stabilised cipa in circulation, improving cipa exposure, further reducing Hex4 levels and was well tolerated in clinical studies in patients with LOPD. Sponsored by Amicus Therapeutics, Inc.

Response times on test items are easily collected in modern computerized testing. When collecting both (binary) responses and (continuous) response times on test items, it is possible to measure the accuracy and speed of test takers. To study the relationships between these two constructs, the model is extended with a multivariate multilevel regression structure which allows the incorporation of covariates to explain the variance in speed and accuracy between individuals and groups of test takers. A Bayesian approach with Markov chain Monte Carlo (MCMC) computation enables straightforward estimation of all model parameters. Model-specific implementations of a Bayes factor (BF) and deviance information criterium (DIC) for model selection are proposed which are easily calculated as byproducts of the MCMC computation. Both results from simulation studies and real-data examples are given to illustrate several novel analyses possible with this modeling framework.

Inhibitory control plays an important role in children’s cognitive and socioemotional development, including their psychopathology. It has been established that contextual factors such as socioeconomic status (SES) and parents’ psychopathology are associated with children’s inhibitory control. However, the relations between the neural correlates of inhibitory control and contextual factors have been rarely examined in longitudinal studies. In the present study, we used both event-related potential (ERP) components and time-frequency measures of inhibitory control to evaluate the neural pathways between contextual factors, including prenatal SES and maternal psychopathology, and children’s behavioral and emotional problems in a large sample of children (N = 560; 51.75% females; Mage = 7.13 years; Rangeage = 4–11 years). Results showed that theta power, which was positively predicted by prenatal SES and was negatively related to children’s externalizing problems, mediated the longitudinal and negative relation between them. ERP amplitudes and latencies did not mediate the longitudinal association between prenatal risk factors (i.e., prenatal SES and maternal psychopathology) and children’s internalizing and externalizing problems. Our findings increase our understanding of the neural pathways linking early risk factors to children’s psychopathology.

Magnetic reconnection is an important process in astrophysical environments, as it reconfigures magnetic field topology and converts magnetic energy into thermal and kinetic energy. In extreme astrophysical systems, such as black hole coronae and pulsar magnetospheres, radiative cooling modifies the energy partition by radiating away internal energy, which can lead to the radiative collapse of the reconnection layer. In this paper, we perform two- and three-dimensional simulations to model the MARZ (Magnetic Reconnection on Z) experiments, which are designed to access cooling rates in the laboratory necessary to investigate reconnection in a previously unexplored radiatively cooled regime. These simulations are performed in GORGON, an Eulerian two-temperature resistive magnetohydrodynamic code, which models the experimental geometry comprising two exploding wire arrays driven by 20 MA of current on the Z machine (Sandia National Laboratories). Radiative losses are implemented using non-local thermodynamic equilibrium tables computed using the atomic code Spk, and we probe the effects of radiation transport by implementing both a local radiation loss model and $P_{1/3}$ multi-group radiation transport. The load produces highly collisional, super-Alfvénic (Alfvén Mach number $M_A \approx 1.5$), supersonic (Sonic Mach number $M_S \approx 4-5$) strongly driven plasma flows which generate an elongated reconnection layer (Aspect Ratio $L/\delta \approx 100$, Lundquist number $S_L \approx 400$). The reconnection layer undergoes radiative collapse when the radiative losses exceed the rates of ohmic and compressional heating (cooling rate/hydrodynamic transit rate = $\tau _{\text {cool}}^{-1}/\tau _{H}^{-1}\approx 100$); this generates a cold strongly compressed current sheet, leading to an accelerated reconnection rate, consistent with theoretical predictions. Finally, the current sheet is also unstable to the plasmoid instability, but the magnetic islands are extinguished by strong radiative cooling before ejection from the layer.

The carotid artery is unique; it is the only vessel to bifurcate into a bulb larger than itself. The history of its anatomic description, understanding of its pathophysiology and evolution of its imaging are relevant to current controversies regarding measurement of stenosis, surgical/endovascular therapies and medical management of carotid stenosis in stroke prevention. Treatment decisions on millions of symptomatic and asymptomatic patients are routinely based on information from clinical trials from over 30 years ago. This article briefly summarizes the highlights of past research in key areas and discuss how they led to current challenges of diagnosis and treatment.

