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Many questions remain about the prevalence and effects of SARS-CoV-2 infection in malaria-endemic African countries like Uganda, particularly in vulnerable groups such as pregnant women. We describe SARS-CoV-2 immunoglobulin (Ig)G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda. From December 2020-February 2022, among 400 unvaccinated pregnant women enrolled at 12-20 weeks gestation and followed through delivery, 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time, consistent with affinity maturation of the antibody response in the cohort. No women experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infect (-1.54 versus -0.37 and -0.51, P = 0.009). These findings suggest that pregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with transient shorter stature in early infancy. Further research should explore the significance of this finding and define targeted measures to prevent infection in pregnancy.

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

[This corrects the article DOI: 10.3389/fneur.2024.1451512.].

Enzyme replacement therapy (ERT) is the only approved disease-modifying treatment modality for Pompe disease, a rare, inherited metabolic disorder caused by a deficiency in the acid α-glucosidase (GAA) enzyme that catabolizes lysosomal glycogen. First-generation recombinant human GAA (rhGAA) ERT (alglucosidase alfa) can slow the progressive muscle degeneration characteristic of the disease. Still, most patients experience diminished efficacy over time, possibly because of poor uptake into target tissues. Next-generation ERTs aim to address this problem by increasing bis-phosphorylated high mannose (bis-M6P) N-glycans on rhGAA as these moieties have sufficiently high receptor binding affinity at the resultant low interstitial enzyme concentrations after dosing to drive uptake by the cation-independent mannose 6-phosphate receptor on target cells. However, some approaches introduce bis-M6P onto rhGAA via non-natural linkages that cannot be hydrolyzed by natural human enzymes and thus inhibit the endolysosomal glycan trimming necessary for complete enzyme activation after cell uptake. Furthermore, all rhGAA ERTs face potential inactivation during intravenous delivery (and subsequent non-productive clearance) as GAA is an acid hydrolase that is rapidly denatured in the near-neutral pH of the blood. One new therapy, cipaglucosidase alfa plus miglustat, is hypothesized to address these challenges by combining an enzyme enriched with naturally occurring bis-M6P N-glycans with a small-molecule stabilizer. Here, we investigate this hypothesis by analyzing published and new data related to the mechanism of action of the enzyme and stabilizer molecule. Based on an extensive collection of in vitro, preclinical, and clinical data, we conclude that cipaglucosidase alfa plus miglustat successfully addresses each of these challenges to offer meaningful advantages in terms of pharmacokinetic exposure, target-cell uptake, endolysosomal processing, and clinical benefit.

Abstract As plastic pollution exists in aquatic ecosystems globally, monitoring its abundance and distribution has become crucial for understanding transport pathways, sources, sinks, and impacts. Riverbanks are accumulation zones for plastic, but the selection of monitoring methods is constrained by research goals, available resources, and site-specific conditions. This diversity in approaches has led to disparate datasets, highlighting the need for standardized monitoring protocols. Here, we study the spatial distribution of plastic at the riverbank scale, quantify the uncertainty of existing riverbank methods, and provide recommendations for improved monitoring based on the balance between uncertainty loss and increase in effort. We measured riverbank plastic abundance at eight Dutch riverbanks, categorizing the items using 108 item categories (River-OSPAR). For every riverbank, an area of 100 by 25 meters was subdivided into five-by-five-meter squares, resulting in 100 individual monitored sub-areas. We found riverbank plastic exhibited high spatial variability, with deposition patterns ranging from parallel to the waterline to clustered, random, or uniform (Moran’s I between -0.050 and 0.301). Individual measurements from diverse sampling protocols are 5-49 times less accurate than estimates derived from extensive sampling, highlighting the diminishing impact of specific methods with increased data collection. Lastly, our findings suggest that increasing the sampling area quickly reaches diminishing returns in terms of accuracy. Reducing the sampled area by 80% only increases the uncertainty in estimating the true plastic density by 20%. While standardized protocols are essential for data comparability, a rigid, uniform sampling approach may be less efficient and resource-intensive than a flexible (step-wise) strategy that adapts to local conditions. By demonstrating that extensive sampling can mitigate the differences between unique sampling protocols, this study promotes a shift towards flexible and efficient riverbank plastic monitoring, ultimately accelerating global efforts to combat plastic pollution.

