Search

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.

Yildiray Topcu,1 Robbert JJ Gobbens,2– 5 Tjeerd van der Ploeg,2 Fatih Tufan6 1Prof. Dr. Cemil Taşcıoğlu Şehir Hastanesi, Istanbul, Turkiye; 2Faculty of Health, Sports and Social Work, Inholland University of Applied Sciences, Amsterdam, the Netherlands; 3Zonnehuisgroep Amstelland, Amstelveen, the Netherlands; 4Department Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 5Tranzo, Tilburg University, Tilburg, the Netherlands; 6Istanbul Esenler Avicenna Hospital, Department of Internal Medicine and Geriatrics, Istanbul, TurkiyeCorrespondence: Fatih Tufan, Assoc. Prof. of Geriatrics, Istanbul Esenler Avicenna Hospital, Department of Internal Medicine and Geriatrics, Istanbul, Turkiye, Tel +90 5331683458, Email fatihtufan@gmail.comPurpose: To our knowledge, there have been no comparative studies evaluating the associations of frailty defined using the Tilburg Frailty Indicator (TFI), frailty phenotype by Fried et al, and FRAIL scale with all-cause mortality in Turkiye. In this study, we aimed to evaluate the ability of these instruments in predicting all-cause mortality in outpatients admitted to the outpatient geriatrics clinic of a university hospital.Patients and Methods: This historical prospective study was performed in the geriatrics outpatient clinic of a university hospital in Istanbul, Turkiye. Consecutive older adults (aged ≥ 70 years) who provided written informed consent were enrolled in the study. The survival status of participants was checked electronically using the official death registry system. Univariate analyses and multivariate Cox regression analyses were performed to determine the independent predictors of mortality.Results: A total of 198 participants with a median age of 77 years were enrolled. During the median follow-up period of 2236 days, 54 (27.3%) patients died. In univariate analyses, male sex, history of falls in the previous year, dependency in instrumental activities of daily living, malnutrition, and frailty with respect to the phenotype by Fried et al, FRAIL scale, and TFI were associated with mortality. In multivariate Cox regression analyses, frailty according to each of the three frailty instruments, male sex, older age, history of falls, and malnutrition or malnutrition risk were independently associated with mortality. The Fried scale was the best frailty tool among the three frailty instruments used to predict all-cause mortality.Conclusion: The findings of this study suggest that frailty, determined using each of the three instruments used in the present study, is independently associated with all-cause mortality in patients admitted to the outpatient geriatrics clinic of a university hospital in Turkiye. The Fried scale appears to be the best for predicting all-cause mortality.Keywords: Turkiye, frailty, mortality, malnutrition, falls, dependency

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.

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.

Summary: Background: Female Lynch syndrome carriers have an increased risk of developing endometrial cancer. Regardless, research on endometrial carcinoma tumorigenesis is scarce and no uniform, evidence-based gynaecological management guidelines exist. We therefore described gynaecological surveillance and surgery outcomes in a nation-wide Lynch syndrome cohort. Methods: For this retrospective cohort study, female Lynch syndrome carriers, prospectively registered in the Dutch Lynch syndrome database (StOET), were included up to February 28th 2022. Carriers were linked to the Dutch national pathology (PALGA) database. The number of carriers with/without gynaecological surveillance, number of index carriers with endometrial carcinoma before Lynch syndrome diagnosis were assessed, as well as uptake of risk-reducing surgery and characteristics of endometrial carcinomas including the requisite for adjuvant therapy according to current guidelines. Overall survival after endometrial carcinoma diagnosis was analyzed using Kaplan Meier time to event analyses, cumulative incidence was calculated after adjusting for competing risks (death and prophylactic hysterectomy). Findings: In total, 1046 registered female Lynch syndrome carriers were eligible for surveillance, of whom 313 (30.0%) did not have surveillance and 21.4% (n = 224 of 1046) opted for prophylactic hysterectomy. In carriers with surveillance, more cases of endometrial carcinoma and hyperplasia were found than in those without (37 endometrial carcinomas (7.3%) and 28 hyperplasias (5.5%) in 506 carriers with surveillance versus 14 (2.6%) and 4 (0.7%) in 540 carriers without surveillance, respectively); carriers with surveillance were generally younger than those without (median 56 years [IQR 48–65] versus median 65 years [IQR 49–75] at database assembly, respectively; p