Organisational priorities for health care focus on efficiency as the health and care needs of populations increase. But evidence suggests that excessive planning can be counterproductive, leading to resistance from staff and patients, particularly those living with cognitive impairment. The current paper adds to this debate reporting an Institutional Ethnography of staff delivering care for older patients with cognitive impairment on acute orthopaedic wards in three National Health Service hospitals in the United Kingdom. A key problematic identified in this study is the point of disjuncture seen between the actualities of staff experience and intentions of protocols and policies. We identified three forms of disjuncture typified as: ‘disruptions’, where sequenced care was interrupted by patient events; ‘discontinuities’, where divisions in professional culture, space or time interrupted sequenced tasks; and ‘dispersions’, where displaced objects or people interrupted sequenced care flow. Arguably disruption is an integral characteristic of care work; it follows that to enable staff to flourish, organisations need to confer staff the autonomy to address systemic disruptions rather than attempt to eradicate them. Ultimately, organisational representations of ‘good practice’ as readily joined up, impose a care standard ‘stereotype’ that obscures rather than clarifies the interactional problems encountered by staff.

OBJECTIVES/GOALS: Adolescents with congenital heart defects (CHD) have an elevated risk for future cardiovascular events, but information about their risk for e-cigarette use (“vaping”) is unknown. This study aims to present preliminary findings on gender differences in the association of impulsive behavior and vaping susceptibility from an ongoing investigation. METHODS/STUDY POPULATION: Adolescents with CHD (12-18 years; N=63) reported their vaping susceptibility and completed subjective (UPPS-P)/objective (Iowa Gambling Task; IGT) assessments of impulsive behavior previously associated with tobacco use. The UPPS-P includes 5 facets: 1) negative urgency (impulsivity under negative emotions), 2) positive urgency (impulsivity under positive emotions), 3) lack of premeditation (acting without thinking), 4) lack of perseverance (inability to focus), and 5) sensation seeking (seeking thrilling experiences). The IGT is a computerized task that creates conflict between immediate reward and delayed punishment via selections from advantageous/disadvantageous card decks. Linear regressions stratified by gender determined associations between vaping susceptibility and impulsivity. RESULTS/ANTICIPATED RESULTS: Nearly 30% (29.7%) of adolescents with CHD were susceptible to vaping. Negative urgency was associated with vaping susceptibility among females (β = 0.44, p = .035) but not males (β = 0.25, p = .128). Positive urgency was associated with vaping susceptibility among males (β = 0.37, p = .021) and trended toward significance among females (β = 0.40, p = .058). Lack of premeditation was associated with vaping susceptibility among males (β = 0.36, p = .025) but not females (β = 0.15, p = .490). The association between lack of perseverance and vaping susceptibility trended toward significance among males (β = 0.30, p = .064) but not females (β = -0.18, p = .413). IGT performance was not associated with susceptibility to vaping among either gender. UPPS-P facets and IGT performance were not significantly correlated. DISCUSSION/SIGNIFICANCE: The association of impulsivity and vaping susceptibility appears to be characterized by emotion-based rash action (positive/negative urgency) for females and by decreased conscientiousness (lack of premeditation/perseverance) for males. If replicated, the findings have implications for assessment of vaping risk and tailored intervention.

The Variables and Slow Transients Survey (VAST) on the Australian Square Kilometre Array Pathfinder (ASKAP) is designed to detect highly variable and transient radio sources on timescales from 5 s to $\sim\!5$ yr. In this paper, we present the survey description, observation strategy and initial results from the VAST Phase I Pilot Survey. This pilot survey consists of $\sim\!162$ h of observations conducted at a central frequency of 888 MHz between 2019 August and 2020 August, with a typical rms sensitivity of $0.24\ \mathrm{mJy\ beam}^{-1}$ and angular resolution of $12-20$ arcseconds. There are 113 fields, each of which was observed for 12 min integration time, with between 5 and 13 repeats, with cadences between 1 day and 8 months. The total area of the pilot survey footprint is 5 131 square degrees, covering six distinct regions of the sky. An initial search of two of these regions, totalling 1 646 square degrees, revealed 28 highly variable and/or transient sources. Seven of these are known pulsars, including the millisecond pulsar J2039–5617. Another seven are stars, four of which have no previously reported radio detection (SCR J0533–4257, LEHPM 2-783, UCAC3 89–412162 and 2MASS J22414436–6119311). Of the remaining 14 sources, two are active galactic nuclei, six are associated with galaxies and the other six have no multi-wavelength counterparts and are yet to be identified.