Abstract Clinical pathway recommendations (CPR) are based on existing guidelines and deliver a short overview on how to deal with a specific diagnosis, resulting therapy and follow-up. In this paper we propose a methodology for developing CPRs for Pompe disease, a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. The CPR document was developed within the activities of the MetabERN, a non-profit European Reference Network for Metabolic Diseases established by the European Union. A working group was selected among members of the MetabERN lysosomal storage disease subnetwork, with specific expertise in the care of Pompe disease, and patient support group representatives. The working strategy was based on a systematic literature search to develop a database, followed by quality assessment of the studies selected from the literature, and by the development of the CPR document according to a matrix provided by MetabERN. Quality assessment of the literature and collection of citations was conducted according to the AGREE II criteria and Grading of Recommendations, Assessment, Development and Evaluation methodology. General aspects were addressed in the document, including pathophysiology, genetics, frequency, classification, manifestations and clinical approach, laboratory diagnosis and multidisciplinary evaluation, therapy and supportive measures, follow-up, monitoring, and pregnancy. The CPR document that was developed was intended to be a concise and easy-to-use tool for standardization of care for patients among the healthcare providers that are members of the network or are involved in the care for Pompe disease patients.

Educational policies in the Netherlands reveal that the current mainstream participatory approach to citizenship education jeopardises students' autonomy. Especially in Dutch post-secondary vocational education, citizenship education has been shown to be mainly aimed at socialization: initiating students into tradition, internalising rules, societal norms and values. This article reports on the findings of a research project, which is grounded in the assumption that integrating "Bildung," citizenship education and critical thinking is a promising way to grapple with the perceived overemphasis on socialization strategies. We justify the interrelationship of critical thinking, "Bildung," citizenship education, and professional training from two perspectives -- historical and contemporary. It is only by combining these concepts, we contend, that educational professionals can create teaching materials more geared to developing autonomy, and prepare students in vocational training to navigate the political and societal dilemma's on the work floor. Furthermore, we also clarify our perspective by offering three educational principles, used in our project to guide the design of teaching materials, that form a context for integrating citizenship, critical thinking, and Bildung in vocational education. A practical illustration is subsequently discussed.

Sustainable and innovative programs to support students in their transition to university and improve student progress rates and retention are in high demand and short supply. An institution-wide model was established for an online Embedded Tutor Program. The program supports commencing undergraduate students and is sustainable post-pandemic. Tutors with unit-specific knowledge were embedded in 98 first-year unit offerings across the university in 2022. Tutors met with students via Zoom to provide feedforward on a written assessment. Of the 1080 students who met with a tutor, assessment marks were on average 8% higher and cumulative unit marks were 15% higher, and the one-on-one tutor support improved students' perceived confidence, overall learning and satisfaction. The Embedded Tutor Program had positive outcomes for all participants; however, students with multiple equity factors benefited the most from the support.

Universities actively promote themselves to potential students, control admissions and deliver programs of study. For most students globally, there are financial costs to attending university. At the extreme end of failure are students who receive 'zero-fails': they enrol, do not submit any assessments, and receive a mark of 0 out of 100. A quantitative descriptive analysis was performed and provides student performance details for bachelor-level students enrolled in a large, regional Australian university from 2019-2021. At a unit level, zero-fails accounted for 20% of all failing grades. There was a significant increase in zero-fail grades in 2020 and 2021 compared to 2019. However, zero-fails are not entirely a COVID-19 phenomenon. Only 8% of students who received any zero-fail grade in their commencing semester of study continued onto their second semester and passed most of their units. We argue universities operating in countries with deferred payment schemes such as Australia and the United Kingdom have a responsibility to track unit failure in finer detail and consider ways to mitigate debt associated with students who are clearly not receiving value from their educational experience. This must be done as we continue to expand higher education opportunities to students from non-traditional backgrounds.

Institutional commitment to the student experience in the early stages of university has the greatest potential to exceed student expectations. The cross-institutional Embedded Tutors Program provides undergraduate students with access to subject content experts from 12 first-year subjects across a regional university. Tutors provide one-on-one draft assessment feedback in subjects with a large written assessment task. A total of 428 students attended 615 tutor sessions held online via Zoom. Students who met with a tutor had higher average assessment marks and cumulative subject marks than those students who did not attend a session. Feedback from students was positive, with 78% of students rating the tutor session "extremely helpful." This study provides evidence of the value of subject-specific draft assessment feedback for students in first-year subjects.

