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.

The Lower Jurassic (Toarcian) Posidonienschiefer Formation of southwestern Germany is a classic konservat lagerstätte, yielding some of the world’s best-preserved fossils of marine vertebrates, including ichthyosaurs, thalattosuchian crocodylomorphs, plesiosaurs and fishes. Despite numerous studies concentrating on the taphonomy of ichthyosaurs in this formation, less taphonomic work has focussed on the thalattosuchians of the assemblage. Multiple thalattosuchian species displaying a wide range of body sizes have been recovered. We investigated indicators for seafloor arrival position in thirteen Macrospondylus bollensis and one Platysuchus multiscrobiculatus specimens representing various body sizes using three-dimensional (3D) photogrammetric models. False-colour depth maps were used to interpret the relative topography (depth level) of bone penetration into the sediment and were aligned on the XY plane, making them parallel to the stratigraphic plane. Our results show both headfirst and non-headfirst seafloor arrivals in observed specimens, with headfirst seafloor arrivals exhibiting deeply buried skulls, displacement of select cervical vertebrae and/or characteristic fractures in the cranium and mandible. We (1) interpret seafloor landing types in teleosauroids; (2) recognize and list specific characteristics that are consistently attributed to either a headfirst or non-headfirst seafloor arrival; (3) discuss possible factors that may have contributed to these features, such as body shape and size, substrate and velocity; and (4) provide a new definition for headfirst seafloor arrival that can be readily attributed to other marine vertebrates from various formations. Lastly, our results show that observers must carefully consider how historical specimens might have been prepared, as this may influence taphonomic interpretations.

Behavioral treatments can help people with human immunodeficiency virus (HIV) improve their quality of life and treatment adherence. In Lesotho, where a fifth of adults live with HIV and depression and harmful alcohol use is prevalent among this group, little is known about the local suitability of established behavioral treatment strategies. We explored preferences regarding two strategies evaluated in other settings: involving phones and trusted individuals in treatment. We thematically analyzed 28 semi-structured interviews with potential service users receiving routine HIV care in the Butha-Buthe and Mokhotlong districts. Key concerns included the feasibility of phone-based treatment in rural areas and issues of limited literacy, electricity and network coverage. Others highlighted potential benefits for younger and working individuals for phone-based treatment, preferring calls over texts. Involving trusted individuals in treatment was favored, as this could foster support and accountability. Behavioral issues related to depression and alcohol use were viewed as complex, requiring face-to-face attention from trusted professionals, such as nurses and counselors, who were seen as knowledgeable and capable of maintaining confidentiality. Peer providers were not favored due to privacy concerns. These findings emphasize the need for face-to-face, confidential and health worker-led approaches for integrating behavioral treatment into HIV care in Lesotho.

This paper discusses the propagation of coastal currents generated by a river outflow using a 1 ${1}/{2}$-layer, quasigeostrophic model, following Johnson et al. (2017) (JSM17). The model incorporates two key physical processes: Kelvin-wave-generated flow and vortical advection along the coast. We extend JSM17 by deriving a fully nonlinear, long-wave, dispersive equation governing the evolution of the coastal current width. Numerical solutions show that, at large times, the flow behaviour divides naturally into three regimes: a steady outflow region, intermediate regions consisting of constant-width steady currents and unsteady propagating fronts leading the current. The widths of the steady currents depend strongly on dispersion when the constant outflow potential-vorticity anomaly is negative. Simulations using contour dynamics show that the dispersive equation captures the full quasigeostrophic behaviour more closely than JSM17 and give accurate bounds on the widths of the steady currents.

This manuscript revisits the history of American highway policy from the perspective of the powerful institution at its core: a confederation of state highway departments able to cut through partisan and sectional divides in Congress with two powerful claims: they represent both the advice of experts and the will of the states. After documenting their role in the development of the American highway system, the manuscript applies this perspective to current policy developments with an emphasis on the potential reauthorization of the Bipartisan Infrastructure Act of 2021, scheduled to expire at the end of fiscal year 2026. The manuscript concludes that the intersection of a looming fiscal crisis with the climate crisis creates the opportunity for this still powerful institution to launch a sustained transition away from fossil fuels, with impacts significantly beyond this policy realm.

The description and delineation of trematode species is a major ongoing task. Across the field there has been, and currently still is, great variation in the standard of this work and in the sophistication of the proposal of taxonomic hypotheses. Although most species are relatively unambiguously distinct from their congeners, many are either morphologically very similar, including the major and rapidly growing component of cryptic species, or are highly variable morphologically despite little to no molecular variation for standard DNA markers. Here we review challenges in species delineation in the context provided to us by the historical literature, and the use of morphological, geographical, host, and molecular data. We observe that there are potential challenges associated with all these information sources. As a result, we encourage careful proposal of taxonomic hypotheses with consideration for underlying species concepts and frank acknowledgement of weaknesses or conflict in the data. It seems clear that there is no single source of data that provides a wholly reliable answer to our taxonomic challenges but that nuanced consideration of information from multiple sources (the ‘integrated approach’) provides the best possibility of developing hypotheses that will stand the test of time.