Introduction Type 2 diabetes mellitus (T2DM) is a major burden on public health worldwide. To reduce adverse events and complications, effective T2DM self-management is required. Self-management and glycaemic control are generally poorer in lower educated people compared with higher educated people. This study aims to assess the (cost-)effectiveness and to conduct a process evaluation of a diabetes self-management programme, ‘Powerful Together With Diabetes’ (PTWD), which is specifically developed for patients from lower educational groups.Methods and analysis The PTWD programme is focused on attaining basic knowledge and skills for effective diabetes self-management. In a previous study (the Diabetes in Social Context (DISC) study), lower-educated participants enjoyed the PTWD programme as well as improved their T2DM-related behaviours. The design of the study is an effectiveness-implementation hybrid type 2 trial. We will conduct mixed methods effectiveness, process and economic evaluations. To investigate the (cost-)effectiveness, a two-arm quasi-experimental trial will be conducted with a parallel mixed method process evaluation. The primary outcome of the study is change in haemoglobin A1c levels from baseline to 12 months. Secondary outcomes include use of primary and secondary care, medication use, blood biomarkers, T2DM self-management health behaviours, anthropometrics, and quality of life. Data will be collected with questionnaires, physical activity trackers and registration data from general practitioner registries. To see if the results are maintained, we will also measure the outcomes 24 months after baseline. Study participants are patients from lower educational groups living with T2DM between 35 and 70 years old. Participants will be recruited through general practices, and the intervention will be held in community centres. Our aim is to include 114 participants in the intervention group and 570 participants in the control group.Ethics and dissemination This study has been approved by the Medical Ethics Committee of the Academic Medical Center in Amsterdam (#2021_222). Participants will sign an informed consent form prior to enrolment. Manuscripts with the results of the effectiveness, economic and process evaluations will be published in peer-reviewed journals.Trial registration number ISRCTN12982302 ISRCTN registry (registered on 29 March 2022).

Development of antigen-specific memory upon pathogen exposure is a hallmark of the adaptive immune system. While natural killer (NK) cells are considered part of the innate immune system, humans exposed to the chronic viral pathogen cytomegalovirus (CMV) often possess a distinct NK cell population lacking in individuals who have not been exposed, termed “adaptive” NK cells. To identify the “naïve” population from which this “memory” population derives, we performed phenotypic, transcriptional, and functional profiling of NK cell subsets. We identified immature precursors to the Adaptive NK cells that are equally present in both CMV+ and CMV- individuals, resolved an Adaptive transcriptional state distinct from most mature NK cells and sharing a common gene program with the immature CD56bright population, and demonstrated retention of proliferative capacity and acquisition of superior IFNγ production in the Adaptive population. Furthermore, we distinguish the CD56bright and Adaptive NK populations by expression of the transcription factor CXXC5, positioning these memory NK cells at the inflection point between innate and adaptive lymphocytes.

Objective: Pompe disease is an inheritable metabolic myopathy caused by the deficiency of the lysosomal enzyme acid-⍺-glucosidase. The aim of this study was to investigate self-reported and parent-reported health related quality of life (HR-QOL) and fatigue in children with Pompe disease. Study design: In this cross-sectional study, the validated Child Health Questionnaire and PedsQL Multidimensional Fatigue Scale were used to respectively measure (both self-reported and parent-reported) HR-QOL and fatigue in children with Pompe disease. Results: In total, of 24 patients with Pompe disease (and their parents) participated, with a median age of 9.6 years [IQR 7.7-11.9], 14 had classic infantile Pompe disease. Self-reported HR-QOL was comparable with the healthy Dutch population on most domains, and patients with the classic infantile type scored mainly lower on physical functioning. Parents of patients with classic infantile Pompe disease reported a significantly lower HR-QOL of their children on 9 domains and parents of patients with (non-classic) childhood-onset Pompe disease on 5 domains. Self-reported fatigue levels in children with classic infantile Pompe disease were increased for 2 of 3 domains compared with healthy peers, and fatigue in patients with non-classic Pompe disease did not differ. Parents of patients with classic infantile Pompe disease reported greater levels of fatigue in all 3 domains compared with healthy children, whereas parents of children with childhood-onset disease scored greater on the cognitive fatigue domain. Conclusions: Children with Pompe disease report comparable HR-QOL on most domains compared with healthy peers. Contrarily, parent-reported HR-QOL was substantially lower on most domains compared with references values. As expected in relation to disease severity, unfavorable effects on HR-QOL and fatigue were more pronounced in patients with classic infantile Pompe disease.

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.

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.