Perturbations to the gut microbiome are implicated in altered neurodevelopmental trajectories that may shape life span risk for emotion dysregulation and affective disorders. However, the sensitive periods during which the microbiome may influence neurodevelopment remain understudied. We investigated relationships between gut microbiome composition across infancy and temperament at 12 months of age. In 67 infants, we examined if gut microbiome composition assessed at 1–3 weeks, 2, 6, and 12 months of age was associated with temperament at age 12 months. Stool samples were sequenced using the 16S Illumina MiSeq platform. Temperament was assessed using the Infant Behavior Questionnaire-Revised (IBQ-R). Beta diversity at age 1–3 weeks was associated with surgency/extraversion at age 12 months. Bifidobacterium and Lachnospiraceae abundance at 1–3 weeks of age was positively associated with surgency/extraversion at age 12 months. Klebsiella abundance at 1–3 weeks was negatively associated with surgency/extraversion at 12 months. Concurrent composition was associated with negative affectivity at 12 months, including a positive association with Ruminococcus-1 and a negative association with Lactobacillus. Our findings support a relationship between gut microbiome composition and infant temperament. While exploratory due to the small sample size, these results point to early and late infancy as sensitive periods during which the gut microbiome may exert effects on neurodevelopment.

The onset of magnetic reconnection in space, astrophysical and laboratory plasmas is reviewed discussing results from theory, numerical simulations and observations. After a brief introduction on magnetic reconnection and approach to the question of onset, we first discuss recent theoretical models and numerical simulations, followed by observations of reconnection and its effects in space and astrophysical plasmas from satellites and ground-based detectors, as well as measurements of reconnection in laboratory plasma experiments. Mechanisms allowing reconnection spanning from collisional resistivity to kinetic effects as well as partial ionization are described, providing a description valid over a wide range of plasma parameters, and therefore applicable in principle to many different astrophysical and laboratory environments. Finally, we summarize the implications of reconnection onset physics for plasma dynamics throughout the Universe and illustrate how capturing the dynamics correctly is important to understanding particle acceleration. The goal of this review is to give a view on the present status of this topic and future interesting investigations, offering a unified approach.

Ocean fronts are an important submesoscale feature, yet frontogenesis theory often neglects turbulence – even parameterized turbulence – leaving theory lacking in comparison with observations and models. A perturbation analysis is used to include the effects of eddy viscosity and diffusivity as a first-order correction to existing strain-induced inviscid, adiabatic frontogenesis theory. A modified solution is obtained by using potential vorticity and surface conditions to quantify turbulent fluxes. It is found that horizontal viscosity and diffusivity tend to be readily frontolytic – reducing frontal tendency to negative values under weakly non-conservative perturbations and opposing or reversing front sharpening, whereas vertical viscosity and diffusivity tend to only weaken frontogenesis by slowing the rate of sharpening of the front even under strong perturbations. During late frontogenesis, vertical diffusivity enhances the rate of frontogenesis, although perturbation theory may be inaccurate at this stage. Surface quasi-geostrophic theory – neglecting all injected interior potential vorticity – is able to describe the first-order correction to the along-front velocity and ageostrophic overturning circulation in most cases. Furthermore, local conditions near the front maximum are sufficient to reconstruct the modified solution of both these fields.

In August 2015, Public Health England detected an outbreak of Shiga toxin-producing Escherichia coli (STEC) serotype O157:H7 caused by contaminated salad leaves in a mixed leaf prepacked salad product from a national retailer. The implicated leaves were cultivated at five different farms and the zoonotic source of the outbreak strain was not determined. In March 2016, additional isolates from new cases were identified that shared a recent common ancestor with the outbreak strain. A case–case study involving the cases identified in 2016 revealed that ovine exposures were associated with illness (n = 16; AOR 8·24; 95% CI 1·55–39·74). By mapping the recent movement of sheep and lambs across the United Kingdom, epidemiological links were established between the cases reporting ovine exposures. Given the close phylogenetic relationship between the outbreak strain and the isolates from cases with ovine exposures, it is plausible that ovine faeces may have contaminated the salad leaves via untreated irrigation water or run-off from fields nearby. Timely and targeted veterinary and environmental sampling should be considered during foodborne outbreaks of STEC, particularly where ready to eat vegetables and salads are implicated.