Objectives/Goals: This continuous quality improvement project focuses on the efficiency and effectiveness of social media campaigns for clinical trials and other health research. We analyzed data from 160 studies that recruited via social media campaigns on Meta and used the results to make improvements to MICHR’s Participant Recruitment social media campaigns. Methods/Study Population: Data on 440 ad buys purchased for Meta advertising campaigns designed for 160 studies were collected from U-M’s Research Data Warehouse, Meta, and other administrative sources. MICHR’s participant recruitment team systematically reviewed these data and rated the relevance and effectiveness of the recruitment strategies for each study. Stepwise linear regressions were used to test predictors of the efficiency and effectiveness of social media campaigns on Meta, as measured by the 1) total reach, 2) total clicks, 3) the “click-through rate,” and 4) cost per “click” of the campaign over time. Differences between the impact of campaigns for clinical trials and other clinical and translational research were found. Improvement initiatives informed by these results are underway and their impact is being evaluated. Results/Anticipated Results: 64 clinical trials and 94 non-trials were identified, with an average of $1,635 spent on social media campaigns for trials and $950 spent on non-trials. Across all social media campaigns, an average of 121,500 people were reached at a total cost of $1,220 per campaign, returning 4,288 clicks (4% click through rate) at $0.38 per click. The campaigns for trials reached more people than non-trials (152,998 vs. 101,261) and they attracted a larger number of clicks (6090 vs. 3106). The resulting average click-through rate was higher for clinical trials (4.9% vs. 3.7%), and the cost per click was lower ($0.35 vs. $0.39). Campaigns for clinical trials cost significantly more (Mean  =  $1,635, SD  =  $1,473, p  =  .020) but returned more clicks (Mean  =  6,090, SD  =  5,105, p  =  .007), and higher click-through rates (Mean  =  4.9%, SD  =  2.2%, p  =  .017). Discussion/Significance of Impact: There is great variation in the efficiency and effectiveness of social media advertising campaigns for recruitment into clinical trials and other clinical and translational studies. While the size and cost of these campaigns were found to be higher for clinical trials than for non-trials, the effectiveness of trials’ campaigns can also be greater.

The current study examines the application of the Pediatric-Buccal-Epigenetic (PedBE) clock, designed for buccal epithelial cells, to endothelia. We evaluate the association of PedBE epigenetic age and age acceleration estimated from human umbilical vein endothelial cells (HUVECs) with length of gestation and birthweight in a racially and ethnically diverse sample (analytic sample n = 333). PedBE age was positively associated with gestational age at birth (r = 0.22, p < .001) and infant birth weight (r = 0.20, p < .001). Multivariate models revealed infants with higher birth weight (adjusted for gestational age) had greater PedBE epigenetic age acceleration (b = 0.0002, se = 0.0007, p = 0.002), though this effect was small; findings were unchanged excluding preterm infants born before 37 weeks’ gestation. In conclusion, the PedBE clock may have application to endothelial cells and provide utility as an anchoring sampling point at birth to examine epigenetic aging in infancy.

Conscious but incapacitated patients need protection from both undertreatment and overtreatment, for they are exceptionally vulnerable, and dependent on others to act in their interests. In the United States, the law prioritizes autonomy over best interests in decision making. Yet U.S. courts, using both substituted judgment and best interests decision making standards, frequently prohibit the withdrawal of life-sustaining treatment from conscious but incapacitated patients, such as those in the minimally conscious state, even when ostensibly seeking to determine what patients would have wanted. In the United Kingdom, under the Mental Capacity Act of 2005, courts decide on the best interests of incapacitated patients by, in part, taking into account the past wishes and values of the patient. This paper examines and compares those ethicolegal approaches to decision making on behalf of conscious but incapacitated patients. We argue for a limited interpretation of best interests such that the standard is properly used only when the preferences of a conscious, but incapacitated patient are unknown and unknowable. When patient preferences and values are known or can be reasonably inferred, using a holistic, all-things-considered substituted judgment standard respects patient autonomy.

A computational short cut suggested by Feldman and Klinger for the one-sided Fisher-Yates exact test is clarified and is extended to the calculation of probability values for certain two-sided tests when sample sizes are unequal.

Proof is given for a theorem stated but not proved by Eckart and Young in 1936, which has assumed considerable importance in the theory of lower-rank approximations to matrices, particularly in factor analysis.