Hydro-pedotransfer functions (PTFs) relate easy-to-measure and readily available soil information to soil hydraulic properties (SHPs) for applications in a wide range of process-based and empirical models, thereby enabling the assessment of soil hydraulic effects on hydrological, biogeochemical, and ecological processes. At least more than 4 decades of research have been invested to derive such relationships. However, while models, methods, data storage capacity, and computational efficiency have advanced, there are fundamental concerns related to the scope and adequacy of current PTFs, particularly when applied to parameterise models used at the field scale and beyond. Most of the PTF development process has focused on refining and advancing the regression methods, while fundamental aspects have remained largely unconsidered. Most soil systems are not represented in PTFs, which have been built mostly for agricultural soils in temperate climates. Thus, existing PTFs largely ignore how parent material, vegetation, land use, and climate affect processes that shape SHPs. The PTFs used to parameterise the Richards–Richardson equation are mostly limited to predicting parameters of the van Genuchten–Mualem soil hydraulic functions, despite sufficient evidence demonstrating their shortcomings. Another fundamental issue relates to the diverging scales of derivation and application, whereby PTFs are derived based on laboratory measurements while often being applied at the field to regional scales. Scaling, modulation, and constraining strategies exist to alleviate some of these shortcomings in the mismatch between scales. These aspects are addressed here in a joint effort by the members of the International Soil Modelling Consortium (ISMC) Pedotransfer Functions Working Group with the aim of systematising PTF research and providing a roadmap guiding both PTF development and use. We close with a 10-point catalogue for funders and researchers to guide review processes and research.

Objective Osteosarcoma is the most common primary bone sarcoma. About 50% of patients develop metastatic disease and their 5-year survival lingers at around 20%–30%. T cell checkpoint blockade immunotherapies have revolutionised cancer treatment in the last decade, but their impact remains limited in osteosarcoma.Methods and analysis In order to reveal potentially novel immunotherapeutic strategies for advanced osteosarcoma, we conducted an immunogenomic characterisation of a unique sample set comprising 30 osteosarcoma samples from seven patients, collected throughout disease progression. We performed RNA-sequencing and imaging mass cytometry analysis on these samples to reveal the immunological landscape during osteosarcoma progression.Results Transcriptional and phenotypical hallmarks of cytotoxic T cell-driven anticancer immunity were enriched in metastatic lesions as compared with primary tumours. Spatial analysis showed T cells infiltrating central regions of osteosarcoma metastases, indicating the absence of an immune excluded environment. In parallel, we found a pronounced increase in the expression of cancer testis antigens, particularly melanoma antigen family A (MAGEA)-related antigens, in osteosarcoma metastases, which was validated in an independent cohort (N=91). In addition, we demonstrated the presentation of MAGE-derived peptides in three out of four osteosarcoma cell lines.Conclusion These findings indicate a concurrent augmentation of cytotoxic antitumour immune responses and expression of MAGEA antigens from primary to metastatic osteosarcoma. This observation suggests the exploration of MAGEA antigens as potential targets for immunotherapy in the treatment of advanced osteosarcoma.

Achieving a low-carbon future requires a comprehensive approach that combines emission mitigation options from economic activities with the sustainable use of land for numerous needs: food production, energy production, carbon sequestration, nature preservation and broad ecosystem services. Using the MIT Integrated Global System (IGSM) framework we analyze land-use competition in a 1.5°C climate stabilization scenario, in which demand for bioenergy and natural sinks increase along with the need for sustainable farming and food production. We find that to address the numerous trade-offs, effective approaches to nature-based solutions (NBS) and agriculture practices are essential. With proper regulatory policies and radical changes in current practices, global land is sufficient to provide increased consumption of food per capita (without large diet changes) over the century while also utilizing 2.5–3.5 billion hectares (Gha) of land for NBS practices that provide a carbon sink of 3–6 gigatonnes (Gt) of CO2 per year as well as 0.4–0.6 Gha of land for energy production—0.2–0.3 Gha for 50–65 exajoules (EJ) per year of bioenergy and 0.2–0.35 Gha for 300–600 EJ/year of wind and solar power generation. We list the competing uses of land to reflect the trade-offs involved in land use decisions, and note that while there is sufficient land in our scenario, attaining this outcome, capable of delivering a 1.5°C future, requires effective policies and measures at national and global levels that promote efficient land use for food, energy and nature (including carbon sequestration) and ensure long-term commitments by decision makers from governments and industry in order to realize the benefits of climate change mitigation.

Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.